thesis on covid 19 vaccine

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• Published: 19 May 2023

The efficacy and effectiveness of COVID-19 vaccines around the world: a mini-review and meta-analysis

• Marzieh Soheili 1 ,
• Sorour Khateri 2 ,
• Farhad Moradpour 3 ,
• Pardis Mohammadzedeh 4 ,
• Mostafa Zareie 4 ,
• Seyede Maryam Mahdavi Mortazavi 5 ,
• Sima Manifar 6 ,
• Hamed Gilzad Kohan 7 &
• Yousef Moradi 3  

Annals of Clinical Microbiology and Antimicrobials volume  22 , Article number:  42 ( 2023 ) Cite this article

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This meta-analysis evaluated the Efficacy and Effectiveness of several COVID-19 vaccines, including AstraZeneca, Pfizer, Moderna, Bharat, and Johnson & Johnson, to better estimate their immunogenicity, benefits, or side effects.

Studies reporting the Efficacy and Effectiveness of COVID-19 vaccines from November 2020 to April 2022 were included. The pooled Effectiveness/Efficacy with a 95% confidence interval (95% CI) with Metaprop order was calculated. The results were presented in forest plots. Predefined subgroup analyses and sensitivity analyses were also performed.

A total of twenty articles were included in this meta-analysis. After the first dose of the vaccine, the total effectiveness of all COVID-19 vaccines in our study was 71% (95% CI 0.65, 0.78). The total effectiveness of vaccines after the second dose was 91% (95% CI 0.88, 0.94)). The total efficacy of vaccines after the first and second doses was 81% (95% CI 0.70, 0.91) and 71% (95% CI 0.62, 0.79), respectively. The effectiveness of the Moderna vaccine after the first and second dose was the highest among other studied vaccines ((74% (95% CI, 0.65, 0.83) and 93% (95% CI, 0.89, 0.97), respectively). The highest first dose overall effectiveness of the studied vaccines was against the Gamma variant (74% (95% CI, 0.73, 0.75)), and the highest effectiveness after the second dose was observed against the Beta variant (96% (95% CI, 0.96, 0.96)). The Efficacy for AstraZeneca and Pfizer vaccines after the first dose was 78% (95% CI, 0.62, 0.95) and 84% (95% CI, 0.77, 0.92), respectively. The second dose Efficacy for AstraZeneca, Pfizer, and Bharat was 67% (95% CI, 0.54, 0.80), 93% (95% CI, 0.85, 1.00), and 71% (95% CI, 0.61, 0.82), respectively. The overall efficacy of first and second dose vaccination against the Alfa variant was 84% (95% CI, 0.84, 0.84) and 77% (95% CI, 0.57, 0.97), respectively, the highest among other variants.

mRNA-based vaccines against COVID-19 showed the highest total efficacy and effectiveness than other vaccines. In general, administering the second dose produced a more reliable response and higher effectiveness than a single dose.

Introduction

The coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This β-coronavirus is an enveloped, non-segmented positive-sense RNA virus, which primarily spreads through the respiratory tract [ 1 , 2 , 3 ]. COVID-19 infection is often associated with systemic inflammation and inflammatory biomarkers such as IL-6, IL-10, and TNF-α) increase in the patients [ 4 , 5 , 6 ]. Cough, fever, and shortness of breath are the dominant symptoms of COVID-19 infection. Additionally, fatigue, increased sputum production, sore throat, headache, and gastrointestinal symptoms might be observed [ 6 , 7 , 8 ]. Elderly patients with underlying disorders such as hypertension, chronic obstructive pulmonary disease, diabetes, and cardiovascular complications are more prone to develop acute respiratory distress syndrome. Other severe symptoms include septic shock, metabolic acidosis, and coagulation dysfunction, which might lead to death [ 9 , 10 ]. Various medications have already been tested for treating COVID-19 patients. However, the evidence to support the beneficial effects of these drugs is often controversial [ 11 , 12 , 13 ]. Molnupiravir is the first oral antiviral drug that has recently shown a significant benefit in reducing hospitalization or death in COVID-19 patients [ 14 ].

According to the World Health Organization (WHO) report, from the emergence of COVID-19 in December 2019 to November 2021, more than 250,000,000 confirmed cases of COVID-19 have been reported, and more than five million deaths have been attributed to the disease globally [ 15 ]. Since the COVID-19 pandemic, several studies have started to develop safe and efficacious vaccines. Numerous clinical trials have been conducted to evaluate the efficacy and safety of experimental vaccines [ 16 , 17 , 18 ]. WHO reported as of November 8, 2021, more than seven billion vaccine doses have been administered worldwide [ 15 ]. Additionally, as per the WHO report, until November 9, 2021, 130 vaccine candidates were under clinical development, and 156 candidates were in the pre-clinical development phase. Different types of COVID-19 vaccines have been developed worldwide, including protein subunit, recombinant, viral vector, RNA- and DNA-based, and sub-unit vaccines [ 19 ].

Up to now, several COVID-19 vaccines have been authorized or approved for use. WHO issued an emergency use authorization for the Pfizer COVID-19 vaccine On December 31, 2020 (BNT162b2). Next, on February 15, 2021, the Astra-Zeneca/Oxford COVID-19 vaccine (manufactured by the Serum Institute of India and SKBio) received emergency use approval, followed by Ad26.COV2.S (developed by Janssen (Johnson & Johnson)) on March 12, 2021, and Moderna vaccine on April 30, 2021 [ 20 ]. Pfizer COVID-19 vaccine is a lipid nanoparticle formulation that contains a nucleoside-modified RNA against the S protein of the SARS-CoV-2 virus [ 21 ]. Moderna is a lipid nanoparticle–encapsulated nucleoside-modified messenger RNA vaccine encoding prefusion stabilized full-length spike protein of SARS-CoV-2 (24). The Oxford/AstraZeneca COVID-19 vaccine (ChAdOx1 nCoV-19 vaccine, AZD1222) contains a replication-deficient chimpanzee adenoviral vector ChAdOx1, delivering the SARS-CoV-2 structural surface glycoprotein antigen (spike protein; nCoV-19) gene (22, 23). Janssen is a non-replicating, recombinant human adenovirus type 26, containing a full-length SARS-CoV-2 S protein [ 22 ]. Bharat (CovaxinTM) is an inactivated-virus vaccine developed in Vero cells combined with Alhydroxiquim-II (Algel-IMDG), chemosorbed imidazoquinoline onto aluminum hydroxide gel. This complex is an adjuvant to boost immune response for longer-lasting immunity [ 23 ].

Careful planning for the COVID-19 vaccination program requires comprehensive review studies to evaluate the efficacy and safety of the vaccines. This study aims to conduct a meta-analysis to assess the Effectiveness and Efficacy of COVID-19 vaccines, including AstraZeneca, Pfizer, Moderna, Bharat, and Johnson & Johnson. Well-designed meta-analysis studies will provide a more accurate overview to evaluate Efficacy and safety outcomes compared to individual studies and contribute to a better understanding of the use of the vaccine in different populations.

Materials and methods

The present systematic review and meta-analysis were conducted according to Preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines for reviewing analytical observational studies [ 24 ].

Search strategy and screening

International databases were searched to find all original published articles, including Medline (PubMed), Web of Science, Embase (Elsevier), Cochrane Library, Scopus, Ovid, and CINHAL, to retrieve all articles evaluating and reporting the efficacy and side effects of all COVID-19 vaccine (Pfizer–BioNTech, Oxford–AstraZeneca, Moderna, Janssen, CoronaVac, Covaxin, Novavax and Convidecia) in fully vaccinated and partially vaccinated people. The studies which have compared these items with non-vaccinated individuals were also included. In addition to searching the mentioned databases, gray literature was searched by reviewing articles in the first ten pages of Google scholar. A manual search was performed by reviewing references from related studies. This search was conducted with language limitations from November 2020 to September 2022. The search protocol was developed based on four primary roots involving “vaccination,“ “COVID-19,“ “Side effect,“ and “Efficacy.“ All related components to these keywords were “vaccinated”, “non-vaccinated”, “partial vaccinated”, “fully vaccinated”, “Pfizer–BioNTech”, “Oxford–AstraZeneca”, “Sinopharm BIBP”, “Moderna”, “Janssen”, “CoronaVac”, “Covaxin”, “Novavax”, “Convidecia”, “symptoms”, “signs” (“fever”, “cough”, “malaise”, “dyspnea”, “myalgia”, “sore throat”, and “diarrhea”), “thrombosis”, “emboli”, “thromboembolism”, “thromboembolic”, which were added to the searched queries based on scientific Mesh terms, EMTREE, and Thesaurus. Reference Manager bibliographic software was applied to manage searched citations. Duplicate entries were searched by considering the papers’ title, year of publication, authors, and specifications of types of sources. In case of questionable records, the texts were compared. After reviewing the primary search results, each article was double-checked by title and available abstract, and some of the articles were omitted based on the selection criteria. The evaluation of the considered papers was based on the inclusion and exclusion criteria by the two researchers separately (SM, MS). After the screening, (YM) selected the articles by evaluating their full texts.

Eligibility criteria

We included all observational and interventional studies that assessed the Efficacy/Effectiveness and side effects of all types of COVID-19 vaccines (Pfizer–BioNTech, Oxford–AstraZeneca, Sinopharm BIBP, Moderna, Janssen, CoronaVac, Covaxin, Novavax and Convidecia) in fully vaccinated and partially vaccinated people. The studies comparing these items with non-vaccinated individuals were also included. We excluded duplicate citations, non-peer-reviewed articles in which the abstract and full text were unavailable, and other languages.

Data extraction

After screening according to the three assessment steps for titles, abstracts, and full texts, the full text of each selected article was extracted for detailed analysis. The data were retrieved using a checklist recording author, publication year, type of study, mean age, sample size, number of positive tests, Effectiveness/Efficacy after one dose, Effectiveness/Efficacy after the second dose, and number of confirmed COVID cases, hospitalization, and death. From systematic search to final data extraction, all processes were followed independently by two research experts (PM, FM). After the screening, the data extraction was finally approved by (YM).

Risk of bias

The qualitative evaluation of studies was done according to the Newcastle-Ottawa Quality Assessment Scale (NOS) [ 25 ] by two of the authors (FM, YM). This scale is designed to evaluate the qualitative properties of observational studies (random clinical trials, case-control, retrospective, cohort, and cross-sectional studies). NOS examined each study through six items in three groups: selection, comparability, and exposure. Stars were given to each item, and the maximum score was 9. If the scores assigned to the published articles differed, the external discussion method would be used [ 26 , 27 ].

The Jadad checklist was used by two separate authors (PM and FM) to explore potential risks of bias in interventional studies. These scales include items to assess the adequacy of random sequence generation, allocation concealment, blinding, the detection of incomplete outcome data, selective outcome reporting, and other potential sources of bias [ 28 ].

Statistical analysis

The random-effects model was used to calculate the pooled Effectiveness/Efficacy with a 95% confidence interval (95% CI) with Metaprop order. Calculating the cumulative relative risk (RR) with the 95% confidence interval and the meta set command was used considering the relative risk’s logarithm and logarithm standard deviation. Statistical analysis was performed using STATA 16.0 (Stata Corp, College Station, TX, USA), and statistical significance was considered at P-Value  < 0.05. Heterogeneity among studies was evaluated by applying the I square value and reported as a percentage (%) to show the extent of variation between studies. A forest plot was used for presenting the meta-analysis results schematically. Egger’s test and funnel plot were applied to evaluate the publication bias. In addition, a subgroup analysis was done to identify different sources of heterogeneity.

Results and discussion

Characteristics of included studies and the participants.

A total of 2622 publications were screened for evaluating two items about COVID-19 vaccines: (I) Efficacy and (II) Effectiveness. These two items were assessed according to the virus variant (Alpha, Beta, Delta, and Gamma) and the type of vaccine (AstraZeneca, Pfizer, Moderna, Janssen, and Bharat). Data on other vaccines were not included due to inadequate published data. Of these publications, 20 studies met the systematic reviews’ inclusion criteria (non-randomized and randomized) and were included in our meta-analysis (Fig.  1 ).

Identification of studies via databases and registers

One study was the cohort, four were randomized clinical trials (RCT), and fifteen were case-control. Clinical trials have evaluated vaccines’ efficacy, and observational studies such as cohorts and case controls have assessed their effectiveness. All selected papers were written in English. A total of 1,246,266 cases were included in this study that had received the COVID-19 vaccines. All vaccines were injected intramuscularly (IM). The participants were > 12 years old. The characteristics of included studies have been summarized in Table  1 .

The overall effectiveness of COVID-19 vaccines

After the first dose of the vaccine, the overall effectiveness of all COVID-19 vaccines was estimated to be 71% (95% CI 0.65, 0.78) (Fig.  2 ).

The overall Effectiveness of studied COVID-19 vaccines after the first dose

The overall Effectiveness of vaccines after the second dose was 91% (95% CI 0.88, 0.94), with a significant P-value ( p-value < 0.05 ) (Fig.  3 )

The overall Effectiveness of studied COVID-19 vaccines after the second dose. The overall Efficacy of COVID-19 vaccines

The overall Efficacy of the first dose of the vaccines evaluated in our study was 81% (95% CI 0.70, 0.91) (Fig.  4 )

The overall Efficacy of the first dose of the studied vaccines

After the second dose of vaccination, the overall Efficacy of vaccines was 71% (95% CI 0.62, 0.79) with a significant P-value (Fig.  5 )

The overall Efficacy of the studied vaccines after the second dose

The individual efficacy of COVID-19 vaccines

The efficacy after the first dose was evaluated only in 8 of the selected studies, which assessed the efficacy of the AstraZeneca and Pfizer vaccines. No data was published on the efficacy after the first dose for Moderna, Johnson & Johnson, and Bharat. After the first dose of AstraZeneca and Pfizer vaccines, the pooled efficacy was 78% (95% CI 0.062, 0.95) and 84% (95% CI 0.77, 0.92), respectively. Of the selected publications, eighteen studies reported the efficacy after the second dose of vaccinations. The published data for the second dose Efficacy was only available for AstraZeneca, Pfizer, and Bharat vaccines. The second dose pooled Efficacy for AstraZeneca, Pfizer, and Bharat was 67% (95% CI 0.54, 0.80), 93% (95% CI 0.85, 1.00), and 71% (95% CI 0.61, 0.82) respectively (Table  2 ).

The individual effectiveness of COVID-19 vaccines

The first dose Effectiveness of the vaccines was evaluated in seventeen studies. For Moderna, AstraZeneca, and Pfizer, the pooled effectiveness after the first dose was 74% (95% CI 0.065, 0.83), 69% (95% CI 0.55, 0.82), and 67% (95% CI 0.51, 0.83) respectively. It was observed that the Effectiveness of Moderna after the first dose was higher than other types of vaccines. The second dose Effectiveness of the vaccines was reported in 17 studies. The pooled effectiveness after the second dose of Moderna, AstraZeneca, and Pfizer vaccines was 93% (95% CI 0.89, 0.97), 89% (0.80, 0.97), and 90% (95% CI 0.83, 0.96) respectively; Moderna had higher effectiveness after the second dose, among other studied vaccines (Table  2 ).

Efficacy of the vaccines against the virus variants

The overall first and second-dose vaccination Efficacy against different COVID-19 variants is listed in Table  2 . The first dose of overall vaccine Efficacy against the Alpha variant was 84%, which was higher than other variants (95% CI 0.84, 0.84). The overall efficacy of the first dose vaccination against the delta variant was only 46% (95% CI 0.45, 0.48), which was the lowest. Similarly, the highest second dose Efficacy was observed against the Alpha variant, which was 77% (95% CI 0.57, 0.97). The overall efficacy of the second dose against the Delta and Beta variants was 64% (95% CI 0.58, 0.69) and 10% (95% CI 0.09, 0.12), respectively.

Effectiveness of the vaccines against the virus variants

The overall first and second-dose vaccination Effectiveness against different COVID-19 variants is reported in Table  2 . The first dose Effectiveness of vaccination against the Gamma variant was 74% (95% CI 0.73, 0.75) which was more than other variants. However, the overall first dose Effectiveness was 82% (95% CI 0.81, 0.82). After the second dose, the highest effectiveness was against the Beta variant (96% (95% CI 0.96, 0.96)). The overall effectiveness after the second vaccination dose was 96% (95% CI 0.096, 0.96) (Table  2 ).

The risk of confirmed COVID infection after vaccination (risk ratio)

Two categories of the selected studies assessed the risk ratio of COVID after vaccination: observational and experimental. Only the pooled risk ratio of AstraZeneca was evaluated in the experimental studies, which was 50% (95% CI 0.35, 0.71). In the observational studies, AstraZeneca and Moderna had the lowest pooled risk ratios, which were 18% (95% CI 0.04, 0.84) and 19% (95% CI 0.17, 0.22), respectively. Bharat had the highest pooled risk ratio (82% (95% CI 0.75, 0.89) (Table  3 ); however, the number of studies on the Bharat vaccine was fewer than other types of vaccines. Based on the reported experimental studies for the vaccine variants, the Beta variant had the highest (79% (95% CI 0.43, 1.44)), and the Gamma variant had the lowest risk ratio (31% (95% CI 0.18, 0.54)). In the observational studies, Delta had the highest (52% (95% CI 0.27, 1.01), and Gamma had the lowest risk ratio (2% (95% CI 0.02, 0.02)) (Table  3 ).

Since the emergence of COVID-19, the effort to develop effective vaccines against the infection has been started. Due to the highly contagious nature of the virus, vaccination has been considered a significant measure in the fight against COVID-19. World Health Organization (WHO) allows countries to issue emergency use authorizations for COVID-19 vaccines in line with their national regulations and legislation. Domestic emergency use authorizations are issued at the countries’ discretion and are not subject to WHO approval. Up to now, several vaccines have been developed and marketed to limit the spread of COVID-19 infection. As of January 12, 2022, several COVID 19 vaccines have been given Emergency Use Listing (EUL), including those developed by Pfizer/BioNTech, AstraZeneca, Johnson & Johnson, Moderna, Sinopharm, Sinovac, Bharat Biotech, etc. [ 29 ].

Despite the significant role of COVID-19 vaccination in confining the infection, vaccines’ Efficacy and Effectiveness have not yet been comprehensively discussed. The present study meticulously looked into the Efficacy and Effectiveness of several vaccines.

Our analysis revealed that the overall effectiveness of the studied vaccines after the first dose is significantly less than their effectiveness after the second dose. The first dose’s effectiveness was evaluated in 17 studies. After the first dose, Moderna, AstraZeneca, and Pfizer’s Effectiveness was 74%, 69%, and 67%, respectively. The Effectiveness of Moderna after the first dose was higher than other types of studied vaccines. Second dose Effectiveness was evaluated in 17 studies. After the second dose of Moderna, AstraZeneca, and Pfizer vaccination, the effectiveness was 93%, 89%, and 90, respectively. Moderna provided higher effectiveness after the second dose among other studied vaccines. Therefore, administering the second dose should produce a more reliable response and higher effectiveness than a single dose.

Surprisingly, the overall efficacy of the first dose was significantly more than the second dose; 81% (95% CI 0.70, 0.91) for the first dose compared to 71% (95% CI 0.62, 0.79) for the second dose. This can be explained by the fact that the efficacy after the first dose was evaluated only in 8 studies that assessed only AstraZeneca and Pfizer vaccines. No data was available regarding the efficacy after the first dose of Moderna, Bharat, and Johnson & Johnson vaccines. We observed that the first dose Efficacy of the Pfizer vaccine is significantly more than the AstraZeneca vaccine. The Efficacy for AstraZeneca and Pfizer after the first dose vaccination was 78% and 84%, respectively. Concerning the second dose Efficacy, the published data were available only for AstraZeneca, Pfizer, and Bharat. In Total, eighteen studies evaluated the efficacy of these vaccines after the second dose. The Efficacy for AstraZeneca, Pfizer, and Bharat was 67%, 93%, and 71%, respectively.

We also investigated the Efficacy and Effectiveness of the first and second-dose vaccination against the COVID-19 virus variants. The overall efficacy of vaccination against the Alfa variant after the first dose was 84%, which was more than other variants. The highest efficacy after the second dose vaccination was also observed for the Alpha variant (77%). The first dose’s effectiveness against the Gamma variant was the highest (74%). Although, the overall first dose effectiveness was 82%. The highest second dose Effectiveness was against the Beta variant (96%), and the overall effectiveness after the second vaccination dose was 96% against all variants.

Up to now, there are other meta-analyses published on the efficacy and effectiveness of the COVID-19 vaccines. For example, in the meta-analysis reported by Pormohammad et., al, the efficacy of mRNA-based and adenovirus-vectored COVID-19 vaccines in phase II/III randomized clinical trial has been reported as 94.6% (95% CI 0.936–0.954) and 80.2% (95% CI 0.56–0.93), respectively. Additionally, the mRNA-based vaccines showed the highest reported side effects except for diarrhea and arthralgia [ 30 ]. However, the research had not reported the efficacy against different variants of the COVID-19 virus. Moreover, the Efficacy and Effectiveness of individual vaccines have not been mentioned; the vaccine Efficacy has been reported based on the vaccine classes. Another meta-analysis reported that the effectiveness of the Pfizer-BioNTech and Moderna vaccines was 91.2% and 98.1%, respectively, while the effectiveness of the CoronaVac vaccine was 65.7% in fully vaccinated individuals [ 31 ]. However, this study has not reported the effectiveness of the vaccines against COVID-19 variants or their efficacy.

Additionally, A previously reported network meta-analysis of various COVID-19 vaccines found Moderna was the most effective vaccine against COVID-19 infection, with an efficacy rate of 88%, followed by Sinopharm and Bharat. The least effective vaccines were Coronavac, Curevac, and AstraZeneca. The mRNA-based vaccines were superior in preventing infection and symptomatic infection, while the inactivated vaccines were most effective in preventing severe COVID-19 infection. Concerning safety, Sinopharm had the highest safety profile in local side effects, while ZF2001 had the highest safety in unsolicited side effects. Inactivated vaccines had the best safety profile in local and systemic side effects, while mRNA-based vaccines had the poorest safety profile. Thromboembolic events were reported after J&J, AstraZeneca, Pfizer, and Moderna vaccine administration. However, no confirmed vaccine-Induced Thrombotic Thrombocytopenia (VITT) cases were reported after mRNA vaccines [ 32 ].

It is necessary to mention that some vaccines’ overall or variant-specific Effectiveness and Efficacy are unavailable after the first or second dose. Moreover, the timing of the second dosing of the vaccines is not elicited in some trials, which may have led to the lower observed overall efficacy after the second dose. Additionally, some reports had noticeable bias by not including enough samples or not considering a broad enough geographical, economic, and age diversity.

We searched various databases and websites to include the maximum number of relevant publications to prevent database bias; after performing Egger’s regression test, we did not find significant publication bias. However, publication bias and heterogeneity for some pooled results must be considered when interpreting the outcomes.

Despite the valuable information provided by this meta-analysis, the study has some limitations to consider, such as the time frame of the studies (November 2020 to April 2022), the exclusion of unpublished data or ongoing investigations, the subjectivity of study selection criteria, and the limited number of vaccines evaluated. Additionally, the study did not consider differences in vaccine distribution among countries or provide data on the vaccines’ effectiveness against severe disease, hospitalization, or death. Despite its limitations, the meta-analysis highlights the need to continue monitoring the vaccines’ effectiveness.

In conclusion, Moderna, an mRNA-based vaccine, showed the highest total effectiveness after the first dose. Although the Pfizer vaccine showed a higher Efficacy after the first and second doses than AstraZeneca and Bharat, our conclusion has some limitations due to the lack of any published study regarding the Moderna and Johnson & Johnson vaccines’ efficacy. First-dose vaccination generally showed the highest overall effectiveness against the Gamma variant. Second dose vaccination showed a 96% overall Effectiveness against all variants. The efficacy of vaccination against the Alfa variant after the first dose was more than other variants. The highest efficacy after the second vaccination dose was also observed for the Alpha variant. Due to the timeline of the studies, all the vaccines are missing longer-term Efficacy and Effectiveness evaluations. This meta-analysis incorporated all relevant studies for summarizing and analyzing the Effectiveness and Efficacy of several vaccines for COVID-19. The results of this study support the overall Efficacy and Effectiveness of all studied COVID-19 vaccines and support the ongoing global public health effort for vaccination against COVID-19.

Data Availability

The data extracted for analyses are available by the corresponding author upon reasonable requests.

Abbreviations

Coronavirus Disease 2019

Severe Acute Respiratory Syndrome Coronavirus 2

World Health Organization

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Department of Pharmaceutical and Administrative Sciences, College of Pharmacy, Western New England University, 1215 Wilbraham Road, Springfield, MA, 01119, USA

Marzieh Soheili

Department of Physical Medicine and Rehabilitation, School of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran

Sorour Khateri

Social Determinants of Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran

Farhad Moradpour & Yousef Moradi

Department of Epidemiology and Biostatistics, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran

Pardis Mohammadzedeh & Mostafa Zareie

Pediatric Gastroenterology Fellowship, Department of Pediatrics, School of Medicine, Namazi teaching Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

Seyede Maryam Mahdavi Mortazavi

Massachusetts College of Pharmacy and Health Sciences (MCPHS), 179 Longwood Avenue, Boston, MA, 02115, USA

Sima Manifar

Hamed Gilzad Kohan

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Contributions

Study concept and design: YM. Acquisition, analysis, and interpretation of data: YM, MS, HGK, FM, PM, SK, MZ, SM, and SMMM. Drafting of the manuscript: YM, HGK, MS. Critical revision of the manuscript for the important intellectual content: YM, MS. Project administration: YM and HGK. All authors have approved the final manuscript draft.

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Correspondence to Hamed Gilzad Kohan or Yousef Moradi .

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Soheili, M., Khateri, S., Moradpour, F. et al. The efficacy and effectiveness of COVID-19 vaccines around the world: a mini-review and meta-analysis. Ann Clin Microbiol Antimicrob 22 , 42 (2023). https://doi.org/10.1186/s12941-023-00594-y

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COVID-19 vaccine development: milestones, lessons and prospects

• Maochen Li   ORCID: orcid.org/0000-0001-8786-5039 1   na1 ,
• Han Wang   ORCID: orcid.org/0000-0001-5298-8194 2   na1 ,
• Lili Tian 1   na1 ,
• Zehan Pang   ORCID: orcid.org/0000-0003-4537-2441 1   na1 ,
• Qingkun Yang   ORCID: orcid.org/0000-0002-1548-498X 3 ,
• Tianqi Huang 1 ,
• Junfen Fan 4 ,
• Lihua Song 1 ,
• Yigang Tong 1 , 5 &
• Huahao Fan   ORCID: orcid.org/0000-0001-5007-2158 1  

Signal Transduction and Targeted Therapy volume  7 , Article number:  146 ( 2022 ) Cite this article

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With the constantly mutating of SARS-CoV-2 and the emergence of Variants of Concern (VOC), the implementation of vaccination is critically important. Existing SARS-CoV-2 vaccines mainly include inactivated, live attenuated, viral vector, protein subunit, RNA, DNA, and virus-like particle (VLP) vaccines. Viral vector vaccines, protein subunit vaccines, and mRNA vaccines may induce additional cellular or humoral immune regulations, including Th cell responses and germinal center responses, and form relevant memory cells, greatly improving their efficiency. However, some viral vector or mRNA vaccines may be associated with complications like thrombocytopenia and myocarditis, raising concerns about the safety of these COVID-19 vaccines. Here, we systemically assess the safety and efficacy of COVID-19 vaccines, including the possible complications and different effects on pregnant women, the elderly, people with immune diseases and acquired immunodeficiency syndrome (AIDS), transplant recipients, and cancer patients. Based on the current analysis, governments and relevant agencies are recommended to continue to advance the vaccine immunization process. Simultaneously, special attention should be paid to the health status of the vaccines, timely treatment of complications, vaccine development, and ensuring the lives and health of patients. In addition, available measures such as mix-and-match vaccination, developing new vaccines like nanoparticle vaccines, and optimizing immune adjuvant to improve vaccine safety and efficacy could be considered.

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Introduction.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious positive-sense, single-stranded RNA virus that spreads rapidly worldwide. The resulting infection, known as coronavirus disease 2019 (COVID-19), can cause several symptoms, such as cough, fever, chest discomfort, and even respiratory distress syndrome in severe cases. 1 , 2 As of March 28, 2022, there were 480,905,839 confirmed cases of COVID-19 worldwide, and 6,123,493 patients died of viral infection or other related complications ( https://coronavirus.jhu.edu/ ).

Effective and safe vaccines are essential to control the COVID-19 pandemic. 3 , 4 Several studies have reported the progress in developing SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) vaccines. 5 , 6 , 7 , 8 The preclinical data of these candidate vaccines partly saved the time for developing the current marketed SARS-CoV-2 vaccines and would provide platforms for the future widespread application of SARS-CoV-2 vaccines. The World Health Organization (WHO) classifies COVID-19 vaccines that have been analyzed or approved for clinical trials into the following categories: inactivated vaccine, live attenuated, vector, RNA, DNA, protein subunit, and virus-like particle (VLP) vaccines.

Animal experiments play a critical role in vaccine development, including evaluating the safety and protective efficacy, determining the injection schedule, and establishing the effective dosage. Small animals, especially rodents, are the foundation of biological and immunological studies in vaccine development. 9 , 10 Generally, rats, mice, guinea pigs, rabbits, and other animals can be used as animal models to evaluate candidate vaccines’ immunogenicity, tolerance, and safety. However, due to species differences between these animals and humans, similar biological effects may not be produced after vaccination. The studies of non-human primates (NHPs) are helpful in understanding and illustrating human immune responses, owing to similar innate and adaptive immune responses. 9 Many reagents used to identify human immune molecules also show similar effects on NHPs. In addition to preclinical trials (animal experiments), clinical trials are essential for developing vaccines. The safety, dosage, and tolerance of vaccines are assessed in the Phase I trial, efficacy and adverse effects are investigated in Phase II and III trials.

Vaccination is a pivotal means to prevent the spread of SARS-CoV-2 and ultimately quell the pandemic. However, vaccine performance is affected by the constant acquisition of viral mutations due to the inherent high error rate of virus RNA-dependent RNA polymerase (RdRp) and the existence of a highly variable receptor-binding motif in the spike (S) protein. 11 , 12 , 13 We have previously noted that the B.1.351 (Beta) variant significantly reduces the neutralizing geometric mean antibody titers (GMT) in recipients 14 of mRNA and inactivated vaccines and may cause breakthrough infections. 15 The reduction in neutralization activity has raised concerns about vaccine efficacy. Thus, rapid virus sequence surveillance (e.g. the identification of E484 mutations in new SARS-CoV-2 variants 16 ) and vaccine updates are crucial.

This review systematically introduces the existing COVID-19 vaccine platforms, analyzes the advantages and disadvantages of the vaccine routes, and compares the efficacy and safety of various vaccines, including the possible complications and different protective efficacies in special populations. Moreover, given the continuous mutation of SARS-CoV-2, we analyze the neutralization activities of various vaccines according to the latest research and propose ideas to improve and optimize existing vaccines, including changing the administration route, adopting more vaccination strategies, and applying more vaccine development methods (Fig. 1 ).

The milestones of COVID-19 vaccine development. With the maturity of vaccine platforms, more and more COVID-19 vaccines have entered clinical trials and been approved for emergency use in many countries. However, the appearance of VOCs has brought great challenges to existing COVID-19 vaccines. By changing the administration route, the protection provided by vaccines can be enhanced, and more vaccination strategies are applied to cope with VOCs. In addition, more vaccine development methods are applied, such as developing polyvalent vaccines and improving adjuvant and delivery systems. These enormous changes form a milestone in the COVID-19 vaccine progress compared with post-years

Vaccine-induced immunity

The immune response elicited by the body after vaccination is termed active immunity or acquired immunity. In this process, the immune system is activated. CD4 + T cells depend on antigen peptide (AP)-MHC (major histocompatibility complex) class II molecular complex to differentiate into helper T cells (Th cells). CD8 + T cells depend on AP-MHC class I molecular complex and differentiate into cytotoxic T lymphocytes (CTL). B cells are activated with the help of Th cells to produce antibodies. After antigen stimulation, B and T cells form corresponding memory cells to protect the body from invading by the same pathogen, typically for several years. The development of COVID-19 vaccines is mainly based on seven platforms, which can be classified into three modes according to the antigen category. 17 , 18 The first mode is based on the protein produced in vitro, including inactivated vaccines (inactivated SARS-CoV-2), VLP vaccines (virus particles without nucleic acid), and subunit vaccines (S protein or receptor-binding domain (RBD) expressed in vitro). The second model is based on the antigen gene expressed in vivo, including viral vector vaccines (using replication-defective engineered viruses carrying the mRNA of S protein or RBD), DNA vaccines (DNA sequences of S protein or RBD), and mRNA vaccines (RNA sequences of S protein or RBD). The third mode is the live-attenuated vaccine. These vaccines can induce neutralizing antibodies to protect recipients from viral invasion. Moreover, some mRNA and viral vector vaccines can induce Th1 cell responses 19 , 20 and persistent human germinal center responses, 21 , 22 which provide more efficient protection. In addition, memory cells induced by COVID-19 vaccines play an important role in vaccine immunity. 23 , 24 , 25

Vaccine-induced Th1 cell response

ChAdOx1 nCoV-19 (AZD1222, viral vector vaccine), NVX-CoV2373 (protein subunit vaccine), mRNA-1273(mRNA vaccine), BNT162 (including BNT162b1 and BNT162b2, mRNA vaccine), and other COVID-19-candidate vaccines were reported to induce Th1 cell responses. 19 , 26 , 27 , 28 After recognition of the AP-MHC class II complex and T-cell receptor (TCR), CD4 + T cells distributed in peripheral lymphoid organs can differentiate into Th1 cells, which secrete various cytokines, such as interleukin 2 (IL-2), and simultaneously upregulate the expression of related receptors (IL-2R). After IL-2 binds to IL-2R, T-cell proliferation and CD8 + T-cell activation are promoted. Both CD4 + and CD8 + T-cell responses have been observed in Ad26.COV-2-S recipients. 29 , 30 The activated CD8 + T cells differentiate into CTLs to further induce cellular immunity. In addition, Th1 cells can secrete interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). 31 The former also induces the differentiation of CD4 + T cells and enhances the intensity of the immune response (Fig. 2 ).

Vaccine-induced Th1 cell response. Some COVID-19 vaccines would induce Th1 cell responses. After recognition of the AP-MHC class II complex and T-cell receptor (TCR), CD4 + T cells distributed in peripheral lymphoid organs can differentiate into Th1 cells, which secrete various cytokines, such as interleukin 2 (IL-2), and simultaneously upregulate the expression of related receptors (IL-2R). Through IL-2 and IL-2R, T-cell proliferation and CD8 + T-cell activation are promoted, CD8 + T-cell can differentiate into cytotoxic T lymphocytes (CTLs) through the activation, producing perforin and other cytokines, which may improve the efficacy of vaccines

When the effector cells (Th cells and CTLs) clear the antigen, the signal maintaining the survival and proliferation of T cells no longer exists, the cell responses are reduced, and the immune system returns to homeostasis. However, antigen-specific memory T cells are crucial for long-term protection, typically formed during T-cell-mediated immunity. 23

Vaccine-induced germinal center response and humoral immune regulation

In addition to T-cell responses, follicular helper T cells (Tfh cells) induced by mRNA vaccines can trigger effective SARS-CoV-2 antigen-specific germinal center B-cell (GC B-cell) responses (Fig. 3 ). 21 , 22 , 32 Upon the interaction of T cells and B cells, some activated Th cells move to the lymphatic follicles and then differentiate into Tfh cells. Activated B cells proliferate and divide in lymphatic follicles to form the germinal center. With the help of Tfh cells, high-frequency point mutations occur in the variable region of the antibody gene of GC B cells, and antibody category transformation occurs, finally forming memory B cells and plasma cells, which can produce high-affinity antibodies. In one study, the GC B-cell response of BALB/c mice peaks between 7 and 14 days after the injection of the mRNA vaccine based on full-length S protein. However, the ability of the RBD-based mRNA vaccine to induce GC B-cell response was poor, indicating that the full-length S protein may play an important role in vaccine-induced GC B-cell response. 22 In addition, a strong SARS-CoV-2 S protein-binding GC B-cell response was detected in lymph node fine-needle aspirates of BNT162b2 (based on full-length S protein) vaccine recipients. The GC B-cell response was detected after the first dose and greatly enhanced after the second dose. 21

Vaccine-induced germinal center response. Some COVID-19 vaccines would induce a germinal center response. Upon the interaction of T cells and B cells, some activated Th cells move to the lymphatic follicles and then differentiate into Tfh cells. Activated B cells proliferate and divide in lymphatic follicles to form the germinal center. With the help of Tfh cells, high-frequency point mutations occur in the variable region of the antibody gene of GC B cells, and antibody category transformation occurs, finally forming memory B cells and plasma cells, which can produce high-affinity antibodies

The continuous existence of GC B cells is the premise for inducing long-lived plasma cells. 33 GC B cells that are not transformed into plasma cells will form memory B cells, and memory B cells are activated rapidly with the help of memory Th cells when encountering the same antigen and then produce plenty of antigen-specific antibodies. It can be concluded that the sustained GC B-cell response induced by the vaccine can secrete potent and persistent neutralizing antibodies and trigger strong humoral immunity. 21

COVID-19 vaccine-induced memory cell responses

The COVID-19 vaccine-induced memory cell responses can induce Th1 and sustained germinal center responses, triggering strong cellular and humoral immunity. In this process, antigen-specific memory T cells and B cells are usually formed, significant for long-term protection (Fig. 4 ). 23 Unlike initial T-cell activation, the activation of memory T cells no longer depends on antigen-presenting cells and can induce a stronger immune response. Most memory B cells enter the blood to participate in recycling and are rapidly activated to produce potent antibodies upon encountering the same antigen. The mRNA-1273 and BNT162b2 induced higher-level production of antibodies and stronger memory B-cell response. 24 Moreover, memory B cells could also be detected in patients who have recovered from COVID-19, and a single dose of mRNA vaccine can induce the memory B-cell response to reach the peak in these patients, 24 , 34 indicating that both previous infection and vaccination can induce memory cell responses.

Vaccine-induced memory cell response. In the Th1 and GC B-cell processes, antigen-specific memory T cells and memory B cells are usually formed. Unlike initial T-cell activation, the activation of memory T cells no longer depends on antigen-presenting cells and can induce a stronger immune response. Most memory B cells enter the blood to participate in recycling and are rapidly activated to produce potent antibodies upon encountering the same antigen

Existing vaccine platforms for COVID-19 vaccines

According to WHO data released on March 28, 2022, 153 vaccines have been approved for clinical trials, and 196 vaccines are in preclinical trials. These vaccines mainly include inactivated vaccines (accounting for 14% of the total), live attenuated vaccines (1%), viral vector vaccines (replication and non-replication; 17% of the total), RNA vaccines (18%), DNA vaccines (11%), protein subunit vaccines (34%), and VLP vaccines (4%) ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ). As of March 28, 2022, a total of ten vaccines (including three India vaccines), including inactivated vaccines, viral vector vaccines, mRNA vaccines, and protein subunit vaccines, have been approved for emergency use by WHO (Fig. 5 ) ( https://extranet.who.int/pqweb/vaccines/vaccinescovid-19-vaccine-eul-issued ). The features, advantages, and disadvantages of different COVID-19 vaccines are shown in Tables 1 , 2 .

