latest research on covid vaccine effectiveness

The Updated COVID Vaccines Are Here: 9 Things to Know

BY KATHY KATELLA April 19, 2024

[Originally published: Oct. 2, 2023. Updated: April 19, 2024.]

Note: Information in this article was accurate at the time of original publication. Because information about COVID-19 changes rapidly, we encourage you to visit the websites of the Centers for Disease Control & Prevention (CDC), World Health Organization (WHO), and your state and local government for the latest information.

There has been better protection against severe disease, hospitalization, and death from COVID-19 since newly updated (2023–2024 formula) mRNA COVID vaccines became available last fall. Shots are available to protect everyone 6 months and older from serious illness, hospitalization, and death from the disease.

The Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) approved the updated vaccines by Pfizer-BioNTech and Moderna for everyone 6 months and older, and authorized an updated Novavax vaccine for those 12 and older in the fall of 2023. In February of this year, the CDC recommended an additional dose for adults ages 65 and older.

The vaccines target XBB.1.5, a subvariant of Omicron that dominated the United States—and the world—from November 2021 until last year. The CDC says the updated vaccines should also work against currently circulating variants of the SARS-CoV-2 virus—many of which descended from, or are related to, the XBB strain. The vaccine is also expected to protect against JN.1, the current dominant strain in the U.S.

While COVID has been causing mostly mild illness recently, Yale Medicine infectious diseases specialist Onyema Ogbuagu, MBBCh , reminds people that the disease can still lead to hospitalization and death. “Infections can have long-term consequences,” Dr. Ogbuagu says, adding that even healthy people can develop Long COVID —a condition in which new, continuing, or recurring (and sometimes debilitating) symptoms are present four or more weeks after an initial coronavirus infection.

Below, Yale experts tell you what you need to know about the updated COVID vaccine.

1. Why would another COVID vaccination help?

The updated vaccines are not expected to prevent all cases of COVID, including those causing mild illness; rather, their aim is to reduce severe illness, hospitalization, and death from infection. According to the CDC, COVID is still a major cause of serious respiratory illness. While hospitalizations and deaths from COVID have been declining, 7,318 people were hospitalized with the disease during the first week of April 2024 alone (that number rose as high as 35,000 during one week in January, a month when respiratory diseases tend to peak).

Older people (especially those ages 50 and older) are more likely than younger people to get very sick from COVID. Immunocompromised people and those with chronic medical conditions, such as diabetes or heart disease, are at the highest risk of severe disease and death, but some young, healthy people have also gotten very ill and died from COVID. In addition, the CDC recommends the vaccine for pregnant women to protect both mother and baby.

An analysis by the CDC in September 2023 suggested that making its vaccine recommendation universal could prevent 400,000 hospitalizations and 40,000 deaths in the U.S. over the next two years.

2. How is the updated COVID vaccine different from the previous one?

The bivalent booster, which is no longer available, was introduced in the fall of 2022. It targeted the BA.4 and BA.5 Omicron subvariants and the original SARS-CoV-2 virus. The updated vaccine is monovalent, designed to prevent severe disease from the Omicron XBB.1.5 subvariant. By September 2023, the long-running XBB.1.5 accounted for only about 3% of cases in the U.S., but most of the strains circulating now are descended from (or closely related to) it.

That’s a good example of how the virus has evolved—and it’s still evolving—so rapidly that it may be impossible to match each new vaccine update to the variants circulating at the time it is released, explains Scott Roberts, MD , a Yale Medicine infectious diseases specialist. “But we know from experience that the vaccines hold up very well, even against multiple variants, unless there is a significant shift like we saw with Delta to Omicron in the winter of 2021,” he says. “Basically, if you have some immunity to a variant and are exposed to a new offshoot of it, you’ll have some protection.”

3. Why isn’t the new COVID vaccine considered a booster?

The FDA is calling the newest shots “updated vaccines” in anticipation of needing to provide updated formulas annually, similar to the flu shot, which changes each year.

A booster shot gives a “boost” to the recipient's existing immunity from a previous vaccination. Updated vaccines are different in that they are expected to provide protection against currently circulating variants, helping the body build a new response to those variants. “Barring the emergence of a markedly more virulent variant, the FDA anticipates that the composition of COVID vaccines may need to be updated annually, as is done for the seasonal influenza vaccine,” the FDA noted in its approval and authorization of the new vaccine.