A timeline of critical events in the COVID-19 vaccine development progress. WHO has approved the emergency use of ten vaccines (including three India vaccines, COVISHIELD, COVAXIN, and COVOVAX). Vaccination plays a critical role in protecting people from SARS-CoV-2 infections. However, the appearance of VOCs brought big challenges to the efficacy of approved COVID-19 vaccines. These events were summarized and displayed in the form of a timeline

COVID-19 inactivated vaccines

Inactivated vaccines are produced by inactivating the in vitro cultured viruses using chemical reagents. 35 The vaccine can maintain the integrity of virus particles as immunogens. 17 Wang et al. introduced the manufacturing process of the SARS-CoV-2 inactivated vaccine. In this process, SARS-CoV-2 from throat swabs of COVID-19 patients were used to infect Vero cells, and the HB02 strain with the strongest replication ability was selected from three isolated strains (HB02, CQ01, and QD01). After purification, the P1 library was obtained by subculturing in Vero cells with adaptive culturing, subculturing, and amplification. The seventh-generation virus, BJ-P-0207, was selected as the original strain of the COVID-19 inactivated vaccine, 36 , 37 and then β-propiolactone was used to inactivate the virus. 37

An advantage of inactivated vaccines is using the entire virus as an immunogen. Compared with vaccines based on the SARS-CoV-2 S protein or partial protein fragments, such as RBD, inactivated vaccines can induce a wider range of antibodies against more epitopes. 17 In addition, the overall adverse reaction rate of inactivated vaccines in clinical trials is low, and no deaths have been reported in clinical trials, indicating their good safety. 38 , 39 , 40 However, the production of inactivated vaccines are limited because the production of such vaccines must be carried out in biosafety level-3 laboratory or higher biosafety level. 3

The BBIBP-CorV and CoronaVac inactivated vaccines approved by WHO are independently developed in China. A total of 21 candidate COVID-19 inactivated vaccines have been approved for clinical trials as of March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-COVID-19-candidate-vaccines ).

COVID-19 live attenuated vaccines

Live attenuated vaccines are based on the virus obtained by reverse genetics or adaptation to reduce virulence and are used as non-pathogenic or weakly pathogenic antigens. 17 Currently, the main manufacturing processes include codon pair deoptimization (CPD) and virulence gene knockout. 3 , 41 , 42 Wang et al. and Trimpert et al. reported the CPD-based methods to modify SARS-CoV-2 genes genetically. In their studies, amino acid (aa) 283 deletion was introduced into the S protein, and the furin site was also deleted to attenuate the virulence of the virus but retain its replication ability. 43 , 44

Through the CPD-based method, most of the viral amino acid sequences can be retained and induce extensive responses, including innate, humoral, and cellular immunity against viral structural and nonstructural proteins in the recipient. 3 , 43 The extensive response is unlikely to diminish in efficacy due to antigen drift. In addition, live attenuated vaccines can induce mucosal immunity through nasal inhalation to protect the upper respiratory tract. 3 In contrast, other types of vaccines, such as inactivated and mRNA vaccines, are usually administered intramuscularly and only protect the lower respiratory tract. However, after weakening the virulence gene of the virus, virulence may be restored during replication and proliferation in the host. Thus, the reverse genetic method remains challenging.

Currently, there is no WHO-approved COVID-19 live attenuated vaccine for emergency use. Two candidate COVID-19 live attenuated vaccines, COVI-VAC and MV-014-212, have been approved for clinical trials as of March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-COVID-19-candidate-vaccines ).

COVID-19 viral vector vaccines

Viral vector vaccines are based on replication-attenuated engineered viruses carrying genetic material of viral proteins or polypeptides. 35 The particular antigen is produced by host cells after immune transduction. 17 Zhu et al. reported the manufacturing process of a viral vector vaccine based on human adenovirus type-5 (Ad5). In this process, the signal peptide gene and optimized full-length S protein gene based on the Wuhan-Hu-1 strain were introduced into a human Ad5 engineering virus with E1 and E3 gene deletions to produce a vector expressing S protein. 45 A recombinant chimpanzee Ad25 vector expressing full-length S protein was used to prepare the ChAdOx1 nCoV-19 vaccine. 46 Recombinant vectors based on the combination of human Ad5 and Ad26 were also used to prepare the Sputnik V vaccine. 47 , 48 In addition, the Ad26.COV-2-S vaccine developed by Janssen is based on the S protein modified by the Ad26 expression gene, with the deletion of the furin site and the introduction of aa986-987 mutations. 48 Besides adenovirus, vesicular stomatitis virus can also be modified and used to produce the COVID-19 vaccine, inducing a stronger humoral immune response via intranasal and intramuscular routes. 49

Except for inactivated vaccines and partially attenuated vaccines, there is no need to deal with live SARS-CoV-2 in manufacturing other types of vaccines (e.g., viral vector, protein subunit, mRNA, DNA, and VLP vaccines), so the manufacturing process of these vaccines is relatively safe. 3 In addition, viral vector vaccines can induce Th1 cell responses, 29 , 50 thus inducing strong protective effects. However, adenovirus-based viral vector vaccines can induce complications, especially thrombocytopenia. Thus, it is necessary to pay attention to the platelet levels of the relevant recipients in case of thrombocytopenia. 51 , 52 Although adenovirus is not easily neutralized by pre-existing immunity, the pre-existing Ad5 antibodies (46.4, 80, 78, 67, 64, 60, 45% and less than 30% of the population with neutralizing antibodies titers for Ad5 of >1:200 in China, India, Kenya, Thailand, Uganda, South Africa, Sierra Leone, and America, respectively, 26 , 53 ) these pre-existing adenoviruses antibodies in the serum may reduce the immunogenicity of such vaccines. Thus an additional flexible dose might be needed as a solution. 26 , 54

The WHO has approved two viral vector vaccines (Ad26.COV-2-S and AZD1222). As of March 28, 2022, 25 candidates’ clinical trials for COVID-19 viral vector vaccines have been approved, with four using replicating vectors and 21 using non-replicating vectors. Moreover, 3 viral vectors (a type of nonreplicable vector and two types of replicable vectors) + antigen-presenting cells and a vaccine based on the bacterial antigen-spore expression vector are also approved for clinical trials ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ).

COVID-19 protein subunit vaccine

Protein subunit vaccines are based on systemically expressed viral proteins or peptides using various cell-expressing systems, such as bacteria, yeasts, insects, and mammalian cells (such as human embryonic kidney cells). 17 , 35 , 55 , 56 , 57 These vaccines can be divided into recombinant S protein and RBD vaccines. 3 The ZF2001 vaccine adopts the dimer form of the S protein RBD of SARS-CoV-2 as an antigen. 58 Another subunit vaccine (NVX-CoV2373) adopts a full-length S protein with a pre-fusion conformation containing a furin site mutation, and the modified S protein was produced by the Sf9 insect cell expression system. The S protein with a pre-fusion conformation is usually metastable and easily transformed into the post-fusion conformation. The pre-fusion conformation can be stabilized by mutating two residues (K986 and V987) to proline. 17 , 59 In addition, a recombinant vaccine comprising residues 319–545 of the RBD was manufactured using insect cells and a baculovirus expression system, and the purity of the recombinant protein was more than 98% by adding a GP67 signal peptide in the expression system. 60

The protein subunit can also induce Th1 cell responses. 31 In addition, NVX-CoV2373 can induce higher titer neutralizing antibodies than inactivated and Ad5 viral vector vaccines. 3 However, the S protein has a large molecular weight, and the expression efficiency of the S protein is relatively low compared with that of RBD. Although the RBD has a small molecular weight and is easy to express, it lacks other immune epitopes on the S protein and thus is prone to antigen drift. 3

For emergency use, the WHO has authorized only one COVID-19 protein subunit vaccine (NVX-CoV2373). Furthermore, 51 candidate COVID-19 protein subunit vaccines were approved for clinical trials on March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ).

COVID-19 DNA vaccines

DNA vaccines are based on viral antigens encoded by a recombinant plasmid. Viral proteins or polypeptides are produced by transcription and translation processes in host cells. 17 Smith et al. synthesized the INO-4800 COVID-19 DNA vaccine based on a previously prepared MERS-CoV vaccine. 61 The main steps are as follows: (1) acquisition of the S protein sequence from GISAID; (2) addition of the N-terminal IgE leading sequence; (3) optimization of the IgE-Spike sequence with algorithms to enhance its expression and immunogenicity and synthesize the optimized sequence; (4) ligation of the fragment into the expression vector pGX0001 after digestion. 62 , 63 Brocato et al. constructed the DNA encoding SARS-CoV-2 S protein into the pWRG skeleton plasmid by cloning the gene with optimized human codons, and this skeleton plasmid was used to produce a DNA vaccine against hantavirus. 64

Compared with mRNA vaccines, DNA vaccines have higher stability and can be stored for a long time. 65 Escherichia coli can be used to prepare plasmids with high stability. 3 However, the immunogenicity of the DNA vaccine is low. Furthermore, different injection methods, such as intramuscular or electroporation injection, also affect the vaccine’s efficacy. 3

There is no COVID-19 DNA vaccine authorized by the WHO for emergency use. Sixteen candidate COVID-19 DNA vaccines have been approved for clinical trials on March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ).

COVID-19 mRNA vaccines

mRNA vaccines are based on mRNA encapsulated by vectors (usually lipid nanoparticles), viral proteins, or polypeptides produced during the translation process in the host cells. 17 , 35 In addition to mRNA itself, the 5′ Cap and 3′ Poly (A) also play important roles in regulating the efficiency and stability of translation. 66 , 67 At present, mRNA vaccines usually adopt the Cap 1 structure (m 7 GpppN 1 mp, with an additional 2′ methylated hydroxyl compared with Cap 0), improving translation efficiency. 66 There are two ways of mRNA tailing: use traditional polyadenylate tails to add the 3′ tail of poly (A) or design the DNA template with a proper length of poly (A), and the latter can obtain a length-controlled poly (A) tail. 67 , 68 Corbett et al. introduced a manufacturing process for the mRNA-1273 vaccine. The optimized mRNA encoding SARS-CoV-2 S-2P protein with stable pre-fusion conformation was synthesized (2 P represents double proline mutations of the K986 and V987 residues mentioned above). The synthesized mRNA sequence was purified by oligo-dT affinity purification, and encapsulated in lipid nanoparticles. 69 The BNT162b2 vaccine also adopts a similar mRNA encoding S-2P, 17 , 70 whereas the BNT162b1 vaccine adopts the mRNA encoding RBD and fuses the trimer domain of T4 fibrin to the C-terminus. Furthermore, a proper delivery system like LNP can protect mRNA against the degradation of nuclease 71 and further enhance the efficacy of mRNA vaccines. The capsulation of mRNA with LNP can effectively transfer mRNA into cells and induce a strong immune response; thus is widely used in most mRNA vaccines, including BNT162b2 and mRNA-1273. 71 , 72 In addition, other delivery systems like lipopolyplexes, polymer nanoparticles, cationic polypeptides, and polysaccharide particles also provide unlimited possibilities for the improvement of mRNA vaccine . 72 , 73

The mechanism of mRNA vaccine-induced immunity is similar to that of the DNA vaccines. Both BNT162b1 and BNT162b2 vaccines transmit the genetic information of the antigen rather than the antigen itself, 3 so they only need to synthesize the corresponding RNA of viral proteins, improving the production speed. 35 In addition, mRNA vaccines can induce strong Th1 cell responses and GC B-cell responses and simultaneously produce long-lived plasma cells and memory cells, continuously eliciting SARS-CoV-2 neutralizing antibodies. 21 , 24 However, mRNA vaccines may cause complications, especially myocarditis, 54 , 74 , 75 , and have a higher storage requirement due to the instability of mRNA. 3

The WHO has approved two types of mRNA vaccines: mRNA-1273 and BNT162b2, and a total of 28 candidate COVID-19 mRNA vaccines have been approved for clinical trials as of March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ).

COVID-19 VLP vaccines

VLP vaccines are based on noninfectious particles consisting of in vitro-expressed viral structural proteins and decorated viral polypeptides on the surface. 74 Tan et al. used Spy Tag technology to modify the SARS-CoV-2 RBD on the surface of protein particles by forming covalent iso-peptide bonds based on the previous protein nanoparticle platform and obtained an RBD-Spy VLP. 76 Moreover, a self-assembled VLP vaccine based on the expression of modified full-length S proteins, including R667G, R668S, R670S, K971P, and V972P mutations, has also been developed using a plant expression system. 77

VLP vaccines do not contain viral genomes, and plant-based VLP vaccines have the potential of oral delivery vaccines. 65 By loading a variety of antigens, such as the RBD from different variants on the protein particles, neutralizing antibodies against multi-immune epitopes can be induced to improve the neutralizing activity against SARS-CoV-2 variants. However, the manufacturing process of the VLP vaccine is more complex, and no relevant data was published for human clinical trials.

There is no COVID-19 VLP vaccine authorized by the WHO for emergency use. Six candidates' COVID-19 VLP vaccines have been approved for clinical trials as of March 28, 2022 ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ).

Efficacy of covid-19 vaccines

Animal studies of covid-19 vaccines approved by the who.

Several SARS-CoV-2 animal models have been developed, including mice expressing human ACE2, 78 , 79 , 80 SARS-CoV-2-adaptive mouse, 81 , 82 ferret, 83 hamster, 84 , 85 and NHP models. 86 , 87 , 88 Although mice can be infected with SARS-CoV-2 by transferring the human ACE2 gene or designing a virus-adapted mouse, no mouse model can simulate all the characteristics of human COVID-19, especially pulmonary vascular disease, hyperinflammatory syndrome, observed in adults and children, respectively. 10 The hamster model can simulate serious COVID-19 diseases. Syrian hamsters show mild to severe symptoms 1–2 days after nasal infection, 89 , 90 and progressive weight loss and dyspnea. The NHP model can reflect mild-to-moderate SARS-CoV-2 infection and can be used to test many candidate vaccines. However, due to different adjuvants and vaccine dosages, the use of serum-neutralizing antibody titer as a direct basis for comparing the efficacy of different vaccines is still limited. In addition, different analytical methods, such as 50% plaque reduction neutralization test (PRNT 50 ), 80% plaque reduction neutralization test (PRNT 80 ), and enzyme-linked immunosorbent assay (ELISA), may also affect the final experimental results. These data can objectively show the efficacy of each vaccine. Here, we summarize the immunogenicity, neutralizing activity, and cell response data from animal experiments for the BBIBP-CorV, CoronaVac, AZD1222, Ad26.COV-2-S, NVX-CoV2373, mRNA-1273, and BNT162b2 vaccines (Fig. 6 ).

A timeline of the preclinical and clinical trials of approved COVID-19 vaccines. Preclinical and clinical trials play important roles in evaluating the safety and protective efficacy of COVID-19 vaccines. The information of preclinical to clinical trials of several WHO-approved COVID-19 vaccines are provided in the form of a timeline, and partial Phase III clinical trials’ data were also displayed to show the total efficacy

Immunogenicity testing of BBIBP-CorV was performed in BALB/c mice, rabbits, and guinea pigs. 36 The animals were classified into three groups according to the doses: high (8 μg), medium (4 μg), and low (2 μg). All dosages produced good immunogenicity, and the serum conversion rate reached 100% on day 21 after immunization. In different dosage groups of BALB/c mice, the immunogenicity of the three-dose group was significantly higher than the two- and single-dose groups. In the NHP experiment, after vaccination, the neutralizing GMTs in rhesus monkeys were 1:860 in the high-dose group and 1:512 in the low-dose group, respectively, indicating BBIBP-CorV can effectively prevent SARS-CoV-2 infection in rhesus monkeys.

The PiCoVacc inactivated vaccine, also known as CoronaVac, is highly immunogenic in BALB/c mice. 37 After the injection of PiCoVacc, the serum S-specific antibody level of mice was ten times higher than that of convalescent serum obtained from COVID-19 patients. PiCoVacc could induce high RBD antibodies, 30 times higher than the induced NTD antibodies. The neutralizing antibody titer in rhesus monkeys was 1:50 in the third week after one dose of PiCoVacc, similar to the titers in the convalescent serum of COVID-19 patients. One week after the third dose of PiCoVacc, viral infection was induced through intranasal and organ routes. The viral load of all vaccinated animals decreased significantly 3–7 days after infection, indicating that PiCoVacc played an important anti-SARS-CoV-2 role in the NHP model.

Compared with BBIBP-CorV and CoronaVac, viral vector vaccines and mRNA vaccines can simultaneously induce T-cell responses, 46 , 48 , 69 , 70 mainly a Th1 cell response, while Th2 responses are related to vaccine-induced respiratory diseases, and were not detected. Viral-specific neutralizing antibodies were detected in all BALB/c mice following inoculation with ChAdOx1 nCoV-19 (AZD1222). On day 14, after the first or second dose, the neutralizing antibody titers in rhesus monkey serum were 1:5 to 1:40 (single dose) and 1:10 to 1:160 (two doses). In addition, cytokines, including IL-4, IL-5, and IL-13, in rhesus monkey serum after a single dose or two doses injection were low, indicating the safety of ChAdOx1 nCoV-19 in NHPs.

Another viral vector vaccine, Ad26.COV-2-S (Ad26-S.PP) induced similar neutralizing antibody titers in the NHP model. 48 RBD-specific neutralizing antibodies were detected in 31 of 32 rhesus monkeys (96.9%) 2 weeks after Ad26-S.PP inoculation and the induced titers were 1:53 to 1:233 (median 1:113) 4 weeks after vaccination. In addition, Ad26-S.PP also induced S-specific IgG and IgA responses in bronchoalveolar lavage (BAL) obtained from rhesus monkeys, indicating that Ad26-S.PP has a protective effect on rhesus monkeys’ upper and lower respiratory tracts. 6 weeks after vaccination, 1.0 × 10 5 50% tissue culture infectious dose (TCID 50 ) of SARS-CoV-2 was challenged in intranasal and tracheal routes, and 17 of 32 rhesus monkeys inoculated with Ad26-S.PP were completely protected, and no viral RNA was detected in BAL or nasal swabs, indicating that Ad26-S.PP protects the upper and lower respiratory tracts in the NHP model.

Besides Ad26.COV-2-S, another protein subunit vaccine NVX-CoV2373, also showed the protection efficacy of both upper and lower respiratory tracts in the cynomolgus macaque model. 91 The vaccine induced a remarkable level of anti-S IgG in mice with the titers of 1:84,000-1:139,000 on the 15th day after the single injection. 59 Meanwhile, NVX-CoV2373 also elicits multifunctional CD4 + and CD8 + T-cell responses. In the NHP model, the serum neutralizing antibody titers produced after the second dose of 2.5, 5, 25 μg vaccine could achieve 1:17,920-1:23,040 CPE 100 , which was 7.1–10 times higher than those in convalescent serum. SARS-CoV-2 was challenged in the upper and lower respiratory tract routes after NVX-CoV2373 vaccination, and 91.6% (11 in 12) immunized animals were free of infection. No viral RNA was detected in the nasal swabs, indicating the broader protection of NVX-CoV2373.

The mRNA-1273 vaccine is most immunogenic in the NHP model. The GMTs of rhesus monkey serum obtained from injection dosages of 10 and 100 μg were 1:501 and 1:3,481, respectively, which were 12 times and 84 times higher than that of human convalescent serum. 69 It has been shown that mRNA-1273 induces a strong S-specific neutralizing antibody response. Rhesus monkeys also showed a dose-dependent Th1 cell response after the injection of mRNA-1273, which was similar to the phenomenon observed after the injection of ChAdOx1 nCoV-19. Intranasal and tracheal routes administered all rhesus monkeys 1.0 × 10 6 TCID 50 of SARS-CoV-2 in the 4th week after the second dose. Four days after infection, only low-level viral RNA in two of eight animals in the 10-μg-dose group and one of eight in the 100-μg-dose groups could be detected, indicating good antiviral activity of mRNA-1273 in the NHP model.

BNT162b1 and BNT162b2 (especially the former) also showed high immunogenicity in BALB/c mice while lower than mRNA-1273. 70 On day 28, after single-dose injection, the serum neutralizing antibody titers of mice with BNT162b1 and BNT162b2 reached 1:1056 and 1:296, respectively. Additionally, both vaccines induced high CD4 + and CD8 + T-cell responses. In the NHP model, the neutralizing antibody titers of rhesus monkey serum obtained from 100 μg-dose 14 days after vaccination with the second dose of BNT162b1 and BNT162b2 were 1:1714 and 1:1689, respectively, which were significantly higher than those in the convalescent serum of COVID-19 patients (1:94). All rhesus monkeys were administered 1.05 × 10 6 plaque-forming units of SARS-CoV-2 by intranasal and tracheal routes on 41–55 days after the second dose of BNT162b1 or BNT162b2. On the third day after infection, viral RNA was detected in the BAL of two of the six rhesus monkeys injected with BNT162b1. Viral RNA was not detected in BAL of the BNT162b2 injected monkeys at any time point.

mRNA, viral vector, and protein subunit vaccines showed higher induced-antibody titers than inactivated vaccines and could induce Th1 cell responses. These vaccines mainly induced IgG production and showed a protective effect on the upper respiratory tract. However, the Ad26.S-PP and NVX-CoV2373 vaccines exerted a protective effect on both the upper and lower respiratory tracts. In addition, all injection groups showed significant virus clearance ability after the virus challenge, demonstrating the protection provided by these vaccines in NHPs. Furthermore, all experimental animals injected with the vaccine showed no pathological changes in the lungs and normal tissues, providing strong support for follow-up clinical trials.

Clinical trials of COVID-19 vaccines approved by the WHO

The safety and effectiveness of vaccines are evaluated in preclinical trials. Clinical trials of candidate vaccines can be carried out only after the relevant data meet the standards for such trials. Ten candidate vaccines have been approved for Phase IV clinical trials. They include three inactivated vaccines (BBIBP-CorV, WIBP COVID-19 vaccine, and CoronaVac), three viral vector vaccines (AZD1222, Ad5-nCoV, and Ad26.COV-2-S), one protein subunit vaccine (MVC-COV1901), and three mRNA vaccines (mRNA-1273, BNT162b2, and mRNA-1273.351) ( https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines ). Data from Phase I, I/II, II, II/III, and III trials and some data from Phase IV clinical trials have been released (Fig. 6 ). Here, the neutralization efficacy, adverse reactions, and cell responses, mainly Th1 cell responses of some vaccines in different clinical trial stages, are discussed. Because of the different adjuvants used and different dosages of the vaccines, the titer of serum neutralizing antibodies cannot be used as a direct reflection of neutralization ability. Moreover, different analysis methods also affect the trial results.

Sinopharm announced the results of a randomized, double-blind, placebo-controlled Phase I/II clinical trial of the BBIBP-CorV vaccine (ChiCTR2000032459). 38 The Phase I and Phase II trials included 192 and 448 healthy aged 18–80 participants, respectively. All participants were negative for serum-specific SARS-CoV-2 IgG or IgM. In the Phase I trial, the vaccine group was injected with 2–8 μg BBIBP-CorV on day 0 and day 28. The control group was injected with two doses of normal saline placebo containing aluminum hydroxide adjuvant. In the Phase II trial, the vaccine group was divided into single-dose (day 0, 8 μg) and two doses (day 0, day 14, 21, 28; 4 μg at each time). In the Phase II trial, on day 28, after the second dose in the two-dose group or after the single dose in the single-dose group, serum neutralizing antibody titers against SARS-CoV-2 were detected based on PRNT 50 . The antibody titer in the single-dose group was 1:14.7, and the titers range of the two-dose group were 1:169.5-1:282.7. The serum titers after two doses on days 0 and 21 were the highest, indicating that two doses of vaccination could induce a higher neutralizing antibody level. In addition, the Phase I trial showed that the serum titer of subjects >60 years old after 28 days of the second dose was less than that of subjects aged 18–59, indicating that the elderly may need higher doses or adjuvants with stronger immunogenicity. None of the subjects in Phase I/II trials displayed severe adverse reactions within 28 days after vaccination. BBIBP-CorV was demonstrated safe for humans. Currently, several Phase IV clinical trials of the vaccine are underway (NCT04863638, NCT05075070, NCT05075083, NCT05104333, NCT05105295, and NCT05104216) ( https://clinicaltrials.gov ).

Huang et al. showed that the neutralization ability of serum neutralizing antibody induced by both BBIBP-CorV inactivated vaccine and ZF2001 subunit vaccine to the Beta variant was reduced by 1.6 times. 92 It is worth noting that serum neutralization activity obtained from BBIBP-CorV homologous booster group and BBIBP-CorV/ZF2001 heterologous booster group were increased, while 80% of samples still failed to neutralize B.1.1.529(Omicron) variant. 93 The results showed that it is necessary to closely monitor the neutralization efficacy of the vaccine against variants, especially those with strong immune escape ability, such as Beta and Omicron, and update the sequence of seed strain in time. 94

Sinovac conducted several randomized, double-blind, placebo-controlled Phase I/II clinical trials for the CoronaVac vaccine (NCT04551547, NCT04352608, NCT04383574). 39 , 95 , 96 Two groups received 3–6 μg of the CoronaVac vaccine, and participants aged 3–17 years received 1.5–3 μg. The control group received the same amount of aluminum hydroxide diluent. None of the participants had a history of SARS-CoV-2 exposure or infection, their body temperature was <37 °C, and none was allergic to the vaccine components. The serum neutralizing antibody titer of the subjects was analyzed with a minimum quadruple dilution using microcytosis. The vaccine induced higher titers in children and adolescents groups in the Phase II trial (3 μg adolescent group, 1:142.2; 6 μg adult group, 1:65.4; 6 μg elderly group, 1:49.9). One case of severe pneumonia unrelated to the vaccine was reported in the placebo group in children and adolescents, one case of acute hypersensitivity after the first dose of injection was reported in the adult group, and seven cases of severe adverse reactions were reported in the elderly group. The remaining adverse events were mild or non-toxic. These findings indicated that CoronaVac could be used in children and adolescents, and it is safe for children, adolescents, and adults.

Furthermore, Sinovac performed Phase III (NCT04582344) and IV clinical trials of CoronaVac for patients with autoimmune diseases and rheumatism (NCT04754698). 40 , 97 In the Phase III trial, 1413 participants, were analyzed for immunogenicity; 880 of 981 (89.7%) serum samples in the vaccine group were positive for RBD-specific antibodies, compared to 4.4% in the control group. The titer of neutralizing antibodies in 387 sera samples in the vaccine group ranged from 1:15–1:625 (1:15, 16%; 1:75, 38.7%; 1:375, 21%), indicating that most vaccine recipients could produce neutralizing antibodies after vaccination. No deaths or grade IV adverse events occurred in the Phase III trial. In the Phase IV clinical trial, using the above analysis based on microcytosis, the serum neutralizing antibody titer of vaccines with rheumatism was only 1:27 6 weeks after the second dose, which was lower than healthy subjects (1:67). These findings indicated that the dose should be increased for individuals with immune diseases, or the immune adjuvant should be replaced to improve protection. Seven Phase IV clinical trials of the vaccine are in progress (NCT04911790, NCT04953325, NCT04962308, NCT04993365, NCT05107557, NCT05165732, and NCT05148949) ( https://clinicaltrials.gov ).

According to the study of Chen Y and colleagues, 98 serum-neutralizing activity against D614G, B.1.1.7(Alpha), and B.1.429 variants after inoculation with CoronaVac were equally effective, while B.1.526, P.1(Gamma) and Beta significantly reduced serum neutralization efficiency. Fernández et al. tested serum neutralization in 44 individuals after two doses of the CoronaVac vaccine. Alpha and Gamma variants could escape from the neutralization of antibodies induced by the vaccine, with escape rates of 31.8 and 59.1% in the subjects, respectively. 99 Estofolete et al. 100 reached a similar conclusion that although the CoronaVac vaccine cannot completely inhibit the infection caused by the Gamma variant, the vaccination can help to reduce patients’ clinical symptoms and the rate of death and hospitalization. The Omicron variant can escape neutralizing antibodies elicited by BNT162b2 or CoronaVac, bringing a challenge to existing vaccines. 101

Phase I/II clinical trials of AZD1222 were divided into two stages (NCT04324606). 50 , 102 In the first stage, 1077 healthy subjects aged 18–55 years with negative laboratory-confirmed SARS-CoV-2 infection or COVID-19 symptoms were recruited. Ten individuals were injected with two doses of 5 × 10 10 viral particles (VPs), the remainders were injected with a single dose of 5 × 10 10 VPs. Those in the placebo group were injected with a licensed meningococcal group A, C, W-135, and Y conjugate vaccine (MenACWY). Serum neutralizing antibody levels were evaluated using a standardized ELISA protocol. The median level of serum samples on day 28 after one dose was 157 ELISA units (EU). The median level of 10 individuals injected with the enhancer dose was 639 EU on day 28 after the second dose, indicating that two injection doses can induce higher neutralizing antibodies. In the second stage of the trial, 52 subjects who had been injected with the first dose received a full-dose (SD) or half-dose (LD) of AZD1222(ChAdOx1 nCoV-19) vaccine on days 28 and 56. The titers of 80% virus inhibition detected by the microneutralization assay (MNA80) were 1:274 (day 0, 28 SD), 1:170 (day 0, 56 LD), and 1:395 (day 0, 56 SD) respectively. The highest titer was produced after the full-second dose injection on day 56. In addition, the AZD1222 vaccine can also induce Th1 biased CD4 + and CD8 + T-cell responses and further promote cellular immunity. No serious adverse reactions were reported in any phase of the trial, and prophylactic paracetamol treatment reduced the rate of mild or moderate adverse reactions. 103

In a single-blind, randomized, controlled Phase II/III trial of AZD1222 (NCT04400838), 104 participants were divided into three groups based on age: 18–55, 56–69, and >70 years. The 18–55 years old group was allocated two low doses (2.2 × 10 10 VPs)/two standard doses (3.5–6.5 × 10 10 VPs) ChAdOx1 nCoV-19 and placebo at 1:1 and 5:1, respectively. The 56–69-year-old group was injected with a single dose of ChAdOx1 nCoV-19, a single dose of placebo, two doses of ChAdOx1 nCoV-19, and two doses of placebo (3:1:3:1, respectively). The >70-year-old group was administered a single dose of ChAdOx1 nCoV-19, a single dose of placebo, two doses of ChAdOx1 nCoV-19, and two doses of placebo (5:1:5:1, respectively). All placebo groups received the aforementioned MenACWY vaccine. MNA80 was used to evaluate the titer of serum neutralizing antibodies. The titer of the low-dose group ranged from 1:143 to 1:161, and that of the standard-dose group ranged from 1:144 to 1:193, indicating that ChAdOx1 nCoV-19 can induce high-level neutralizing antibody in all age groups and that two doses of injection can produce higher antibody levels. Thirteen serious adverse events were reported as of October 26, 2020, and none related to vaccine injection. Phase IV clinical trials of the vaccine are in progress (NCT04760132, NCT04914832, NCT05057897, and NCT05142488) ( https://clinicaltrials.gov ).

Supasa et al. tested the neutralizing effect of AZD1222 on the Alpha variant. GMTs of serum neutralizing antibody decreased by 2.5 times on day 14 and 2.1 times on day 28 after the second dose, while no immune escape was observed. 105 Subsequently, the neutralization effect of AZD1222 on the Beta variant was tested. On day 14 or 28 after the second dose, the GMTs of the subjects’ serum neutralizing antibodies against the Beta variant were approximately nine times lower than that of the Victoria variant (an early Wuhan-related viral isolate). 106 In addition, the serum neutralizing antibody GMTs of AZD1222 subjects against the Delta variant decreased by ~4 times compared with the wild type. 107 On the 28th day after the booster dose, the neutralization ability against Omicron was reduced by about 12.7-fold compared with Victoria and 3.6-fold with B.1.617.2 (Delta). 108 These findings indicate that the Omicron and Beta variants have stronger immune escape ability than the Alpha and Delta variants. Monitoring vaccine neutralization ability should be highlighted, and existing vaccines should be optimized or strengthened to maintain vaccine efficacy for emerging SARS-CoV-2 variants.

Ad26.COV-2-S

Janssen performed Phase I and Phase I-II clinical trials of Ad26.COV-2-S (NCT04436276). 29 , 30 A total of 25 healthy adults aged 18–55 with negative nasopharyngeal PCR and serum IgG results participated in the Phase I trial. The participants were equally allocated to receive two doses of low-dose (5 × 10 10 VPs) Ad26.COV-2-S (low-dose/low-dose, LL), one dose of low-dose vaccine and one dose of placebo (low-dose/placebo, LP), two doses of high-dose (1 × 10 11 VPs) (high-dose/high-dose, HH), one dose of high-dose vaccine and one dose of placebo (high-dose/placebo, HP), or two doses of placebo (placebo/placebo, PP). The placebo group received a 0.9% sodium chloride solution. The GMTs of serum neutralizing antibody based on the inhibition of 50% of pseudovirus (ID 50 ) were detected 14 days after the second dose. The ID 50 values were 1:242 (LL), 1:375 (LP), 1:449 (HH), and 1:387 (HP) in the vaccine groups. Moreover, Ad26.COV-2-S induced CD4 + and CD8 + T-cell responses, simultaneously inducing cellular immunity. Adverse events after vaccination were not evaluated in this study.

In the Phase I-IIa clinical trial, 805 healthy adults aged 18–55 and >65 years were equally divided into LL, LP, HH, HP, and PP groups (low-dose: 5 × 10 10 VPs, high-dose: 1 × 10 11 VPs). On day 71 or 72 (2 weeks after the injection of the second dose), serum neutralizing antibody GMT based on 50% virus inhibition (IC 50 ) of the 18–55-year-old group was 1:827 (LL, day 72), 1:1266 (HH, day 72), 1:321 (LP, day 71), and 1:388 (HP, day 71). On day 29, the serum GMT of the participants injected with a single dose of low-dose or high-dose vaccine in the >65-year-old group was 1:277 or 1:212, respectively. These findings indicated that two injection doses significantly improved antibody titers and enhanced protection. On day 15, 76–83% of the participants in the 18–55 age group and 60–67% of participants in the >65 age group had a Th1 biased CD4 + T-cell response, consistent with the results observed in the Phase I trial. After the first dose, most of the reported local adverse events were grade 1 or 2. The most common event was injection site pain. These collective findings indicated that Ad26.COV-2-S is safe. Four Phase IV clinical trials of the vaccine are ongoing (EUCTR2021-002327-38-NL, NCT05030974, NCT05037266, and NCT05075538) ( https://www.ncbi.nlm.nih.gov , https://clinicaltrials.gov ).

Alter et al. systematically evaluated the neutralization efficacy of the Ad26.COV-2-S vaccine against SARS-CoV-2 variants. 109 Pseudovirus neutralization test results showed the neutralization titer of the antibody induced by the Ad26.COV-2-S to Gamma variant was 3.3 times lower than the wild type. The neutralization of the Beta variant was five times lower than that of the wild type. The live virus neutralization test showed that the neutralization activity of this variant (Beta) dropped approximately ten times in titers. Garcia Beltran et al. found the neutralization activity of serum samples from Ad26. COV-2 vaccinees against the Omicron variant was reduced by 17 times. 110

NVX-CoV2373

NVX-CoV2373 is a protein subunit vaccine based on the full-length S protein of pre-fusion conformation (rSARS-CoV-2). Relevant Phase I-II clinical trial (NCT04368988) data has been released. 31 A total of 131 healthy men and non-pregnant women aged 18–59 years were enrolled. All participants had no history of COVID-19 infection and had a low risk of COVID-19 exposure. Among them, six participants were assigned 5 μg/25 μg rSARS-CoV-2 + Matrix-M1 at a ratio of 1:1 as an initial safety measure and were observed for 48 h. The remaining 125 participants received 9% saline (placebo) as group A, two doses of 25 μg rSARS-CoV-2 without adjuvant Matrix-M1 as group B, two doses of 5 μg rSARS-CoV-2 + 50 μg Matrix-M1 as group C, two doses of 25 μg rSARS-CoV-2 + 50 μg Matrix-M1 as group D, and one dose of 25 μg rSARS-CoV-2 + 50 μg Matrix-M1 as group E, at a ratio of 1:1:1:1:1, respectively. ELISA-based neutralization test was used to detect the antibody titers on the 14th day after the second dose. Group C and D showed the most efficacy with the titers of 1:3906 and 1:3305, respectively, four to six times more than convalescent serum. In addition, T-cell responses were also induced and boosted by the adjuvant Matrix-M1. No serious adverse event was reported in this trial except a subject terminated the second dose due to mild cellulitis.

Results of the Phase III clinical trial of NVX-CoV2373 have also been released. 111 This trial included 16,645 healthy men, non-pregnant women, and people with chronic diseases aged 18–84 without COVID-19 infection and immune disease history. The recipients received two doses of 5 μg NVX-CoV2373 or equivalent placebo (0.9% saline) at a ratio of 1:1. The rate of COVID-19 or SARS-CoV-2 infection 7 days after the vaccination was ~6.53 per thousand in the vaccine group versus 63.43 per thousand in the control group, indicating an overall efficacy of 89.7%. Based on the analysis of subgroups, the effectivity of NVX-CoV2373 in people aged over 65 was 88.9%, and the efficacy against the Alpha variant was 86.3%. The overall rate of adverse events among the recipients was higher in the vaccine group than in the placebo group (25.3 vs. 20.5%). The proportion of serious adverse events was similar in both groups, at about 1%, with one person in the vaccine group reporting severe myocarditis. The vaccine and placebo groups reported one death caused by respiratory failure and one sepsis caused by COVID-19 infection.

A clinical trial was further performed to evaluate the efficacy of NVX-CoV2373 in AIDS patients, in which the Beta variant infected most people. The results indicated that this vaccine showed 60.1% efficacy in HIV-negative participants, indicating that the NVX-CoV2373 vaccine was efficacious in preventing COVID-19. 112

Similar to the viral vector vaccines, mRNA vaccines, especially mRNA-1273, also induced Th1 biased CD4 + T-cell responses in clinical trials. 28 , 113 Moderna performed a Phase I clinical trial of mRNA-1273 (NCT04283461). In the first stage, 45 healthy adults aged 18–55 received two doses of 25, 100, and 250 μg mRNA-1273 at a ratio of 1:1:1. In the second stage, 40 subjects aged >56 years were injected with two doses of 25 and 100 μg vaccine at a ratio of 1:1. The interval between all injections was 28 days. There was no control group. PRNT 50 was used to detect the titers of serum neutralizing antibodies in different age groups 14 days after the second dose, and the titers were 1:343.8 (100 μg, 18–55 years old), 1:878 (100 μg, 56–70 years old), and 1:317 (100 μg, >70 years old). The vaccine induced potent neutralizing antibodies in different age groups, and the highest titer was induced in the 56–70 age group. After the first dose, 23 participants aged 18–55 (51.1%) reported systemic adverse reactions. All the adverse reactions were mild or moderate. After the second dose, three subjects reported serious adverse reactions. No serious adverse events occurred in the group aged over 56 years.

Moderna also performed a Phase III clinical trial of the mRNA-1273 vaccine. The number of participants was 30,420, aged over 18 years and had no history of SARS-CoV-2 infection. Subjects were injected with two doses of mRNA-1273 vaccine (100 μg) at a 28-day interval or with normal saline at a 1:1. 114 From the first day to November 25, 2020, 196 cases of COVID-19 were diagnosed by preliminary analysis, with 11 cases in the vaccine group and 185 cases in the placebo group, indicating a 94.1% effectiveness of mRNA-1273. After the first dose, adverse events occurred in 84.2% of the participants in the vaccine group, and 88.6% of the participants in the vaccine group reported adverse events after the second dose. The adverse events were mainly graded 1 or 2.

Furthermore, there were three deaths in the placebo group (one each from intraperitoneal perforation, cardiopulmonary arrest, and systemic inflammatory syndrome) and two deaths in the vaccine group (one from cardiopulmonary arrest and suicide). Although the death rate was low and unrelated to vaccination, the effects of nucleic acid vaccines on cardiopulmonary and other functions still need to be further studied. Phase IV clinical trials of the mRNA-1273 vaccine are currently underway (NCT04760132, NCT05060991, NCT04952402, NCT05030974, NCT05047718, NCT05075538, and NCT05075538) ( https://clinicaltrials.gov ).