“I think we're going to fall into a pattern very similar to the flu, where every year the virus is going to mutate slightly, and the vaccine formulation for the fall will be an educated guess,” says Dr. Roberts. “We will make a vaccine targeted against whatever we predict or whatever is currently circulating and hope our vaccines are a good match, because we will be developing them before we know what variants will be circulating in the fall."

4. How safe is the updated COVID vaccine?

COVID vaccines are safe and effective, according to the CDC . The safety of COVID vaccines has been rigorously monitored and evaluated since their emergency use authorization (EUA) in December 2020. According to the CDC, the updated mRNA COVID vaccines for 2023-2024 are manufactured using a similar process to the previous vaccines.

The benefits of the COVID vaccine continue to outweigh any potential risks, and serious reactions after COVID vaccination are rare, according to the CDC. The agency cited a study showing the risk of cardiac complications, including myocarditis (an inflammation of the heart muscle) was significantly higher after a COVID infection for both males and females in all age groups.

5. Are there any special COVID vaccine recommendations for children?

The FDA approved the updated mRNA vaccines for adolescents and teenagers ages 12 and older and authorized them for emergency use in children ages 6 months through 11 years.

Children are less likely to get seriously ill with COVID, but some still do, says Magna Dias, MD , a Yale Medicine pediatric hospitalist. She tells parents who are still not sure whether they should get the vaccine for their children to talk to their pediatrician, especially if their child is immunocompromised. “In that case, I think it’s a no-brainer to protect them,” she says.

6. Is there an updated COVID vaccine from Novavax?

The FDA authorized an updated version of a vaccine Novavax developed to target the XBB.1.5 strain. Individuals 12 and older previously vaccinated with a COVID vaccine (and who have not already been vaccinated with a recently updated mRNA COVID vaccine) are eligible to receive one dose; unvaccinated individuals can receive two doses.

According to the FDA , the updated vaccine addresses currently circulating variants to provide better protection against serious consequences of COVID, including hospitalization and death.

The Pfizer-BioNTech and Moderna vaccines use messenger RNA (mRNA) technology, which instructs the body’s cells to make proteins that trigger an immune response against COVID. The Novavax protein-based vaccine uses an older, more traditional technology and a different mechanism—it directly injects the spike protein (formulated in a laboratory) and another ingredient into the body, leading to the production of virus-fighting antibodies and T cells. The Novavax vaccine is the only non-mRNA COVID vaccine available in the U.S.

7. When should I get the updated COVID vaccine?

People 5 years and older may get one dose of the updated vaccine at least two months after the last dose of any previous COVID vaccine. Babies and young children usually need more doses than older children and teens. Anyone who recently had COVID may consider delaying their vaccine by 3 months.

People who are 65 or older should receive their second dose of the updated vaccine at least four months after the first dose. Those in that age group who are immunocompromised should get the additional dose earlier—at least 2 months after the first one.

8. Should I get the updated COVID vaccine and other seasonal shots at the same time?

The CDC considers it safe to get the COVID shot and annual flu vaccine simultaneously. There is even research in progress to explore the effects of administering both vaccines in a single shot.

But the respiratory syncytial virus (RSV) vaccines for older adults and pregnant women (who can pass the antibodies along to their newborns) were brand new in fall 2023, and there isn’t data to say for sure whether giving those at the same time as the other two shots is the best strategy.

9. Where can I get the updated COVID vaccine?

As with previous COVID vaccines, this one will be available at participating pharmacies and provider offices. To find a location near you that carries the vaccine and to schedule an appointment, go to Vaccines.gov . You can also call 1-800-232-0233 (TTY 1-888-720-7489). Be aware that current distribution and insurance issues may delay availability of the vaccines temporarily in some places.

According to the CDC, the vaccines are covered by insurance, including private insurance, Medicare plans, and Medicaid plans. Uninsured children and uninsured adults also have access through the Vaccine for Children Program and Bridge Access Program , respectively.

Information provided in Yale Medicine articles is for general informational purposes only. No content in the articles should ever be used as a substitute for medical advice from your doctor or other qualified clinician. Always seek the individual advice of your health care provider with any questions you have regarding a medical condition.

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Cochrane review of COVID-19 vaccines shows they are effective

A comprehensive review of all the evidence available from randomised controlled trials of COVID 19 vaccines up to November 2021 has concluded that most protect against infection and severe or critical illness caused by the virus.