The mRNA-1273 vaccine is still effective for the Alpha variant, but its neutralization effect on the Beta variant is reduced. The pseudovirus neutralization test showed that the antibody titers of mRNA-1273 against the Beta variant were 6.4 times lower than that of the D614G mutant. 115 McCallum et al. tested the neutralization efficacy of mRNA-1273 against the B.1.427/B.1.429 variant and found that the neutralizing antibody GMTs induced by the vaccine decreased by 2–3.5 times compared to the wild type. 116 Furthermore, more than 50% of mRNA-1273 recipients’ serum failed to neutralize the Omicron variant, with the GMTs reduced by about 43 times. 110 , 117

Phase I and III clinical trials of the BNT162b2 mRNA vaccine have also been performed (NCT04368728). 117 The Phase I clinical trial performed by Pfizer-BioNTech involved two candidate vaccines, BNT162b1 encoding RBD and BNT162b2 encoding the full-length of S protein. This trial included 185 healthy adults aged 18-55 and 65–85. With 15 individuals per group, they were divided into 13 groups (seven groups aged 18–55 and six groups aged 65–85) and inoculated with two doses of 10/20/30 μg BNT162b1 or BNT162b2, and an additional group aged 18–55 received a single dose of 100 μg BNT162b2. Twelve individuals in each group were vaccinated with BNT162b1/BNT162b2, and three were vaccinated with a placebo. The 50% neutralization titers were determined on the 14th day after the second dose, ranging from 1:33 to 1:437 (BNT162b1) and 1:81 to 1:292 (BNT162b2). BNT162b1 and BNT162b2 both induced high-level production of antibodies. The local adverse reactions caused by these two vaccines were similar, mainly pained at the injection site. However, the overall rate of adverse events of BNT162b2 was low, with less use of antipyretic analgesics and these findings indicated that BNT162b2 is safer.

The Phase III clinical trial involved 43,548 participants aged 16 years and over, who were injected with two doses of BNT162b2 (30 μg at an interval of 21 days) or placebo at a ratio of ~1:1. 118 At least 7 days after the second dose, eight cases of COVID-19 were observed in the vaccine group, while 162 cases of COVID-19 were observed in the placebo group, indicating the effectiveness of 94.6%. Mild-to-moderate pain at the injection site within 7 days of the first dose of BNT162b2 was the most common local adverse reaction. Less than 1% of all subjects reported severe pain, and none of the participants reported grade 4 local adverse reactions. Two BNT162b2 vaccinees died (one from arteriosclerosis and one from cardiac arrest), four placebo subjects died (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). None of the deaths was related to the vaccine or placebo. Like the mRNA-1273 vaccine, heart disease also occurred in the BNT162b2 vaccine injection group, indicating that the mRNA vaccine needs to be strictly evaluated. Phase IV clinical trials of the BNT162b2 vaccine are currently underway (NCT04760132, NCT05060991, NCT04961229, NCT04775069, NCT04878211, NCT04952766, NCT04969250, NCT05047718, NCT05057169, NCT05057182, and NCT05075538) ( https://clinicaltrials.gov ).

Collier et al. tested the neutralization efficacy of the sera of single-dose BNT162b2 vaccine subjects against the Alpha variant. 119 Ten of 23 samples showed a decrease in neutralization efficacy, with a maximum decrease of about six times. Supasa et al. showed that the neutralization activity of the BNT162b2 vaccine against the Alpha variant decreased by 3.3 times. 105 Subsequently, the researchers further tested the neutralization activity of BNT162b2 against the Beta variant and found that the GMTs of neutralizing antibodies decreased by 7.6 times. 106 In addition, the neutralization activity of the BNT162b2 vaccine against Kappa, Delta, B.1.427, and B.1.429 variants was reduced by at least two times (Kappa and Delta), 1.2 times (B.1.427), and 1.31 times (B.1.429). 120 Although the Delta variant has high infectivity and can cause immune escape, Liu et al. reported that BNT162b2 retained neutralizing activity against the delta variant. 121 In the study carried out by Cameroni E and colleagues, the neutralization activity of BNT162b2 booster-dose recipients’ serum significantly increased, but its neutralization capability against the Omicron variant still decreased by at least fourfold compared with the Wuhan-Hu-1 strain. 122

The effectiveness of COVID-19 vaccines in the real world

Although clinical trials can reflect the effectiveness of vaccines, the outcomes are partly dependent on the status of participants. Thus, the data were not very objective. The real-world study can help to establish clinical trial evidence and provide information for adjusting the vaccination strategy. Here, we summarize several current real-world studies to support these vaccines’ efficacy further. A study on the effectiveness of mRNA vaccine in American healthcare workers (HCW) showed that the overall efficacy of BNT162b2 and mRNA-1273 vaccines were 88.8 and 88.9%, respectively. 123 A study involving six locations in the United States, HCW, and the first responders also showed that after two doses of mRNA vaccine, the effective rate was about 90%. 124 In addition, the 2nd dose of BNT162b2 was shown to reduce 94% of COVID-19 cases in a 1.2 million person dataset. 125 A large-scale study in Scotland showed that the first BNT162b2 vaccination could achieve an efficacy of 91%, and the number of COVID-19 hospitalization decreased in 28–34 days after vaccination. The efficacy of AZD1222 in the same period was 88%, and these two vaccines showed a similar effect on preventing infection. 126 There are limited real-world data on inactivated vaccines. The effectiveness of the CoronaVac vaccine was evaluated in a St. Paul study and showed more than 50% efficacy. 127

These real-world studies showed that the approved COVID-19 vaccines effectively prevent SARS-CoV-2 infections, especially reducing the infection in susceptible people like healthcare workers.

Variants of Concern (VOC)

As mentioned earlier, the emergence of VOC poses great challenges to the efficacy of existing vaccines. WHO has designated five VOCs, including Alpha, Beta, Gamma, Delta, and Omicron (Fig. 5 ), among which Alpha and Delta variants had strong contagious activity, while Beta and Gamma variants gained powerful immune escape ability. However, the Omicron variant obtained high infectivity and can evade most COVID-19 vaccines simultaneously. Understanding the relationship between the mutations and pathogenic characteristics (like infectivity and immune escape ability) is useful to analyze the efficacy of vaccines better and adjust the vaccination strategy properly. Here, the origin of these VOCs has been systematically reviewed, and the influence of mutations on the pathogenic characteristics is illustrated (Fig. 7 ). Furthermore, the effectiveness of approved vaccines on the Omicron variant was also discussed, given that the Omicron variant has caused large-scale infections worldwide and aroused people’s worries.

A systemic illustration of the mutation in the S protein of VOCs. VOCs were designated by WHO because of the enhanced infectivity or immune escape ability (or with both), the specific mutations in the S protein of VOC Alpha to Omicron are displayed, and the mutations related to enhanced immune escape ability were marked in green color, while the mutation related to decreased immune escape ability was marked into orange color

B.1.1.7 is the first variant circulating worldwide, which was first detected in the southeast of the UK in September 2020 and became the dominant variant in the UK during the following 3 months. On December 18, 2020, B.1.1.7 was designated as Variants of Concern (VOC) and labeled Alpha by WHO ( https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ ). Compared with other variants at that time, the Alpha variant had a stronger transmission ability, with a higher reproduction number. 128 Interestingly, the variant lineage contained three subgroups initially, but the variant with Del69/70 in the S protein eventually occupied the mainstream, and 96.6% of all detected sequences of Alpha variants contained the mutation ( https://outbreak.info/ ), which indicated the existence of selective advantage in the transmission of SARS-CoV-2. 12 Apart from Del69/70, other mutations (like D614G in each VOC and E484K in Beta and Gamma) also proved the selective advantage. Variants with certain mutations gained stronger infectivity, fitness, or immune escape ability and are prone to survive and spread in the struggle between humans and COVID-19.

The analysis of these mutations with the selective advantage will further help to understand the pathogenic characteristics of these variants, such as infectivity, contagious ability, and immune escape ability. In addition to Del69/70, there are eight mutations in the S protein of Alpha variant: Del144 (contained in 95% of all detected sequences of Alpha variants), N501Y (97.6%), A570D (99.2%), D614G (99.3%), P681H (99%), T716I (98.7%), S982A (98.8%), and D1118H (99.2%) ( https://outbreak.info/ ). Among these mutations, Del69/70 and Del144 can significantly reduce the neutralization of NTD targeted antibodies, 105 because most of the immune epitopes of NTD antibodies are located in N3 (residues 141-156) and N5 (residues 246–260) loops, while Del144 can alter the N3 loop and cause the immune escape of such antibodies, 129 Del69/70 can enhance the infectivity. 130 The characteristic mutation N501Y can significantly increase the binding of S protein to ACE2, 131 and further enhance the infectivity. In addition, N501Y was also related to the immune escape, in which the epitope of class A antibodies was located. 129 This mutation was also in other VOCs like Beta, Gamma, and Omicron. Not only VOC, but almost all circulating variants also had a D614G mutation. Plante JA et al. found that D614G can alter the fitness and enhance the replication of SARS-CoV-2 in the lungs. However, D614G will reduce the immune escape ability of the virus and improve the sensitivity to neutralizing antibodies. 131 , 132 The above studies suggested that this mutation may be essential to maintaining the survival of SARS-CoV-2. Thereby, it can be retained continuously. The P681H mutation near the furin-cleavage site may enhance the cleavage of S1 and S2 subunits and increase the Alpha variant’s entry. The P681R in VOC Delta may improve fitness compared with P681H in the Alpha variant. 133

In general, the Del69/70, N501Y, D614G, and P681H of the Alpha variant were helpful to improve the infection, which can explain the high reproduction number of about 3.5–5.2 ( https://aci.health.nsw.gov.au/covid-19/critical-intelligence-unit/sars-cov-2-variants ). However, Del144 and N501Y affected the neutralization of antibodies, the vaccines approved by WHO showed strong neutralization ability to VOC Alpha, shown in Table 3 .

B.1.351 (also known as 501Y.V2) was first detected in South Africa in May 2020 and firstly appeared after the first epidemic wave in Nelson Mandela Bay. This variant had different characteristics from the dominant variants B.1.154, B.1.1.56, and C.1 in the first wave of pandemic 134 and had spread rapidly in Eastern Cape, Western Cape, and KwaZulu-Natal provinces in just a few weeks, causing the second wave of epidemic in South Africa (October 2020). 135 On December 18, 2020, B.1.351 was designated as VOC by WHO and named Beta ( https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ ). Similar to the Alpha variant, B.1.351 lineage also included three subtypes 501Y.V2-1/-2/-3, and 501.Y.V2-1 occupied mainstream, then the 501Y.V2-2 with additional mutations of amino acid site 18 and 417 appeared, and finally Del241/243 mutation occurred in 501Y.V2-3. 136 Among all detected sequences of VOC Beta, 89.6 and 93% had K417N and Del241/243 mutations, indicating that 501Y.V2-3 was the dominant subgroup of VOC Beta ( https://outbreak.info/ ).

There were nine mutations in the S protein of Beta variant: L18F (found in 43.6% reported Beta variants), D80A (97.1%), D215G (94.6%), Del241/243 (89.6%), K417N (93%), E484K (86.5%), N501Y (87%), D614G (97.8%), and A701V (96.4%) ( https://outbreak.info ). The glycans of amino acid site 17, 174, 122, and 149 in the NTD region combined into seven targeted epitopes of NTD antibodies 137 and L18F may interfere with the binding between antibodies, and residue 17 affect the neutralization of antibody. The Del241/243 map to the same surface as the Del144 in the Alpha variant, 138 which may also interfere with the neutralization of antibodies. In addition, several studies have shown that K717N and E484K mutations (as well as the K417T in Gamma variant and E484A in Omicron variant) both contribute to the immune escape against group A-D antibodies, 129 , 136 , 139 , 140 and K417N can enhance the infectivity at the same time. 129 , 141

Overall, the L18F, Del241/243, K417N, E484K, and N501Y mutations all contribute to the immune escape ability of VOC Beta, while K417N, N501Y, and D614G can enhance the viral infection. Therefore, compared with the Alpha variant, the Beta variant has poor transmissibility, but a very strong immune escape ability and can reduce the neutralization efficacy of WHO-approved vaccines by more than 10 times.

P.1 was first detected in Brazil in November 2020 and caused the second wave of the epidemic in this country, causing more than 76% infection of the population, 142 and the average number of daily-confirmed COVID-19 patients in Manaus increased by 180 from January 1 to 19, which was about 30 times of the average increased cases in December. On January 11, 2021, P.1 was designated as VOC by WHO and labeled Gamma.

There were 12 mutations in the S protein of Gamma variant: L18F (found in 97.9% reported P.1 strains), T20N (97.9%), P26S (97.6%), D138Y (95.5%), R190S (93.6%), K417T (95.5%), E484K (95.2%), N501Y (95.3%), D614G (99%), H655Y (98.5%), T1027I (97.2%), V1176F (98.1%) ( https://outbreak.info ). Since most of the mutations of interest like K417T, E484K, N501Y, and D614G have been introduced in the Alpha and Beta variants mentioned above, they will not be repeated here.

Among these mutations, L18F, K417T, E484K, and N501Y help to enhance the immune escape ability, while K417T, N501Y, and D614G can enhance the viral infection. Therefore, VOC Gamma showed a similar immune escape ability to VOC Beta, but less than the Beta variant, which may be caused by mutations outside the RBD region, 143 the infectivity of both Beta and Gamma variants were less than the Alpha variant ( https://aci.health.nsw.gov.au/covid-19/critical-intelligence-unit/sars-cov-2-variants ).

B.1.617.2 was first detected in Maharashtra, India, in October 2020 and spread rapidly in a few months due to the relaxation of prevention and control measures for COVID-19, causing the death of more than 400,000 people. 107 On May 11, 2021, this variant was designated as VOC by WHO and labeled Delta ( https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ ). VOC Delta was a worldwide circulating VOC after VOC Alpha and was detected by at least 169 countries ( https://outbreak.info ).

There were ten mutations in the S protein of Delta variant: T19R (found in 98.3% reported delta strains), T95I (38.3%), G142D (66.1%), E156G (92.1%), Del157/158 (92.2%), L452R (96.9%), T478K (97.2%), D614G (99.3%), P681R (99.2%), D950N (95.3%) ( https://outbreak.info ). G142D and E156G are located in the N3 loop, which NTD antibodies could target, 129 thus may affect the neutralization activity of NTD antibodies. The Del157/158 map to the same surface as the Del144 in the Alpha variant and the Del241/243 in the Beta variant, respectively, which may affect the neutralization of antibodies. 138 In addition, both L452R and T478K are located in immune epitopes targeted by group A-B antibodies, enhancing the immune escape ability of Delta variant, 129 , 138 , 144 and L452R is related to a higher infectivity. 145 The P681R mutation enhanced the infectivity of the virus and further improved the fitness compared with P681H, 138 which explained the higher infectivity of VOC Delta than VOC Alpha.

Although the mutations like L452R, T478K have not been reported in previous VOC Alpha, Beta, and Gamma, these mutations gave VOC Delta a stronger transmission ability (with a reproduction number of 3.2–8, mean of 5) and immune escape ability than VOC Alpha, which made Delta variant quickly become a dominant variant and reduce the efficacy of approved vaccines ( https://aci.health.nsw.gov.au/covid-19/critical-intelligence-unit/sars-cov-2-variants ).

In November 2021, B.1.1.529 appeared in many countries. Since the S protein of this variant contains more than 30 mutation sites, and many of them coincide with the S protein mutations of previous VOCs, B.1.1.529 was designated as VOC by WHO on 26 November 2021 and labeled Omicron ( https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ ). Although the Omicron variant has more mutations, the severity of the Omicron infected patient was less than Delta. After infection with the Omicron variant, hamsters did not have progressive weight loss similar to that after infection with Alpha/Beta/Delta, and the number of virus copies in the lungs was lower, 146 indicating that Omicron has less effect on the lower respiratory tract. By evaluating Omicron infection on different cells, Thomas P. Peacock et al. found that the infection degree of Omicron on Calu-3 (a lung cell line, whoseTMPRSS2 expression is normal, but lack of CTSL expression, hindering the nuclear endosome pathway of virus entry) is weaker than Delta, indicating that Omicron entry is more dependent on the nuclear endosome mediated endocytosis pathway 147 rather than the membrane fusion pathway involved in TMPRSS2, and TMPRSS2 is mainly distributed in human lung epithelial cells. Therefore, Omicron has less infectivity to the lungs and causes mild symptoms, mainly causing upper respiratory tract infection.

The S protein of the Omicron variant contains 31 mutations: A67V, Del69/70, T95I, G142D, Del143/145, N211I, Del212-212, G339D, S371L, S373P, S375F, K417N, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, and L981F (since the proportion of mutations is constantly changing, it is not shown here) ( https://outbreak.info ). Cao Y and colleagues systematically analyzed the effect of these mutations on immune escape. Among them, 477/493/496/498/501/505 mutations affected the neutralization activity of group A antibodies, 477/478/484 mutations affected the neutralization activity of group B antibodies, while the neutralizing activity of group C/D/E antibodies was affected by 484, 440/446, and 346/440 mutations, respectively, Group F antibodies are disturbed by 373/375 mutations. 94 , 129 However, group E and F antibodies showed effective neutralization of the Omicron variant among these antibodies. These two groups of antibodies were rarely used in the clinic and formed lower immune pressure on the virus, reducing the viral mutation of these antibodies and maintaining the binding of antibodies to corresponding epitopes.

Although the Del69/70, K417N, N501Y, D614G, and P681H mutations can enhance the viral infection (with a reproduction number of 2.6–4.0) and Del143/145, K417N, T478K, E484A, and N501Y are related to the immune escape, the infection of Omicron variant has less impact on the lung and is unlikely to cause serious diseases compared with VOC Delta. In addition, many vaccines serum almost lost the neutralization effect on the Omicron variant, indicating that new strategies (such as booster vaccination, sequential vaccination, and the development of new platforms such as nanoparticle vaccine) should be considered.

Pajon et al. and Nemet et al. evaluated the enhanced protection of the third dose of mRNA-1273 and BNT162b2 against the Omicron variant, respectively. 148 , 149 Although a booster dose can enhance the response of memory cells and increase the antibody titers to produce stronger neutralization activity of 20 to100-fold, the enhanced immune response is still limited. An Israeli study showed that the fourth dose of the BNT162b2 or mRNA-1273 vaccine still could not prevent Omicron infection ( https://www.shebaonline.org/ ). In addition, Wang J and colleagues evaluated the protection of the fourth BBIBP-CorV against the Omicron variant. Although the additional inoculation successfully recalled memory cell response in the 6th month after the third dose, the production of antibodies targeting the RBD region was suppressed due to the enhanced immune pressure and decreased peak level 150 The suppression of RBD-targeted antibodies may induce the change of immune epitopes, and a vaccine inducing diverse epitopes antibodies (like a polyvalent vaccine) may decrease the immune pressure on certain epitopes and maintain the efficacy on different VOCs.

SCTV01E is a protein subunit vaccine under development that uses the S trimer of Alpha/ Beta/ Delta/ Omicron variants, and two clinical trials evaluating the safety and immunogenicity of SCTV01E are on the way (NCT05239806 and NCT05238441) ( https://clinicaltrials.gov ). In addition to the polyvalent vaccine, the mRNA vaccine used the VOC Beta sequence also showed better protection against Omicron in the hamster model than existing vaccines. 151

Relevant data of COVID-19 vaccines not yet approved by the WHO

According to the WHO data, as of March 28, 2022, 196 candidate vaccines are in the preclinical stage, and 153 candidate vaccines based on different vaccine platforms have been approved for clinical trials. Here, we present some data for each type of vaccine that the WHO has not approved.

Inactivated vaccines

As of March 28, 2022, 12 inactivated virus vaccines underwent Phase II/III and Phase IV clinical trials. Of these Phase III clinical trials, the QazCovid-in ® -COVID-19 inactivated vaccine developed by the Research Institute for Biological Safety Problems, Republic of Kazakhstan, showed superiority in many aspects, including good immunogenicity and high seroconversion ( https://clinicaltrials.gov/ct2/show/NCT04691908 ).

Live attenuated vaccine

As of March 28, 2022, only one live attenuated vaccine-COVI-VAC has entered a Phase III clinical trial (ISRCTN15779782). The vaccine was developed by the Codagenix and Serum Institute of India. The study starts in August 2021 and runs until September 2023 to objectively evaluate the benefit and risk of COVI-VAC as a candidate vaccine, and relevant data have not been released ( https://www.isrctn.com/ISRCTN15779782 ).

Viral vector vaccine

As of March 28, 2022, two replicating viral vector platform vaccines and eight non-replicating viral vector platform vaccines have been tested in Phase II/III and Phase IV clinical trials. The Gam-COVID-Vac aroused many concerns owing to its effectiveness of 91.6%. 152 A Phase III trial was conducted in Moscow on September 7, 2020 (NCT04530396). 21,977 adults were randomly assigned to the vaccine and placebo groups in this trial. The vaccine group received 0.5 mL Gam-COVID-Vac. Only 0.1% of recipients were infected with SARS-CoV-2, while the percentage of the placebo group was 1.3%. No severe adverse events related to the vaccine were reported.

Protein subunit vaccine

As of March 28, 2022, 22 candidate protein subunit vaccines were in Phase II/III and Phase IV clinical trials. The CpG 1018/Alum-adjuvanted SCB-2019 vaccine was developed by Clover Biopharmaceuticals Inc. and Dynavax. A Phase III clinical trial (NCT05012787), beginning on August 19, 2021, was conducted to evaluate the safety and immunogenicity of the investigational SCB-2019 in adult participants with stable chronic inflammatory immune-mediated diseases (IMDs) ( https://clinicaltrials.gov/ct2/show/NCT05012787 ). Moreover, an RBD-based subunit vaccine developed by the West China Hospital, Sichuan University, and WestVac Biopharma Co., Ltd, showed strong induction of potent functional antibodies, as well as CD4 + T-cell responses in the preclinical trial, 60 and the phase III clinical trial (NCT04887207) of this vaccine, has been completed ( https://clinicaltrials.gov/ct2/show/results/NCT04887207 ).

DNA and mRNA vaccines

As of March 28, 2022, nine RNA and four DNA vaccines have undergone Phase II/III and Phase IV clinical trials. An mRNA vaccine called mRNA ARCoV, developed by the Academy of Military Science, Walvax Biotechnology, and Suzhou Abogen Biosciences was conducted for a Phase III clinical trial of 28,000 subjects (NCT04847102). The subjects were inoculated with a vaccine or placebo in a 1:1 ratio with an interval of 28 days between two injections. It was reported that expected efficacy and good safety had been achieved. The effects of cross-injection will be assessed, including an immunogenic subgroup and a reactive subgroup, to evaluate the humoral immunity induced by the vaccine ( https://clinicaltrials.gov/ct2/show/NCT04847102 ).

Safety of vaccines

Vaccine-induced complications.

Although the currently approved COVID-19 vaccines were safe in clinical trials, the resulting adverse reactions are numerous, including fever, headache, fatigue, injection site pain, and nausea. 3 , 153 As the vaccination campaign progressed, complications occurred in some subjects, and several patients died of cardiovascular diseases, such as arteriosclerosis. Furthermore, cardiac arrest occurred in Phase III clinical trials of the mRNA-1273 and BNT162b2 vaccines. 114 , 118 The possible complications induced by COVID-19 vaccines mainly include the following categories: (1) coagulation dysfunction, such as thrombocytopenia; 52 , 154 (2) heart diseases, such as myocarditis; 74 , 75 (3) immune diseases, such as allergic reactions, 155 autoimmune hepatitis, 156 and autoimmune thyroid diseases; 157 (4) nervous system diseases, such as facial paralysis 158 , 159 and functional neurological disorders; 153 (5) lymphatic system diseases; 160 and (6) other diseases, such as Rowell’s syndrome, 161 macular rash, 162 and chilblain-like lesions 163 (Fig. 8 ). Although the incidence of these complications is low, the relationship between vaccines and these diseases needs to be explored. Here, we describe related COVID-19 vaccine complications and analyze the factors.

A summary of some possible complications induced by COVID-19 vaccines. The possible complications induced by COVID-19 vaccines mainly include the following categories: (1) coagulation dysfunction, such as thrombocytopenia; (2) heart diseases, such as myocarditis; (3) immune diseases, such as allergic reactions, autoimmune hepatitis, and autoimmune thyroid diseases; (4) nervous system diseases, such as facial paralysis and functional neurological disorders; (5) lymphatic system diseases; and (6) other diseases, such as Rowell’s syndrome, macular rash, and chilblain-like lesions

Blood coagulation dysfunction

Greinacher et al. and Lee et al. reported thrombocytopenia in an adenovirus vector vaccine and mRNA vaccine recipients. 154 , 164 A large number of platelet factor 4 (PF4) antibodies were presented in the patients, and the antibody heparin PF4 complex acted on platelet FC γ receptors, activating platelets and further producing procoagulant substances. 154 Adenoviruses can bind to platelets and activate them. 165 , 166 However, trace adenoviruses in vaccines injected one or two weeks before onset seem unlikely to cause platelet activation. Further analysis of PF4 structure revealed that PF4 antibodies from vaccine-induced immune thrombocytopenia patients induced heparin-induced thrombocytopenia by binding eight surface amino acids on PF4. 51 One study counted the cases of thrombosis sequelae voluntarily reported after vaccination, of which at least 169 cases of possible cerebral venous thrombosis and 53 cases of possible visceral venous thrombosis were reported among 34 million individuals vaccinated with ChAdOx1 nCoV-19 vaccine, and 35 cases of central nervous system thrombosis among 54 million individuals vaccinated with BioNTech mRNA vaccine. Among the 4 million subjects receiving the Moderna mRNA vaccine, cerebral venous sinus thrombosis may have developed in five cases. Among the more than 7 million subjects receiving Ad26.COV-2-S vaccine, cerebral venous thrombosis may have developed in six cases. 52 Although the relevant pathogenesis is unclear, a possible trigger factor for these PF4 antibodies is free RNA or DNA in the vaccine. 167

Moreover, platelet activation may also relate to the injury and inflammation induced by mast cell (MC) degranulation. Wu ML et al. found that SARS-CoV-2 can induce degranulation of MCs located in the mucosa, and a rapid MC degranulation could be recapitulated through the binding of RBD to ACE2, resulting in supra-alveolar dermatitis and lung injury. 168 In addition, in the case of inflammation induction and lung epithelial injury, many plasminogen activators may be released. 169 Thus, the increased D-dimer (one of the products formed when plasminase degrades fibrine) concentration was observed in many COVID-19 patients, with a decreased level of platelets. 169 These pathological characteristics of patients were very similar to the thrombotic thrombocytopenia caused by the COVID-19 vaccination. Combined with the above studies, this mechanism may be explained as follows: after the SARS-CoV-2 infection or mRNA vaccine vaccination, S protein stimulated lung epithelial cells and induced MC degranulation, increasing the level of inflammatory mediators. These mediators increased the destructive effect of monocyte macrophages on erythrocytes and led to abnormal platelet levels. In addition, the injury of epithelial cells activated platelets and released coagulation factors, finally forming fibrin and forming extensive micro thrombosis. In this process, the over-consumed platelets and coagulation factors lead to the reduction of coagulation activity, further imbalance of coagulation and anticoagulation, secondary hyperfibrinolysis, and the release of a large number of plasminogen activators, eventually leaded to disseminated intravascular coagulation (DIC), which appeared in most COVID-19 patients. 154 , 169 , 170 Compared with COVID-19 patients, fewer mRNA vaccine subjects reported DIC, which may be due to the lower amount of S protein produced after vaccination than natural infection, and the inflammation is also lower.

Relevant indexes (e.g., measuring prothrombin time, platelet count, and D-dimer concentrations of the receptors) should be tested within 2–3 days after vaccination to prevent the platelet abnormalities caused by COVID-19 vaccination. 169 For patients with abnormal index, preventive treatment (usually heparin or low molecular weight heparin transfusion, the latter is safer) should be taken as soon as possible. 169 In addition, degranulation inhibitors may also be a feasible means to inhibit the inflammatory response and prevent lung injury and platelet abnormalities. 168

Heart diseases

Myocarditis is a rare cardiac complication after COVID-19 vaccine injection. 74 , 75 Rosner et al. reported seven patients hospitalized for acute cardiomyoid disease after vaccination with Pfizer-BioNTech/AstraZeneca ( n  = 6) and Janssen ( n  = 1) vaccines. Larson et al. reported eight patients hospitalized for chest pain within 2–4 days of vaccination with the BNT162b2 or mRNA-1273 vaccine. The laboratory diagnostic cardiac magnetic resonance imaging analysis revealed that these patients have myocarditis. All the subjects had left ventricular ejection dysfunction. The median ejection blood percentage was 48–59%. 74 , 75 These two studies showed a significant temporal correlation between mRNA-based COVID-19 vaccines (including viral vector and mRNA vaccines) and myocarditis. Such systemic adverse events usually occur within 48 h after the second dose. 114 , 118 There may be two potential mechanisms for COVID-19 mRNA vaccines causing heart diseases, such as myocarditis. The first is the nonspecific innate inflammatory responses induced by mRNA. The second is the interaction of the S protein produced by mRNA after the translation within the heart or blood vessels, resulting in cardiovascular injury. 171 Since protein subunit vaccines like ZF2001 and NVX-CoV2373 have not been used widely, and the relevant data are still unreleased, it is not easy to judge whether the S protein causes myocarditis.

Immune diseases

Immune diseases caused by the injection of the COVID-19 vaccine mainly include allergic reactions and autoimmune diseases that include autoimmune hepatitis and autoimmune thyroid diseases. 155 , 156 , 157

Allergic reactions

From December 14 to 23, 2020, 175 of the first batch of 1,893,360 individuals vaccinated with BNT162b2 developed severe allergic reactions within 24 h. These cases were submitted to the vaccine adverse events reporting system (VAERS). 155 Finally, 21 cases were identified as allergic reactions based on the Brighton Collaboration definition criteria. 155 , 172 , 173 Between December 21, 2020, and January 10, 2021, ten of the 4,041,396 subjects vaccinated with the first batch of mRNA-1273 vaccine were identified as allergic reactions. 155 , 173 Risma et al. analyzed the causes of allergic reactions induced by the COVID-19 vaccine. The reasons included nucleic acid of COVID-19 vaccine activated contact system; complement system that was directly activated by the nano lipid plasmid (LNP) vector of the vaccine, resulting in complement-related pseudoanaphylaxis; 174 pre-existing antibodies to polyethylene glycol (PEG) that induced allergic reactions; 175 and direct activation of mast cells leads to degranulation. Allergic reaction mainly includes classical pathway and non-classical pathway. The classical pathway is activated by mast cells and cross-linked IgE, 176 which PEG IgE antibodies may activate in the inoculant. Non-classical pathways mainly involve complement antibody-dependent activation of mast cell activation. 177 To further understand the causes of allergic reactions to the mRNA vaccine, Troelnikov et al. evaluated the ability of PEG, polysorbate 80, BNT162b2 vaccine, and AZD1222 vaccine to activate basophils and mast cells in patients with a previous allergic history of PEG. The authors clarified that PEG covalently modified on vaccine LNP carriers was a potential factor that triggered allergic reactions. 178 For the allergic reaction caused by mRNA vaccines, molecules with better biocompatibility and lower immunogenicity should be considered vaccine carriers to reduce the rate of hypersensitivity reactions.

Autoimmune diseases

Vaccination can trigger a series of immune reactions and the production of neutralizing antibodies against antigens. An excessively strong immune response may simultaneously produce antibodies targeting normal organs or tissues, leading to autoimmune diseases like hepatitis and autoimmune thyroid diseases.

Lodato et al. 156 reported that two days after the second dose of the BNT162b1 vaccine, a 43-year-old woman developed jaundice. A liver biopsy revealed moderate portal inflammatory infiltration, accompanied by bile duct injury and hepatic lobular punctate necrosis. After eight weeks of corticosteroid treatment, the clinical indices of the liver returned to normal. Given the beneficial effect of steroid treatment and the overall period from vaccination to onset consistent with the progress of the immune response, the patient was diagnosed with autoimmune hepatitis. Furthermore, the causal relationship between vaccine injection and autoimmune hepatitis has not yet been fully determined.

In addition to autoimmune hepatitis, cases of immune hypothyroidism caused by vaccination have been reported. Two female medical staff members showed increased thyroid hormone secretion and elevated thyroid antibody levels three days after receiving the COVID-19 vaccine, indicating inhibited thyroid functions. 157

The relationship between autoimmune diseases and COVID-19 vaccines has not been clarified. However, the above cases emphasize the importance of regular follow-up and close observation of the physical condition of vaccines. While vaccination is an effective weapon in ending the COVID-19 epidemic, immune-related complications need to be considered.

Nervous system diseases

Facial paralysis.

Bell’s palsy, also known as acute peripheral facial paralysis of unknown cause, is usually characterized by sudden unilateral facial paralysis. 159 This type of nerve paralysis is typically temporary. Most patients recover within 6–9 months without drug or steroid treatment, 179 but a few patients may have facial dysfunction. Facial paralysis may occur after vaccination, such as the influenza vaccine, caused by viral reinfection. 180 In a clinical trial of the COVID-19 mRNA-1273 vaccine, three of 15,210 subjects developed facial paralysis. 114 , 118 Wan et al. used the reporting systems of medical institutions to evaluate the proportions of facial paralysis within 42 days after vaccination with BNT162b2 and CoronaVac vaccines and found that they were 66.9 cases/100,000 individuals/year in CoronaVac recipients and 42.8 cases/100,000 individuals/year in BNT162b2 recipients, respectively. A higher proportion of facial paralysis occurred in inactivated vaccine recipients, 159 indicating that this complication may be related to the vaccine adjuvant as the inactivated vaccine is unlikely to cause virus reinfection and does not contain active viral nucleic acid. Renoud et al. conducted a disproportionate data analysis based on the WHO pharmacovigilance database and found that 844 cases among 133,883 mRNA vaccination cases had facial paralysis-related events. 181 Although the COVID-19 vaccine may cause acute peripheral facial paralysis, the beneficial and protective effects outweigh the risk of this generally self-limiting adverse event. Adverse event monitoring and controlling should be improved and strengthened to ensure a timely treatment in case of complications.

Functional neurological disorder (FND)

FND is a nervous system disease that can produce neurological symptoms caused by biological, psychological, or environmental factors. 153 The predisposing factors for FND include head injury, surgery, and vaccination. Currently, at least one vaccinated individual has been diagnosed with FND. Kim et al. 153 described the potential relationship between FND and COVID-19 vaccination. Vaccine components are unlikely to be the main cause of FND because FND also occurs after normal saline injection.

Moreover, adverse events, such as local pain at the injection site or systemic muscle pain, may occur after vaccination, which may increase the sensitivity of the patient’s nerves. The reason for FND attacks caused by COVID-19 vaccines has not been determined. Close attention should be paid to the adverse events of vaccinated individuals. Improving the reporting of such events, the public’s confidence in the government and medical institutions will greatly reduce recipients’ psychological and mental pressure, reducing the incidence of FND.

Lymphatic diseases

Injection of the COVID-19 vaccine may lead to inhibition of thyroid function. Since the time window from vaccination to the disease is consistent with the immune process, such adverse reactions are classified as immune diseases, namely autoimmune diseases. In addition, lymphatic diseases, such as abnormal lymph nodes, 160 may also occur after receiving the COVID-19 vaccine. For example, three days after receiving the first dose of the AZD1222 vaccine, eosinophils were detected in the left axillary lymph nodes of a 75-year-old male using [18 F] Choline positron emission tomography/computed tomography (PET/CT), demonstrating the mild uptake ability of choline. The choline uptake occurred in his left arm 3 days after AZD1222 vaccination, indicating the AZD1222 vaccine-induced abnormal lymph node exists. Eifer et al. also described that a 72-year-old woman vaccinated with BNT162b2 subsequently displayed the same phenomenon of increased choline uptake by lymph nodes. 182 The vaccine recipients had tumors resected or treated by other means in both cases. [18 F] Choline PET/CT is an effective method to determine the location of tumor infiltration and the prognosis of tumor patients. Therefore, close follow-up of patients with tumors inoculated with the COVID-19 vaccine should be prudent to avoid incorrect interpretation of the imaging results and incorrect diagnoses of diseases.

Other diseases

In addition to the diseases mentioned above, some COVID-19 vaccines recipients may also have skin diseases, including Rowell syndrome, 161 macula, 162 and chilblain-like lesions. 163

Gambichler T et al. 161 found that a 74-year-old woman developed a severe rash one day after receiving the BNT162b2 vaccine. Clinical examinations showed that the patient had red cohesive spots and papules on the trunk and limbs but no mucosal infiltration. The patient was diagnosed with Rowell’s syndrome (RS), a relatively rare disease characterized by lupus erythematosus with pleomorphic erythematosus lesions and immunological manifestations through further skin biopsy. 183 Subsequently, the patient received steroid treatment, and the symptoms were relieved. In this case, the BNT162b2 vaccine was considered a possible cause of RS, but the patient took pantoprazole for a long-time treatment of chronic gastrointestinal ulcers. Combining this drug and the COVID-19 vaccine may lead to the onset of RS. Some studies have pointed out that omeprazole, a proton pump inhibitor, may cause RS. 184 Therefore, special vaccination groups, especially the elderly or patients with underlying diseases, should be paid attention to their post-vaccination status, and corresponding treatment should be given in time.

Jedlowski P et al. 185 have reported a measles-like rash and papules caused by the BNT162b2 vaccine. After the first dose of the vaccine, a 30-year-old male had adverse reactions such as fever and pain at the injection site, followed by a measles-like rash. After the second dose of the vaccine, he had a recurrent measles-like rash and flesh-colored papules, which had subsided after corticosteroid treatment. Similarly, a 55-year-old man suffered pain and pruritus erythema at the injection site after the first dose of the BNT162b2 vaccine, accompanied by impaired liver function. 162 Subsequently, the patient’s symptoms were significantly improved after corticosteroid therapy.

Piccolo et al. noted that a 41-year-old woman had chilblain-like lesions (CLL) on her fingers and was accompanied by severe pain after receiving the second dose of the BNT162b2 vaccine. 163 This symptom is most likely related to the strong activation of innate immunity and the production of potent antibodies. 186 Additionally, CLL was observed in another 41-year-old female vaccinee, accompanied by severe pain. 187 Although the reasons for CLL in the above cases have not been clarified, the occurrence of CLL after the COVID-19 mRNA vaccine proves the correlation of CLL with the vaccination. 186

In conclusion, although COVID-19 vaccination may be associated with diseases such as thrombosis, myocarditis, and allergy, the proportion of adverse events is low, and vaccination is still an effective means to control and block the epidemic.

Effect of COVID-19 vaccination in different populations

COVID-19 vaccine mainly functions by inducing neutralizing antibodies and memory cells. However, for patients with innate immune diseases, such as autoimmune rheumatism and a history of allergies or tumors, COVID-19 vaccination may cause adverse events. In addition, elderly and pregnant women are also of concern. Compared to adults, vaccine immunization of the elderly may not achieve the desired protective effect due to their weakened immune system functions. 188 , 189 , 190 For pregnant women, the COVID-19 vaccine may cause adverse events, such as abortion, premature birth, or fetal malformation. 191 , 192 Here, we summarize the effects of vaccination in different populations (Fig. 9 ).

Effect of vaccination in different populations. COVID-19 vaccines are still effective for pregnant women, patients with autoimmune diseases, and controlled HIV-infected patients, and the overall efficacy can maintain about 80–90%, while the 30% neutralization reduction occurs in older people. Moreover, the overall neutralizing activity of COVID-19 vaccines in solid organ transplant recipients, cancer patients, and uncontrolled AIDS patients is significantly reduced

Pregnant women

Previous studies have shown that complications including lung injury, diabetes, and cardiovascular diseases in pregnant women after SARS-CoV-2 infection are higher than that in non-pregnant women. 193 However, adverse events, such as abortion or fetal malformation, may occur after COVID-19 vaccination, 191 , 192 which have raised concerns. Shimabukuro et al. 192 evaluated the effects of COVID-19 vaccination on pregnant women and fetuses using the V-safe monitoring and VERS systems. The results indicated that adverse reactions were higher in pregnant women than in non-pregnant women. The most significant adverse event was pain at the injection site. After mRNA vaccination, pregnancy loss occurred in 13.9% of the pregnant women, 86.1% had a normal pregnancy, and 9.4% had a premature delivery. Although pregnancy loss and premature birth could occur, both are low-probability cases, and the benefits of vaccination far outweigh the risks. In addition, the proportion of local or systemic adverse reactions in elderly non-pregnant women was similar to that in pregnant women, 191 indicating that physiological changes during pregnancy did not significantly impact the occurrence of adverse events.

Two other studies analyzed the immunogenicity of COVID-19 in pregnant women and fetuses, and COVID-19 vaccines overall are approximately 90% effective for the vaccinated women. 194 , 195 R Collier et al. analyzed the immune condition of pregnant or lactating women and fetuses after COVID-19 vaccination. 194 Both pregnant and lactating women could produce binding, neutralizing, and functional non-neutralizing antibodies, accompanied by CD4 + and CD8 + T-cell responses. More importantly, binding and neutralizing antibodies were also detected in infant umbilical cord blood and breast milk. These results show that vaccinated pregnant women experience a personal protective effect and produce antibodies that can be delivered to the fetus through the umbilical cord or breast milk to provide immune protection.

Furthermore, a multicenter study conducted in Israel also showed that after vaccination with the BNT162b2 vaccine, IgG antibodies could be produced in the mother. These antibodies can pass through the fetal barrier, and newborns can detect antibody reactions. 195 These two studies showed that after the COVID-19 vaccination, the antibodies in pregnant women could be transferred into the fetus through efficient mother-to-child transmission, effectively protecting the fetus.

Although pregnant women are more likely to experience adverse events after vaccination than non-pregnant women, this proportion is still limited. Within the ideal range, the COVID-19 vaccine can simultaneously protect mothers and infants, reducing the probability of fetal infection with SARS-CoV-2 after birth to a certain extent. Therefore, pregnant women should be voluntarily vaccinated with the COVID-19 vaccine. Meanwhile, government and medical institutions should further improve the health monitoring of pregnant women in the trial to ensure the safety of pregnant women and fetuses.

Elderly individuals

Several studies have analyzed the related immunization levels in the elderly (> 80 years of age) after the COVID-19 vaccination. About 70% protection suggested that at least two vaccination doses should be given to these people. 189 , 190 Lisa et al. 190 compared the production of serum neutralizing antibodies between elderly (>80 years old) and young (<60 years old) vaccine recipients after vaccination with BNT162b2. The IgG antibody titer of the elderly subjects was generally lower than that of the young subjects. Although the antibody levels increased after secondary immunization, 31.3% of the elderly did not produce SARS-CoV-2 neutralizing antibodies, while the antibodies were not detected in only 2.2% of the young subjects after the second dose. Because virus variants, especially variants of concern (VOC), have stronger infectivity or immune escape ability and are prevalent globally. Collier et al. 189 evaluated the effect of serum neutralizing antibodies in elderly individuals on VOC strains Alpha, Beta, and Gamma after two doses of the BNT162b2 vaccine. Neutralizing antibodies against the VOC strain were detected in all age groups. Therefore, the COVID-19 vaccination can still protect the elderly. However, compared with young vaccinated individuals, the CD4 + T-cell response of elderly participants was poor and manifested as low levels of IFN-γ and IL-2. Consequently, government and medical institutions should conduct long-term monitoring of the elderly population and timely deliver “booster shot” vaccination or increase the vaccine dosage to maintain immune efficacy.

Although the COVID-19 vaccine is an effective method to control the pandemic, the current global vaccine resources are still relatively scarce, and complete immunization has not been achieved in most countries. Shrotri et al. 196 conducted a prospective cohort study to systematically analyze the protective effect of a single dose of AZD1222 or BNT162b2 vaccine in individuals aged ≥ 65. After the first dose of the vaccine, evident protection for the elderly lasted for at least 4 weeks, and SARS-CoV-2 transmission was reduced to a certain extent. Another study showed that a single dose of the COVID-19 vaccine could reduce the risk of hospitalization in elderly patients infected with SARS-CoV-2. 197

The collective findings support the view that the elderly should be actively vaccinated against COVID-19. If two doses of vaccine cannot be administered, they should be vaccinated with a single dose. The COVID-19 vaccine can reduce the risk of SARS-CoV-2 transmission to a certain extent, decrease the risk of hospitalization, and promote the safety of the elderly.

Organ transplant recipients

To reduce the immune system’s recognition and attack, patients with solid organ (e.g., kidney and heart) transplantation require long-term immunosuppressants, such as tacrolimus, corticosteroids, and mycophenolate organs. 198 Although immunosuppressive drugs can maintain transplanted organs, they may also affect the body’s antiviral immunity, making solid organ transplant patients more susceptible to SARS-CoV-2 infection and increased mortality risk. 198

Effective immunization of this population is necessary to reduce the infection and death caused by SARS-CoV-2. Several studies have reported that the efficiency of COVID-19 vaccines in solid organ transplant patients after single-dose/two-dose vaccination and enhanced immunization (third dose) was only 20–50%. 199 , 200 , 201 Boyarsky et al. evaluated the effect of a single dose of BNT162b2 or mRNA-1273 vaccine in organ transplant patients. 199 Only 76 (17%) of the 436 subjects elicited neutralizing antibodies, and the titer of these antibodies in elderly patients was lower than that in young individuals. Individuals vaccinated with mRNA-1273 produced higher levels of antibodies. These results showed that a single dose of the COVID-19 vaccine could not effectively prevent SARS-CoV-2 infection in organ transplant patients. Subsequently, this group analyzed two vaccine doses in 658 organ transplant patients. 200 15% of the subjects produced neutralizing antibodies after the first dose of vaccine, whereas 54% after the second dose, indicating that complete vaccination should be fully deployed for organ transplant patients and that these individuals should be closely monitored after vaccination to prevent SARS-CoV-2 infection. Another study carried out by Benotmane I et al. showed that after the third dose of the mRNA-1273 vaccine, neutralizing antibodies were detected in the serum of 49% of renal transplant patients. 201 However, some patients still did not produce neutralizing antibodies, especially those receiving triple immunosuppressive therapy with tacrolimus, corticosteroids, and mycophenolate mofetil after vaccination. In addition to the mRNA vaccine, the protective effect of an inactivated vaccine—the CoronaVac vaccine on organ transplant patients was also evaluated 31 days after two doses. 198 Sixteen of the 85 renal transplant patients had neutralizing antibody reactions.

Furthermore, this result may be related to some participants’ small sample size and impaired renal function. Monitoring neutralizing antibody levels in organ transplant patients should be strengthened, and a booster shot should be administered in time. Mazzola et al. 202 assessed antibody levels in other organ transplant patients after two doses of the BNT162b2 vaccine. In liver, kidney, and heart transplant patients, serum conversion rates were 37.5, 16.6, and 34.8%, respectively. The lower neutralization level in kidney transplant patients was consistent with the study by Sadioğlu et al. 198

The collective findings support the view that for solid organ transplant patients who take immunosuppressants, timely vaccination is important, and clinicians should closely monitor their appropriate antibody levels. Based on the actual situation of this population, immunosuppressive programs and vaccination countermeasures should be formulated to reduce SARS-CoV-2 infection rates.

Cancer patients

Besides organ transplant patients, cancer patients are also a COVID-19 high-susceptible population. Anti-tumor treatments, including radiotherapy and chemotherapy, may lead to systemic hypoimmunity. 203 Several studies have indicated that vaccination can protect about 50–60% of cancer patients from the SARS-CoV-2 infection; thus, they should receive COVID-19 vaccines as soon as possible and complete at least two doses of injection. 204 , 205 , 206

Monin et al. 204 evaluated the safety and immunogenicity of a single dose and two doses of the BNT162b2 vaccine in cancer patients. Twenty-one days after the first dose of the vaccine, 21 of the 56 patients with solid tumors and eight of the 44 patients with blood cancer displayed an anti-S protein immune response. These findings showed that a single dose of the COVID-19 vaccine could not effectively prevent cancer patients, especially those with blood cancer, from the infection with SARS-CoV-2. In contrast, 18 patients with solid cancer and three patients with blood cancer were seroconverted after the second dose of the vaccine. In addition, the BNT162b2 vaccine was safe for patients with breast and lung cancer, and no death caused by vaccination was reported during the trial.

Similarly, Palich et al. evaluated the neutralization activity of the BNT162b2 vaccine in patients with cancer. 206 The seroconversion rate after vaccination was only 55%. Terpos et al. 207 and Maneikis et al. 208 studied the effectiveness of the BNT162b2 vaccine in elderly patients with multiple myeloma and hematological malignancies, respectively. After the first dose of the vaccine, low levels of neutralizing antibodies were detected in the serum of the myeloma patients, which may be due to the inhibition of B-cell proliferation and antibody production by myeloma cells. Patients with hematological malignancies who received two doses of the BNT162b2 vaccine could display serious SARS-CoV-2 breakthrough infections since malignant hematological tumors can destroy immune homeostasis, and the immunosuppressive drug used in the treatment can also affect the production of neutralizing antibodies.

The above studies demonstrate that patients with malignant tumors are susceptible to COVID-19 and should receive timely vaccinations. The vaccination schedule should be based on the patient’s antibody titers to appropriately shorten the interval between the two vaccine injections 205 and ensure a strong immune response. Moreover, patients with malignant tumors should be closely monitored after receiving the COVID-19 vaccine to prevent serious breakthrough infections.

Human immunodeficiency virus (HIV) infected persons and patients with autoimmune diseases

Organ transplant patients and tumor patients may be affected by immunosuppressive drugs and systemic hypoimmunity. 198 , 207 In addition, HIV-infected and autoimmune disease patients are also susceptible to SARS-CoV-2 infection due to their impaired immune system function and immunosuppressants. Several studies have shown that the overall efficacy of the COVID-19 vaccine in controlled HIV-infected people and people with autoimmune disease was about 80%, while the vaccination could not prevent the breakthrough infection in patients with progressive AIDS. 209 , 210

In one study, the AZD1222 vaccine induced strong neutralization reactions in HIV-negative individuals and AIDS patients with well-controlled infections after receiving antiretroviral therapy (ART). 27 Fourteen days after the second dose of the AZD1222 vaccine, HIV-negative individuals and HIV-positive patients treated with ART showed similar neutralizing antibody levels, and antibodies were detected in 87% (13/15) of HIV-infected persons. The results indicate that for HIV patients receiving ART, COVID-19 vaccination can produce an immune response similar to HIV-negative individuals. In contrast, for HIV patients whose condition is not effectively controlled, especially those with progressive AIDS, two doses of the vaccine may not prevent breakthrough infection. 209

In addition to individuals infected with HIV, patients with autoimmune diseases (e.g., autoimmune rheumatism) may also get impaired immunity from the COVID-19 vaccine because of their medication with immunosuppressants, such as mycophenolate mofetil and corticosteroids. 210 In one study, after two doses of the BNT162b2 vaccine, 86% of patients with autoimmune rheumatism experienced serum transformation, but the levels of S1/S2 neutralizing antibodies were significantly lower than that in healthy individuals. Some patients with enteritis who received immunosuppressive treatment also showed reduced immunogenicity following the BNT162b2 and AZD1222 vaccines. 211 These findings highlight that immunization should be completed promptly for individuals receiving the immune drug and that the drug dosage should be adjusted appropriately during vaccine injection to ensure the production of neutralizing antibodies.

Antibody-dependent enhancement (ADE) of vaccines

ADE is a phenomenon in which the pathogenic effect of some viral infections is strengthened in sub-neutralizing antibodies or non-neutralizing antibodies. 212 , 213 , 214 In other words, after natural immunization or vaccination, when contacting the relevant virus again, the antibody produced before might enhance the infection ability of the virus and eventually aggravate the disease. Currently, there is no definitive mechanism to explain the causes of this phenomenon. 215 The ADE simulated in vitro attributes to the pathogenic mechanism as follows: (1) The entry of virus-mediated by the Fcγ receptor (Fcγ R) increases viral infection as well as replication; 216 , 217 (2) Excessive antibody Fc-mediated effector functions or immunocomplex formation enhances inflammation and immunopathology. 214 , 215

Previous studies have shown that HIV, Ebola, influenza, and flaviviruses may induce ADE. 215 And it was reported that respiratory syncytial virus and dengue virus vaccines could also cause ADE, so it is necessary to evaluate the ADE risk of COVID-19 vaccines. 218 Although no serious ADE event caused by the COVID-19 vaccine has been released, 217 the data obtained from other coronaviruses like SARS-CoV and MERS-CoV vaccines can provide experience. 215

Pathogen-specific antibodies that can promote the incidence of pathological ADE should be considered during the development of COVID-19 vaccines. In vitro studies of antibodies against viral infection have identified factors associated with ADE, such as insufficient concentration or low-affinity antibodies. 18 However, protective antibodies may also induce ADE. For instance, the antibody against feline infectious peritonitis virus also enhances infection of monocytes, 214 and data from SARS-CoV or other respiratory virus studies suggest that SARS-CoV-2 antibodies may exacerbate COVID-19. 217 Clinical studies have shown that SARS-CoV-2 antibodies can bind to mast cells, which may be related to the multisystem inflammatory syndrome in children (MIS-C) and multisystem inflammatory syndrome in adults (MIS-A) after COVID-19. 219 The binding of SARS-CoV-2 antibodies to Fc receptors on macrophages and mast cells may represent two different mechanisms of ADE in patients. The above findings indicate the possibility of ADE induced by COVID-19 vaccines, to which more attention should be paid to. 220

The preclinical results suggest that vaccination with formalin-inactivated SARS-CoV virions, MVA vaccine expressing SARS-CoV S protein, and S-derived peptide-based vaccine may induce lung disorders in the NHP model. 214 When macaques were inoculated with inactivated SARS-CoV vaccine, they showed ADE after viral infection, manifesting as extensive macrophage and lymphocyte infiltration in the lungs and edema in the alveolar cavity. Mice and hamsters inoculated with trimeric S protein vaccine were not infected with SARS-CoV, but the serum produced could promote the entry of ACE2-independent pseudovirus. 221 Rhesus monkeys inoculated with a high dose of COVID-19 vaccine had elevated body temperature within 1 day, increased respiratory rate, and decreased appetite within 9–16 days. 216 Monkeys euthanized on days 3 and 21 displayed multifocal lung injury, alveolar septum thickening due to edema and fibrin, the slight appearance of type II lung cells, and perivascular lymphocyte proliferation. 214

These models and data emphasize the importance of developing a safe anti-antibody-independent COVID-19 vaccine. At the same time, it is necessary to pay close attention to ADE caused by vaccination against COVID-19. Some studies have shown that antibodies with low affinity and poor neutralization ability may aggravate this disease, while current clinical markers cannot distinguish between severe infection and enhanced antibody dependence. 214 , 218 Therefore, data and mitigation methods from SARS-CoV and MERS-CoV are referential to analyze the ADE phenomenon caused by COVID-19 vaccination. It is important to develop better COVID-19 vaccines and immunotherapy, overcome the identified mutants, and reduce possible ADE pathology.

Improvement of COVID-19 vaccines

Although COVID-19 vaccines can reduce the risk of infection and the mortality of patients, problems with the vaccines at present include declining neutralization activity of variants and vaccination-related adverse events. 14 , 153 , 222 Adopting mix-and-match vaccines 223 and developing new vaccines, such as VLPs and nanoparticle vaccines, 224 improving existing vaccine adjuvants, 225 and changing the vaccination route 226 might enhance the efficacy of vaccines and reduce the occurrence of adverse events to some degree (Fig. 1 ).

Mixed inoculation

In the absence of available vaccine resources, the second injection of an allogeneic vaccine may effectively advance the immunization process. However, vaccination with non-homologous vaccines may raise concerns about safety and effectiveness. Borobia et al. assessed the immunogenicity after inoculating a heterogeneous COVID-19 vaccine and indicated that the heterogeneous vaccine might provide greater immune protection. An initial dose of AZD1222, followed by the BNT162b2 vaccine, can induce strong immune responses and is safe. 227 The research of Hillus et al. 228 reached a similar conclusion. Compared with two doses of AZD1222 administered 10–12 weeks apart and BNT162b2 administered 2–3 weeks apart, the AZD1222 and BNT162b2 vaccines administered at an interval of 10–12 weeks were more effective, with better tolerance and immunogenicity. Heterologous vaccination can complement the advantages of different vaccines, 229 as vaccination with BNT162b2 can elicit strong B-cell immunity and induce high levels of neutralizing antibodies, whereas the AZD1222 vaccine can induce strong T-cell responses. Therefore, this scheme is suitable for individuals with decreased immune function (e.g., organ transplants and cancer patients). Several studies evaluated the neutralization activity of the Omicron variant by the booster dose of homologous or heterologous inoculation. 230 , 231 Both homologous and heterologous enhancers could increase the neutralization activity of subjects’ serum against the Omicron variant, but the neutralization efficiency of an additional heterologous vaccine was higher, supporting the sequential vaccination with heterologous vaccines.

In addition, several studies have shown that individuals previously infected with SARS-CoV-2 have a stronger immune response after the vaccination. 138 , 232 , 233 , 234 Planas et al. tested the serum and antibody levels of 21 medical staff infected with SARS-CoV-2 12 months before vaccinating with a single dose of COVID-19 vaccine (vaccinated 7–81 days before sampling). 138 The serum effectively neutralized Alpha, Beta, and Delta variants, and similar results were obtained by Mazzoni et al. 232 After a single dose of the vaccine, the cellular and humoral immunity levels of patients who had rehabilitated from COVID-19 were further strengthened, 233 and memory B-cell responses were significantly enhanced. These findings explain the significant increase in antibody levels after the first vaccination of rehabilitation patients. 24 Havervall et al. showed that a single dose of COVID-19 vaccine could be used as an effective immune enhancer within at least 11 months after being infected with SARS-CoV-2. 234 Liu and colleagues evaluated the efficiency of the BNT162b2 booster dose against B.1.1.529 (Omicron) variant and found that the serum neutralizing antibody levels from previous-infected recipients with booster dose is higher than naive-uninfected counterparts. 235

The collective findings support the view that vaccination should be actively carried out, regardless of whether the individuals have been infected with SARS-CoV-2 or not. Although previously infected individuals are better protected after a single dose of vaccine, the possibility of breakthrough infection still exists as this immune enhancement may be related to the body’s level of memory B cells. 24 However, there may be individual differences in the level of memory B cells. Therefore, regular antibody testing should be performed for rehabilitated persons who have received a single dose of vaccine to ensure lasting immunity. In addition, it is also a feasible method to implement heterologous vaccination in case of a vaccine shortage. The mixed-vaccination results of CoronaVac and ZF2001 vaccines also supported this view, as the former is much safer while the latter has better immunogenicity. 236 In addition, Zhu et al. found that the mix-vaccination of CoronaVac and Ad5-nCoV can induce higher neutralizing antibodies and provide more effective protection than homologous vaccination. 237

Nanoparticle vaccines

New vaccine platforms, such as mRNA vaccines, provide more powerful immune protection than traditional vaccines. However, these vaccines have lower neutralizing activity against variants, especially the Beta and Delta. 14 , 222 Nanoparticle vaccines may have better neutralizing activity than mRNA vaccines, 224 , 238 , 239 providing a new direction for vaccine development.

Ko et al. 224 designed a nanoparticle vaccine consisting of 24 polymer SARS-CoV-2 RBD nanoparticles and a ferritin skeleton. The vaccine caused cross-neutralizing antibody reactions to bat coronavirus, SARS-CoV, and SARS-CoV-2, including Alpha, Beta, and Gamma variants. The DH1041-DH1045 potent neutralizing antibody induced by the vaccine had neutralizing activity against various mutations, including K417N, E484K, and N501Y. Walls et al. designed a self-assembled protein nanoparticle immunogen composed of 60 SARS-CoV-2 S protein RBDs. The immunogen can target different immune epitopes and still induce high levels of neutralizing antibody expression at low doses. 239 Moreover, compared with traditional vaccines, nanoparticles can exist in B-cell follicles for a long time, producing a sustained germinal center reaction to ensure the high-level production of antibodies. 238 In addition, according to the self-assembly function of ferritin, S protein RBD, 224 hemagglutinin, 240 , and other important viral proteins can be inserted and act as the physiologically relevant trimeric viral spike form to further improve the vaccine efficacy. 238 Therefore, by optimizing the packaging of antigens and producing a stronger, longer-lasting immune response, nanoparticle vaccines are likely to play an important role in future COVID-19 vaccines.

Improvement of immune adjuvants

An adjuvant is a vaccine component to enhance the immune response, playing a very important role in improving the efficacy of vaccines and reducing adverse events to ensure safety. 225 , 241 In the past two decades, a series of new adjuvants have been used in licensed vaccines, including Aluminum hydroxide, MF59, AS03, CpG 1018, and CoVaccine HT, 241 among which the Aluminum hydroxide can reduce the immune-related pathological reactions while other adjuvants can trigger specific cell receptors and induce an innate immune response in the injection site as well as the draining lymph nodes, further promoting the production of antibodies. 225 , 242 Therefore, appropriate adjuvants are critical for maintaining vaccines’ durability and effectiveness. Here, some brief information on existing adjuvants used in COVID-19 vaccines is provided in Table 4 .

Alum is the most widely used adjuvant in global vaccine development, which can induce the antibody response and different CD4 + cell responses (low level). 225 , 241 Relevant mechanisms can be explained as enhancing anti-phagocytosis and activating the proinflammatory NLRP3 pathway. 242 In addition, Aluminum adjuvants can reduce immune-related pathological reactions and improve safety, explaining the excellent safety of BBIBP-CorV and CoronaVac (both of the vaccines used Aluminum hydroxide as adjuvants). 221 , 243 However, the immunogenicity of aluminum adjuvant is poor. The chemical modification of alum with short peptide antigens composed of repeated serine phosphate residues can significantly enhance GC cell and antibody responses. 244

MF59 is a squalene oil-in-water emulsion adjuvant approved for use in influenza vaccines in more than 38 countries, and it is biodegradable and biocompatible. 245 MF59 showed good tolerance and safety, and the inoculation of vaccines that use this adjuvant can motivate the activation of macrophages and the production of chemokines. These chemokines will recruit neutrophils, eosinophils, and monocytes to the lymph nodes, further form a cascade amplification reaction, and activate B cells and T cells. 225 In addition, MF59 can stimulate IL-4 and STAT6 signal pathways and induce the antibody response. It is worth noting that the above response does not depend on type 1 interferon or inflammatory pathway. 246 Thereby, MF59 has been selected as the adjuvant of COVID-19 vaccines.

AS03 is similar to MF59 but has an additional immune-enhanced component α- tocopherol (vitamin E). Thus, it can induce the expression of proinflammatory cytokines and chemokines independently (not depending on the type I interferon). 242 In addition, AS03 can trigger a transient innate immune response, the injection of AS03 induces the transient production of cytokines in the mice model, and vitamin E can further enhance the expression of some chemokines and cytokines like CCL2, CCL3, and IL-6. 225 AS03 is evaluated as the adjuvant of several recombinant S protein vaccines in the clinical trial, the add of AS03 further improve Th2-unbiased cell responses and the production of IFN-γ, which may enhance the efficacy of COVID-19 vaccines. 247

CoVaccine HT is also an oil-in-water (O/W) emulsion, while CpG is a synthetic DNA sequence containing an unmethylated CpG sequence. 242 , 248 Compared with the aluminum hydroxide adjuvant, AMP-CpG and CoVaccine HT showed better immunogenicity. 249 Using AMP-CpG as an adjuvant, persistent antibody and T-cell reactions were still induced in elderly mice at low-dose S protein levels. Reducing the dose of S protein may decrease the occurrence of adverse events and improve vaccine safety. Compared to aluminum hydroxide, CoVaccine HT can promote the production and maturation of neutralizing antibodies to a greater extent, thereby quickly inducing an immune response to SARS-CoV-2. 248

The use of aluminum adjuvants may reduce the adverse events of related vaccines and improve vaccine safety. However, the immunogenicity of aluminum adjuvants is poor. Therefore, the common use of different adjuvants may improve immunogenicity while ensuring subjects’ safety.

Change of inoculation route

In addition to sequential immunization (mixed-vaccination), development of new vaccines (such as nanoparticle vaccine), and adjuvant improvement, changing the vaccination route is also a feasible measure to improve the protection and efficacy of existing COVID-19 vaccines. 3 , 250 All WHO-approved vaccines adopt the intramuscular route (i.m route), and most of them can only protect the lower respiratory tract except for Ad26.COV-2.S, which can both protect the upper and lower respiratory tract. 48 However, the new VOC Omicron has stronger infectivity of the upper respiratory tract and mainly causes symptoms of the upper respiratory tract, so the existing vaccine is difficult to protect effectively. 122 , 235 , 251 Mucosal immunity plays an important role in preventing pathogen invasion. The intranasal administration(inhalation route, i.n route) of vaccines may achieve a better protection effect on preventing SARS-CoV-2 infection (especially Omicron variant). 3 , 250 , 252 , 253 Compared with the traditional i.m route, the i.n route can effectively induce a local immune response. Vaccine antigen enters the respiratory tract and passes through the mucus layer through inhalation to induce the production of local IgA and provide protection at the pathogen’s entry site. 253 In addition, the i.n route can induce the production of higher levels of mucosal antibodies. Although some IgG can be detected on the mucosal surface after the intramuscular injection, the lack of mucosal IgA still makes the respiratory tract vulnerable to infection. 3 In addition, the i.n route has better compliance than the i.m route, and the administration is more convenient. However, the i.n route still has some disadvantages: the systemic immune response induced by this administration method is often lower than that of the i.m route because the titer of the virus may decrease when it is made into aerosol; the i.n route may cause antigen or vaccine adjuvant to enter the central nervous system and cause an adverse reaction; and i.n route usually needs auxiliary drug delivery devices (such as pressure device, atomizer), and the cost is higher, which limits the application of this approach.

Among the currently approved inactivated vaccine, viral vector vaccine, protein subunit vaccine, and mRNA vaccine, only viral vector vaccine has the potential to apply intranasal administration because inactivated vaccine, protein subunit vaccine, and mRNA vaccine antigens cannot actively enter cells, so it is difficult to stimulate mucosa effectively, and they remain difficult to commercialize. 250 Van Doremalen N and colleagues evaluated the efficacy of AZD1222 in macaques and hamsters via intranasal administration. They found that the viral load in the nasal cavity of the experimental group decreased significantly after enhanced intranasal inoculation. No virus particle or RNA was detected in the lung tissue, indicating that intranasal administration is a prospect route for COVID-19 vaccines. 254 Wu S et al. evaluated the safety, tolerability, and immunogenicity of the aerosolized Ad5-nCoV. The inhalation group(2 doses via i.n route on days 0 and 28) reported fewer adverse events compared with the injection group(2 doses of Ad5-nCOV via i.m route on days 0 and 28) and the mixed group(1 dose via i.m route on day 0 and the second dose via i.n route on day 28). The mixed group showed the highest induced-immune level, but the antibodies produced by the inhalation group were less than those of the injection group, suggesting that the inhalation route of Ad5-nCoV is an effective measure to boost immunity. 226

The above study shows that the i.n route can protect the upper respiratory tract and inhibit virus infection more effectively than the i.m route, and relevant adverse events are fewer. However, the immune response induced by the i.n route alone is lower than that induced by the i.m route. Thus i.n route is more suitable for strengthening immunity. Through the mix route (i.m route at first and then i.n route), higher levels of antibodies can be induced compared with the repeat i.m route and provide stronger protection. As more and more vaccines are approved for clinical trials, the i.n route will be used more widely.

Prospects and perspectives

More than 153 candidate vaccines have entered human clinical trials. New vaccine platforms will undoubtedly be evaluated, such as nanoparticle and VLP vaccines.

After vaccination against COVID-19, T-cell immunity (such as the Th1 cell response), B-cell immunity (such as the germinal center response), and other immune responses may be produced. 19 , 21 Differentiated Th cells can enhance the immune response in the body by promoting the activation of CD8 + T cells and secreting IFN-γ. 31 With the aid of Th cells, activated B cells proliferate and divide in lymphatic follicles to form germinal centers, eventually form plasma cells, and memory B cells secret high-affinity antibodies. In addition, COVID-19 vaccines can produce memory B cells and memory T cells. 24 The antiviral immune barrier in the host body can be constructed through the combined action of the humoral immune response, cellular immune response, and memory cells.

Although the COVID-19 vaccines have achieved exciting results in both animal studies and clinical trials, 3 and seven vaccines have been authorized for emergency use by the WHO, adverse events that include pain at the injection site and fever, 114 , 118 as well as complications such as coagulation dysfunction, 154 myocarditis, 74 immune diseases, 155 nervous system diseases 159 and lymphatic system diseases 160 caused by vaccination, have raised concerns about vaccine safety. Given the low proportion of overall incidence of adverse events of vaccines and the fact that some complications occur mainly in patients with underlying diseases (e.g., cardiovascular diseases and tumors). Governments and relevant agencies are recommended to accelerate the vaccine immunization process. Simultaneously, special attention should be paid to the health status of the recipients, timely treatment of complications, vaccine development, and ensuring the lives and health of patients. In addition, considering the characteristics of some individuals (e.g., the elderly, pregnant women, organ transplant patients, cancer patients, and patients infected with HIV), relevant agencies should closely monitor adverse events and detect antibody titers after immunization. 190 For organ transplant and cancer patients, the COVID-19 vaccine showed approximately 50% overall protective efficacy due to the continuous use of immunosuppressive drugs, which is unsatisfactory. 201 , 206 Those populations are susceptible to SARS-CoV-2 infection, and timely immunization-enhanced measures should be performed to reduce breakthrough infections. For HIV-infected individuals, the viral level in the body should be effectively controlled during vaccination. Otherwise, breakthrough infections may still occur. 27 , 209

New SARS-CoV-2 variants like Omicron often have high infectivity and high immune escape ability in the post epidemic era. The existing vaccine strategies are difficult to effectively prevent infections caused by the Omicron variant, which is not only due to the accumulation of more mutation sites in the S protein, but also because the Omicron variant mainly causes upper respiratory tract infection, while the protective antibodies induced by i.m route are often directed at the lower respiratory tract (lung). In this case, changing or adjusting vaccination strategies is very significant to control the infections and alleviate public health pressure. We believe that the following points deserve attention: (1) Although a booster dose can enhance the response of memory cells and increase the antibody titers to produce a stronger protective effect, the fourth dose injection might not effectively Omicron variant infection. 150 (2) The optimization of COVID-19 vaccines, such as changing the administration route (use the inhaled vaccine and induced mucosal immunity to protect the upper respiratory tract further), developing new vaccines (for inactivated vaccines, the combined use of seed strain of VOCs like Beta + Delta may induce antibodies with multi-epitopes, as well as the use of VOC sequence for mRNA or viral vector vaccines, 151 ) and adopting sequential immunization (the use of vaccines developed in different routes like inactivated + viral vector vaccine/mRNA vaccine) will provide better protection than existing vaccination strategies. (3) Although the adoption of inhalable and sequential immunization can improve the efficacy of COVID-19 vaccines, the incidence of adverse reactions of additional Ad5-nCoV was higher than the additional inoculation with homologous inactivated vaccine. 226 In addition, the inoculation with viral vector vaccines or mRNA vaccines may lead to the complications mentioned above (such as myocarditis and thrombosis). The vaccine’s safety and effectiveness should be balanced. Although the new vaccine platform (such as the mRNA vaccine) may provide more effective protection, its safety is lower than the inactivated vaccine. Suppose multivalent inactivated vaccines like Beta + Delta inactivated vaccine strategies are adopted. In that case, the development can only be carried out after the emergence of a new variant, and the developing speed is lower than the mRNA vaccine uses new variants’ sequences. (4) The emergence of the Omicron variant may indicate the change of the main infection site of SARS-CoV-2 (other VOC usually cause the lung infection except for Omicron), and the symptoms of Omicron infected people are lighter, the hospitalization rate is lower than Delta, infected patients. 255 In this case, there are many asymptomatic Omicron infected people. Convenient and effective COVID-19 antiviral drugs (especially oral-taken drugs) will greatly alleviate the severe epidemic situation and contribute to the early end of the COVID-19 pandemic. 256 In addition, Omicron might not be the last VOC, a new recombinant variant Delta 21 J/AY.4-Omicron 21 K/BA.1, also called “Deltamicron”, has appeared in many countries like France and America, and the NTD of Delta combined with the RBD of Omicron may lead to optimization of viral binding to host cell membranes. 257 Although the detected sequence of Deltacron was lower than Omicron, and the main symptom is mild upper respiratory tract infection, surveillance should be enhanced for this emerging variant.

Furthermore, previously SARS-CoV-2-infected individuals produced high-level antibody responses after a single dose of the COVID-19 vaccine, which may be associated with the strong memory cell response. 24 For those who have not been infected with SARS-CoV-2, nanoparticle vaccines may be a better choice to bestow immunity to infections by mutant strains. Compared with traditional vaccines, nanoparticles can remain in germinal center B cells and ensure the production of high-level antibodies by generating a sustained germinal center reaction. 238 In addition to developing new vaccines, adjuvants with better immunogenicity or combined adjuvants may reduce adverse events and improve the vaccine’s protective efficacy. 248

With the launch of new vaccines and the approval of oral antiviral drugs, such as molnupiravir, the stalemate between humans and SARS-CoV-2 will be broken. 256 , 258 A study conducted by Swadling et al. of 58 medical staff with high exposure risk but had not been infected with SARS-CoV-2 found a higher anti-replication transcription complex (RTC) T-cell reaction. 258 These findings may provide new ideas for vaccine design by targeting RTC and inducing similar T-cell responses. And a nasal-delivery IgY antibody based on SARS-CoV-2 RBD showed multi-protection against Beta, Delta, and Omicron variants in the animal model, which promised to be an additional measure of pre-exposure prophylaxis of SARS-CoV-2 infection. 259 These new achievements in the pharmaceutical field will undoubtedly become powerful weapons against COVID-19 and help end the pandemic.

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Acknowledgements

We thank Fuxing Lou, Ruolan Hu (Beijing University of Chemical Technology, China), and Prof. Chunfu Zheng (University of Calgary, Canada) for language and grammar editing.

H.F. declares grants from the National Key Research and Development Program of China (Grant No. 2022YFC0867500, BWS21J025, 20SWAQK22 and 2020YFA0712102), National Natural Science Foundation of China (Grant No. 82151224), Key Project of Beijing University of Chemical Technology (Grant No. XK1803-06, XK2020-02), Fundamental Research Funds for Central Universities (Grant No. BUCTZY2022), and H&H Global Research and Technology Center (Grant No. H2021028).

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These authors contributed equally: Maochen Li, Han Wang, Lili Tian and Zehan Pang

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College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China

Maochen Li, Lili Tian, Zehan Pang, Tianqi Huang, Lihua Song, Yigang Tong & Huahao Fan

Laboratory for Clinical Immunology, Harbin Children’s Hospital, Harbin, China

College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, China

Qingkun Yang

Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China

Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, China

Yigang Tong

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H.F., Y.T., and L.S. designed the research; M.L., H.W., Z.P., and L.T. read and analyzed the papers; Q.Y., T.H., and J.F. participated in the discussion; M.L. and H.F. wrote and revised the manuscript. All authors have read and approved the article.

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Correspondence to Lihua Song , Yigang Tong or Huahao Fan .

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Li, M., Wang, H., Tian, L. et al. COVID-19 vaccine development: milestones, lessons and prospects. Sig Transduct Target Ther 7 , 146 (2022). https://doi.org/10.1038/s41392-022-00996-y

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A model of factors influencing COVID-19 vaccine acceptance: A synthesis of the theory of reasoned action, conspiracy theory belief, awareness, perceived usefulness, and perceived ease of use

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing – original draft

* E-mail: [email protected]

Affiliation Department of Accounting & Information Systems, Faculty of Business Studies, Jagannath University, Dhaka, Bangladesh

Roles Data curation, Investigation, Project administration, Writing – review & editing

Affiliation Institute of Chartered Accountants of Bangladesh, Dhaka, Bangladesh

• Taslima Akther, 
• Tasnima Nur

• Published: January 12, 2022
• https://doi.org/10.1371/journal.pone.0261869
• Reader Comments

The aim of this study is to investigate the key factors influencing the acceptance of COVID-19 vaccines and develop a model based on the theory of reasoned action, belief in conspiracy theory, awareness, perceived usefulness, and perceived ease of use. The authors created and distributed a self-administered online questionnaire using Google Forms. Data were collected from 351 respondents ranging in age from 19 to 30 years, studying at the graduate and postgraduate levels at various public universities in Bangladesh. The Partial Least Squares Structural Equation Modeling (PLS-SEM) method was used to analyze the data. The results indicate that belief in conspiracy theory undermines COVID-19 vaccine acceptance, thereby negatively impacting the individual attitudes, subjective norms, and acceptance. Individual awareness, on the other hand, has a strong positive influence on the COVID-19 vaccine acceptance. Furthermore, the perceived usefulness of vaccination and the perceived ease of obtaining the vaccine positively impact attitude and the acceptance of immunization. Individuals’ positive attitudes toward immunization and constructive subjective norms have a positive impact on vaccine acceptance. This study contributes to the literature by combining the theory of reasoned action with conspiracy theory, awareness, perceived usefulness, and perceived ease of use to understand vaccine acceptance behavior. Authorities should focus on campaigns that could reduce misinformation and conspiracy surrounding COVID-19 vaccination. The perceived usefulness of vaccination to prevent pandemics and continue normal education will lead to vaccination success. Furthermore, the ease with which people can obtain the vaccine and that it is free of cost will encourage students to get vaccinated to protect themselves, their families, and society.

Citation: Akther T, Nur T (2022) A model of factors influencing COVID-19 vaccine acceptance: A synthesis of the theory of reasoned action, conspiracy theory belief, awareness, perceived usefulness, and perceived ease of use. PLoS ONE 17(1): e0261869. https://doi.org/10.1371/journal.pone.0261869

Editor: Dejan Dragan, Univerza v Mariboru, SLOVENIA

Received: August 27, 2021; Accepted: December 12, 2021; Published: January 12, 2022

Copyright: © 2022 Akther, Nur. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting information files.

Funding: The authors receive no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

1. Introduction

In December 2019, the first human cases of COVID-19, a coronavirus disease caused by SARS-CoV-2, were reported in Wuhan, China [ 1 , 2 ]. The virus was initially called the novel or “New” coronavirus, but was later renamed SARS-CoV-2 by the International Committee on Taxonomy of Viruses, and the disease it causes was named “coronavirus disease 2019 or “COVID-19” by the World Health Organization (WHO) on February 11, 2020 [ 3 ]. Within a month, the novel coronavirus spread to 25 countries, including China and the WHO Director-General declared COVID-19 as the first pandemic caused by a coronavirus, causing over 118,000 infections in 114 countries and 4,291 deaths [ 4 , 5 ]. After the initial infection in Wuhan, China, the first million COVID-19 cases were reported on April 2, 2020; the highest daily case count of 906,008 was on April 28, 2021. On May 18, 2021, over 4,500 people died in India, and over 4,400 people died in the US on January 12, 2021 [ 6 ]. The first COVID-19 patient was discovered in Bangladesh on March 8, 2020, and it was fatal on March 18, 2020. By June 2021, there were 840,000 cases, with 112 deaths in a single day on April 19, 2021. In Bangladesh, the Case Fatality Rate (CFR), which is the ratio of confirmed deaths to confirmed cases, increased by 58%, indicating that a greater proportion of infected people began to die [ 7 ].