The review, a collaboration of independent, international experts, also found there was little or no difference between the number of people experiencing serious side effects after vaccination compared to those who were unvaccinated.

The researchers, led by Isabelle Boutron, Professor of Epidemiology at Universit é Paris Cité and Director of Cochrane France, analysed published data from 41 randomised controlled trials of 12 different COVID-19 vaccines, involving 433,838 people in various countries around the world. They assessed the certainty of the evidence and the risk of bias in the different studies.

The trials compared COVID-19 vaccines with placebo, no vaccine, or each other, and were published before 5 November 2021.  The vaccines investigated were: Pfizer/BioNTech, Moderna, Oxford-AstraZeneca, Bharat (Covaxin), Janssen, Sinopharm-Beijing (WIBP-CorV and BBIBP-CorV), Novavax, Coronavac-Sinovac, Soberana 2 (Finlay-FR-2), Sputnik V (Gam-COVID-Vac) and Cure Vac AG (CVnCoV).  Most trials were no longer than two months in length.

The review found that the following vaccines reduced or probably reduced the risk of COVID-19 infection compared to placebo: Pfizer/BioNTech, Moderna, CureVac COVID-19, Oxford-AstraZeneca, Janssen, Sputnik V (Gam-COVID-Vac), Sinopharm (WIBP CorV and BBIBP-CorV), Bharat (Covaxin), Novavax and Soberana 2 (Finlay-FR-2) . The following reduced or probably reduced the risk of severe or critical disease: Pfizer/BioNTech, Moderna, Janssen, Sputnik V, Bharat and Novavax. In addition, the Janssen and Soberana 2 vaccines probably decreased the risk of death from any cause. There were very few deaths recorded in all the trials and so evidence on mortality for the other vaccines is uncertain.

For most of the vaccines investigated, more people who had been vaccinated reported localised or temporary side effects compared to those who had no treatment or placebo. These included tiredness, headache, muscle pains, chills, fever and nausea. With respect to the very rare side effects associated with some vaccines such as thrombosis, the team found that the reporting of these events was inconsistent, and the number of events reported in the trials was very low.

Given the evidence of efficacy of these vaccines, the researchers question whether further placebo-controlled trials are ethical. They suggest that further research compares new vaccines with those already in use.

The current review analysed data available up to November 2021. Since then, analyses have been updated and will continue to be made publicly available every two weeks by the COVID-NMA Initiative , which provides live mapping of COVID-19 trials. A living, systematic review of clinical trials is available to researchers and policy-makers alike on the COVID-NMA platform. This enables the team to provide the most up-to-date evidence on which to base further research and decisions about prevention and treatment for COVID-19.

Prof. Boutron said:

“The evidence on COVID-19 vaccines is constantly changing and updating. Everything moves so quickly that by the time the next Cochrane review is published, or other papers are published, the data are likely to be out of date. There are more than 600 randomised trials of vaccines registered at present, and about 200 of them are recruiting. COVID-NMA is the only initiative that continues to monitor the developing evidence from trials and provides a platform for researchers to conduct their own analyses via the metaCOVID tool on the website. Researchers, clinicians and policy-makers have to take very rapid decisions about what to do to prevent and treat COVID-19. I hope that this initiative will help them to have access to the most up-to-date evidence on which to base their decisions.”

• Read the plain language summary and full review  
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• How to talk about vaccines when you’re not an expert: a Lifeology and Cochrane collaboration
• Evidently Cochrane Blog : Are COVID-19 vaccines effective and safe? New Cochrane evidence

Full citation: Graña C, Ghosn L, Evrenoglou T, Jarde A, Minozzi S, Bergman H, Buckley BS, Probyn K, Villanueva G, Henschke N, Bonnet H, Assi R, Menon S, Marti M, Devane D, Mallon P, Lelievre J-D, Askie LM, Kredo T, Ferrand G, Davidson M, Riveros C, Tovey D, Meerpohl JJ, Grasselli G, Rada G, Hróbjartsson A, Ravaud P, Chaimani A, Boutron I. Efficacy and safety of COVID-19 vaccines. Cochrane Database of Systematic Reviews TBD, Issue TBD. Art. No.: CD015477. DOI: 10.1002/14651858.CD015477.