During the public health emergency caused by COVID-19, the WHO placed unlicensed, still-in-development vaccines on the Emergency Use List as a temporary measure to make such vaccines available to those in need [ 8 ]. The WHO approved five vaccines for emergency use against COVID-19 as of June 3, 2021, because they met the necessary safety and efficacy criteria, including AstraZeneca/Oxford, Johnson and Johnson, Moderna, Pfizer/BioNTech, Sinopharm, and Sinovac [ 9 ]. Up until June 9, 2021, more than 944 million people received vaccine doses, and more than 480 million were fully vaccinated, representing 6.16 percent of the world’s population [ 6 ]. COVID-19 vaccines are expected to provide minimal protection against new virus variants while also preventing serious illness and death [ 10 ]. Rumors and conspiracy theories, on the other hand, contribute to COVID-19 vaccine hesitancy [ 11 ].

Conspiracy theories are primarily inferential beliefs derived from outside sources that extend beyond observable events [ 12 ]. Belief in conspiracy theories (BC) historically impeded population immunization. Previously, people refused immunizations due to false claims that vaccines contained infertility agents or spread infectious pathogens like the human immunodeficiency virus (HIV) [ 13 ]. People in many countries boycotted the polio vaccine due to rumors that it caused infertility, resulting in an increase in polio cases [ 13 , 14 ]. Conspiracy theories about COVID-19 being a hoax or a bioweapon designed in a Chinese laboratory began to circulate on social media almost immediately after the first reports of the virus [ 15 ]. Bertin et al. [ 16 ] found that the more participants believed in COVID-19 conspiracy theories, the less likely they were to support vaccination. Sallam et al. [ 17 ] report a high prevalence of COVID-19 vaccine hesitancy among Jordanian university students, associated with conspiracy beliefs such as COVID-19 is a man-made disease, vaccination will be used to implant microchips into humans to control them, and vaccination can lead to infertility.

The theory of reasoned action (TRA) explains individual behavior by emphasizing the importance of beliefs in predicting behavior [ 18 ]. According to TRA, an individual’s attitude toward the outcome of the behavior and subjective norms (the opinions of the person’s social environment) predict individual behavior intention [ 19 ]. Positive vaccination attitudes will increase the rate of COVID-19 vaccine acceptance. Those who intend to receive the COVID-19 see high perceived benefits in doing so for the purpose of protecting themselves and others in their circle, implying vaccination compliance [ 20 ]. Raising public and individual awareness is the most important factor in the fight against diseases, crime, and social injustice [ 21 , 22 ]. People are either unaware of or fearful of the current vaccination program [ 23 ].

This study investigates the factors that influence COVID-19 vaccine acceptance among the young generations of Bangladeshi public university students. Bangladesh, a developing country in South Asia, accounts for 0.58% of the world’s COVID-19 cases and is in the top 26 countries worldwide.. As a tertiary educational institute, public universities provide higher education, and the pandemic wreaked havoc on the students’ education and future prospects. At the height of the pandemic, we assessed the acceptance of COVID-19 vaccines among students at various public universities in Bangladesh, for whom vaccination is a critical issue in allowing them to resume their education and prepare them for their profession. We construct a model of COVID-19 vaccine acceptance using the frames of TRA, belief in conspiracy theory (BC), awareness (AW), perceived usefulness (PU), and perceived ease of use (PE). Our findings are a valuable resource for understanding vaccine acceptance behavior during this critical pandemic period and providing policymakers with some practical recommendations. Furthermore, this study makes a significant theoretical contribution to the literature by decomposing TRA using BC, AW, PU, and PE.

The remainder of the paper proceeds as follows. Section 2 discusses the COVID-19 pandemic and vaccination in the context of Bangladesh. Section 3 describes the theoretical framework and hypothesis development, followed by a description of the data and methodology in Section 4. Section 5 reports the analysis and results, and Section 6 provides a discussion, the implications of the study, the limitations, and conclusion.

2. The COVID-19 pandemic in Bangladesh and the vaccination context

Till June 2021, Bangladesh had 840,000 cases and over 13,000 deaths due to COVID-19. Prothomalo [ 24 ] published news of a study by the International Centre for Diarrhoea Disease Research, Bangladesh (ICDDR,B) showing that 71% and 55% residents of Dhaka and Chittagong, respectively, developed COVID-19 antibodies between October 2020 and February 2021 and many of these people were asymptomatic and so more dangerous to others in terms of spreading the virus unknowingly. Data reported by WHO in the following Fig 1 depicts that among the Southeast nations, Bangladesh has an upward trend in active cases, deaths, and the CFR rate from 1 January 2020 to 18 July 2021.

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• TIFF original image

https://doi.org/10.1371/journal.pone.0261869.g001

COVID-19 primarily infected young professionals, students, and working people in Bangladesh. According to the IEDCR, 68% of COVID-19 cases were observed in people aged 21 to 50 years, whereas infected patients aged >50 years made up 21% of total infected people, and children and youths aged 20 years made up were 11% of total infected cases [ 25 ]. Aside from direct consequences such as infection and death, COVID-19 affected the economic and social lives of Bangladeshis due to the nationwide lockdowns beginning March 24, 2020. The COVID-19 pandemic also highlighted flaws in Bangladesh’s healthcare system. As healthcare workers work to save the lives of COVID-19 patients, regular healthcare services and vaccination programs are hampered [ 26 , 27 ]. On February 7, 2021, mass vaccination against COVID-19 began across the country based on online registration. Bangladesh has 53 government-funded public universities that operate as self-governing organizations. These universities are classified into agricultural universities, science and technology universities, engineering universities, medical universities, and general studies universities [ 28 ]. Due to the COVID-19 pandemic outbreak in Bangladesh, all educational institutions have been closed since March 2020. Many of these students also live in rented houses, as residential halls are also closed, which increases their expenses or reduces their savings. Due to a lack of digital learning opportunities in rural areas, education for a whole generation was disrupted.

3. Theoretical framework and hypothesis development

3.1. belief in conspiracy theories and covid-19 vaccination.

Conspiracy theories are explanations for significant events that involve secret plots by powerful malevolent groups [ 29 ]. Commonly accepted conspiracy theories contend that climate change is a hoax [ 30 ]; NASA faked the moon landings [ 31 ]; the US government orchestrated the 9/11 terrorist attacks [ 32 ]; and vaccinations are harmful, but this fact is concealed to maintain profits [ 33 ]. A conspiracy belief is the unwarranted assumption of a conspiracy when other explanations are more likely [ 34 ]. A growing body of research shows that BC can have negative consequences on attitudes and behavior [ 35 ]. In addition to the social and political domains, BC has a significant impact on health. Conspiracy beliefs about the origin and treatment of HIV/AIDS had a negative impact on attitudes toward preventative measures and adherence to treatment programs [ 36 ]. Fears about the safety of childhood vaccinations contributed to a drop in polio vaccination rates in some countries [ 37 ].

3.2. Impact of conspiracy beliefs on attitude toward vaccination

Although vaccines are the most effective way to prevent infectious diseases, their safety and efficacy have long been the subject of conspiracy theories, with the central argument being that large pharmaceutical companies and/or governments conceal vaccine information for personal gain [ 37 , 38 ]. Belief in anti-vaccine conspiracy theories reduces vaccination intentions [ 39 ]. Rumors about COVID-19 vaccine development delays, or that vaccines will be freely available only to supporters of the ruling government, may foster distrust between government stakeholders and the general public. This could affect the implementation of any vaccine-related policy. Online health information is frequently amplified by rumors and conspiracy theories that are not always based on scientific evidence [ 40 ]. Users who seek health information on online platforms are at risk of exposure to misinformation that could endanger public health [ 41 ]. Stecula et al. [ 42 ] discovered that people exposed to COVID-19 vaccine-related information on social media were more likely to be misinformed and vaccine-hesitant. We therefore hypothesize that

H1: BC has a negative impact on attitude toward COVID-19 vaccine acceptance .

3.3. Impact of conspiracy beliefs on subjective norms

Conspiracy beliefs are widespread and can have negative consequences because perceived social norms have a strong influence on individuals [ 43 ]. Social influence is the process by which perceptions of what other people think and do influence beliefs and behaviors [ 44 ]. Social norms guide behavior by implicitly defining what is and is not acceptable in a given context [ 44 ]. Sherif [ 45 ] defined social norms as mutually agreed-upon rules for social behavior. People who identify more strongly with the group are more likely to act in accordance with group norms [ 46 ]. Thus, perceived norms of conspiracy belief may influence personal BC, especially if people perceive groups with which they identify strongly as endorsing conspiracy theories [ 46 , 47 ].

BC, particularly anti-vaccine conspiracy theories, is regarded as more normative than it is [ 43 ]. This is significant because the overestimation of in-group conspiracy beliefs may result in unwarranted social pressure to also endorse conspiracy beliefs given the negative social and health consequences of harboring conspiracy beliefs, particularly anti-vaccine conspiracy theories [ 30 , 48 ]. It is concerning that perceived social norms may be driving conspiracy belief. We thus hypothesize

H2: BC has a negative impact on subjective norms regarding COVID-19 vaccine acceptance .

3. 4. Impact of conspiracy beliefs on COVID-19 vaccine acceptance

Rumors and conspiracy theories can contribute to vaccine apprehension [ 49 ]. Negative claims about vaccine effectiveness historically influenced vaccine uptake. Rumors about vaccination campaigns being used for political purposes are not new, and such rumors affected vaccination campaigns in some countries [ 50 ]. One prevalent rumor holds that critical phases of clinical trials in the vaccine development were skipped because pharmaceutical companies would not compensate participants for adverse side effects experienced during the trial. The most widely circulated rumor is that the COVID-19 vaccine would be a messenger Ribonucleic acid (mRNA) vaccine that could change people’s Deoxyribonucleic acid (DNA), transforming them into genetically modified humans, or cause cancers and infertility. Some claims emphasize that the COVID-19 vaccine was intended to reduce the global population. In Bangladesh, there was a rumor that China wanted to use Bangladeshi citizens as genuine pigs for a vaccine trial [ 49 ]. Therefore, we hypothesize

H3: BC has a negative impact on COVID-19 vaccine acceptance .

3. 5. Awareness

Awareness is the extent to which a target population is aware of an innovation and formed a general perception of what it entails [ 51 ]. The concept of awareness first appeared in innovation diffusion theory, which states that the decision-making process for adopting new technologies includes awareness, attitude formation, decision, implementation, and confirmation [ 52 ]. It is further defined as an individual’s active participation and increased interest in focal issues [ 53 , 54 ]. The concept of awareness is central to human behavior in the social science, criminal justice, and medical behavioral science literature [ 21 ]. Awareness is one of the most important components of consciousness-raising because it fosters an understanding of the needs, impetus, and specificity of issues, events, and processes, and it is positively related to individuals’ attitudes and cognitive development [ 22 , 55 ].

One study shows that people are either unaware of or fearful of the current vaccination program [ 23 ]. Vaccine hesitancy and misinformation are major impediments to achieving coverage and population immunization in many countries [ 56 , 57 ]. Awareness can have positive impact on the vaccine acceptance. Thus, we propose

H4: Awareness positively influences attitudes toward COVID-19 vaccine acceptance .

In addition to an individual’s attitude toward behavior, the behavioral norms of an individual user’s social group have a strong influence on the individual’s behavioral intention [ 58 ]. The process of increasing problem awareness guides the development of a social network of organizations that strongly advocate for policies and programs to reduce such problems [ 59 ]. In the case of the COVID-19 vaccine, raising awareness among various social groups and communities raises community norms about COVID-19 and influences immunization through the COVID-19 vaccine. We therefore hypothesize that

H5: Awareness positively influences subjective norms about taking the COVID-19 vaccine .

Awareness is critical to technology acceptance. Identity theft, negative publicity, significant financial loss, and uncertain legal consequences could be devastating to individuals and organizations if they do not adopt protective technologies. Because such consequences are frequently reported in the popular media, we contend that awareness alone can motivate a user to act, regardless of whether he or she formed a positive attitude or is influenced by social group norms. Other studies on crime and disease prevention show that increased awareness has a direct influence on the intention to engage in certain behaviors [ 60 , 61 ]. Consequently, we postulate that

H6: Awareness has a positive impact on COVID-19 vaccine acceptance .

3. 6. Perceived usefulness (PU) and perceived ease of use (PE)

3. 6. 1. perceived usefulness (pu)..

PU is peoples’ subjective assessments of the extent to which using a system would improve their job performance [ 62 ]. It is the magnitude to which an individual considers using something that provides more benefits [ 63 ]. PU is a predictor of attitude [ 62 , 64 – 66 ]. Users can develop a positive attitude because engaging in a particular behavior has numerous benefits. Islam et al. [ 67 ] demonstrated that the majority of participants had a positive attitude toward vaccination for its usefulness in protecting against COVID-19 disease. Perceived benefits, such as the COVID-19 vaccine’s high effectiveness in preventing significant suffering and complications of the disease, as well as the risk of becoming infected or infecting others, can predict COVID-19 vaccine acceptance. For recent graduates, a vaccine certificate may be required for new job applications, higher education applications, and proper continuation of their current studies and life activities. The usefulness of the vaccine creates a favorable attitude toward the acceptance of vaccines and the COVID-19 vaccine. Thus, we hypothesize that

H7: The PU of the COVID-19 vaccine is positively related to attitude toward its acceptance .

H8: The PU of the COVID-19 vaccine has a positive impact on its acceptance .

3. 6. 2. Perceived ease of use (PE).

PE is an individual’s expectation of how easy the target system will be to understand, learn, and use [ 62 , 63 ]. The complexity of a single system will impede the adoption of an innovation [ 52 ]. With less complexity in a system’s operation, a user can develop a positive attitude toward intention and behavior. PE has a direct relationship with attitude and acceptance [ 62 , 66 , 68 ]. Vaccination convenience is the ease of obtaining the vaccine, including factors such as physical availability, affordability, and accessibility [ 69 ]. When investigating vaccine acceptability, it is critical to consider vaccine convenience in terms of availability and affordability. If the COVID-19 vaccine can be obtained with less effort and is freely available, its acceptance will increase. Therefore, we propose

H9: The PE of the COVID-19 vaccine is positively related to its acceptance .

H10: The PE of the COVID-19 vaccine is positively related to its acceptance .

3. 7. Attitude, subjective norms, and COVID-19 vaccine acceptance

The theory of reasoned action, TRA [ 19 ], developed in the field of Social Psychology, has been widely used to explain individual behavior. The TRA hypothesizes that an individual’s intention to engage in a given behavior predicts behavior. In turn, subjective norms, that is, the individual’s attitude toward the outcome of the behavior and the opinions of the person’s social environment predict intention [ 19 ]. TRA is a general structure designed to explain almost all human behavior based on the significance of an individual’s beliefs in predicting their behavior [ 19 , 70 ].

Vaccines are effective interventions that can help to reduce the global disease burden. Public vaccine hesitancy, on the other hand, is a pressing issue for public health officials. With the availability of COVID-19 vaccines, there is little information available on public acceptability and attitudes toward the COVID-19 vaccines. A positive attitude toward the vaccination will help to prevent COVID-19 and impact vaccinate acceptance. In a survey conducted across 19 countries, 71.5% respondents stated that they would take a vaccine if it were proven safe and effective [ 71 ]. We anticipate that positive attitudes toward vaccination will increase the rate of COVID-19 vaccine acceptance.

H11: COVID-19 vaccine acceptance is related to attitude .

Subjective norms are an individual’s perception of the social pressure to perform or refrain from performing a target behavior [ 19 ]. Normative beliefs reflect an individual’s perception of the influence of opinion among reference groups, whereas motivation to comply reflects the extent to which the individual wishes to comply with the wishes of the referent other [ 72 ]. Hence, people frequently act based on their perception of what others think they should do, and people close to them may influence their intention to adopt a behavior.

Subjective norms and self-efficacy are significant predictors of COVID-19 vaccination intention [ 73 ]. Subjective norms that particularly influenced respondents were when friends and family members responded positively to the vaccination. Individuals with a constructive outlook regarding COVID-19 vaccines would recommend it to their friends, family and the community. Hence, we postulate that

H12: COVID-19 vaccine acceptance is related to subjective norms .

Fig 2 depicts the conceptual model of this study, while Table 1 summarizes the constructs and measurement items.

https://doi.org/10.1371/journal.pone.0261869.g002

https://doi.org/10.1371/journal.pone.0261869.t001

4. Materials and methods

We examined COVID-19 vaccine acceptance using a structured questionnaire. The survey questionnaire was answered using a five-point Likert scale, with 5 indicating strong agreement and 1 indicating strong disagreement. The model was evaluated using PLS-SEM. This study aims to predict the key target construct and test new hypotheses. We used the PLS-SEM technique to evaluate the model because it offers the required features. PLS-SEM has widely used to measure causal relations among indicators and to reveal pivotal connections between the latent constructs [ 75 , 76 ]. With the innovations in PLS simulations, PLS is a fully-fledged SEM approach [ 77 – 79 ].

4.1 Measurements of constructs and items

The Belief in conspiracy theory (BC) scale about COVID-19 vaccine was measured with a seven-item scale adopted from Brotherton et al. [ 34 ]. The adopted scales relate mostly to conspiracy belief about diseases or vaccines. We measured aawareness (AW) with a five-item scale adopted from Dinev and Hu [ 51 ]. PU, PU, and AB are measured on a three-item scale; slightly modified based on the purpose of the current study and adopted from Davis [ 62 ] and Thurasamy et al. [ 74 ]. Subjective norm (SN) is measured on a five-item scale adopted from Thurasamy et al. [ 74 ]. Finally, we measured COVID-19 vaccine acceptance (AV) using a four-item scale slightly modified for our context inspired by Davis et al. [ 64 ] and Taylor and Todd [ 66 ]. All the items were measured on a 5-point Likert scale ranging from 1 = strongly disagree, 3 = neutral, and 5 = strongly agree. The BC scale was reverse-coded. The questionnaire contains three parts. Part A contains demographic information; part 2 is on COVID-19 vaccine acceptance in terms of BC, AW, PU, PE, and the TRA. Finally, we asked some general questions about vaccines. We asked general questions in part 3 so that the respondents do not lose patience and answer the questions about the COVID-19 vaccine acceptance carefully.

4.2 Participants and data collection

The country was about to experience the third wave of COVID-19 at the time of this paper’s writing. The country-wide shutdown began with lockdowns. Almost all public universities are closed, and students are being housed in villages or in remote locations far from their universities. The best way to collect data was thus through an online survey. The ability to use an online survey is attributed to the proliferation of internet usage in Bangladesh as a result of increased government digitalization initiatives [ 80 ]. Using Google Forms, we created an online questionnaire and distributed the questionnaire to various universities’ Facebook pages. The most effective method was to ask teachers to distribute the questionnaire to different class and batch groups of students. Various Facebook Messenger and WhatsApp groups are being used during the pandemic to ensure proper communication with the students and to conduct online classes smoothly. Teachers distributed the survey to those groups, and the data were gathered from them between June 23rd and July 11th, 2021. We polled 351 respondents for their opinions. Participants in the survey were asked to provide informed consent. We kept a section in the Google form for respondents to express their open-ended opinions about the survey, and the majorities of respondents appreciated this research effort and see the survey as a medium to present their thoughts about the current pandemic and vaccination issues. 351 correct answers were used in this study, leaving out cases where the answers were incorrect or incomplete. In order to avoid overstating or exaggerating the study’s findings, all unmatched and incomplete cases were omitted. We include a mandatory step before submitting a response to the questionnaire in Google form to agree to the survey’s voluntary participation. The survey was conducted solely for research purposes and will not be used for commercial gain, with strict adherence to anonymity. Respondents were also assured that they could opt out of the study at any time. Table 2 contains the demographic information.

https://doi.org/10.1371/journal.pone.0261869.t002

4. 2. 1. Ethics statement.

Respondents provided informed consent and written statements about the voluntary participation, and their anonymity was strictly maintained. The study does not report a retrospective study of medical records or archived samples, and no minorities were reported.

Further, we asked the respondents in part 3 of the questionnaire to rank the currently available and approved vaccines (as of 15th June 2021) in Bangladesh. Moderna Vaccine is not included in the rank as it was approved in Bangladesh on 29th June, 2021 (see Fig 3 ). We also inquired whether or not the vaccine would be provided free of charge (see Fig 4 ).

https://doi.org/10.1371/journal.pone.0261869.g003

https://doi.org/10.1371/journal.pone.0261869.g004

5.1 Measurement model

As a variance-based SEM technique, the PLS path model involved two sets of linear equations: the measurement model and the structural model. The measurement model stipulates the interactions between a construct and its observed indicators, while the structural model stipulates the interactions between the constructs [ 77 ]. The reflective indicators are measured in terms of internal consistency, indicator reliability, convergent validity, and discriminant validity. To assess indicator reliability, indicator loadings should be higher than 0.70. For internal consistency, the Cronbach’s alpha value should be higher than 0.70, although in exploratory studies, 0.6 is acceptable. [ 81 ]. Composite reliability should be higher than 0.70 (in exploratory research, 0.60 to 0.70 is considered acceptable) [ 82 ]. Convergent validity is indicated by the average variance extracted (AVE), which should be higher than 0.50. For discriminant validity, the AVE of each latent construct should higher than the construct’s highest squared correlation with any other latent construct (Fornell–Larcker criterion) and an indicator’s loadings should be higher than all of its cross loadings [ 83 ]. We deleted BC2 and BC4 as they had considerably lower loadings; all other loadings were above 0.70. The reliability and convergent validity were quite satisfactory. Table 3 summarizes the assessment of the measurement model.

https://doi.org/10.1371/journal.pone.0261869.t003

5.2 Structural model evaluation

The bootstrapping technique (resampling = 5,000 minimum) was implemented to evaluate the statistical significance of the path coefficients [ 82 ]. In this step, we examined the proposed relationships between the exogenous and endogenous variables by the path coefficient (β) and t- statistics at a significance level of 0.1% (p< .001) and 5% (p< .05). As Table 4 reports, all postulated hypotheses for this study are confirmed and all were significant. We provide the structural model test results in Fig 5 and Table 4 .

https://doi.org/10.1371/journal.pone.0261869.g005

https://doi.org/10.1371/journal.pone.0261869.t004

5.3 Predictive relevance, R 2 and Q 2

The R 2 indicates the variance explained in each of the endogenous constructs by the exogenous construct. It ranges from 0 to 1, with higher levels indicting more predictive accuracy. Hair et al. [ 82 ] advocated that R 2 values of 0.25, 0.50, or 0.75 for dependent constructs in the structural model can be treated as weak, moderate, or strong, respectively. We find moderate R 2 values for AB (0.412), SN (0.682), and AV (0.709), which are close to high, indicating that the proposed conceptual model explains an adequate portion of the variance in the COVID-19 vaccine acceptance.

The Q 2 value provides another means to assess a model’s predictive accuracy [ 84 , 85 ]. The Q 2 value builds on the blindfolding procedure, which omits single points in the data matrix, imputes the omitted elements, and estimates the model parameters. Using these estimates as input, the blindfolding procedure predicts the omitted data points. This process is repeated until every data point has been omitted and the model re-estimated. The smaller the difference between the predicted and the original values, the greater the Q 2 criterion and, thus, the model’s predictive accuracy and relevance. As a rule of thumb, Q 2 values larger than zero for a particular endogenous construct indicate that the path model’s predictive accuracy is acceptable for this particular construct [ 86 ]. Our Q 2 values for AB (0.299), SN (0.205), and AV (0.458) show good predictive relevance for the model of COVID-19 vaccine acceptance (see Table 5 ).

https://doi.org/10.1371/journal.pone.0261869.t005

6. Discussion, contribution, limitation and conclusion

6.1 discussion on the results.

We aim to assess the factors that influence COVID-19 vaccine acceptance in the context of the pandemic. As 62.96% of the respondents were between the ages of 19 and 22, this study included a young sample with a university education. Females made up 41.88% of those polled. This survey was carried out at various universities throughout Bangladesh. The highest number of respondents came from two universities in Dhaka, the capital city, namely Jagannath University (38.18%) and the University of Dhaka (27.17%). We obtained no responses from Barisal out of the eight divisions of Bangladesh, and the highest response from Dhaka, 54.99%.

According to the study’s findings, BC undermines COVID-19 vaccine acceptance. The results for H1, H2, and H3 show that BC has a negative impact on individual attitudes and subjective norms toward immunization, which ultimately has a negative effect on COVID-19 vaccine acceptance. Individual awareness (AW), on the other hand, has a strong positive influence on COVID-19 vaccine acceptance. The results for H4, H5, and H6 show that AW has a positive impact on attitude, subjective norms, and COVID-19 vaccine acceptance. Furthermore, according to the findings for H7, H8, H9, and H10, PU and PE have a positive impact on attitude, subjective norms, and acceptance of immunization to protect against COVID-19. Individuals’ positive attitudes toward acceptance and constructive subjective norms have a positive impact on vaccine acceptance, as stated in H11 and H12.

Individual BC and rumors about vaccine formulation, development, distribution, and even effectiveness would have a negative impact on willingness to immunize. These negative thoughts would spread as normative behavior among their social groups, communities, and circles of belonging, potentially jeopardizing the overall success of the immunization program. Individual-level awareness can spread good thoughts among individuals and groups, leading to vaccination success and a reduction in overall infection. The perception that vaccination can protect against COVID-19 virus infection, severe illness, and death, can make students more willing to take the vaccine and to encourage others in their community to do so. The perceived ease of registering for and receiving vaccines without hassle or difficulty and receiving vaccines at no cost would encourage more students to get vaccinated.

6.2 Contribution of the study

Protective behaviors are critical in pandemic management, and vaccination may be a key protective behavior for COVID-19. Theoretically, we evaluate factors influencing COVID-19 vaccine acceptance by combining TRA with BC, individual awareness level, PU, and PE. Thurasamy et al. [ 74 ] decomposed the TRA and stated that PU and PE affect attitude. We find that BC affects attitude and subjective norms negatively and that awareness (AW), PU, and PE affect attitudes, which also affects acceptance positively.

Additionally, each of these objects can directly impact acceptance without affecting attitude or subjective norms. In this study, the path relationship of BC on AB is BC-AB, subjective norms BC-SN, and vaccine acceptance BC-AV is theoretically unique. BC has a negative impact on AB, SN, and AV. Individual-level awareness is related to AB, AW-AB, subjective norms AW-SN, and vaccine acceptance. Theoretically, AW- AV is also distinct here. AW has a negative impact on AB, SN, and AV. We also find that PU and PE have a positive impact on individual attitudes toward vaccination, which leads to acceptance. Both PU and PE have a positive effect on AB and AV.

This study makes an important contribution to policy development. Bangladesh is already considered a high-risk country, with the highest daily positive rate of 22.6% and an average positive rate of more than 9% from January to June 2021. Many of these people were asymptomatic and thus more dangerous to others in unknowingly spreading the virus. Hence, all people require vaccinations. Due to an increase in COVID-19 cases and a lack of vaccination, the plan to reopen universities has been postponed several times. This study aims to understand vaccine acceptance behavior among young people who attend public universities, whose health is a concern, and who will lead the nation in the future. The findings of this study will assist policymakers in their effort to improve vaccination success in a developing country context such as Bangladesh.

6.3 Limitations

This study employs an online questionnaire survey rather than a face-to-face administration. Students took part in the survey during the COVID-19 pandemic, when they were likely to be worried, frustrated, and living in uncertainty. This type of survey can be conducted with people from various segments of society, and comparisons can be made between their attitudes, beliefs, level of awareness, and acceptance of vaccines. In addition, we found a strong relationship between predictor variables and endogenous constructs. This model can be further tested by including mediating or moderating variables such as age, gender, religious beliefs, previous vaccination history, and so on, to gain a thorough understanding and exploration of the other influential factors to guide policymakers and save humanity from the COVID-19 pandemic.

6.4 Conclusion

This study investigated the factors influencing COVID-19 vaccine acceptance, which is a critical issue in the fight against the pandemic. The respondents were public university students studying various courses at the graduate and postgraduate levels, who will lead the nation in the future. Misinformation and conspiracy theories harmed vaccination programs in the past, including the recent COVID-19 outbreak. It is a cause for concern that if university students believe in conspiracy theories, they will spread faster and discourage people from taking vaccines. Additionally, if they are aware, have a positive attitude and beliefs, find vaccination useful in combating COVID-19, and can obtain the vaccine easily and free of charge, they can spread positivity, which will spread rapidly. According to our findings, BC has a negative impact, whereas individual awareness has a positive impact on individual attitude toward vaccination; group beliefs, which represent subjective norms; and actual acceptance of vaccines. The PU of the vaccines in combating COVID-19 disease, as well as the ease of the vaccination process, would have a positive impact on attitudes toward vaccination and ultimately vaccination acceptance.

The relevant authorities should focus on campaigns that could reduce misinformation and conspiracy surrounding the COVID-19 vaccine. Awareness programs are more important than ever, and individual-level awareness raising programs are required. Universities are tertiary-level educational institutes where students prepare for their future careers. A greater sense of awareness (free from conspiracy belief), usefulness of the vaccines, and ease of getting the vaccine would definitely help students immunize through the COVID-19 vaccine. If students are encouraged to believe that a vaccination certificate will be required to return to classes, continue their education, apply for full- or part-time jobs, apply for competitive government recruitment examinations, and that it may be necessary to travel abroad for higher education or a better job, they will gladly vaccinate themselves. Furthermore, easy, cost-free access to the vaccine will encourage them to get vaccinated. Because no medicine has yet been invented, vaccination is the only way to reduce infection, spread, serious illness, and deaths. Vaccination is the most effective way to protect individuals, families, and society as a whole. Families and communities will be able to gradually return to a more normal routine as more people are vaccinated.

Supporting information

https://doi.org/10.1371/journal.pone.0261869.s001

Acknowledgments

The authors express their gratitude to the anonymous reviewers for their insightful comments. We appreciate the time and effort of the survey respondents who participated voluntarily and made this research possible in the midst of the pandemic and strict lockdowns.

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• Volume 12, Issue 11
• Perspectives on the COVID-19 vaccine uptake: a qualitative study of community members and health workers in Zambia
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• http://orcid.org/0000-0002-9077-1436 Cephas Sialubanje 1 ,
• http://orcid.org/0000-0003-2360-2752 Nawa Mukumbuta 1 , 2 ,
• Mary Ng'andu 3 ,
• Ernest Malangizo Sumani 2 ,
• Mpala Nkonkomalimba 2 , 4 ,
• Daniel EM Lyatumba 2 ,
• Alick Mwale 2 ,
• Francis Mpiana 2 ,
• Joseph Makadani Zulu 2 ,
• Basil Mweempwa 5 ,
• Denise Endres 5 ,
• Maurice Mbolela 4 ,
• Mpatanji Namumba 4 ,
• Wolff-Christian Peters 5
• 1 School of Public Health , Levy Mwanawasa Medical University , Lusaka , Zambia
• 2 COVID-19 Advisory Centre for Local Authorities , Local Gover Government of Association of Zambia , Lusaka , Zambia
• 3 Health Sciences , Levy Mwanawasa Medical University , Lusaka , Zambia
• 4 Administrative unit , Local Government Association of Zambia , Lusaka , Zambia
• 5 Decentralisation for Development (D4D), Deutsche Gesellschaft für Internationale Zusammenarbeit (GIZ) GmbH /German Cooperation , Lusaka , Zambia
• Correspondence to Dr Cephas Sialubanje; csialubanje{at}yahoo.com

Objective Since introduction of the programme in April 2021, COVID-19 vaccine uptake has been low at less than 20%. This study explored community members’ and health workers’ perspectives on the COVID-19 vaccine uptake and its influencing factors in Zambia.

Study design A qualitative study employing focus group discussions (FGDs) and in-depth interviews (IDIs).

Study setting Sixteen primary healthcare facilities selected from Lusaka, Copperbelt, Central and Southern provinces.

Participants A total of 32 FGDs comprising local community members and 30 IDIs including health workers, traditional, religious and civic leaders (n=272). FGDs were separated based on age (youth and adults), sex (male and female) and place of residence (urban and rural).

Results Both FGD and IDI participants agreed that vaccine uptake was low. Limited knowledge, access to information, myths and misconceptions, negative attitude, low-risk perception and supply in remote areas affected vaccine uptake. Overall, FGD participants expressed limited knowledge about the COVID-19 vaccine compared with health workers. Further, FGD participants from urban sites were more aware about the vaccine than those from rural areas. Health workers perceived the vaccine to be beneficial; the benefits included prevention of infection and limiting the severity of the disease. Moreover, FGD participants from urban sites expressed a negative attitude towards the vaccine. They believed the vaccine conferred no benefits. By contrast, participants from rural communities had mixed views; they needed more information about the vaccine benefits. Participants’ attitude seems to have been influenced by personal or family experience with the COVID-19 disease or vaccination; those who had experienced the disease had a more positive attitude. In contrast, most young people believed they were not at risk of the COVID-19 disease. Misinformation from social media influenced their attitude.

Conclusion These results provide starting points for future policies and interventions for increasing COVID-19 vaccine uptake.

• public health
• primary care
• qualitative research

Data availability statement

Data are available on reasonable request. Data are available on reasonable request from the corresponding author and with permission of the UNZABREC Institutional review board.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjopen-2021-058028

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STRENGTHS AND LIMITATIONS OF THIS STUDY

Purposive sampling of participants comprising health workers and community members with different demographic and socioeconomic characteristics (sex: male and female; age; place and province of residence: urban and rural settings) allows for comparing and contrasting of participant views, which in turn provides an in-depth understanding of the subject under investigation.

Use of different data collection techniques (focus group discussions and in-depth interviews) as well as data sources allow for triangulation of findings and increases internal validity of the study.

Training data collectors and use of an inductive approach to data analysis increase the internal validity of study findings.

Conducting the study at the beginning of the COVID-19 national mass vaccination when the programme was still new in the country may have affected the views of the participants.

Use of the qualitative design affects external validity and limits generalisation of the study findings.

Introduction

SARS-CoV-2 has spread to most parts of the world, including Zambia. 1 2 As at the end of August, 2022, a total of 332, 058 cases and 4016 deaths had been reported in the country. 3 To prevent further spread of the virus and increased mortality in the country, the Zambian government enacted the public health statutory instrument number 22, 4 5 which instituted preventive and control measures—restricting social gatherings (ie, work places, church services, weddings, kitchen parties, casinos, funerals), local and international travel, and closing public institutions such as schools and markets. 6 In addition, the Zambian government implemented a national mass vaccination campaign 7 following approval of the COVID-19 vaccines in developed countries. 8–10 Initially, the COVID-19 national vaccination programme targeted the health workers and persons aged above 65 years. 10 The criteria were later revised to include all persons aged 18 years and above. 10 A second revision was made to include children aged 10 years and above. Three types of COVID-19 vaccines have been administered: Oxford/AstraZeneca, Sinopharm, John and Johnson and Pfizer vaccines. Access to the COVID-19 vaccine is voluntary and free in the country; people do not need to pay anything. 11 To be protected, one needs to receive two doses of the Oxford/AstraZeneca vaccine−8 weeks apart. On the contrary, only one dose of Johnson & Johnson vaccine is needed to be fully immunised. 12 13

Over the centuries, vaccines have been shown to be an effective way to combat outbreaks and the only efficient and reliable method for disease prevention. 14 15 COVID-19 vaccines—with an efficacy ranging from 70% to 95%, have been shown to provide protection against the virus 15 by preventing its spread in the community, mitigating the severity of the disease and reducing mortality among the infected people. 16 17 Studies and ongoing clinical trials 18–22 have shown that COVID-19 vaccines offer the best means to control the ongoing pandemic. They are effective in preventing a wide range of COVID-19-related outcomes, reduce symptomatic cases, hospitalisation, disease severity and death among the infected individuals. Nevertheless, national reports show that the vaccine uptake has been low in the country. At the end of August 2022, a total of 5 576 827 have been fully vaccinated with the AstraZeneca, Sinopharm and Johnson & Johnson vaccine since the commencement of the programme in April 2021. This represents a national vaccine coverage of 52.9% of the eligible population. 23

Limited supply and vaccine hesitance—the delay in acceptance or refusal of vaccination despite availability of vaccination services 24 —have been attributed to the low vaccine coverage in the country. Vaccine hesitance has been reported both in Zambia and other countries, and has been shown to be an important obstacle to the fight against COVID-19. 25–27 For example, in their recently published article, Mutombo et al 28 observed that the gradual effort to distribute COVID-19 vaccines to low-income and middle-income countries (LMICs) is threatened by the ubiquitous vaccine hesitancy, especially in Africa, where it undermines efforts to fight the COVID-19 pandemic. A qualitative study 29 using focus group discussions (FGDs) with mothers who brought their children for measles vaccination in southern Zambia a few months before the COVID-19 national vaccination programme was implemented, reported that, although parents were willing to allow their children to receive the vaccine, majority expressed substantial uncertainty and hesitancy about receiving the vaccine themselves. The study also revealed beliefs around COVID-19 risk and severity, as well as vaccine safety and effectiveness affected the participants’ intention to be vaccinated. However, vaccine hesitance is not peculiar to the COVID-19 vaccine. For example, Garcia and others 30 reported low levels of Cholera vaccine acceptance among community members and health workers in the slums of Lusaka, Zambia. The authors also showed that religious beliefs and distrust towards western medicine, fear of injections and adverse events, low perceived need for immunisation and limited understanding of how vaccines work were important factors affecting acceptance of the cholera vaccine.

Although these studies provided important insights on vaccine hesitance and its contributing factors, most were conducted outside the country. The one conducted in Zambia explored mothers’ intentions to receive the COVID-19 vaccine and not the actual behaviour. Moreover, the study was conducted before the COVID-19 was implemented. The other Zambian study focused on the Cholera vaccine. It thus, not clear how the Zambian population perceive the COVID-19 vaccination programme. Available evidence suggests that vaccine hesitance is complex and context specific, varying across time, place and vaccines. A study is therefore needed to explore people’s perspectives and attitude towards COVID-19 vaccine uptake in the country. The aim of this study, therefore, was to explore community members’ and health workers’ perspectives on the COVID-19 vaccine uptake and the reasons that affect its uptake in Zambia. This information can provide insight to the COVID-19 vaccine hesitancy and the contributing factors, which in turn, can inform design of interventions to increase vaccine intentions and uptake in the general population. To date, no such study has been conducted in Zambia.

Study design

This study employed a qualitative design comprising FGDs and in-depth interviews (IDIs) as the data collection techniques. FGDs have been used in public health research for over three decades now. 31 They aim to explore participants’ experiences, beliefs and attitudes towards a target behaviour, by using group processes to stimulate responses and gain insights through participants’ exchanging views, questioning and challenging one another. 32 IDIs enable the researcher to understand participants' lived experiences through their own words and perspectives. 32 33 Use of both FGDs and IDIs allows for in-depth exploration and understanding of various aspects regarding the subject under investigation. The approach also allows for triangulation and corroboration of the FGD and IDI findings, which, in turn, increases the internal validity of the study. 34 35

Study setting

The study was conducted in 16 primary health facilities and their catchment communities—3 from Lusaka city, 2 each from Chongwe, Ndola, Masaiti, Kabwe, Chibombo and Kafue, 1 one from Mazabuka districts. Selection of health facilities was done in consultation with various stakeholders including health staff working in the COVID-19 vaccination programme and health promotion departments at the provincial and district health offices, Zambia National Public Health Institute and Ministry of Health (MoH) headquarters. To be selected, health facilities needed to have been providing COVID-19 vaccination services as well as other COVID-19 prevention, control and care services including screening, contact tracing, isolation and treatment facilities. In addition, health facilities needed to be accessible by road during the study period. Health facilities from Lusaka and Copperbelt provinces were selected because they were COVID-19 epi-centres due to huge populations and commercial activities; Central province is a transit area for traffic from Tanzania and the Democratic Republic of Congo in the north and north-east, respectively; Southern province is a transit region for travellers from the Southern region (South Africa, Zimbabwe, Namibia and Botswana)—all of which reported high numbers of COVID-19 cases. 36 37

From each health facility one community was selected, in consultation with the health facility managers and local community leaders. Efforts were made to ensure an equable distribution of urban and rural communities in the study. To be included in the study, communities needed to be accessible with passable roads, and within 2 hours drive from the health facility. In addition, the local community leaders needed to authorise the team to conduct the study in the community.

Participants and sampling technique

Fgd participants.

A total of 32 FGD (n=242) were conducted with community members. Each FGD comprised between 6 and 10 participants (n=242). To gain insight into the differences and similarities in the participants’ views, FGDs were separated based on age, sex and place of residence. Half of the FGDs (50%) were held in urban communities and the other half in rural settings. To compare and contrast the views based on sex, separate FGDs were held with male and female participants. In addition, a total of eight FGDs were separately held with the youth to gain insight into their perspectives on the subject. Efforts were made to balance the eight FGDs on sex (four male and four female) and place of residence. Initially, a total of 40 FGDs (10 per province) were planned by the research team. However, after conducting 10 FGDs in Lusaka province (men=4, women=4, youth=2), the point of saturation was achieved (ie, no further substantial information was obtained from the participants). At this point, the research team decided to reduce the number of FGDs and conduct only a few more FGDs in the other districts. At the end, 24 FGDs were conducted with the adults (males=12, females=12) and 8 with the youth (18–24 years) (see table 1 ).

• View inline

Distribution of FGDs

Using a purposive sampling technique, community health workers assisted by local community leaders (traditional and civic) conducted the recruitment of FGD participants from the local communities. Purposive sampling allows for selection of participants with similar experiences regarding the health behaviour under investigation (ie, perspective and attitude towards COVID-19 vaccine), while, at the same time, allowing for recruitment of participants with different demographic and socioeconomic characteristics—such as age, sex and place of residence and occupation. This, in turn, helps provide insight into the similarities and differences in the participants’ experiences with regard to the health problem under investigation.

Recruitment of the participants was done in multiple steps. First, the research field supervisor together with the district health promotion officer held meetings with the local health facility staff, community health workers and community leaders to inform them about the study and its objectives, and to identify the communities where the FGD participants would be recruited from. Following this meeting, community health workers and local leaders called for a meeting to inform the community members about the study. Community members willing to participate in the study were asked to register with the community health workers and leave their details (place of residence and phone number). A few days after the meeting, the community health workers contacted the potential participants to provide more details about the study and assess their suitability to participate in the study. The assessment was based on the participant eligibility criteria described below. Next, the community health workers compiled a comprehensive list of community members who were eligible to participate in the FGDs and made arrangements for the selected participants to come for the actual discussion to an agreed on place (usually the headman’s place, school or church) on the set time.

In-depth Interviews

To gain insight into the views of the local health staff and community leaders, a total of 30 IDIs (n=30) were conducted. IDI participants were recruited from their places of work and homes. Health promotion officers helped recruit the health staff; community health workers recruited the community leaders. Following identification of the potential participants, the recruiting staff compiled a comprehensive list of IDI participants and contacted them before the day of the interview. Health staff were selected from the district health offices and local health facilities and comprised public health officers, clinicians, nurses and community health workers (n=16). Community leaders were selected from the local communities and included traditional, religious and civic leaders (n=10). In addition, staff (n=4) from non-governmental organisations (NGOs) working with the MoH in the provision of COVID-19 services at the local district level were included in the study.

Eligibility criteria

To participate in both the FGDs and IDIs, participants needed to be:

Aged 18 years and above.

Residing or working in the study area for not less than 3 months.

Health workers involved in the COVID-19 vaccination programme from the selected primary health facilities.

Prisoners and mentally ill people were not included in the study.

Before each FGD/ IDI, written informed consent was obtained from each participant; those who could not read or write were asked to mark with an ‘X’. To make it easy for the study participants to understand, the consent form ( online supplemental material 1 ) was translated into the local language (Bemba, Nyanja and Tonga). After signing the consent form ( online supplemental material 2 ), each FGD/IDI participant was asked to complete a short demographic questionnaire ( online supplemental material 3 ). To make it easy for those who could not read or write, research assistants read the consent form and the short questionnaire and filled it in for them.

Supplemental material

Training of data collectors.

Research assistants were a group of six (three male and three female) final year Master of Public Health (MPH) students recruited from the Schools of Public Health at the University of Zambia (n=3) and Levy Mwanawasa Medical University (n=3) in Lusaka. MPH students were selected because they were skilled and experienced in qualitative research methods: facilitating FGDs and conducting IDIs. To avoid information concealment during FGDs and IDIs, efforts were made to select students who spoke both English and one or two of the local languages, Nyanja, Bemba or Tonga. Before commencement of the data collection process, research assistants underwent a 5-day training in FDG facilitation and interviewing techniques: 3 days of theory and 2 days of practical fieldwork. Topics covered during the 3 days theoretical training included: (1) basic principles of qualitative research, (2) objectives of the study, (3) FGD facilitation techniques, (4) interviewing techniques, (5) research ethics and informed consent in human subjects’ research and (6) FGD and IDI interview guide. Phase 2 of the study was a practical exercise in FGD facilitation techniques, conducting interviews and obtaining informed consent. On the first day of the pactical phase, the research assistants worked in pairs and took turns to facilitate an FGD with their fellow trainees. They also took turns interviewing each other. At the end of eachFGD/IDI, research assistants were asked to provide feedback on each other’s performance. At the end, the trainer also provided feedback and guidance on group dynamics, participant interaction, body language, avoiding conflict and managing it when it arises. On the second day, the team was taken into the nearby neighbourhood to facilitate FGDs with community members and conduct IDIs with health staff and community leaders. The FGDs and IDIs were transcribed and analysed, after which the FGD and interview guides were revised based on the analysed data and feedback from the data collectors.

Data collection

Each FGD was facilitated by a pair of research assistants: one facilitated the discussion and took notes, the other one was in charge of the digital voice recorder. As they facilitated the FDGs, research assistants ensured that each participant was given an opportunity to speak; they also tactfully controlled the dominant individuals and prompted the passive ones to speak. They also ensured that the discussion flowed smoothly among the participants without turning it into an interview, personal attack or conflict. Where necessary, the facilitator asked for elaboration, clarification or probed for detail. Interviews were also conducted by a pair of research assistants: one conducted the interview and took notes; the other recorded the interview with a digital audio recorder. IDIs were conducted at the participant’s preferred place including the office or home. On average, each FGD lasted between 1 hour and 1.5hrours. IDIs lasted between 30 and 45 min. To ensure quality in data collection, a digital voice recorder was used for both IDIs and FDGs.

Data collection tools

FGDs/IDIs were conducted using a paper-based, FGD/interview guide ( online supplemental material 2 ). The FGD/interview guide had predetermined themes, including: (1) perspectives on acceptance of the COVID-19 vaccine and (2) factors affecting vaccine uptake. The second theme had several probes including knowledge and information sources, and attitude towards COVID-19 vaccine. The same interview guide was used for both the FGDs and IDIs, with minor elaboration for the IDIs to elicit some detail. During the FGDs, the focus was on the community perspectives; for IDIs the focus was more on the participant’s perspectives regarding the issues under investigation. In addition, a short questionnaire ( online supplemental material 3 ) was prepared to collect FGD and KII participants’ demographic, socioeconomic and vaccination data. To ensure internal validity, the FGD/interview guide went through a rigorous development process. First, the principal investigator with vast experience in qualitative research and familiar with the subject, drafted the initial version. The themes in the FGD/interview guide were adapted from various sources, including review of the available literature on COVID-19 vaccine and the researchers’ experience in qualitative research methods. Next, the document was shared with the research team members for their comments and feedback. The document was revised based on the research team’s comments. Two independent bilingual experts translated the document into the local languages, Bemba, Tonga and Nyanga. The translated document was pretested in an urban slum of Lusaka during the research assistant training, after which both the KII and FGD recordings were transcribed and analysed. The tool was then revised based on the pre-test findings and feedback from the data collectors.

The data management and analysis

Audiorecordings from the FGDs and IDIs were transcribed and translated into English by four independent people who never participated in the data collection, and were proficient in English and the local language. To check for accuracy, 10% of the transcripts were back-translated into the local language. NVivo V.11 MAC was used for coding and analysis. To make it easy to compare differences and similarities in the participants’ perspectives by different attributes, a separate codebook was created for FGD and IDI data using a framework based on the FGD/interview guide. An inductive approach to data analysis was used, ensuring that subthemes were derived from the predetermined themes and grouping all similar statements concerning particular themes. In order to determine similarities and differences in the responses, findings for the FGDs and IDIs were analysed separately, according to the FGD participants: age (adults vs youth), sex (male vs female) and place of residence (urban vs rural). Summary and descriptive statistics were computed for FGD and IDI participants' demographic characteristics using SPSS V.25 (IBM SPSS Statistics 25)

Quality assurance and control

The team ensured the quality of data collection by: (A) recruiting skilled and experienced data collectors who were trained for 5 days on the theoretical and practical aspects of the study, (B) ensuring that data collectors worked in pairs, (C) using an interview guide (translated into the local language), (D) using a digital voice recorder and taking extensive notes during the FGDs and interviews, (E) by comparing notes and voice recordings each day after the interviews, (F) using experienced and independent staff to transcribe the recordings from the FGDs and KIIs.

Patient and public involvement

Study participants and the public were not directly involved in the design of the study. Rather, the study was designed in response to the call for consultancy for a research proposal on COVID-19 vaccine issued by the COVID-19 Centre, funded by GIZ in Lusaka. However, selection of the primary health facilities, communities and study participants was done in collaboration with stakeholders from the provincial, district and primary health facility and community levels. First, prefield meetings were held with the provincial and district managers to select primary healthcare facilities and local communities to be included in the study. Next, local district managers selected the primary health facilities to be included in the study. In turn, primary healthcare facilities together with the local community leaders recruited the FGD participants and made arrangements for them to come for the actual discussion; they also contacted and prepared a comprehensive list of IDI participants. Finally, a report was written and shared with the funding organisation, GIZ and the COVID-19 centre for dissemination of study findings.

Demographics

Our sample comprised a total of 272 respondents (FGD=242 and IDIs=30). The majority (51.5%) of the participants were female, with a mean age just above 34.04 years and between 2 and 3 children. Almost half (47.1%) of the participants were married. Most participants (55.2%) had secondary school education, 18% had tertiary level education and 1.5% had never attended school. Majority (62.1%) of the participants had an average income of less than K500 per month. Most of the participants (69.5%) mentioned that they were aware about COVID-19, and 52.9% reported that the COVID-19 vaccine was beneficial. Less than 1/10th (9.9%) of the respondents were vaccinated (see table 2 ).

Demographic characteristics of the respondents (n=272)

Theme 1: perspectives on acceptance of the COVID-19 vaccine

Analysis of the findings from the short demographic questionnaire administered to the respondents before each FGD and IDI showed that less than 1/10th (9.9%) of the total sample (FGD and IDI participants) had received the vaccine ( table 2 ). Out of the 27 (9.9%) that reported being vaccinated, 18 (66.7%) were health workers. Our analysis of IDIs also confirmed that most health workers and participants from the NGOs had a positive attitude towards the COVID-19 vaccine and were willing to be vaccinated. Both the community leaders and participants from the NGOs confirmed that they had accepted the vaccine and that many people were willing to be vaccinated. They clarified that the low vaccine coverage reported, especially in rural areas, was a result of the limited access, low supply and stock-out of the vaccine. They mentioned that the vaccine was mainly available and administered in the urban health facilities. Those that lived in remote areas, far from the health facilities, had difficulties accessing the vaccine.

The vaccine has been accepted…. because people have been vaccinated; if they had not accepted the vaccine, they wouldn't have been vaccinated ( IDI informant, health worker, Ndola district ). They aren’t so many people that have been vaccinated. It is because the people vaccinating are rarely seen here ( Community leader, IDI participant, Pemba district ). For those who live in far-flung places, we don’t know if they get vaccinated. I think it would be best to ask them ( Community leader, IDI participant, Mazabuka district )

Most adult participants (both male and female) confirmed that they had not been vaccinated. However, most expressed willingness to be vaccinated. Especially, participants from the rural sites mentioned that many people would accept the vaccine if they had adequate information about its benefits and if it were made available in the health facilities. Our analysis showed no much difference between male and female FGD participants with regard to their attitude towards the COVID-19 vaccine and their intention to be vaccinated.

We can accept the vaccine, but we need sensitisation because even when we were going to school, our parents would tell us whether to accept the vaccine or not ( FGD participant, Lusaka ).

In contrast, analysis of FGD findings showed a striking difference in perspectives between the youth and adult participants. Most youth participants (from both the urban and rural areas) believed that the vaccine was not beneficial and confirmed that most young people had not accepted it.

We have not accepted the vaccine because we don’t know how it’s going to affect the life of someone in future. In short, we don’t know what the life span of people will be. This is the reason why we have not accepted it in our communities ( Youth FGD participant, Kabwe district ).

Theme 2: factors affecting acceptance of the COVID-19 vaccine

Our analysis of both FGD and IDI data showed various factors contributing to the low acceptance of the vaccine among study participant including lack of knowledge and information, myths and misconceptions, and negative attitude towards the vaccine. These factors are presented below.

Knowledge about COVID-19 vaccines

Overall, IDI participants (ie, health workers and participants from the NGOs) expressed better knowledge about COVID-19 vaccine than the FGD participants. Health workers and participants from NGOs knew the types of the COVID-19 vaccines, their mode of administration, benefits and side effects. They also knew about the COVID-19 national vaccination programme. Although most community members (both IDI and FGD participants) perceived the vaccines to be beneficial, majority lacked information about the vaccine-–the various types, mode and frequency of administration. They explained that many would accept the vaccine if they had adequate information. Limited access to information, especially in rural areas, was cited as the main reason for the low acceptance of the vaccine. Community leaders and health workers were unanimous on the information gaps in their communities.

People don't have the truth about the vaccine. The health team should come to educate us on how the vaccine works. They should come to communities, gather people and teach them about the COVID-19 vaccine ( Female FGD participant, Masaiti district )

A contrast was noted among the FGD participants with regard to their knowledge about the vaccine. In general, participants from urban areas expressed better knowledge than those from rural communities. Differences were also noted between the adults and youth FGD participants. Although most youth confessed that they did not know much about the vaccines, they explained that young people had heard about the vaccine, especially those from urban areas.

We know about the COVID-vaccine…most of us youth have heard about COVID-19 and know about the new vaccine ( Youth FGD Participant, Chainda, Lusaka city )

Limited access to information about the COVID-19 vaccine

Overall, our findings show that there was limited access to correct and quality information about the COVID-19 vaccine among most community members who participated in both the FGDs and IDIs. Limited access to information was mentioned as a major reason for the low vaccine acceptance among the participants. Participants from urban settings had better access to information than those from rural areas. Both the IDI and FGD participants confirmed that mass media (radio, televion (TV)), internet and social media were the main sources of information on the COVID-19 vaccine.

A contrast was observed in perspectives on the access to information between the FGD participants from urban and rural settings. Most adult FGD participants from urban sites confirmed that they had access to the major sources of information—media (radio and TV). However, they complained that they could not understand most messages on TV and radio because they were in English. They observed that broadcasting the same messages in local languages would greatly help increase community awareness about the vaccine.

Many people get the information from the radio and TV. They listen to the radio and TV to hear what the Minister is saying. ( Community leader, IDI participant, Chongwe district )

Participants from rural sites did not perceive the media (TV and radio) and internet to be the main sources of COVID-19 information. Poor TV and radio signal reception limited their access to information. Rather, they received information from the health staff, schools, churches, community health workers and community leaders (during community meetings). Health staff disseminated the information about the COVID-19 vaccine when people visited health facilities for various health needs. Community health workers shared the information during community meetings; community members, in turn, would share the information with their families and social networks.

Many people don’t watch TV here….they try to listen to the radio… They have TVs but they can’t see anything….the signal is poor. Government needs to improve TV and radio signal here ( Health worke, IDI participant, Pemba district )

Although community health workers played an important role in disseminating information about the COVID-19 vaccine in the community, most IDI and FGD participants (mainly community leaders and health staff) expressed concerns about the accuracy of the information. They complained that most community health workers did not have adequate knowledge about the vaccine and that, in some instances, the information was incorrect and distorted. As a result, most people did not trust the information they received from the community health workers. They suggested that people in their communities needed more sensitisation and education about the COVID-19 vaccine. They bemoaned that the local health facility staff did not do much to disseminate the information about the COVID-19 vaccine in their communities. Asked on the kind of information their communities needed, most community health workers and leaders mentioned information on the vaccine benefits, safety and the associated risks or side effects. They believed that accurate and adequate information would help the community members make an informed decision about taking the vaccine.

People in this area know nothing about the vaccine because they have never been sensitised. We need to be told what we can do so that we have an idea, but the way it is at the moment, we don't have any idea ( Community leaders, IDI participant, Pemba district ) We just hear from others in the community, because here most of the things we just hear them from these health workers when they pass and tell us, so we also believe what they tell us ( Female FGD participant, Masaiti district ).

In contrast, most young people, especially from urban sites, cited the internet and social media accessed through their phones as their main sources of information for COVID-19-related matters including the vaccine. However, poor internet and mobile phone signals in rural and remote areas made it difficult for most young people to access information.

Most of us use our phones to get information….we get everything from social media on our phones ( Youth FGD participant, Ndola city )

Myths and misconceptions about the COVID-19 vaccine

Our findings elicited many myths and misconceptions about the COVID-19 vaccine among both the IDI and FGD participants. Especially FGD participants were unanimous on the existence of various myths and misconceptions concerning the vaccine. These myths and misconceptions had a negative influence on people’s attitude towards the COVID-19 vaccine and seem to be some of the most important reasons for the high vaccine hesitance.

One of the myths held among most FGD participants (especially in urban settings) was that western countries brought the vaccine in order to eliminate the African population. According to them, westerners brought the vaccine because they wanted to collect people’s blood and kill them. They were concerned why certain vaccines given to the Africans had been rejected in Western countries.

There is a rumour that people in our community are spreading that the medicine [vaccine] was made to kill us Africans because we are too many. So even as we accept that this must be true ( Community leader, IDI participant, Ndola ).

The other strongly held belief by both male and female FGD participants from urban and rural sites (but not the youth) was that the vaccine was brought into the country for political reasons. They explained that politicians had gone into some contractual agreement with western countries to administer vaccines to their people in exchange for money. The money would then be used for political campaigns since it was a presidential and parliamentary election year (2021) in the country.

Some people are saying that they have brought the vaccine in an election period because they want them [community members] to die after giving them the injection so that they are sacrificed ( Female FGD participant, Lusaka )

The other firmly held belief (especially among rural participants) seemed to be influenced by participants’ religious background or inclination. They explained that people believed that the COVID-19 vaccine was part of the mark of the beast (666) mentioned in the Bible (see Revelation 13) and that those who receive the vaccine are initiated into the ritual.

Some people say this is 666, that’s what I heard others say. So that’s why we are scared, because we think that they will initiate us into the 666 rituals ( Female FGD participant, Kabwe ).

Other beliefs seem to be influenced by health reasons. For example, both the FGD and IDI participants from rural and urban settings explained that people in their communities believed that the vaccine is a slow poison which health staff introduced into the body.They believed that the vaccine dries up and makes the blood clot and that one will die after several months or years. Some participants also believed that after receiving the vaccine, one would start fitting and die immediately after being vaccinated; those who survived would only live for a few years afterwards.

Some say when you get vaccinated, you will just live for a few years, and then you get sick and die; that is why we are scared of getting vaccinated ( Traditional leader, IDI participant, Mazabuka district ).

Attitude towards the COVID-19 vaccine

Overall, our analysis of the data from the short demographic questionnaire showed that half (52.9%) of participants (both the FGD and IDI participants) perceived the vaccine to be beneficial ( table 2 ). However, analysis of FGD and IDI data shows that participants expressed different types of attitude towards the COVID-19 vaccine: positive, negative and ambivalent. The detailed findings on these attitudes are presented below.

Most health workers and some FGD participants from both urban and rural settings expressed a positive attitude towards the COVID-19 vaccine and perceived it to be beneficial. Perceived benefits were that the vaccine confers protection against the coronavirus infection among the vaccinated individuals. They also believed that the vaccine reduces the chances of a vaccinated individual to transmit the virus to other people. The other cited benefit was that the vaccine reduces the risk of developing severe disease. If one got infected, the disease would not be as severe as it is among those who are not vaccinated.

Most FGD participants expressed a negative attitude towards the COVID-19 vaccine. Interestingly, our findings did not show differences in attitude between male and female participants. Rather, rampant myths and misconceptions about the COVID-19 vaccine and personal or family’s previous experience with the COVID-19 disease or vaccination seemed to have influenced the participants’ attitude. In general, individuals or families who had not experienced the disease or seen someone suffer or die from COVID-19 disease expressed a negative attitude. They believed that the vaccine was not beneficial. Further, lack of information (especially in rural areas) and wide spread misinformation about the COVID-19 vaccine—such as exaggeration of the vaccine side effects—seemed to influence participants’ attitude towards the COVID-19 vaccine.

I know the benefits are building our immunity and we don’t get a chance to catch COVID-19, though people are saying even those that got the jab have tested positive, they don't have severe disease (IDI participant, Health worker, Ndola district).

Moreover, cultural beliefs and stigma about COVID-19 seem to have affected many people’s attitude and prevented them from accepting the vaccine. Especially health staff explained that some people did not believe in the existence of COVID-19. They cited examples of communities where a family member would suffer and die from COVID-19, but relatives would hide the information and mention another disease, such as asthma, as the cause of death. Because of denial and low-risk perception, such people refused to take the vaccine.

Lack of confidence in the health workers (who came from outside their communities) was perceived as an important factor influencing participants’ attitude towards the vaccine, especially among the community leaders and FGD participants from rural communities. They argued that people in their communities would only be convinced to take the vaccine if the health workers from their local communities administered the vaccine.

The people to vaccinate us must be from our community; otherwise, when an outsider comes to vaccinate us, we will be sceptical because we don't know them ( Village headman/IDI participant, Chongwe district )

In addition, most participants from rural towns and communities expressed an ambivalent attitude towards the vaccine; they were not sure about the benefits of receiving the vaccine. They argued that they did not know the vaccine benefits because they had not seen anyone take it. They explained that they would only believe in the vaccine benefits if someone or a group of people who had taken the vaccine went to explain how they felt after receiving it.

We do not know the truth, and we are scared, that is why we don't go for the vaccine injection. We have been told that the vaccine injection is harmful to consumers ( Male FGD participant, Masait district ). What we are saying is that they should bring us someone who has been vaccinated so that they tell us about the goodness of being vaccinated ( Male FGD participant, Chongwe district) We don't know how these things came, we are scared that we may die, and we can also be infected with other diseases. We don't see people who have been vaccinated, to tell us how they feel ( Civic leader, IDI participant, Masaiti district).

In general, young FGD participants from both urban and rural communities had a negative attitude towards the COVID-19 vaccine. Low-risk perception seemed to influence their attitude towards the vaccine. They believed that they were not at risk of getting the infection and that those who got infected would have mild or no symptoms at all. They also believed that the vaccine was not beneficial. Access to the internet and use of social media among the young people (especially from the urban communities with good internet connectivity) seems to have exposed them to incorrect information regarding the benefits and side effects of the vaccine. This, in turn, influenced their attitude. In addition, poor mobile phone signals, TV and radio reception in rural areas made it difficult for most young people to access information about the COVID-19 vaccine.

The aim of this study was to explore community members’ and health workers’ perspectives on the COVID-19 vaccine and the reasons that affect its uptake in Zambia. Overall, our findings showed low vaccine uptake among the participants. Several factors including limited knowledge, access to information, myths and misconceptions, negative attitude towards the vaccine and low-risk perception about the COVID-19 disease contributed to vaccine hesitance among the participants.

Our finding corroborates previous studies from LMICs and elsewhere which reported vaccine hesitance among health staff and community members. For example, a study conducted in Zambia 29 reported substantial uncertainty and hesitancy about receiving the vaccine among parents, despite expressing high intentions to have their children receive the COVID-19 vaccine. Similar findings were reported by Botwe et al 38 in Ghana who reported a vaccine hesitance of 44% among the health staff. These findings are also consistent with those by Baniak et al 39 who reported vaccine hesitance among nursing staff in the USA. The authors concluded that, despite the increase in vaccine uptake during the active vaccine rollout, there was still widespread and sustained hesitancy and unwillingness to take the vaccine. Other authors, Wong et al 40 and Luk et al 41 in Hong Kong also reported a low intention to vaccinate. They concluded that vaccine hesitance was a major challenge to effective programming and implementation. Thus, formulation and implementation of evidence-based vaccination strategies focusing on increasing the intention to take the vaccine has a potential to mitigate vaccine hesitance

Limited knowledge about the COVID-19 vaccine, its benefits and potential harms, was found to be one of the important barriers to effective vaccine uptake. The media (TV, radio and internet) play an important role in informing people about the vaccine. However, poor TV and radio signal reception in rural and remote areas limit access people’s access to these important sources of information. This explains the stark contrast in the levels of knowledge about the COVID-19 vaccine between participants from rural and urban communities. Moreover, our findings suggest that social media accessed through the internet on mobile phones is a major source of information among young people. However, poor internet and mobile phone signals in rural areas make it difficult for young people to access information. This finding is consistent with previous studies 42–46 which reported low knowledge levels concerning the COVID-19 vaccine. Interestingly, these studies showed that knowledge about the vaccine was positively correlated with one’s vaccine uptake. This finding suggests that information is an important factor influencing vaccine acceptance, and that lack of information affects peoples' willingness to take the vaccine. This result is consistent with the theory of reasoned action which highlights the importance of background factors such as knowledge and access to information in influencing people’s intention to adopt a health behaviour such as COVID-19 vaccination. 47–49 Public health interventions aiming at mitigating vaccine hesitancy and increasing vaccine uptake could benefit from focusing on knowledge and access to information about the COVID-19 vaccine, its benefits and safety.

Widespread myths and misconceptions about the reality of the COVID-19 disease and the benefits of the vaccine appear to be an important factor contributing to vaccine hesitance among our sample. These myths and misconceptions seem to be more rampant in rural communities where there is limited or no access to accurate information about the benefits and safety of the vaccine. For example, due to limited access to accurate information, many people in rural communities depend on the information from health workers and traditional leaders. Our findings suggest that such information, though important, is either inadequate or inaccurate with a potential to be misinterpreted. When people discover that such information is inaccurate untrustworthy, they seek alternative sources such as social media−which may also be misleading, resulting in the emergency of conspiracy and rampant myths and misconceptions. 49 However, especially in urban areas the situation is different; most myths and misconceptions seem to be influenced by the incorrect information spread by social media users, especially young people, with ready access to the phone and internet. For example, many participants (both FGDs and IDIs) believed that the vaccine is a poison: it dries up one’s blood, causes it to clot and eventually kills the victim. Our findings suggest that these strongly held beliefs have a negative influence on people’s intention to take the vaccine. These findings corroborate those reported elsewhere 50–53 regarding the importance of social media in propagating myths and misconceptions about the vaccine. These findings are also consistent with previous studies, for example, Bertin et al , 54 which reported that myths and misconceptions do not only instil fear among the people, but also influence them not to take the vaccine. Public health interventions can benefit from provision of correct and accessible information to prevent and address myths and misconceptions which negatively influence people’s perspectives and adoption of health behaviour, such as vaccine uptake. Thus, increasing access to correct information in the community has the potential to prevent and address the widespread myths and misconceptions about the vaccine and help mitigate vaccine hesitance. 55

Our findings suggest that attitude towards the COVID-19 vaccine has an important influence on the intention to take the vaccine. Although half of the participants perceived the COVID-19 vaccine to be beneficial, most had mixed attitudes towards the vaccine: positive, negative and ambivalent. Participants’ attitude seems to have been influenced by various factors including place of residence, age, access to information, myths and misconceptions about the vaccine, and one’s experience with the COVID-19 disease and the vaccine. Participants who had either experienced the disease, seen a friend or family member suffer from the disease expressed a positive attitude towards the vaccine compared with those who had not. Similarly, those who had either been vaccinated, seen or heard about someone who had been vaccinated appreciated the benefits of the vaccine and expressed a more positive attitude than those who had no such experience. Protection against COVID-19 and reduction in the severity of the disease if one got infected were the main perceived benefits. Perceived benefits appear to play an important role in influencing people’s attitude towards the vaccine. Participants who perceived no benefits from the vaccine expressed a negative attitude. This finding is in keeping with the reasoned action approach which postulates that, before engaging in a healthy behaviour, people evaluate the benefits against the risks. 56 An individual’s attitude, therefore, will depend on their evaluation of the perceived benefits compared with the risks. Those who perceive more benefits are likely to have a positive attitude towards the target behaviour, and possibly adopt it. This finding is also consistent with those reported by Elhadi et al in Libya. 57 These authors found that people who had a family member or friend infected with COVID-19 were more likely to accept the vaccine. Strategies that use a collaborative approach with community role models who have either experienced the disease or received the vaccine have the potential to change community attitudes towards the vaccine and possibly increase vaccine uptake.

Finally, our findings on low-risk perception and personal susceptibility to the COVID-19 disease, especially among young people, are worthy noting. It appears that young people’s ‘false sense of safety’—that they are not susceptible to the COVID-19 disease and that, if they get infected, the disease would not be severe—seem to influence their attitude towards the vaccine. Access to social media and incorrect information from the internet, especially among the young participants from urban communities, appears to contribute to the low-risk perception and vaccine hesitance. Interestingly, we did not find a striking difference in risk perception between the male and female participants or according to place of residence (urban or rural). This finding contradicts Elhadi et al 57 who reported low vaccine hesitance among young people—that, compared with older people, young people were more likely to accept the vaccine. However, this finding is in line with Lazarus et al 58 who (in their survey of over 13 420 people from 19 countries) reported that young people were less likely to accept the vaccine than older people. The finding is consistent with previous studies that reported that age, and not sex, had a significant association with one’s attitude towards acceptance of the vaccine. These studies also reported a positive correlation between age and vaccine acceptance. They also showed that high risk perception about the severity and one’s personal susceptibility to the disease, benefits from the vaccine, cues to action and trust in the healthcare system or vaccine manufacturers were positive correlates of vaccine acceptance. Interventions that use social media to provide correct information to young people—about their personal risk and susceptibility to the disease—has a potential to mitigate vaccine hesitance among this age group. To be successful, such interventions should focus on addressing behavioural beliefs, risk perception and outcome expectancy. 59

Study limitations

Potential limitations of our study should be noted. First, this study was conducted at the beginning of the COVID-19 national mass vaccination programme in the country when people’s knowledge about the vaccine was still limited; it is not clear how knowledge in the community has evolved over time. Second, like other qualitative study designs, this study could not establish a causal link between knowledge and attitude, and vaccine uptake. Further research with a longitudinal quantitative design is required to measure knowledge and attitude, and test their relationship with vaccine uptake in order to establish the causal pathway.

Nevertheless, we believe that use of FGDs and IDIs comprising adult male and female as well as young participants from both urban and rural settings provided in-depth information on vaccine uptake and the influencing factors, based on the views of the health workers and community members. We believe this study design increased the validity of our findings. Furthermore, selecting participants (both community members and health staff) from both urban and rural settings, increased the internal validity of the study. It also provides a balanced view of the Zambian people’s perspectives on the subject under investigation. Our study also highlights the importance of using an integrated community-based approach to maximise vaccine uptake. This approach is in accordance with the WHO guidelines, 60 which suggest that a comprehensive approach, targeting multiple facets of social interaction, is more likely to dispel COVID-19 myths and misconceptions, and address vaccine hesitancy. Thus, our findings can save as basis for policy and intervention design to mitigate vaccine hesitance and increase vaccine uptake. To our knowledge, no such study has been conducted in Zambia; this is the first one.

Our findings demonstrate low vaccine uptake among our participants; it also highlights several factors—including limited knowledge and access to information, myths and misconceptions, negative attitude towards the vaccine and low-risk perception about COVID-19 disease–which affect vaccine uptake. These results can provide starting points for future Public health policies and interventions which, in our opinion, should focus on: (A) increasing access to information and knowledge about the benefits and safety of the vaccine; (B) addressing myths and misconceptions about the vaccine; (C) increasing risk perception and perceived personal susceptibility to the COVID-19 and its severity, especially among young people; (D) making the vaccine accessible, especially in the rural and remote areas; (E) identifying role models in the community who have either experienced the disease or received the vaccine; (F) establishing linkages and collaboration between health workers and role models; (G) establishing a community operational and vaccine delivery mechanism through strengthened linkages with key community leaders such as local traditional, civic and religious leaders, and (H) addressing systemic barriers such as human resource shortage and stock-outs of the vaccine to increase access to the vaccine in the rural and remote communities.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

This study involves human participants and was approved by University of Zambia Biomedical Research Ethics Committee (ref: 1774-2021). Participants gave informed consent to participate in the study before taking part.

Acknowledgments

We thank Levy Mwanawasa medical University, Mary Ng’andu for supervising the data collection and the research assistants who helped with the data collection. Our gratitude also goes to the study participants for their valuable time and input into the study.

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1
• Data supplement 2
• Data supplement 3

Contributors All authors contributed substantially to the development of the manuscript. CS designed the study. Under the oversight of CS, MN supervised the data collection process. CS and NM conducted data analysis. CS wrote the first draft of the manuscript. NM, EMS, W-CP, JMZ, DEML, AM, BM, DE and MM read and provided feedback on the draft manuscript. CS, NM and EMS revised the manuscript. All other coauthors advised on the final draft of the manuscript. All authors read, commented on and approved the final manuscript. CS had access to the data, controlled the decision to publish and is the study guarantor.

Funding The study was made possible by grant number 20.2095.6-001.00 from Deutsche Gesellschaft für Internationale Zusammenarbeit (GIZ)/German Cooperation through the Decentralisation for Development (Zambia).

Competing interests None declared.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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A National Strategy for COVID-19 Medical Countermeasures : Vaccines and Therapeutics

• 1 Council on Foreign Relations, New York, New York
• 2 The Rockefeller Foundation, New York, New York
• 3 Perelman School of Medicine and The Wharton School, University of Pennsylvania, Philadelphia
• Viewpoint The First 2 Years of COVID-19—Lessons to Improve Preparedness for the Next Pandemic Jennifer B. Nuzzo, DrPH, SM; Lawrence O. Gostin, JD JAMA
• Viewpoint A National Strategy for the “New Normal” of Life With COVID Ezekiel J. Emanuel, MD, PhD; Michael Osterholm, PhD, MPH; Celine R. Gounder, MD, ScM JAMA
• Viewpoint A National Strategy for COVID-19—Testing, Surveillance, and Mitigation Strategies David Michaels, PhD, MPH; Ezekiel J. Emanuel, MD, PhD; Rick A. Bright, PhD JAMA
• Viewpoint The Pandemic Preparedness Program Eli Y. Adashi, MD, MS; I. Glenn Cohen, JD JAMA
• Medical News & Perspectives Former Biden-Harris Transition Advisors Propose a New National Strategy for COVID-19 Jennifer Abbasi JAMA

The US needs a strategy for a “new normal” of living that includes COVID-19. This “new normal” will occur when total respiratory viral infections, hospitalizations, and deaths inclusive of those from COVID-19 are no higher than what typically occurred in the most severe influenza years before the current pandemic. Integral to achieving and sustaining this “new normal” are both faster development and more efficient deployment of vaccines and therapeutics. While COVID-19 has ushered in new vaccine platforms, repurposed existing therapies, and stimulated rapid development of monoclonal antibody and oral antiviral treatments in record time, much remains to be done to ensure these life-saving medicines are accessible to all.

Even without population-wide coverage, COVID-19 vaccines have significantly reduced the number of disease-related hospitalizations and deaths from SARS-CoV-2 in the US. For instance, states with higher vaccination rates have lower hospitalizations and deaths. 1 But given the continuing rates of hospitalization and mortality from COVID-19, more needs to be done.

To minimize the effects of COVID-19 on daily life and return to normalcy, some estimates suggest that 90% or more of individuals in the US are likely to need some immunity to SARS-CoV-2, whether from vaccination or prior infection. 2 Nine of 10 Organisation for Economic Co-operation and Development countries with full vaccination rates greater than 75% have neared or exceeded the target of less than 1 COVID-19 death per 100 000. 3 In January 2022, approximately 60% of the US population has been vaccinated.

COVID-19 vaccines authorized or licensed by the Food and Drug Administration (FDA) include 2-dose mRNA vaccines and a single-dose adenovirus-vectored vaccine, with additional doses recommended for older adults and immunocompromised persons. In November 2021, the Centers for Disease Control and Prevention recommended people 18 years and older receive an additional vaccine dose 6 months after the last vaccination with a goal of reducing overall infections and, perhaps, transmission rates. Preliminary findings show boosters are more effective in neutralizing the Omicron variant compared with a 2-dose mRNA regimen, although early indications suggest this effect may not be sustained. Early data suggest immunity from prior infection is insufficient to neutralize the Omicron variant, but is likely to protect against severe disease and death. Immunological responses vary among individuals. Unless SARS-CoV-2 evolves to become more attenuated than its current form, the nation should anticipate needing regular, possibly annual, COVID-19 vaccines. It is still unclear at what point protection against severe disease will wane. As with yearly influenza vaccines, an updated formulation targeted to the circulating variants will likely be needed to maximize protection from infections and severe disease.

Achieving 90% population vaccination coverage will require mandates. Few countries have ever achieved such levels of coverage of any vaccine without vaccination requirements. Mandates have been shown to be effective, especially among individuals who are not fundamentally opposed to vaccination, but are procrastinating, confused, or have barriers to access. Thus, proposed vaccine requirements for government employees and contractors, health care and long-term care workers, and employees of businesses with 100 or more employees will be necessary to achieve levels of coverage to return to pre–COVID-19 life expectancy and social and economic vitality. For example, as New York City has done, such a requirement may need to be expanded to include all workplaces. Additional requirements for consideration may include vaccination for public transportation and indoor events, with proof of a recent negative SARS-CoV-2 test for those who are not vaccinated.

Once analysis of a large pool of vaccinated children determines that the risk-benefit profile of COVID-19 vaccines is completed and vaccines are licensed, vaccination should be required for school attendance. Vaccination requirements must be paired with appropriate paid sick and family leave for parents and adult workers to accommodate recovery from reactions to the vaccine.

To reduce virus transmission and infections, next-generation COVID-19 vaccines that match circulating SARS-CoV-2 variants need to be deployed. Genomic surveillance coupled with nimble vaccine technology allow for rapidly adapting vaccines to emerging variants. The FDA has indicated a pathway to implement a rapid, strain-change regulatory process with a minimal amount of clinical data, a review process similar to that applied to seasonal influenza vaccines. Over the next few months, vaccines specific to circulating variants should be phased-in. The vaccine manufacturers and FDA should work expeditiously to ensure the prompt submission of data and their review.

In addition, the government needs to facilitate further development of vaccines, including alternate dosing and administration approaches. Despite COVID-19 vaccines being authorized for more than 12 months, there is insufficient data on what constitutes an optimal vaccine combination and schedule. Is there a more effective prime/boost regimen when combining mRNA, viral-vectored, or protein vaccines? Is there an optimal dosing interval? Is there a correlate of protection to expedite further vaccine development? The government needs a focused research program to get these answers as soon as possible.

The government should accelerate efforts to develop a universal coronavirus vaccine to protect against known coronaviruses, including SARS-CoV-2. 4 A more broadly protective vaccine would allow the world to limit the effects of emerging variants and nimbly react to novel coronaviruses that are likely to emerge in the future. There may be tradeoffs between increased breadth of protection against severe disease and reduced effectiveness against infection.