About Cochrane Cochrane is a global independent network of researchers, professionals, patients, carers, and people interested in health. Cochrane produces reviews which study all of the best available evidence generated through research and make it easier to inform decisions about health. These are called systematic reviews. Cochrane is a not-for profit organization with collaborators from more than 130 countries working together to produce credible, accessible health information that is free from commercial sponsorship and other conflicts of interest. Our work is recognized as representing an international gold standard for high quality, trusted information.  https://www.cochrane.org/

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Disclaimer: The Spanish COVID-19 site is currently undergoing significant updates which may lead to a delay in translated content. We apologize for any inconvenience.

COVID-19 Vaccine Effectiveness

Vaccine effectiveness is a measure of how well vaccination works under real-world conditions to protect people against health outcomes such as infection, symptomatic illness, hospitalization, and death.

Results of vaccine effectiveness studies are critical to the CDC’s vaccine program and national vaccine policy decision-making.

The overall goal of CDC’s vaccine effectiveness program is to generate the comprehensive evidence needed to inform COVID-19 vaccine policy decisions and CDC guidance on other prevention measures. To accomplish this, CDC in collaboration with public health and academic partners, conducts observational studies  to evaluate the real-world effectiveness of authorized and licensed COVID-19 vaccines in the United States.

These studies generate data on how well vaccines work according to:

• Age group (e.g., young children, adolescents, adults, and adults ages 65 and older)
• Risk group (e.g., people with underlying health conditions and pregnant women)
• Risk setting (e.g., residents of long-term care facilities and healthcare workers)
• Outcome (e.g., against severe outcomes, such as hospitalization or death; and milder outcomes, such as symptomatic infection)
• Vaccine product (e.g., original monovalent, bivalent, or updated [2023-24] monovalent)
• Vaccine dose (e.g., primary series, additional doses, time since last dose)

CDC is committed to routinely evaluating vaccine effectiveness to detect changes that could be due to:

• Emerging SARS-CoV-2 variants
• Waning of vaccine protection

This work helps CDC identify population subgroups who may benefit from additional doses in the future.

Updates summarizing the results of CDC led vaccine effectiveness evaluations are provided on COVID Data Tracker .

Guiding Principles for Monitoring Vaccine Effectiveness

Goals of CDC’s COVID-19 vaccine effectiveness program are to evaluate existing COVID-19 vaccines and inform decisions by the  U.S. Advisory Committee on Immunization Practices  regarding COVID-19 vaccine policy. CDC accomplishes these goals by:

• Assessing COVID-19 vaccine effectiveness in key populations and against key outcomes (see below)
• Provide timely data to evaluate effectiveness of new vaccine recommendations
• Detecting changes in COVID-19 vaccine effectiveness due to waning of vaccine-induced protection and emergence of new variants
• Including populations at high risk for severe COVID-19
• Communicating findings to policy makers, the scientific community, the public, and other stakeholders

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• Introduction
• Conclusions
• Article Information

CLI indicates COVID-19–like illness; ICU, intensive care unit; VE, vaccine effectiveness.

VE estimates were adjusted for age, geographic region, calendar time (days since January 1, 2021), and local virus circulation (percentage of SARS-CoV-2–positive test results from testing within the counties surrounding the facility on the date of the encounter) and weighted for inverse propensity to be vaccinated or unvaccinated (calculated separately for each VE estimate). Generalized boosted regression trees were used to estimate the propensity to be vaccinated based on the following sociodemographic, facility, and medical factors: age, sex, race, ethnicity, Medicaid status, calendar date, geographic region, local SARS-CoV-2 circulation on the day of each medical visit, urban-rural classification of facility, hospital type, number of hospital beds, chronic respiratory condition, chronic nonrespiratory condition, asthma, chronic obstructive pulmonary disease, other chronic lung disease, heart failure, ischemic heart disease, hypertension, other heart disease, stroke, other cerebrovascular disease, diabetes type 1, diabetes type 2, diabetes due to underlying conditions or other specified diabetes, other metabolic disease (excluding diabetes), clinical obesity, clinical underweight, kidney disease, liver disease, blood disorder, dementia, other neurological/musculoskeletal disorder, Down syndrome, and the presence of at least 1 prior molecular or rapid antigen SARS-CoV-2 test record documented in the electronic medical record at least 15 days before the medical encounter date (prevaccination, if vaccinated). VE estimates are not shown for vaccination status comparisons with CIs greater than 50 percentage points around the VE estimate. Adjusted VE could not be calculated for 1 subgroup due to lack of model convergence: hospitalizations, 50-64 years, 2 doses (14-149 days earlier). In vaccination status subgroups with fewer than 10 patients with SARS-CoV-2–positive test results, all numbers in the row were removed because of small cell sizes. ED indicates emergency department; NA, not available; UC, urgent care.