The government needs to invest in and provide a full incentive for innovative approaches to improve vaccine access and uptake globally. Some examples include mucosal vaccines that may offer greater protection from infection and skin patches that decrease the complex logistical challenges of vaccination campaigns, such as cold chain delivery. These approaches will reduce supply chain constraints and deployment logistics while reducing the overall cost of vaccinations globally.

In addition, to facilitate verification of vaccination status and to better track postvaccination infections, there needs to be an electronic vaccine certificate platform. Relying on forgeable paper cards is unacceptable in the 21st century. Current state immunization information systems are incomplete, fragmented, and not interoperable, hindering national efforts to control the virus. A national electronic vaccine certificate platform is needed, such as the SMART Health Card, that ensures interoperability across states and countries, safeguards individual privacy, and is based on open-source technology publicly available for vetting to help satisfy any concerns over government surveillance. While controversial, this is not unprecedented. State and national databases are in use for other information, including for driver’s licenses, Social Security, voter registration, and specific health purposes, such as organ donation.

Therapeutics

Several effective therapeutics for COVID-19 are available, including remdesivir and dexamethasone. 5 Monoclonal antibodies targeting the virus are highly effective when administered early, but myriad barriers, such as poor coordination between COVID-19 testing sites and the health care system and limited supplies, have limited their utility. 6 In addition, the Omicron variant has rendered all but one of the monoclonal antibodies essentially ineffective, requiring them to be redesigned to match evolving variants. Host-targeted therapies that can reverse cytokine-induced inflammation should be further explored to rescue patients with late-stage disease.

A more effective response to COVID-19 will require rapid development of efficacious oral antiviral treatments. Molnupiravir and Paxlovid were recently authorized by the FDA. Molnupiravir has a relatively low effectiveness and there are questions about potentially serious adverse effects, such as mutagenicity and birth defects. 7 Paxlovid, a novel oral protease inhibitor combined with an existing protease inhibitor, seems more effective with fewer safety concerns. 8 As is the case with monoclonal antibodies, the clinical benefits of these drugs may be limited due to inadequate coordination between testing and treating patients within the health care system and severely limited supply. Further, the use of antiviral agents warrants close monitoring for emergence of viruses resistant to treatment. The US government should accelerate development, production, and procurement of COVID-19 drugs that are easier to manufacture and administer.

Outpatient COVID-19 treatments need to be made widely available at no cost—no deductible, no co-pay, no pay for the uninsured—for anyone testing positive for SARS-CoV-2 infection and meeting FDA indications. Importantly, there must be a mechanism to ensure every person who tests positive is proactively offered appropriate and rapid treatment. If a patient tests positive, whether at home, a pharmacy, or hospital clinic, there must be a mechanism for treatment to be initiated immediately following diagnosis. Certain COVID-19 treatments should also be made more readily available for preexposure prophylaxis in high-risk groups, especially those who do not respond to vaccination.

Conclusions

There has been tremendous progress in rapidly creating novel COVID-19 vaccines and therapeutics. Nevertheless, these efforts have been insufficient to achieve a “new normal,” in which the combined risk of all viral respiratory illnesses, including COVID-19, does not exceed the risk during pre–COVID-19 years. The US needs investment in variant-specific vaccines, alternative vaccine administration mechanisms, and research into the optimal vaccination strategies. Having effective vaccines are of real value in reducing the spread of COVID-19 and serious illness, but their benefits will be limited without near universal coverage. This coverage can be augmented through additional vaccination requirements. Finally, research needs to be expedited to develop and use effective COVID-19 oral therapeutics. The short window for administration requires a much closer linkage between COVID-19 testing and treatment.

Corresponding Author: Ezekiel J. Emanuel, MD, PhD, Perelman School of Medicine, Medical Ethics and Health Policy, University of Pennsylvania, 423 Guardian Dr, Blockley Hall, Ste 1412, Philadelphia, PA 19104 ( [email protected] ).

Published Online: January 6, 2022. doi:10.1001/jama.2021.24165

Conflict of Interest Disclosures: Dr Borio reported being a venture partner at Arch Venture Partners, receiving personal fees from Resilience Corp, and serving on the scientific advisory board for the Coalition for Epidemic Preparedness Innovations and on the board of directors for Eagle Pharmaceuticals and Insulet Corp. Dr Emanuel reported personal fees, nonfinancial support, or both from companies, organizations, and professional health care meetings and being a venture partner at Oak HC/FT; a partner at Embedded Healthcare LLC, ReCovery Partners LLC, and COVID-19 Recovery Consulting; and an unpaid board member of Village MD and Oncology Analytics. Dr Emanuel owns no stock in pharmaceutical, medical device companies, or health insurers. No other disclosures were reported.

Additional information: Drs Borio, Bright, and Emanuel were members of the Biden-Harris Transition COVID-19 Advisory Board from November 2020 to January 2021.

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Borio LL , Bright RA , Emanuel EJ. A National Strategy for COVID-19 Medical Countermeasures : Vaccines and Therapeutics . JAMA. 2022;327(3):215–216. doi:10.1001/jama.2021.24165

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Coronavirus disease (COVID-19): Vaccine research and development

Reviewed and current on 10 August 2021.

WHO and its partners are committed to accelerating the development of COVID-19 vaccines while maintaining the highest standards on safety.

Vaccines go through various phases of development and testing – there are usually three phases to clinical trials, with the last one designed to assess the ability of the product to protect against disease, which is called efficacy. All phases assess safety. The last phase, phase III, are usually conducted in a large number of people, often 10’s of thousands.  After that, the vaccine needs to go through a review by the national regulatory authority, who will decide if the vaccine is safe and effective enough to be put on the market, and a policy committee, who will decide how the vaccine should be used.      

In the past, vaccines have been developed through a series of consecutive steps that can take many years. Now, given the urgent need for COVID-19 vaccines, unprecedented financial investments and scientific collaborations are changing how vaccines are developed. This means that some of the steps in the research and development process have been happening in parallel, while still maintaining strict clinical and safety standards. For example, some clinical trials are evaluating multiple vaccines at the same time. It is the scale of the financial and political commitments to the development of a vaccine that has allowed this accelerated development to take place. However, this does not make the studies any less rigorous.

The more vaccines in development the more opportunities there are for success.

Any longer-term safety assessment will be conducted through continued follow up of the clinical trial participants, as well as through specific studies and general pharmacovigilance of those being vaccinated in the roll out.  This represents standard practise for all newly authorized vaccines.

In a regular vaccine study, one group of volunteers at risk for a disease is given an experimental vaccine, and another group is not; researchers monitor both groups over time and compare outcomes to see if the vaccine is safe and effective.

In a human challenge vaccine study, healthy volunteers are given an experimental vaccine, and then deliberately exposed to the organism causing the disease to see if the vaccine works. Some scientists believe that this approach could accelerate COVID-19 vaccine development, in part because it would require far fewer volunteers than a typical study.

However, there are important ethical considerations that must be addressed – particularly for a new disease like COVID-19, which we do not yet fully understand and are still learning how to treat; it may be difficult for the medical community and potential volunteers to properly estimate the potential risks of participating in a COVID-19 human challenge study. For more information, see this WHO publication on the ethics of COVID-19 human challenge studies . 

Small (phase I) safety studies of COVID-19 vaccines should enroll healthy adult volunteers. Larger (phase II and III) studies should include volunteers that reflect the populations for whom the vaccines are intended. This means enrolling people from diverse geographic areas, racial and ethnic backgrounds, genders, and ages, as well as those with underlying health conditions that put them at higher risk for COVID-19. Including these groups in clinical trials is the only way to make sure that a vaccine will be safe and effective for everyone who needs it. 

Opportunities to volunteer for a COVID-19 vaccine trial vary from country to country. If you are interested in volunteering, check with local health officials or research institutions or email [email protected] for more information about vaccine trials.

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Exploring COVID-19 vaccine adverse events among pregnant women: a cross-sectional study, 2022

Affiliations.

• 1 Department of Obstetrics and Gynecology, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
• 2 Department of Community, Environmental and Occupational Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
• 3 Administration of Health Awareness, Ministry of Health Jeddah, Jeddah, Saudi Arabia.
• 4 Faculty of Medicine, Beni Suef University, Beni Suef, Egypt.
• 5 Department of Medicine and Surgery, Liaquat National Hospital and Medical College, Karachi, Pakistan.
• 6 Department of Clinical Health Education, Administration of Health Awareness, Ministry of Health, Jeddah, Saudi Arabia.
• 7 Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
• 8 Population Health Management and Research, Riyadh First Health Cluster, Ministry of Health, Riyadh 11564, Saudi Arabia.
• 9 VP Community Health Excellence, Riyadh First Health Cluster Ministry of Health, Riyadh, Saudi Arabia.
• PMID: 39376246
• PMCID: PMC11457191
• DOI: 10.1177/25151355241285594

Background: Clear and trustworthy information is crucial to improving public acceptance of COVID-19 vaccinations, especially among pregnant women. Given the increased risk of severe viral pneumonia in pregnant women, it is critical to foster confidence in the vaccine's safety and understand any potential adverse events (AEs). So, we did this study in Jeddah, Saudi Arabia (SA), from March to May 2022 to compare women who did not get any doses of the COVID-19 vaccine during pregnancy (Group A) to women who did get at least one dose during pregnancy (Group B) regarding (1) the frequency, types, AEs, and management of its AEs of the COVID-19 vaccination; and (2) exploring pregnancy, delivery, and fetus-related complications (e.g., miscarriage, birth defects, and preterm labor).

Methods: A cross-sectional study targeted 438 women who gave birth or were pregnant within the previous 8 weeks. Data was collected through face-to-face interviews with skilled nurses in 13 randomly selected primary healthcare facilities, using a validated, well-structured questionnaire that included the Centers for Disease Control (CDC) COVID-19 vaccination-related AEs. We analyzed the collected data using SPSS version 27.

Results: Most participants were aged 25 to less than 35 (58.8%), and 287 (61.3%) were university graduates. There was no statistically significant difference among the studied groups regarding demographics. However, women in Group B had a significantly higher rate of abortions, oligohydramnios (24.4%), abnormal placentas (size and location), 103 (42.7%) abnormal fetal growth, 122 (53.7%) problems breastfeeding, blood pressure problems, and more cases of malaise, headaches, chest pain, breathing problems, and sleep problems than women in Group A. After the second and third doses, the confirmed post-vaccination COVID-19 rates in Group B were lower than those in Group A.

Conclusion: The COVID-19 vaccine significantly reduces post-vaccination COVID-19. Although COVID-19 vaccine-related AES are prevalent, analgesics and antipyretics effectively treat most of them.

Keywords: COVID-19; Jeddah; adverse events; pregnancy; vaccination.

Plain language summary

Prevalence and issues of COVID-19 vaccine adverse events among pregnant women.

Background: Clear and trustworthy information is essential for increasing public acceptance of COVID-19 vaccinations, particularly among pregnant women who face higher risks of severe illness. This study, conducted from March to May 2022 in Jeddah, Saudi Arabia, aimed to explore issues related to COVID-19 vaccination in pregnant women. The study focused to compare those who did not receive any vaccination doses during pregnancy (Group A) and those who received at least one dose or more during pregnancy (Group B) regarding 1) the frequency, types, AEs, and management of the COVID-19 vaccination among moms; and 2) exploring pregnancy, delivery, and fetus-related complications (e.g., miscarriage, birth defects, preterm labor, etc.).

Methods: We conducted the study on 438 women who had given birth within the past 8 weeks. Data were collected through face-to-face interviews with skilled nurses at 13 randomly selected primary healthcare facilities using a validated questionnaire.

Results: In this study, it is observed:• Most participants were aged 25 to less than 35 years old (58.8%), and 61.3% were university graduates.• No significant demographic differences were found between groups.• The study groups showed a statistically significant difference in the occurrence of spontaneous abortions, oligohydramnios, abnormal placentas (size and location), abnormal fetal growth, blood pressure problems, breastfeeding problems, malaise, headaches, chest pain, breathing problems, and sleep problems. However, most reported AEs required only analgesics and antipyretics.• Post-vaccination COVID-19 rates were lower in vaccinated women after the second and third doses.

Conclusions: The COVID-19 vaccine significantly reduces post-vaccination COVID-19. Although COVID-19 vaccine-related AES are prevalent, analgesics and antipyretics effectively treat most of them.

© The Author(s), 2024.

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(a) Antenatal pregnancy symptoms and…

(a) Antenatal pregnancy symptoms and differences between the studied groups. (b) Delivery-related issues…

Fetus-related issues and their differences…

Fetus-related issues and their differences among the studied groups.

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Novavax's Updated 2024-2025 Nuvaxovid™ COVID-19 Vaccine Receives Authorization in the EU

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Oct 09, 2024, 07:00 ET

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GAITHERSBURG, Md. , Oct. 9, 2024 /PRNewswire/ -- Novavax, Inc. (Nasdaq: NVAX ), a global company advancing protein-based vaccines with its Matrix-M™ adjuvant, today announced that the European Commission granted Marketing Authorization for Novavax's updated 2024-2025 Nuvaxovid™ COVID-19 Vaccine (recombinant, adjuvanted) (NVX-CoV2705), dispersion for injection, for use in individuals aged 12 and older for the prevention of COVID-19 in the European Union (EU). This decision follows the positive opinion from the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA).

Authorization was based on non-clinical data that showed Novavax's updated vaccine provides cross-reactivity against JN.1 and numerous JN.1 lineage viruses, including KP.2.3, KP.3, KP.3.1.1 and LB.1. 1 In clinical trials, the most common adverse reactions associated with Novavax's prototype COVID-19 vaccine (NVX-CoV2373) included headache, nausea or vomiting, muscle pain, joint pain, injection site tenderness, injection site pain, fatigue and malaise.

Novavax's vaccine is also authorized for use in the U.S. , and is in line with guidance from the U.S. Food and Drug Administration (FDA), EMA and the World Health Organization  to target the JN.1 lineage this fall. 2-5

AUTHORIZED USE IN THE U.S. Novavax COVID-19 Vaccine, Adjuvanted (2024-2025 Formula) has not been approved or licensed by the FDA but has been authorized for emergency use by the FDA, under an Emergency Use Authorization (EUA) to prevent Coronavirus Disease 2019 (COVID-19) for use in individuals 12 years of age and older. Refer to the full Fact Sheet  for information about the Novavax COVID-19 Vaccine, Adjuvanted.

The EUA of this product will remain in effect for the duration of the COVID-19 EUA declaration justifying emergency use of the product, unless the authorization is revoked sooner.

VACCINE AUTHORIZATION (U.S.) Novavax COVID-19 Vaccine, Adjuvanted (2024-2025 Formula) is indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older.

IMPORTANT SAFETY INFORMATION Contraindications

• Do not administer the Novavax COVID-19 Vaccine, Adjuvanted to individuals with a known history of a severe allergic reaction (e.g., anaphylaxis) to any component of the Novavax COVID-19 Vaccine, Adjuvanted.

Warnings and Precautions

• Management of Acute Allergic Reactions:  Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following administration of the Novavax COVID-19 Vaccine, Adjuvanted.
• Myocarditis and Pericarditis : Clinical trials data provide evidence for increased risks of myocarditis and pericarditis following administration of Novavax COVID-19 Vaccine, Adjuvanted.
• Syncope (fainting):  may occur in association with administration of injectable vaccines. Procedures should be in place to avoid injury from fainting.
• Altered Immunocompetence: Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the Novavax COVID-19 Vaccine, Adjuvanted.
• Limitations of Vaccine Effectiveness:  The Novavax COVID-19 Vaccine, Adjuvanted may not protect all vaccine recipients.

Adverse Reactions Solicited adverse reactions included: Injection site pain/tenderness, fatigue/malaise, muscle pain, headache, joint pain, nausea/vomiting, injection site redness, injection site swelling and fever.

Reporting Adverse Events and Vaccine Administration Errors

The vaccination provider is responsible for mandatory reporting of certain adverse events to the Vaccine Adverse Event Reporting System (VAERS) online at https://vaers.hhs.gov/reportevent.html , by calling 1-800-822-7967 or send an email to [email protected] .

About the Novavax COVID-19 2024-2025 Formula (NVX-CoV2705) NVX-CoV2705 is an updated version of Novavax's prototype COVID-19 vaccine formulated to target the JN.1 variant. It is a protein-based vaccine made by creating copies of the surface spike protein of SARS-CoV-2 that causes COVID-19. With Novavax's unique recombinant nanoparticle technology, the non-infectious spike protein serves as the antigen that primes the immune system to recognize the virus, while Novavax's Matrix-M adjuvant enhances and broadens the immune response. The vaccine is packaged as a ready-to-use liquid formulation and is stored at 2° to 8°C, enabling the use of existing vaccine supply and cold chain channels.

About Matrix-M™ Adjuvant When added to vaccines, Novavax's patented saponin-based Matrix-M adjuvant enhances the immune system response, making it broader and more durable. 3 The Matrix-M adjuvant stimulates the entry of antigen-presenting cells at the injection site and enhances antigen presentation in local lymph nodes.

About Novavax Novavax, Inc. (Nasdaq: NVAX ) promotes improved health by discovering, developing and commercializing innovative vaccines to help protect against serious infectious diseases. Novavax, a global company based in Gaithersburg, Md. , U.S., offers a differentiated vaccine platform that combines a recombinant protein approach, innovative nanoparticle technology and Novavax's patented Matrix-M adjuvant to enhance the immune response. The Company's portfolio includes its COVID-19 vaccine and its pipeline includes COVID-19-Influenza Combination and stand-alone influenza vaccine candidates. In addition, Novavax's adjuvant is included in the University of Oxford and Serum Institute of India's R21/Matrix-M malaria vaccine. Please visit novavax.com  and LinkedIn  for more information.

Forward-Looking Statements Statements herein relating to the future of Novavax, its operating plans and prospects, the immunogenic response of its vaccine technology against variant strains including JN.1 lineage viruses, and the scope, timing and outcome of future regulatory filings and actions, including any EMA or FDA recommendations, the expectation to have unit dose vials available in select European countries this fall season, are forward-looking statements. Novavax cautions that these forward-looking statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. These risks and uncertainties include, without limitation, antigenic drift or shift in the SARS-CoV-2 spike protein, challenges satisfying, alone or together with partners, various safety, efficacy and product characterization requirements, including those related to process qualification and assay validation, necessary to satisfy applicable regulatory authorities; difficulty obtaining scarce raw materials and supplies; resource constraints, including human capital and manufacturing capacity, on the ability of Novavax to pursue planned regulatory pathways; challenges or delays in obtaining regulatory authorization for a JN.1 protein-based COVID-19 vaccine or for future COVID-19 variant strain changes; challenges or delays in clinical trials; manufacturing, distribution or export delays or challenges; Novavax's exclusive dependence on Serum Institute of India Pvt. Ltd. for co-formulation and filling and the impact of any delays or disruptions in their operations on the delivery of customer orders; and those other risk factors identified in the "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" sections of Novavax's Annual Report on Form 10-K for the year ended December 31, 2023 , and subsequent Quarterly Reports on Form 10-Q, as filed with the Securities and Exchange Commission (SEC). We caution investors not to place considerable reliance on forward-looking statements contained in this press release. You are encouraged to read our filings with the SEC, available at www.sec.gov  and www.novavax.com , for a discussion of these and other risks and uncertainties. The forward-looking statements in this press release speak only as of the date of this document, and we undertake no obligation to update or revise any of the statements. Our business is subject to substantial risks and uncertainties, including those referenced above. Investors, potential investors, and others should give careful consideration to these risks and uncertainties.

Contacts: Investors Luis Sanay , CFA 240-268-2022 [email protected]

Media Giovanna Chandler 240-720-7804 [email protected]

• Kaku Y, Uriu K, Okumura K; Genotype to Phenotype Japan (G2P- Japan ) Consortium, Ito J, Sato K. Virological characteristics of the SARS-CoV-2 KP.3.1.1 variant.  Lancet Infect Dis . 2024;24(10):e609. doi:10.1016/S1473-3099(24)00505-X
• U.S. Centers for Disease Control and Prevention. Interim Clinical Considerations for Use of COVID-19 Vaccines in the United States . September 6, 2024 . Available at:  https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html .
• U.S. Centers for Disease Control and Prevention. CDC Recommends Updated 2024-2025 COVID-19 and Flu Vaccines for Fall/Winter Virus Season. June 27, 2024 . Available at: https://www.cdc.gov/media/releases/2024/s-t0627-vaccine-recommendations.html .
• World Health Organization. Statement on the antigen composition of COVID-19 vaccines. April 26, 2024 . Available at:  https://www.who.int/news/item/26-04-2024-statement-on-the-antigen-composition-of-covid-19-vaccines .
• European Medicines Agency. ETF recommends updating COVID-19 vaccines to target new JN.1 variant. April 30, 2024 . Available at: https://www.ema.europa.eu/en/news/etf-recommends-updating-covid-19-vaccines-target-new-jn1-variant .

SOURCE Novavax, Inc.

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COVID-19 in NYC: New variant appears as infection rates decline; vaccines still recommended

A new COVID-19 variant is starting to spread in the United States and has been found in NYC — possibly becoming the virus’ dominant strain as the country enters into cold and flu season , doctors are reporting.

XEC is the new variant. It is a subvariant of the infamous Omicron strain, which, according to a Yale Medicine article, gave rise to “ multiple descendants ” since it hit the United States in 2021.

XEC first appeared in Germany in June 2024 before it spread throughout Europe. By the end of September, XEC had been detected in at least 25 U.S. states , according to Yale Medicine . It has also been detected in a hospital in NYC.

COVID-19 declining in NYC, at least for now

Despite the emergence of a new variant, there is good news: The U.S. Centers for Disease Control and Prevention (CDC) reports that current COVID-19 rates are declining across the country and in New York as of Oct. 1.

Isaac Dapkins, M.D., chief medical officer at the Family Health Centers at NYU Langone Health, said COVID-19 rates are down in the city, but that could easily change once the weather cools down .

“I t really has to do a lot with the weather, ” he said. “ When it gets cold, people are more likely to be around each other , more inside, more runny noses arise. People are more likely to be cooped up. So we haven’t really had that seasonal change yet to really push everybody to be indoors. So the illness level hasn’t gone up yet. ”

He added that becoming infected with COVID-19 has a lot to do with risk, as has historically been the case with the virus.

“ Y ou’re talking about risk. Your risk of getting infected, and then your risk of getting sick once you’re infected, ” the doctor said. “ Omicron was way more infectious, but didn’t necessarily make you more sick if you are healthy and well . But if you’re somebody who has immunodeficiency or who has a lot of other medical problems, then still getting COVID still has risks .”

At the height of the pandemic, people tested for COVID-19 at hospitals, medical offices and various pop-up sites. But now that at-home tests are more popular, COVID-19 data is primarily based on in-patient testing and hospitalizations , Dapkins explained .

“T hankfully, that really has not been something  we have seen a lot of in the past three months, ” Dapkins said. “ We have not had any significant number of severe COVID cases. Every once in a while we do have one person who ends up in the ICU, but it’s very, very rare .”

“COVID cases rose in July, reaching a peak in mid to late July 2024 and have been steadily declining over August and September,” Sharma said. “The same applies to hospitalizations related to COVID.”

The new variant of COVID-19: Are symptoms, illness and risk factors the same?

XEC is not expected to cause worse symptoms or more severe disease than other recent strains , according to Yale Medicine .

“P eople who are at risk are the same people as before, ” Dapkins said. “ These are people with chronic lung disease, people who have had treatment for cancer . Obesity is still a risk factor .”

What about vaccines?

Doctors recommend vaccination for anyone who has a risk factor for COVID-19. Even with XEC circulating, updated vaccines can help prevent infection.

“T hose folks really benefit from vaccination, including the new vaccines, ” Dapkins said. “ Although there is a new variant, it’s a combination of a Omicron-related variants . The new vaccine, like the flu vaccine, is put together based on what’s circulating at the time they make the vaccine. So, this new variant is very related to the old variant, and therefore, we expect it to have protection, although it is still up in the air.”

Machelle Allen, M.D., chief medical officer and senior vice president of NYC Health and Hospitals, added that updated COVID-19 vaccines offer “ the best ” protection against current and emerging variants.

“I cannot emphasize enough the importance of being vaccinated. The flu and COVID-19 vaccines are safe, effective, readily available, and can save your life, ” Allen said. “ The updated vaccines provide the best protection against current strains. I encourage all New Yorkers to do their part—get vaccinated to take care of yourself, your family, and your community .”

NYC Health and Hospitals said this year’s flu and COVID-19 vaccines are available for patients at its hospitals and Gotham Health sites.

There are some medications doctors use to treat COVID-19, and there are steps individuals can take to help prevent the spread of infection, including:

• Cover your coughs and sneezing. Coughing into your elbow instead of your hand is ideal.
• Wash your hands.
• Stay home if you’re sick.

More information about COVID-19, including when you should see a doctor , is available at cdc.gov.

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Novavax's updated 2024-2025 nuvaxovid(tm) covid-19 vaccine receives authorization in the eu.

GAITHERSBURG, Md. , Oct. 9, 2024 /PRNewswire/ -- Novavax, Inc. (Nasdaq: NVAX), a global company advancing protein-based vaccines with its Matrix-M™ adjuvant, today announced that the European Commission granted Marketing Authorization for Novavax's updated 2024-2025 Nuvaxovid™ COVID-19 Vaccine (recombinant, adjuvanted) (NVX-CoV2705), dispersion for injection, for use in individuals aged 12 and older for the prevention of COVID-19 in the European Union (EU). This decision follows the positive opinion from the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA).

Authorization was based on non-clinical data that showed Novavax's updated vaccine provides cross-reactivity against JN.1 and numerous JN.1 lineage viruses, including KP.2.3, KP.3, KP.3.1.1 and LB.1. 1 In clinical trials, the most common adverse reactions associated with Novavax's prototype COVID-19 vaccine (NVX-CoV2373) included headache, nausea or vomiting, muscle pain, joint pain, injection site tenderness, injection site pain, fatigue and malaise.

Novavax's vaccine is also authorized for use in the U.S. , and is in line with guidance from the U.S. Food and Drug Administration (FDA), EMA and the World Health Organization to target the JN.1 lineage this fall. 2-5

AUTHORIZED USE IN THE U.S. Novavax COVID-19 Vaccine, Adjuvanted (2024-2025 Formula) has not been approved or licensed by the FDA but has been authorized for emergency use by the FDA, under an Emergency Use Authorization (EUA) to prevent Coronavirus Disease 2019 (COVID-19) for use in individuals 12 years of age and older. Refer to the full Fact Sheet for information about the Novavax COVID-19 Vaccine, Adjuvanted.

The EUA of this product will remain in effect for the duration of the COVID-19 EUA declaration justifying emergency use of the product, unless the authorization is revoked sooner.

VACCINE AUTHORIZATION (U.S.) Novavax COVID-19 Vaccine, Adjuvanted (2024-2025 Formula) is indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older.

IMPORTANT SAFETY INFORMATION Contraindications

• Do not administer the Novavax COVID-19 Vaccine, Adjuvanted to individuals with a known history of a severe allergic reaction (e.g., anaphylaxis) to any component of the Novavax COVID-19 Vaccine, Adjuvanted.

Warnings and Precautions

• Management of Acute Allergic Reactions: Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following administration of the Novavax COVID-19 Vaccine, Adjuvanted.
• Myocarditis and Pericarditis : Clinical trials data provide evidence for increased risks of myocarditis and pericarditis following administration of Novavax COVID-19 Vaccine, Adjuvanted.
• Syncope (fainting): may occur in association with administration of injectable vaccines. Procedures should be in place to avoid injury from fainting.
• Altered Immunocompetence: Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the Novavax COVID-19 Vaccine, Adjuvanted.
• Limitations of Vaccine Effectiveness: The Novavax COVID-19 Vaccine, Adjuvanted may not protect all vaccine recipients.

Adverse Reactions Solicited adverse reactions included: Injection site pain/tenderness, fatigue/malaise, muscle pain, headache, joint pain, nausea/vomiting, injection site redness, injection site swelling and fever.

Reporting Adverse Events and Vaccine Administration Errors

The vaccination provider is responsible for mandatory reporting of certain adverse events to the Vaccine Adverse Event Reporting System (VAERS) online at https://vaers.hhs.gov/reportevent.html , by calling 1-800-822-7967 or send an email to [email protected].

About the Novavax COVID-19 2024-2025 Formula (NVX-CoV2705) NVX-CoV2705 is an updated version of Novavax's prototype COVID-19 vaccine formulated to target the JN.1 variant. It is a protein-based vaccine made by creating copies of the surface spike protein of SARS-CoV-2 that causes COVID-19. With Novavax's unique recombinant nanoparticle technology, the non-infectious spike protein serves as the antigen that primes the immune system to recognize the virus, while Novavax's Matrix-M adjuvant enhances and broadens the immune response. The vaccine is packaged as a ready-to-use liquid formulation and is stored at 2° to 8°C, enabling the use of existing vaccine supply and cold chain channels.

About Matrix-M™ Adjuvant When added to vaccines, Novavax's patented saponin-based Matrix-M adjuvant enhances the immune system response, making it broader and more durable. 3 The Matrix-M adjuvant stimulates the entry of antigen-presenting cells at the injection site and enhances antigen presentation in local lymph nodes.

About Novavax Novavax, Inc. (Nasdaq: NVAX) promotes improved health by discovering, developing and commercializing innovative vaccines to help protect against serious infectious diseases. Novavax, a global company based in Gaithersburg, Md. , U.S., offers a differentiated vaccine platform that combines a recombinant protein approach, innovative nanoparticle technology and Novavax's patented Matrix-M adjuvant to enhance the immune response. The Company's portfolio includes its COVID-19 vaccine and its pipeline includes COVID-19-Influenza Combination and stand-alone influenza vaccine candidates. In addition, Novavax's adjuvant is included in the University of Oxford and Serum Institute of India's R21/Matrix-M malaria vaccine. Please visit novavax.com and LinkedIn for more information.

Forward-Looking Statements Statements herein relating to the future of Novavax, its operating plans and prospects, the immunogenic response of its vaccine technology against variant strains including JN.1 lineage viruses, and the scope, timing and outcome of future regulatory filings and actions, including any EMA or FDA recommendations, the expectation to have unit dose vials available in select European countries this fall season, are forward-looking statements. Novavax cautions that these forward-looking statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. These risks and uncertainties include, without limitation, antigenic drift or shift in the SARS-CoV-2 spike protein, challenges satisfying, alone or together with partners, various safety, efficacy and product characterization requirements, including those related to process qualification and assay validation, necessary to satisfy applicable regulatory authorities; difficulty obtaining scarce raw materials and supplies; resource constraints, including human capital and manufacturing capacity, on the ability of Novavax to pursue planned regulatory pathways; challenges or delays in obtaining regulatory authorization for a JN.1 protein-based COVID-19 vaccine or for future COVID-19 variant strain changes; challenges or delays in clinical trials; manufacturing, distribution or export delays or challenges; Novavax's exclusive dependence on Serum Institute of India Pvt. Ltd. for co-formulation and filling and the impact of any delays or disruptions in their operations on the delivery of customer orders; and those other risk factors identified in the "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" sections of Novavax's Annual Report on Form 10-K for the year ended December 31, 2023 , and subsequent Quarterly Reports on Form 10-Q, as filed with the Securities and Exchange Commission (SEC). We caution investors not to place considerable reliance on forward-looking statements contained in this press release. You are encouraged to read our filings with the SEC, available at www.sec.gov and www.novavax.com , for a discussion of these and other risks and uncertainties. The forward-looking statements in this press release speak only as of the date of this document, and we undertake no obligation to update or revise any of the statements. Our business is subject to substantial risks and uncertainties, including those referenced above. Investors, potential investors, and others should give careful consideration to these risks and uncertainties.

Contacts: Investors Luis Sanay , CFA 240-268-2022 [email protected]

Media Giovanna Chandler 240-720-7804 [email protected]

• Kaku Y, Uriu K, Okumura K; Genotype to Phenotype Japan (G2P- Japan ) Consortium, Ito J, Sato K. Virological characteristics of the SARS-CoV-2 KP.3.1.1 variant. Lancet Infect Dis . 2024;24(10):e609. doi:10.1016/S1473-3099(24)00505-X
• U.S. Centers for Disease Control and Prevention. Interim Clinical Considerations for Use of COVID-19 Vaccines in the United States . September 6, 2024 . Available at: https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html .
• U.S. Centers for Disease Control and Prevention. CDC Recommends Updated 2024-2025 COVID-19 and Flu Vaccines for Fall/Winter Virus Season. June 27, 2024 . Available at: https://www.cdc.gov/media/releases/2024/s-t0627-vaccine-recommendations.html .
• World Health Organization. Statement on the antigen composition of COVID-19 vaccines. April 26, 2024 . Available at: https://www.who.int/news/item/26-04-2024-statement-on-the-antigen-composition-of-covid-19-vaccines .
• European Medicines Agency. ETF recommends updating COVID-19 vaccines to target new JN.1 variant. April 30, 2024 . Available at: https://www.ema.europa.eu/en/news/etf-recommends-updating-covid-19-vaccines-target-new-jn1-variant .

SOURCE Novavax, Inc.

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In Defense of Vaccine Mandates: An Argument from Consent Rights

Daniel a wilkenfeld.

Department of Acute and Tertiary Care, University of Pittsburgh School of Nursing, USA

Christa M Johnson

Department of Philosophy, University of Dayton, United States of America

This article will focus on the ethical issues of vaccine mandates and stake claim to the relatively extreme position that outright requirements for people to receive the vaccine are ethically correct at both the governmental and institutional levels. One novel strategy employed here will be to argue that deontological considerations pertaining to consent rights cut as much in favor of mandating vaccines as against them. The presumption seems to be that arguments from consent speak semi-definitively against forcing people to inject something into their bodies, and so any argument in favor of mandates must produce different and overriding logical and ethical considerations. Our central claim will be that the same logic that might seem to prohibit vaccine mandates as violations of consent actually supports such mandates when viewed from the perspective of the potential bystander who might otherwise be exposed to COVID-19.

Introduction

Recently, the question has arisen of the ethics of pressuring people into getting one of the COVID-19 vaccines. Debates exist along several crisscrossing axes, including:

• The acceptable form of any potential mandate: incentives vs. outright requirement.
• The acceptable locus of any potential mandate: governmental vs. institutional.
• Legal vs. ethical vs. policy considerations with respect to any potential mandate.

This article will focus on the ethical issues and stake claim to the relatively extreme position that outright requirements for people to receive the COVID-19 vaccine are ethically correct at both the governmental and institutional levels. By ‘outright requirement’, we do not mean to suggest that people will be forcibly vaccinated, but rather that some penalty will be assessed for most of those who choose to forgo a vaccine. One novel strategy employed here will be to argue that deontological considerations–and consent rights in particular—cut as much in favor of mandating vaccines as against them. To make allowances for a (narrow) realm of vaccine refusal, we do carve out an exception for those who are willing to take what we call Maximal Preventive Measures (MPMs): doing all of masking, social distancing and providing evidence of a negative test whenever they go into a public space; this carve-out would be sufficiently onerous for most people that it would act as another form of mandate, while allowing for certain legitimate exceptions. Note that our thesis is specifically applicable only to COVID-19 vaccines; we will however explore to what extent our argument might generalize to other vaccines. Even more precisely, our argument was originally formed in the context of variants of COVID-19 through delta. We comment below on how circumstances have changed with omicron (though not in a way that invalidates our argument), but of course given the likelihood that facts on the ground will continue to evolve, it is possible that some of our arguments might prove outdated. Even should that be the case, we maintain that the following ethical analysis of vaccine mandates in the era through delta (and to a lesser extent omicron) still has value in manifesting general argumentative positions that will likely apply to future variants or other viruses altogether.

We take it that one of the strongest arguments against requiring vaccines is that people generally have a right to refuse consent to any infringement on bodily integrity. We frequently hear vaccine opponents invoking the language of medical choice or informed consent. The presumption seems to be that arguments from consent speak semi-definitively against forcing people to inject something into their bodies, and so any argument in favor of mandates must produce different and overriding logical and ethical considerations.

Other defenses of vaccine mandates in the literature have generally taken this structure of rights vs. some other good. For example, they have focused on the unvaccinated’s contribution to a collective harm ( Brennan, 2018 ), the protection of the general public ( Flanigan, 2014 ; Savulescu, 2021 ), the protection of the otherwise unvaccinated ( Giubilini and Savulescu, 2019 ), herd immunity ( Giubilini, 2020 ) and considerations of fairness ( Giubilini, 2020 ). In most of these arguments, the general idea is that the considerations in favor of the mandate outweigh whatever claims or rights an unvaccinated person has to remain unvaccinated. The exception to this strategy is Brennan’s (2018) libertarian argument. Since the libertarian does not allow that considerations of the wellbeing of others can ever outweigh one’s right to liberty, a mandate will only be viable if the mandate falls outside the scope of one’s liberty rights. As such, Brennan argues that the unvaccinated contributes to a collective harm that the government is justified in preventing via vaccine mandate.

Our argument comes closest to Brennan’s in that we also do not focus on benefits of the vaccine mandate outweighing any harms or rights to the otherwise unvaccinated. Where it differs, however, is that our focus is not on a contribution to a collective harm that a government may protect against, but rather on a conflict of rights between the would-be unvaccinated and individuals with an interest in people with whom they interact being vaccinated. Indeed, our central claim is that this is a conflict of the very same right, i.e. one’s purported right to remain unvaccinated is undergirded by the same deontological logic of consent rights that we contend motivate the right of a potential bystander to not be unnecessarily exposed to COVID-19. As a catch-all term, we speak of a general right to engage in the world free of harms imposed on one’s body without consent; we mean by this construal to pick out whichever right or rights vaccine refusers and bystanders alike seek to invoke. The crux of the argument is that when one defends one’s right to remain unvaccinated, one inevitably also accepts infringement upon a bystander’s right to not be exposed to COVID-19 by the unvaccinated. What justifies a vaccine mandate, or so we will argue, is how this conflict of rights in kind gets settled.

We will be focusing our arguments exclusively on the justification of mandates for vaccines in Western cultures. We suspect that the strongest case against individual mandates can be made for a Western culture such as that of the USA, for two reasons. First, given their emphasis on individualism and individual rights, one would suspect a stronger cultural norm against essentially overriding individual decision making. Second—and we will return to this in the objections and replies—given the emphasis in at least the more liberal corners of Western culture on bodily integrity in support of reproductive rights, we might expect similar logic to speak in favor of preserving bodily integrity in the case of vaccine refusal.

We will also largely be omitting one standard argument in favor of vaccine mandates, as hinted to above. One might think that the sheer scope of the COVID-19 pandemic would justify overriding what would normally be ethical rights for the sake of avoiding catastrophe. While the scope of the pandemic will play a role in our argument, we do not intend to argue that otherwise unethical action is justified in this case on purely utilitarian (i.e. outcome-based) grounds. Rather, we argue that—properly thought of—mandating COVID-19 vaccines is not unethical in the first place. While others (especially Brennan, 2018 ) have argued that vaccine mandates do not violate general constraints against government restriction, we take our advance to be framing the defense of mandates in the very language of rights and consent most commonly used by their opponents.

For purposes of this paper, we begin with three assumptions. First, we assume the extreme safety and relative efficacy of the COVID vaccines. More specifically, we assume that there are very low odds of unforeseen serious side-effects ( Blumenthal et al. , 2021 , Klein et al. , 2021 ), that being vaccinated reduces one’s odds of acquiring COVID-19 ( Thompson et al. , 2021 ) and that being vaccinated greatly reduces the odds of transmitting COVID-19 to other people. This could be true because it reduces viral load ( Petter et al. , 2021 ; Vitiello et al. , 2021 ) or because it reduces the length of one’s contagion ( Thompson et al. , 2021 ), but if nothing else it follows as at least plausible from the fact that vaccinated individuals are less likely to be infected in the first place ( Centers for Disease Control and Prevention, 2021b ). Obviously many people who oppose vaccines on any level are likely to dispute this assumption, arguing either that vaccines are unsafe or that they are ineffective. However, the fact that people argue something does not in itself imply that it is a plausible position, and so—given the overwhelming empirical evidence—in this case it is reasonable to simply set aside for the purposes of ethical analysis claims that deny the vaccine’s (general) safety and effectiveness, so long as there is support for those who suffer side effects, as well as a very limited set of exceptions for those with legitimate medical reasons not to get the vaccine. That said, while the safety of the vaccines is unlikely to change, the soundness of the assumption that they reduce infection and transmission might wax and wane as new variants become dominant. For example, when this paper was drafted the dominant variant was delta (see citations above), but during revision the omicron strain became responsible for almost all infections in the USA ( Centers for Disease Control and Prevention, 2022 ). While the omicron variant exhibits significantly more vaccine escape than earlier variants ( Lyngse et al. , 2022 ), preliminary results indicate that vaccines are still somewhat effective at reducing infection and transmission ( Lyngse et al. , 2022 ) Perhaps by the time this paper is published or read the situation will have changed sufficiently that our underlying assumptions are no longer sound. If so, we present our arguments as pre-emptive considerations for how to treat vaccine mandates in the face of future variants or pandemics where these assumptions do apply.

Second, we assume that in the absence of a mandate there will be a large number of people who do not get the vaccine and that in the presence of a mandate this number will go down. The former claim is undeniably empirically accurate—there are as of this writing large swaths of the population who refuse to get the vaccine. The latter point is more speculative—it is possible that a mandate would somehow backfire and lead to fewer total vaccinations. However, evidence suggests that at least at the institutional level when mandates are enacted people become more likely to get the vaccine ( Greyson et al. , 2019 ; Gostin, 2021 ); so this seems like a reasonable assumption. (We do not however commit to how many more people would be likely to get it.) Finally, we assume that the vaccine is readily available—obviously it would be unjust to mandate someone get something that there is no way for them to get.

Note also that the exception for people taking MPMs discussed above (masking + distancing + testing whenever entering a shared public space) also entails that our discussion only applies to people who enter shared public spaces. If one really lives one’s entire life in a wholly insular fashion (as in a hermit in the woods), then one can trivially satisfy the mandate by doing nothing new (since one is not entering publicly shared spaces). In addition, there is likely a gray area where one has such minimal contact with outsiders—perhaps in a rural farming community—that taking MPMs is sufficiently doable that it represents a reasonable alternate path such that the vaccine is in some sense no longer ‘mandated’. Given how interconnected most people are (even those who spend most time in isolated locations generally have some need of interacting with the broader population) we thus focus our discussion on those who have some interest in regularly being in shared public spaces.

The structure of this paper is as follows. The next section provides the major arguments in the paper, showing how the very same deontological considerations that might speak against mandating vaccines in support of the consent rights of the recipient also speak in favor of mandating vaccines in support of the consent rights of those who might potentially be exposed. We will then discuss how to address these competing rights-claims and argue that the best resolution is to favor the rights of potential victims of COVID-19. In the following section, we will build on well-known analogies from clinical/medical/nursing ethics—this is intended merely to be illustrative. We then expand the argument from governmental mandates also to defend on similar grounds institutional mandates at effectively any sort of institution. We conclude with objections and replies.

Rights-Based Arguments for and against Mandates

Vaccines and individual rights.

When someone makes a decision not to get a COVID-19 vaccine, they are of course making a decision pertaining to their own healthcare. However, what is sometimes overlooked is that they are making a decision pertaining to others’ healthcare as well. Though there is no guarantee that anyone who is not vaccinated will be exposed to COVID-19 and will pass it on, not being vaccinated makes it more likely that they will do so (see above). In that way, they affect the rights of future people with whom they interact. By analogy, it is clearly wrong to put toxic chemicals in someone else’s water; we can then consider a person or company that allows potentially (but not certainly) dangerous chemicals into a local water supply. They might not know that they are putting anyone in danger and certainly would not be able to point to a specific individual who will be harmed. However, the potentially more diffuse nature of the wrong in not knowing whom will be hit seems on the surface almost exactly counterbalanced by the very real possibility that they will harm multiple people. In the same way, while we cannot point to a specific individual Y who will get COVID-19 as a result of person X’s decision not to get vaccinated, there are a whole host of individuals Y 1 – Y n who suddenly find themselves in unwanted harm’s way. It is also worth noting that some of the Y i s might not be able to get the vaccine themselves, either due to overriding medical reasons or the simple fact that (as of this writing) it is not yet approved for or available to all populations. In the case of pollutants, the right being violated is Y’s ability to live their life and assume a certain level of safety in their water supply, or more generally the right to engage in the world free of harms imposed on one’s body without consent.

What right then is being violated with respect to a person who is forced to get a vaccine? The clearest answer is the same as above, i.e. one’s right to engage in the world free of harms imposed on their bodies without their consent. This suggests we look at the literature on consent to ascertain whether their rights are more sacrosanct than the victims of any potential COVID-19 exposures. In the remainder of this section, we speak as if there is one particular person who will be exposed to COVID-19 as a result of an individual’s vaccine refusal—as pursuant to the previous paragraph, we take this to be morally similar to the more realistic scenario where there are multiple people with massively increased potential exposure.

Sources of Consent Rights

In this section, we will go over some common justifications for people’s right to refuse interventions on their bodies and argue that those same justifications provide at least some prima facie reason to think that they in most cases do not have a right to refrain from getting a COVID-19 vaccine. The key to this strategy is arguing not that there are conflicting kinds of rights, but rather that the very same kind of right that would justify vaccine refusal also justifies vaccine mandates.

For example, the right to refuse interventions is most frequently grounded in autonomy, which is literally the right to make laws for oneself. Spelling out precisely why this is the case is complicated by the fact that philosophers have no clear unified conception of autonomy ( Buss and Westlund, 2018 ). We do not need a full account of autonomy however to note that one necessary condition for autonomy is the liberty to decide for oneself how to live one’s life free of unnecessary externally imposed impediments. It is this liberty criterion that vaccine mandates are often thought to violate, but we will argue that the absence of mandates is responsible for violations of that same liberty criterion. For approximately as long as philosophers have discussed anything like autonomy or liberty there has been a general recognition that liberty rights can conflict in such a way as to make it impossible for everyone to have maximal liberty all of the time. Hobbes (2016 /1651, Chapter 13) famously observed that if everyone were free to do as they would, life for everyone would be ‘nasty, brutish, and short’, and even John Stuart Mill’s (2011 /1859) most famed statement of maximal individual freedoms in ‘On Liberty’ acknowledged that one’s liberty always needs be curtailed when its exercise would infringe upon the liberty of others. Yet—given our assumptions about the effectiveness of the vaccine and the need for common areas—this seems like a paradigmatic example of where one person’s liberty would limit another’s. My liberty to be able to engage in society without being ‘assaulted’ by a vaccine is no more obviously sacrosanct than your liberty to be able to engage in society without being ‘assaulted’ unnecessarily by deadly virus. I cannot govern myself as I will when I am willfully exposed to COVID-19.

Two notes are in order. First, some would argue that the battery of having a needle puncture your body violates one’s rights in a way that an increased risk of contracting COVID-19 does not (for one such argument, see Kowalik, 2021 ). For the most part we simply reject the reasonableness of this distinction on several grounds. First, on the actuality of the harm the needle causes vs. the mere possibility of contracting COVID-19, we note that the harm of the needle itself is quite minimal and that is the only harm 100% guaranteed. The reception of the vaccine itself is not a harm, unless there are adverse side effects, which are simply an added risk—not unlike the added risk of contracting COVID-19. Thus, if we step back and look at the overall expected utility of the actual needle jab and the possibility of adverse side effects of the vaccine with the overall expected utility of the increased risk of COVID-19 exposure, we contend that the latter is much worse. The risks of COVID-19 include unpleasant symptoms [ Ma et al. (2021) recently provided a headline-generating result that 40% of cases are asymptomatic, but that suggests that 60% might not be], ‘Long COVID’ ( Crook et al. , 2021 ), hospitalization ( Scobie et al. , 2021 , especially Figure 2) and death. The seeming similarity in kind and relative seriousness of potential harms from the virus as compared to the risks of the vaccine ( Blumenthal et al. , 2021 ; Klein et al. , 2021 ) + the actual harm of the jab make it seem like the rights violation are minimally of a piece (leading to our discussion in the next section of how they should be adjudicated). Second, focusing on the unwanted foreign agent itself, whether one receives an unwanted vaccine or an unwanted infection, the issue is that an unwanted foreign agent is entering one’s body without one’s consent–drawing a sharp distinction based on the foreign agent’s mode of entry would suggest that a vaccine mandate would be ethically worse than making the vaccine airborne and spreading it throughout the country. We suspect that most of those we have encountered who argue against mandates on the grounds that they do not consent to the intervention of a shot would be unlikely to accept the intervention being thrust on them via a different and more pervasive mechanism such as being omnipresent in the atmosphere. Finally, one might argue that there are different levels of consent violations–an unapproved cheek swab is an ethical problem, but clearly a smaller one than an unapproved surgery. Precisely what makes one violation worse than another is beyond the scope of this paper, but presumably one vector of evaluation is the expected harm done (as measured in the severity of possible outcomes multiplied by the likelihood of those outcomes obtaining). As just discussed, the calculus of expected harms speaks in favor of mandating a vaccine—the point here is that this same calculus might well also speak to the severity of a rights violation in exposing someone to that harm without consent relative to the consent violation of being mandated to get an unwanted vaccine.

Of course, one might argue that we are underestimating vaccine risks and overestimating how severe COVID-19 is to everyone. After all, there have been cases of reactions to COVID-19 vaccines (Centers for Disease Control and Prevention, 2021a) and there are populations for whom severe cases of COVID-19 are rare ( American Academy of Pediatrics, 2021 ). On the first issue, (of underestimating vaccine risks) we make three points. First, we began with the assumption that the vaccines are safe. To that end, it may be that certain vaccines, e.g. Johnson and Johnson or AstraZeneca, may not be ethically mandated due to their increased safety risks and lower efficacy ( Centers for Disease Control and Prevention, 2021c ). Second, we remind the reader that the mandate we propose does include MPMs as an alternative to receiving the vaccine. Those unwilling to receive the jab may choose N95 masking, distancing and testing as an alternate route to avoid violating the consent rights of bystanders. Third, we would agree that we can set aside the relatively rare instances of vaccine side effects, so long as there are accommodations for those who have side effects, as well as an exemption for legitimate medical reasons. The idea here is that when there are indeed side effects from the vaccine received due to a mandate, the ethical mandate will include provisions for compensation. On the latter issue of overestimating the severity of COVID-19, we again make three points. First, there are cases of severe COVID-19 across all age-groups, even if prevalence of cases is lower in certain age-groups ( American Academy of Pediatrics, 2021 ). Indeed, the prevalence of severe COVID-19 across groups is higher than the prevalence of severe reactions to COVID-19 vaccines (compare Centers for Disease Control and Prevention, 2021d to Delahoy et al ., 2021 for cases of adverse reactions to the vaccine to COVID-19 hospitalizations). Second, unless the unvaccinated can be sure only to interact with individuals from those groups who do not regularly suffer from severe COVID-19, it will not matter that some individuals fall into that camp. The unvaccinated will inevitably interact with those for whom severe COVID-19 has a higher prevalence. Finally, while it is possible to offer compensation and accommodation to those few who react poorly to the vaccine, a parallel proposal for those who ultimately suffer from severe COVID-19 is untenable. That is, it seems much more plausible to make whole those who have bad side effects from the vaccine mandate than to make whole those who suffer severe COVID-19 due to the lack of a vaccine mandate.

As a second note on the liberty argument, Brennan (2018) has already argued that variants of Mill’s harm principle are sufficient to justify vaccine mandates. Our approach is subtly different in that Mill’s harm principle is characterized as a general limit on person X’s liberty whereas we are grounding our argument in the very same rights justifying vaccine refusal (e.g. liberty). This has an advantage that it defends against those who might think that unwanted medical interventions are a different kind of consent violation that cannot be overridden by Brennan’s ‘clean hands principle’—we argue that those the very same principles that support the vaccine refuser’s argument also undermine it. (Brennan’s approach has other advantages in engaging with specific libertarian concerns–as such we consider the two complementary rather than in competition.)

Similar strategies of looking at the question of rights from the potential of the prospective victim of COVID-19 exposure suffices to defray many other concerns with other intrusions on bodily integrity without consent. For example, some people ground the right to refuse intrusions in the fact that we own our own bodies (Eyal, 2012: 14). But just as my ownership right to a field gives me a claim against a neighbor whose conduct polluting risks dropping soot on my crops, so my ownership of my body gives me a claim against someone whose conduct risks dropping unnecessary SARS-CoV-2 droplets in my breathing area. Likewise, while your bodily integrity is undermined by receiving an unwanted shot, mine is undermined by receiving an unwanted COVID exposure.

One final worry worthy of special mention is that allowing the right to refuse bodily infringements is necessary to prevent abuse at the hands of authority figures ( Manson and O’Neill, 2007 ). In this case, one might worry that allowing the government the authority to mandate one shot will open the door for allowing future governments to mandate shots for more nefarious purposes. Another version of this concern might be a ‘slippery slope’ objection, which acknowledges that a vaccine mandate might be justified in this case but that allowing one would open the door to instances where such a mandate would be unjustified. However, the proper response to this is perhaps the standard one to most slippery slope arguments, which is that if the current action is justified but a future later one might not be then we need a mechanism in place that pulls the brakes right at the juncture between the justified and the unjustified. The way to prevent unjustified behavior is not to ban justified behavior, but rather to be vigilant regarding when one might cross the relevant boundary. This objection reasonably speaks against giving the government carte blanche authority to institute vaccine mandates but does not speak against allowing it to mandate this specific one. We would in effect require a new analysis to be done for each prospective vaccine. For example, current flu vaccines might not be amenable to mandates, as they violate the assumptions of strong effectiveness and high likelihood of spread and conceivably alter the calculation of expected harm that might be relevant for weighing consent violations against each other. As the effectiveness of flu vaccines increases and if the contagiousness and severity of flu infections increase the case will approach to COVID-19; our current situation provides a clear case against which other vaccine mandates could be compared—if the harms of the virus and safety/effectiveness of the vaccine are at least as great as they are for COVID-19, then a mandate is justified. Anything less must be evaluated on a case-by-case basis.

Competing Rights Claims

Suppose one accepts as above that there are competing rights claims—of the same kind—between potential unwilling vaccine recipients and potential unwilling victims of COVID-19 exposure. The next question is how we adjudicate between such conflicting rights claims. One move that would be reasonable here would be to reinvoke the societal costs of COVID-19 and argue the default should be the permissibility of a vaccine mandate unless there is a rights-based argument against having one. If the rights-based arguments all turn out to counterbalance, that would leave in place the default need to protect society of a rampaging pandemic. We think this would be a perfectly reasonable argument; however, as the ‘consequentialism vs. deontology’ argument (basically an argument between achieving positive outcomes at the cost of violating ethical ‘rules’) is well-trod ground, we table that line of reasoning in favor of arguing that a consideration of rights on their own terms favors vaccine mandates.

It is of course well beyond the scope of this paper to consider every way in which one might resolve conflicts among different people’s rights. We will thus argue from a framework inspired by Rawls’ landmark A Theory of Justice (1971/1999), widely considered to be the dominant work of political philosophy of the last century. We believe that the choice of this framework is not necessary for our ultimate conclusion and that virtually any system for trading off rights would get the same result—however, we obviously save proving this claim for future work. We will however entertain the possibility that this whole approach is wrong-headed and that a proper deontological (i.e. rule-based rather than outcome based) perspective demands that rights cannot really be weighed against each other or traded off in the first place.

Rawls’ central innovation is the ‘Veil of Ignorance’, wherein people in an ‘Original Position’ determine what is just by what one would agree to if one did not know exactly who one was. The basic idea is to imagine a group of people setting the rules for a new society, in particular the allocation of primary goods [including (at least in our version) such ‘goods’ as rights]. However, no one in that room has any idea who they are in the society; they do not know their race, gender, economic status, or any other identifying feature. Since they do not know who they are, anyone can be reasonably expected to represent all of humankind. Rawls, for his part, concludes that two principles of justice fall out of this setup. However, there is a wealth of literature debating whether Rawls is correct about what principles would fall out of the Original Position as well as how and to what those principles should apply, if correct. We do not wish to get bogged down in Rawlsian interpretation here. For our purposes, we instead turn to a Rawlsian lesson: the contractarian under-pinning of moral principles.

In envisioning the social contract, we need to discern what we would all agree to if we were fully rational and free of prejudice. This is what the Original Position and Veil of Ignorance are meant to establish. Though individual public health issues go beyond the scope of Rawls’s vision, we can use his thought experiment to develop one way of thinking through how a society ought to trade off rights when they conflict. We maintain that when setting up a society, if you do not know who you will be in that society, it is in your interest to protect those worst-off, in case you are one of those people. As such, when an issue arises in which not everyone’s rights can be met, one way of thinking through how to resolve the conflict of rights is to focus on protecting the rights of whoever would be worse off for the violation. Getting back to COVID-19 vaccine mandates, we contend that this reasoning speaks fairly clearly in favor of mandates. Given that we carve out exceptions for those with legitimate medical needs, the person who gets a vaccine they did not want is significantly better positioned than the person who gets COVID-19 exposure they did not want.

Given our use of Rawls’s setup, it is worth considering some of the push back it has received. First, some ( MacIntyre, 1981 ; Sandel, 1982 ) have argued that it is problematic to deny people in the original position all knowledge about their identity. How can I make a rational choice if I have no knowledge about my values or aims? If what is rational is whatever is in my best interest, I need to know what interests I have. Minimally, one should be offered their probability of belonging to a particular group that has particular interests. For example, if one knew that there was only a 1/7,000,000,000 chance of being a single person picked out for human sacrifice in a world where everyone else is obscenely rich, one might reasonably choose to take one’s chances. However, providing knowledge of probabilities would only make the case for mandating vaccines that much stronger, since one is much more likely to be harmed by exposure to COVID-19 from an unvaccinated individual than to receive any harm from the vaccine (see previous section). Others ( Harsanyi, 1975 ) have worried that even in the absence of probabilities Rawls (and in turn we) overestimates how risk averse people either are or should be. Psychologically speaking, perhaps people would be willing to risk a low well-being floor in the hopes of achieving a high well-being ceiling. This may be true, but notice that in this case, since one’s well-being floor and ceiling both go up if there are vaccine mandates (with suitable narrow medical exemptions), for each individual person in the population one’s odds of harm are greater if there is no mandate than if there is a mandate. Thus—whomever one thinks one might be—one is better off with the mandate. And the same math works for average utility. Given that the question of rights was a wash, this suggests that anyone in the Original Position should opt for a mandate.

One might at this point object that this entire section is based on a faulty assumption that rights claims can be traded off at all. One might think that certain rights are inviolate, even if respecting them involves a greater infringement on the rights of others ( Thomson, 1990 ; Kamm, 1996 ). There are countless cases used to show that one may not harm an individual to prevent harm to others. For instance, many argue that one may not push a hiker off a footbridge to stop an out-of-control trolley from killing five others ( Thomson, 1976 ). Likewise, it is argued that one may not kidnap an innocent person and harvest their organs to save the lives of five people in need of organ transplants ( Foot, 1967 ). To generalize the point, if there is an existing threat to some group of people, it is wrong to introduce a new threat to a third party to protect the group already under threat (or so the argument goes). In the case of COVID-19, one might argue that those who might get COVID-19 are already under threat and that the vaccine mandate introduces a new threat to the unvaccinated to protect the group already under threat. However, there is a clear disanalogy here insofar as the unvaccinated individuals are the threat. There is a morally important difference between putting an individual at risk when an out-of-control trolley will possibly cost lives and putting an individual at risk when that very individual will possibly cost lives.

There is another way to see the case, however. We have been arguing that there is a conflict of rights in the vaccine mandate case. Yet, the trolley and surgeon cases above are not necessarily conflicts of rights. These cases involve violating a right to save people, and few actually argue that individuals have a genuine right to be saved from harm. Many do argue, however, that one may not infringe a right to prevent others from having their rights violated ( Kamm, 1989 ; Heuer, 2011 ; Johnson, 2019 ). Indeed, one may not even do so when the same right is at issue. That is, I am not permitted to kill one even if it would stop five others from being killed. In the literature, this particular case has been dubbed the ‘paradox of deontology’. After all, it seems a bit odd that one would think killing is bad, yet not try to minimize them ( Nozick, 1974 ; Scheffler, 1988 ). However, deontologists (i.e. ethicists who focus on rules rather than outcomes) have argued at length, and in many ways, that we are not permitted to treat an individual as a mere means to an end. In these cases, violating that one right would be akin to using that individual as a mere means to the end of preventing other rights violations. Bringing this back to the vaccine mandate, it seems that we have a case of violating an individual’s liberty/consent rights (as characterized above) to prevent the violation of the liberty/consent rights of others, a clearly impermissible action according to these deontologists.

In response, again we can see a disanalogy. In ordinary cases discussed in the literature, there are a number of people whose rights will be violated, unless the rights of a neutral third party are violated. In the vaccine mandate case, however, the unvaccinated individual is not a neutral third party. Rather, the unvaccinated individual is the one who, if their rights are not violated, will violate the rights of the masses. To summarize, we have two parties at issue (the potential COVID-19 getter and the unvaccinated) and two possible situations (mandate or no mandate). Both parties have the potential to have their rights violated, depending on the situation. However, it is only the unvaccinated that would become a rights violator (in the no mandate situation). As such, this is not an ordinary conflict of rights. Rather, we have an innocent party at risk from a potential guilty party. And, although one might argue that seen this way, the mandate constitutes a sort of Pre-Crime preventative justice measure, a safe and effective vaccine can hardly be seen as a punishment, and prior to vaccination, we would argue that the unvaccinated is already violating the rights of potential COVID-19 getters. As such, it is not merely preventative. This marks a key area where our argument reaches farther than Brennan’s (2018) —since that piece was not addressed to deontologists, it (quite reasonably) does not consider the position of those who would take certain specific rights to be inviolable even to protect the rights of others. Our argument does so. (In a sense, our task has been made much easier by the sheer virulence of COVID-19 allowing us to assign individual culpability rather than rely upon concerns relating to collective action.)

There is another disanalogy worth mentioning before moving on. In the cases deontologists normally discuss, it is an ordinary bystander that we imagine either initiating the new threat or else violating the rights of the individual. Deontologists then argue that a bystander is not morally permitted to perform such acts to prevent harm or rights violations. However, in the vaccine mandate case, we do not have a mere bystander, we are considering government and institutional mandates. A bystander has no special obligation to the persons whom they would protect. Governments do have such special obligations, and some institutions might as well. So, not only do the stakes change insofar as the unvaccinated individual is the threat or potential rights violator, but the Government or institution who would infringe the rights of the unvaccinated via a mandate also have a special obligation to all parties involved to do what is necessary to protect them.

While one might seem to have a liberty/consent right not to be forced to get a vaccine, refraining from getting a vaccine makes one a perpetrator violating the liberty/consent rights of others. As such, it is legitimate for the government to prohibit one from doing so.

Analogies: Rights Violations and the Protection of Others

In this section, we point out that not only are there other circumstances (even in the medical domain) where we think that it is acceptable to infringe on what seem to be the rights of someone to protect the rights of others, but that (again) the same logic applies even more forcefully in the case of mandating COVID-19 vaccines. Some of the claims in this section will be controversial, so we note that our central argument in the previous section can (and should) be accepted independently of the analogies presented here. However, we believe the present analogies are still instructive regarding when it might be acceptable to infringe on what seem to be the rights of X for the sake of protecting the rights of Y.

To take perhaps the most obvious example, psychiatrists are required (legally and presumably also ethically) to break what is otherwise a strong right of confidentiality if not doing so would endanger the health and safety of a potential victim of violence ( Kahn, 2020 ). That case on the surface is fairly analogous to the present one, where mere potential harm to someone else suffices to override someone’s rights. Nor do we think the ethical calculus changes dramatically if—instead of threatening a specific individual—a psychiatric patient ‘just’ threatens to put potentially toxic chemicals into a shared water reserve—a diffuse risk of harm to a large number of anonymous people seems just as ethically relevant as a more specific risk of harm to a named individual.

However, one might believe that confidentiality rights are somehow more contingent or defeasible than consent rights, and so we turn to a second analogy perhaps more closely aligned with vaccine mandates. Parents generally have a right to decide for their children whether or not they will receive a medical intervention ( Wilkinson and Savulescu, 2018 ). However, the default view of ethicists in the relevant domains is that there are generally some (limited) circumstances where it is acceptable to override those rights for the sake of protecting someone else’s—in this case the child’s. For example, it is generally believed (e.g. Conti et al. , 2018 ) that it is acceptable to provide blood transfusions for the children of Jehovah’s Witnesses, even if the parents believe that doing so will cost the child their soul. If this position is correct (and we think that it is), then by itself it shows that we can override X’s rights for the sake of Y’s health. One might object that in this case the parental right is really just the child’s right by proxy, and hence, the cases are not relevantly analogous. However, there is still a conflict of autonomous individuals even in this case. While parents have default decisional authority on behalf of their children, the child still has a liberty interest of their own, which the parent is potentially violating by making a decision that has the potential to harm the child. (For more on the distinction between decisional authority and children’s liberty/autonomy, see Wilkenfeld and McCarthy, 2020 ). Seen as a potential conflict of liberty rights, we argue that a recent look at the best logic behind overriding parental rights also suggests overriding the apparent right to refuse a vaccine.

A recent article by Brummett (2021) makes the point that despite ethicists’ best efforts, it is not really plausible to ground the acceptability of overriding parental refusal in terms of neutral criteria like ‘minimizing harm’ ( Salter, 2012 ) or demanding internal consistency ( Bester, 2018 ). Brummett’s insight is that if one really took seriously the prospect that receiving a blood transfusion might cost a child their soul, then one could not reasonably maintain that doing so minimizes harm or in some way enforces consistency. Rather, we override the parent’s judgment not based on neutral procedural grounds, but based on our firm conviction that they believe a metaphysical claim that is simply false. If Brummett has correctly identified the justification for overriding parental rights, then it applies one thousand-fold to the question of vaccine mandates. The reason is that while we might believe that Jehovah’s Witnesses are wrong about blood transfusions costing children’s souls, it is hard to reasonably claim that we could possibly know it, and impossible to reasonably claim that we could ever prove it. However, per our assumptions, we do know that beliefs about the dangers of vaccines are simply incorrect and we have already proven it. Thus, if X’s endangering Y being based on a false belief is reason to override X’s rights, then the case is significantly stronger here than it is in the case of blood transfusions. Lest one worry that this logic could prove too much by allowing clinicians to paternalistically override patients’ wishes whenever those wishes are based on a provably false belief, note that when X’s decision only endangers himself there is no competing rights claim and the issue never arises in the first place.

Institutional Mandates

If the case has been successfully made that government vaccine mandates are ethically acceptable, then most of the logic applies doubly to institutional mandates, such as a university requiring vaccination as a condition of enrollment (subject to legitimate medical exemptions and corresponding precautions for those cases). The concern with government mandated vaccines is that they infringe on someone’s rights; however, if we are correct that doing so is part of the best system of overall rights protection then it is just as legitimate for institutions to respect potential victims’ rights in the same way.

In addition, there is the obvious point that groups of people are—with various exceptions—ethically free to associate as they see fit, and so they are likely entitled to demand people waive certain genuine rights as a condition of association. Presumably people have a right against being tackled by others, yet it is reasonable for professional sports associations such as the National Football League to demand that athletes waive that right to participate in on-field activities. It is their game, so they get to set the rules—if one does not want to waive that right, one always has the options not to play or to start one’s own group.

There are several lines of resistance one could put up to this argument. First, one might argue that some institutions (e.g. hospitals) have an ethical obligation to be open to the public, and so logic gleaned from a football organization does not apply. One might also point out that if every institution instituted a mandate then there would be nowhere else for people who did not want vaccines to go. However, in both cases the answer is the same—at the limit, the most restrictive institutional mandates can be is akin to government mandates, depriving individuals of a choice regardless of their own decisions to associate. If we have already established that government mandates are acceptable, at most these arguments show that there are no additional reasons in support of institutional mandates.

Another objection might be that similar logic to that used to defend institutional mandates above (i.e. freedom to associate) has historically been used for pernicious ends such as refusing minorities service (e.g. by refusing to make wedding cakes for gay marriages). For the most part, the ethics of allowing refusal of service based on minority status are complex and beyond the scope of this paper. However, there are two clear disanalogies between requiring that (for example) students receive vaccines and requiring that wedding cake customers be heterosexual. First, in the bakery case there would be a concern that if all bakeries had similar policies, then it would be impossible for gay couples to get wedding cakes at all. However, in this case, one can acquire the services simply by getting the vaccine, so there is no risk of being shut out simply in virtue of one’s identity. (We do assume that a gay person cannot just choose to be heterosexual, but even if they somehow could, it would be metaphysically impossible for this gay couple qua gay couple to somehow be heterosexual.) Second, we suspect (though will not here defend) that part of the issue with the bakery example is that refusing service on the grounds of sexual orientation is a capricious reason to do so—it seems exclusionary for no legitimate reason. Since there are clearly strong legitimate reasons that an institution would want its students/workers/customers/etc. to be vaccinated, there is no worry about capriciousness here.

Objections and Replies

Objection 1: If one can be required to waive bodily rights for the sake of another person, that will be used as a reason to limit abortion rights. That functions as a reductio against the original argument.

Reply 1: First, let us grant for the sake of argument that the fetus is a fully rights-bearing person. Note that if it is anything less than fully rights-bearing then there is no conflict of rights among equals, and the arguments above never get off the ground. But in any event the argument still does not go through, because the translation of our original premise that the vaccine is safe is simply false ( Kazemi et al. , 2017 ). Many pregnancies go relatively smoothly, but even then the woman is severely restricted for roughly nine months. And quite a lot of pregnancies do not go smoothly. Women can develop wrenching and dangerous nausea ( Bustos et al. , 2017 ), heart problems ( Iftikhar and Biswas, 2019 ), blood clots ( Devis and Knuttinen, 2017 ), etc. So there is simply no analogy between mandating a vaccine and mandating a continued pregnancy. One might get the result that if a fetus is fully rights-bearing and if a woman can do so without cost or danger and if no one else can do so then she might have some minimal obligation to aid the safe extraction of a post-viability fetus. But such a triply conditional conclusion does not seem like an obvious reductio. Arguably it is just a restatement of famed abortion rights philosopher Judith Jarvis Thomson’s (1976) concession that the right to an abortion is the right to end a pregnancy rather than a right to a dead baby. Note also that the limited conclusion might not allow for an enforcement mechanism as readily as would a vaccine mandate—knowing in the first place who is pregnant and what they are doing for their fetus would require a level of invasion of every woman’s privacy (even those not actually pregnant) that has no analogy in the case where everyone is required to get vaccinated (or show evidence of MPMs) to enter public spaces.

Objection 2: Institutional mandates risk unintended consequences. For example, if a hospital mandates that nurses get the vaccine, then nurses might quit and go work at a less well-regulated care facility where still more vulnerable people will be exposed to the virus.

Reply 2: We consider this a very real concern, though note that it has only limited application. While unvaccinated nurses congregating at less well-regulated nursing homes might be a risk, there is no reason to expect (for example) unvaccinated students would gather anywhere vulnerable and less well-regulated. This is also more of a policy question than an ethical one, where what really needs be resolved is not whether institutional mandates are ethical but rather how we can make sure that the absence of mandates are not disproportionately burdensome on particular populations. Interestingly this very objection strengthens the case for a government mandate, as one of the points of government action is to make sure that we avoid a race-to-the-bottom where some institutions see advantages in refusing to enact vaccine mandates.

Objection 3: We do (and presumably should?) let people take all sorts of actions that pose risks to others, such as driving. Similarly, we should let people walk around unvaccinated.

Reply 3: This objection is potentially more potent in the wake of omicron than it was upon drafting this paper. As mentioned at the start, vaccines are potentially less effective against the omicron variant than past variants. If the vaccine is not as effective, then one might to tempted to think that we might as well allow people to walk around unvaccinated at this stage in the pandemic. Unless we are endorsing a strict lockdown, people’s rights to not be assaulted by COVID-19 will be infringed, vaccine or not. To reiterate the objection, we allow people to take all sorts of actions that post risks to other, so why not the act of walking around unvaccinated? There are several disanalogies between cases like being allowed to drive and being allowed to refuse a vaccine. First, there are legitimate societal reasons for wanting people to be able to drive. Even if sometimes people drive for no discernible reason, it is still at least potentially in everyone’s interests for people to be able to drive generally. Returning to the Original Position, if no one were allowed to drive that would severely hamper one’s unknown self’s potential well-being in a way that being forced to receive a particular vaccine would not. Second, as Giubilini et al. (2021) argues, even in the case of driving, there is massive government regulation regarding how precisely it must be done. We cannot (and should not be able to) just drive as we see fit—if one wants to enter the sphere of drivers, there are certain rules. In fact, to even enter the sphere of drivers at all one needs to meet a certain government-imposed requirement (getting a license)—in the same way, to enter the sphere of societal interaction one might need to meet another condition. One might argue that one could simply refuse to drive, but the foregoing is still sufficient to address the issue that we simply allow people to risk the lives of others. We can also see from this example why general lockdowns are less ethically justifiable than vaccine mandates, even in the face of a more transmissible variant such as omicron. The vast majority of people would be significantly harmed by being barred from public spaces altogether, so it is unlikely people would choose such an option from our version of the original position. As with driving, allowing and regulating the valuable activity is significantly more justifiable than simply banning it outright.

Objection 4: One reviewer notes that we generally countenance communities running risks of spreading the common cold or the flu, so we have no principled reason to deny localities the right to run the risk of spreading COVID-19.

Reply 4: As noted above, there are several disanologies between COVID-19 and the flu (and a fortiori even more disanlogies with the common cold). The flu is not analogous to COVID-19 in terms of either virulence or severity, and the vaccines are not analogous in terms of effectiveness (even in the era of omicron). As such, the diseases/vaccines are different in kind and a reasonable individual within a community with high disease risk tolerance could more justly complain of their neighbors’ actions with regard to COVID-19 than the flu. We remain neutral on where the line is at which point an individual’s objectively defensible claim to a rights violation become decisive, but COVID-19 is clearly on one side of it. Note that this is particularly true where high risk tolerance of a particular disease is based on false empirical beliefs about its severity (e.g. that COVID-19 is no worse than the flu), as this undermines the validity of everyone’s consent to take the risk.

Objection 5: Once herd immunity nears or is reached, the risk of contracting COVID-19 in public spaces is reduced to the point that the conflict of rights ought to favor the unvaccinated, i.e. mandates are no longer permissible ( Giubilini, 2020 ; Williams, 2021 ).

Reply 5: This objection is interesting insofar as it may grant our argument up to a point. What our argument gets thus far is that when the risk of COVID-19 (or some other infectious disease) is sufficiently high, the consent rights of the bystander trump the consent rights of the would-be unvaccinated. One goal of vaccination is to achieve herd immunity, such that a disease is unable to find a host, and eventually the spread peters out. This is especially important in protecting those that cannot be vaccinated due to age or medical conditions. Our argument largely set herd immunity aside, insofar as we were not defending a mandate as a way to achieve herd immunity. Here, however, it is important to acknowledge that herd immunity is indeed a hopeful and likely result of a successful vaccine mandate. Yet, once herd immunity is reached, and the risk of COVID-19 exposure diminishes, it seems that the bystander’s right can no longer be said to trump the right of the would-be unvaccinated individual, such that the mandate is no longer ethical based on our argument.

A number of points are worth noting in response. First, as of this writing, herd immunity with respect to COVID-19 is far from becoming a reality. As new variants continue to emerge, the prospect of reaching herd immunity anytime soon continues to dwindle. As such, our argument stands strong for a COVID-19 vaccine mandate for the immediate and likely protracted future, even if not for all times. Second, removing a vaccine mandate once herd immunity has been reached invites new outbreaks and a general breakdown of the herd immunity. That is, it remains plausible that the risks of being unvaccinated, even once herd immunity is reached, continue to be high, insofar as herd immunity can easily be lost. We are seeing this occur presently with measles outbreaks and the prediction of many more to come in 2022 ( Center for Disease Control and Prevention, 2020 ; World Health Organization, 2021 ). Finally, if herd immunity is reached in such a way that a disease is eliminated entirely, with no clear risk of reemergence, then we concede our argument for a vaccine mandate has concluded—as we are making specific claims about the applied ethics of a particular policy in a particular context, the fact that it would no longer be applicable in a radically different context is no objection.

In summation, we think the case is extremely strong for requiring everyone who is able to receive a COVID-19 vaccine, ideally at the level of governmental mandate and also at the level of individual institutions. This case is strong even without looking at the utilitarian arguments that allowing the virus to spread and mutate can have catastrophic consequences, which arguments seem fairly impressive on their own. Rather, we argue that the same logic of a deontological right to consent or not to bodily infringements that speaks in favor of not requiring people to be injected with a vaccine also speaks in favor of not requiring people to be unnecessarily exposed to COVID-19, and so a full reckoning will involve a tradeoff of rights that will speak in favor of vaccine mandates.

Acknowledgments

We would like to thank Allison McCarthy for extensive comments and feedback and Dean Jacqueline Dunbar-Smith for the original impetus for this project.

This work was not supported by any particular funding mechanism.

Conflict of Interest

None declared.

Contributor Information

Daniel A Wilkenfeld, Department of Acute and Tertiary Care, University of Pittsburgh School of Nursing, USA.

Christa M Johnson, Department of Philosophy, University of Dayton, United States of America.

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UK doctor admits trying to kill his mother's partner with poison disguised as a COVID-19 vaccine

A British doctor has admitted trying to kill his mother’s long-term partner by injecting him with poison disguised as a COVID-19 vaccine

LONDON -- A British doctor on Monday admitted trying to kill his mother’s long-term partner, who stood between him and an inheritance, by injecting the man with poison disguised as a COVID-19 vaccine.

Prosecutors say Thomas Kwan pretended to be a community nurse delivering booster shots and injected Patrick O’Hara with a toxic substance, likely a pesticide. O’Hara, 72, developed a rare flesh-eating disease that left him in intensive care.

Kwan, 53, initially denied attempted murder but changed his plea to guilty after prosecutors laid out their case at Newcastle Crown Court in northeast England.

Prosecutor Thomas Makepeace told the court that Kwan was a “respected and experienced” family doctor based in Sunderland, about 15 miles (24 kilometers) from Newcastle. The lawyer said Kwan used his “encyclopedic knowledge” of poisons in his plot to kill O’Hara, who was “a potential impediment to Mr. Kwan inheriting his mother’s estate upon her death.”

Makepeace said Kwan forged documentation, used a vehicle with fake license plates and disguised himself with head-to-toe protective clothing, tinted glasses and a surgical mask to visit the home in Newcastle that O’Hara shared with Kwan’s mother, Jenny Leung, in January.

“As I suspect, would any of us, Mr. O’Hara fell for it hook, line and sinker,” the prosecutor said.

The next day, in pain and with a blistered arm, O’Hara went to a hospital, where he was diagnosed with necrotizing fasciitis. Part of his arm was cut away to stop it spreading, and O’Hara spent several weeks in intensive care.

Kwan was identified with the help of surveillance camera footage. Police who searched his home found an array of chemicals, including arsenic and liquid mercury, as well as castor beans which can be used to make the chemical weapon ricin.

Police have not been able to confirm what substance was used.

Christopher Atkinson of the Crown Prosecution Service said Kwan had refused to identify the poison, “allowing the victim’s health to further deteriorate.”

“While the attempt on his victim’s life was thankfully unsuccessful, the effects were still catastrophic," he said.

Kwan will be sentenced later.

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