eAppendix 1. Supplementary Methods

eTable 1. Characteristics of VISION Network Study Sites

eTable 2. COVID-19–Like Illness Categories and Corresponding International Classification of Diseases, Ninth Revision ( ICD-9 ), and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision ( ICD-10 ), Diagnosis Codes

eTable 3. Covariates with Remaining Imbalances Between Vaccinated and Unvaccinated Patients After Application of Inverse Propensity-to-Be-Vaccinated Weighting for Calculation of Adjusted Odds Ratios

eTable 4. Relative Vaccine Effectiveness Associated With Protection Against Laboratory-Confirmed COVID-19–Associated Emergency Department or Urgent Care Encounters of 3 vs 2 or 4 vs 3 mRNA COVID-19 Vaccine Doses, by Age Group

eTable 5. Relative Vaccine Effectiveness Associated With Protection Against Laboratory-Confirmed COVID-19–Associated Hospitalization of 3 vs 2 or 4 vs 3 mRNA COVID-19 Vaccine Doses, by Age Group

eFigure 1. Flowchart for the Selection of Emergency Department and Urgent Care Encounters

eFigure 2. Effectiveness Associated With mRNA COVID-19 Vaccine for Protection Against Laboratory-Confirmed COVID-19–Associated Emergency Department or Urgent Care Encounters and Hospitalization Among All Adults

eFigure 3. Effectiveness Associated With mRNA COVID-19 Vaccine for Protection Against Laboratory-Confirmed COVID-19–Associated Intensive Care Unit Admission and/or In-Hospital Death, by Age Group

eFigure 4. Effectiveness Associated With mRNA COVID-19 Vaccine for Protection Against Laboratory-Confirmed COVID-19–Associated Emergency Department or Urgent Care Encounters, by mRNA Vaccine Product(s) Received

eFigure 5. Effectiveness Associated With mRNA COVID-19 Vaccine for Protection Against Laboratory-Confirmed COVID-19–Associated Hospitalization, by mRNA Vaccine Product Received

eFigure 6. Effectiveness Associated With mRNA COVID-19 Vaccine for Protection Against Laboratory-Confirmed COVID-19–Associated Intensive Care Unit Admission and/or In-Hospital Death, by mRNA Vaccine Product Received

eFigure 7. Effectiveness Associated With mRNA COVID-19 Vaccine for Protection Against Laboratory-Confirmed COVID-19–Associated Emergency Department or Urgent Care Encounters, by Age Group, Among Patients Without a Prior Documented SARS-CoV-2 Infection

eFigure 8. Effectiveness Associated With mRNA COVID-19 Vaccine for Protection Against Laboratory-Confirmed COVID-19–Associated Hospitalization, by Age Group, Among Patients Without a Prior Documented SARS-CoV-2 Infection

eFigure 9. Effectiveness Associated With mRNA COVID-19 Vaccine for Protection Against Laboratory-Confirmed COVID-19–Associated Intensive Care Unit Admission and/or In-Hospital Death, by Age Group, Among Patients Without a Prior Documented SARS-CoV-2 Infection

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Link-Gelles R , Levy ME , Natarajan K, et al. Estimation of COVID-19 mRNA Vaccine Effectiveness and COVID-19 Illness and Severity by Vaccination Status During Omicron BA.4 and BA.5 Sublineage Periods. JAMA Netw Open. 2023;6(3):e232598. doi:10.1001/jamanetworkopen.2023.2598

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Estimation of COVID-19 mRNA Vaccine Effectiveness and COVID-19 Illness and Severity by Vaccination Status During Omicron BA.4 and BA.5 Sublineage Periods

• 1 Centers for Disease Control and Prevention COVID-19 Response Team, Atlanta, Georgia
• 2 Westat, Rockville, Maryland
• 3 Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York
• 4 New York–Presbyterian Hospital, New York, New York
• 5 Kaiser Permanente Center for Health Research, Portland, Oregon
• 6 Center for Biomedical Informatics, Regenstrief Institute, Indianapolis, Indiana
• 7 School of Medicine, Indiana University, Indianapolis
• 8 Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California Division of Research, Oakland
• 9 HealthPartners Institute, Minneapolis, Minnesota
• 10 Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora
• 11 Baylor Scott and White Health, Temple, Texas
• 12 Texas A&M University College of Medicine, Temple
• 13 Paso del Norte Health Information Exchange, El Paso, Texas
• 14 Division of Infectious Diseases and Clinical Epidemiology, Intermountain Healthcare, Salt Lake City, Utah
• 15 Children’s Minnesota, Minneapolis
• 16 Fairbanks School of Public Health, Indiana University, Indianapolis
• 17 Department of Public Health, Brigham Young University, Provo, Utah
• 18 Department of Internal Medicine, Division of Infectious Disease, Columbia University Irving Medical Center, New York, New York
• 19 Vanderbilt University Medical Center, Nashville, Tennessee

Question   What is the estimated vaccine effectiveness (VE) associated with first-generation COVID-19 mRNA vaccines against medically attended COVID-19 during Omicron BA.4 and BA.5 sublineage predominance?

Findings   This case-control study included 82 229 emergency department or urgent care encounters and 21 007 hospitalizations for COVID-19–like illness. Among hospitalized patients, estimated 3-dose VE was 68% for those with the third dose 7 to 119 days prior, but was lower by 120 days or longer after vaccination (VE, 36%).

Meaning   These findings suggest that first-generation COVID-19 mRNA vaccines were associated with protection against COVID-19 during the Omicron BA.4/BA.5 sublineage-predominant periods but protection declined over time.

Importance   Recent SARS-CoV-2 Omicron variant sublineages, including BA.4 and BA.5, may be associated with greater immune evasion and less protection against COVID-19 after vaccination.

Objectives   To evaluate the estimated vaccine effectiveness (VE) of 2, 3, or 4 doses of COVID-19 mRNA vaccination among immunocompetent adults during a period of BA.4 or BA.5 predominant circulation; and to evaluate the relative severity of COVID-19 in hospitalized patients across Omicron BA.1, BA.2 or BA.2.12.1, and BA.4 or BA.5 sublineage periods.

Design, Setting, and Participants   This test-negative case-control study was conducted in 10 states with data from emergency department (ED) and urgent care (UC) encounters and hospitalizations from December 16, 2021, to August 20, 2022. Participants included adults with COVID-19–like illness and molecular testing for SARS-CoV-2. Data were analyzed from August 2 to September 21, 2022.

Exposures   mRNA COVID-19 vaccination.

Main Outcomes and Measures   The outcomes of interest were COVID-19 ED or UC encounters, hospitalizations, and admission to the intensive care unit (ICU) or in-hospital death. VE associated with protection against medically attended COVID-19 was estimated, stratified by care setting and vaccine doses (2, 3, or 4 doses vs 0 doses as the reference group). Among hospitalized patients with COVID-19, demographic and clinical characteristics and in-hospital outcomes were compared across sublineage periods.

Results   During the BA.4 and BA.5 predominant period, there were 82 229 eligible ED and UC encounters among patients with COVID-19–like illness (median [IQR] age, 51 [33-70] years; 49 682 [60.4%] female patients), and 19 114 patients (23.2%) had test results positive for SARS-CoV-2; among 21 007 hospitalized patients (median [IQR] age, 71 [58-81] years; 11 209 [53.4%] female patients), 3583 (17.1 %) had test results positive for SARS-CoV-2. Estimated VE against hospitalization was 25% (95% CI, 17%-32%) for receipt of 2 vaccine doses at 150 days or more after receipt, 68% (95% CI, 50%-80%) for a third dose 7 to 119 days after receipt, and 36% (95% CI, 29%-42%) for a third dose 120 days or more (median [IQR], 235 [204-262] days) after receipt. Among patients aged 65 years or older who had received a fourth vaccine dose, VE was 66% (95% CI, 53%-75%) at 7 to 59 days after vaccination and 57% (95% CI, 44%-66%) at 60 days or more (median [IQR], 88 [75-105] days) after vaccination. Among hospitalized patients with COVID-19, ICU admission or in-hospital death occurred in 21.4% of patients during the BA.1 period vs 14.7% during the BA.4 and BA.5 period (standardized mean difference: 0.17).

Conclusions and Relevance   In this case-control study of COVID-19 vaccines and illness, VE associated with protection against medically attended COVID-19 illness was lower with increasing time since last dose; estimated VE was higher after receipt of 1 or 2 booster doses compared with a primary series alone.

COVID-19 vaccines are estimated to have prevented tens of thousands of COVID-19–associated hospitalizations and deaths in the US. 1 However, over the course of the pandemic new SARS-CoV-2 variants have continued to emerge and evade vaccine-induced immunity. 2 Following a Delta variant–predominant period, the Omicron BA.1 sublineage became predominant in the United States by December 2021. Compared with earlier SARS-CoV-2 variants, BA.1 demonstrated increased transmissibility and immune evasion with a reduction in vaccine effectiveness (VE) offset by COVID-19 vaccine booster doses. 3 , 4 Omicron has since diversified into additional sublineages, including several with greater immune escape potential compared with BA.1 (eg, BA.2.12.1, BA.4, and BA.5). 5 , 6 BA.4 and BA.5 sublineages, which share a common spike protein, became the predominant sublineages in the US in June 2022. 7

As new variants emerge, ongoing monitoring of VE is critical for informing public health strategies and policies. COVID-19 VE estimation has become increasingly complex as additional vaccine booster doses are authorized, vaccine-induced protection wanes over time, new variants or subvariants emerge, and most of the US population has experienced previous infection (57%-94%, depending on source). 8 - 12 In November 2021, all adults were recommended to receive a third (first booster) vaccine dose after a 2-dose primary series of mRNA vaccine; in March 2022, adults aged 50 years or older were recommended to receive a fourth dose (second booster) at least 4 months after dose 3. 13 In September 2022, bivalent mRNA vaccine booster doses for all individuals aged 12 years or older (Pfizer-BioNTech) and adults aged 18 years or older (Moderna) were recommended at least 2 months after completing a primary series or receiving a third dose. 14 Like first-generation vaccines, bivalent vaccines contain an mRNA component targeting the ancestral virus in addition to a new component targeting the BA.4 and BA.5 spike protein.

The objectives for this analysis were (1) to estimate the VE associated with first-generation mRNA vaccines (BNT162b2 from Pfizer-BioNTech and mRNA-1273 from Moderna) against medical encounters for COVID-19–related illness during a period of BA.4 and BA.5 Omicron sublineage predominance among adults without immunocompromising conditions and (2) to describe the characteristics and illness severity among hospitalized patients with COVID-19 during the Omicron BA.4- and BA.5-predominant period compared with prior Omicron sublineage periods (BA.1 and BA.2 or BA.2.12.1). Understanding changes in the epidemiology of COVID-19 and VE will inform interpretation of VE studies for recently authorized bivalent vaccines.

This case-control study was reviewed and approved by the institutional review boards at participating sites and under a reliance agreement between the Centers for Disease Control and Prevention (CDC) and the Westat institutional review board. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy (eg, 45 CFR part 46.102(l)(2), 21 CFR part 56; 42 USC §241(d); 5 USC §552a; 44 USC §3501). This study presented minimal risk to participants because there was no interaction or intervention with patients; therefore, a waiver of informed consent was granted. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

The VISION Network is a multistate collaboration between the CDC and health care systems with integrated medical, laboratory, and vaccination records. The VISION Network performs serial assessments of COVID-19 VE in emergency department (ED), urgent care (UC), and hospital settings using the test-negative case-control design. 15 Nine VISION Network health care systems in 10 states contributed data for this analysis (eTable 1 in Supplement 1 ), including 268 hospitals, 292 EDs, and 140 UC clinics.

To calculate estimated VE, we assessed ED and UC encounters and hospitalizations with 1 or more discharge codes related to COVID-19–like illness ( International Classification of Diseases, Ninth Revision [ ICD-9 ] and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ ICD-10 ]) (eTable 2 in Supplement 1 ) and a molecular test (primarily reverse transcription–polymerase chain reaction [RT-PCR] assay) for SARS-CoV-2 performed within 14 days before or up to less than 72 hours after the encounter during a BA.4- and BA.5-predominant period prior to authorization of bivalent booster doses, June 19 to August 20, 2022. Site-specific start dates were defined from local sequencing data when the combined prevalence of BA.4 and BA.5 was at least 50% and continued through the end of the study period (August 20, 2022). COVID-19 cases included patients with at least 1 COVID-19–like illness code and a positive SARS-CoV-2 molecular test result; controls included patients with at least 1 COVID-19–like illness code and a negative SARS-CoV-2 molecular test result.

For the comparison of severity by Omicron sublineage period, we included hospitalized patients with COVID-19 during BA.1 predominance (encounters December 2021 to March 2022), combined BA.2 and BA.2.12.1 (encounters March to June 2022), and BA.4 and BA.5 (encounters June to August 2022) sublineage-predominant periods. Baseline characteristics of hospitalized patients with COVID-19, including demographics, underlying medical conditions, prior vaccination and prior infection histories, and in-hospital outcomes (hospital length of stay, intensive care unit [ICU] admission, invasive mechanical ventilation, and in-hospital death within 28 days of admission), were obtained through electronic medical records and compared by period.

We included adults aged 18 years or older with a medical encounter related to COVID-19–like illness and SARS-CoV-2 molecular testing. COVID-19–like illness encounters include ICD-9 or ICD-10 codes for acute respiratory clinical diagnoses (eg, pneumonia, respiratory failure) or COVID-19–related signs or symptoms (eg, shortness of breath, cough, fever) during an UC or ED visit or a hospital admission with at least 24 hours’ duration. Repeat ED or UC visits within a 24-hour period or multiple hospital admissions that occurred within a 30-day period (from prior discharge) were combined into a single event with the earliest date used as the index date to determine vaccination status. One individual could contribute more than 1 event during the analysis period. Information on patients’ baseline characteristics, including demographic characteristics, such as race (Black, White, and other [eg, Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiracial, and other not listed]) and ethnicity (Hispanic and non-Hispanic), underlying medical conditions, and prior SARS-CoV-2 testing results, was obtained through the health systems’ electronic medical records and ICD-9 and ICD-10 codes. Only completed hospitalizations (ie, hospital events in which a patient was discharged or died) were included in this analysis.

COVID-19 vaccination status was ascertained through state or local immunization information systems, electronic medical records, and claims data. Only mRNA vaccines were considered in this analysis. Vaccination status was assigned using doses received prior to a medical encounter index date, defined as either the date of collection of a respiratory specimen associated with the most recent positive or negative SARS-CoV-2 test result before the medical visit or the date of the medical visit (if testing occurred only after the admission or visit date). Patients were considered unvaccinated if no mRNA vaccine doses were received before the index date; vaccinated with a primary series if 2 doses were received with the second dose at least 14 days before the index date; vaccinated with a first booster if 3 doses were received with the third dose at least 7 days before the index date; or, among patients aged at least 50 years, vaccinated with second booster if a fourth dose was received at least 7 days before the index date. Patients were excluded if they received a third or fourth dose before recommended for immunocompetent adults or received a dose with a shorter interval than recommended (ie, less than 5 months between second and third dose or less than 4 months between third and fourth dose). Patients were excluded if they received only 1 mRNA vaccine dose, received a non-mRNA vaccine (eg, viral vector), or had a likely immunocompromising condition, as previously defined. 16

The association of symptomatic laboratory-confirmed SARS-CoV-2 infection at an ED or UC encounter or hospitalization with vaccination status was estimated among individuals with COVID-19-like illness using multivariable logistic regression. Odds ratios (ORs) were calculated by comparing the odds of prior receipt of 2, 3, or 4 vaccine doses vs unvaccinated status (reference group) between patients with confirmed SARS-CoV-2 infection vs those with negative results from SARS-CoV-2 testing. VE was estimated as (1 – OR) × 100% for the ORs for 2, 3, and 4 doses vs unvaccinated against COVID-19–related ED or UC encounters or hospitalizations. To evaluate VE against more severe COVID-19, a further analysis was performed among hospitalized patients with COVID-19 comparing only patients who were admitted to the ICU or experienced in-hospital death with hospitalized controls. 17 Two-dose, 3-dose, and 4-dose VE estimates were further stratified by time periods since most recent vaccination dose (ie, 2-dose, 14-149 days; 2-dose, ≥150 days; 3-dose, 7-119 days; 3 dose, ≥120 days; 4-dose, 7-59 days; and 4-dose, ≥60 days).

In addition to estimating absolute VE (ie, VE for receipt of vaccine compared with unvaccinated), ORs were also calculated to estimate relative VE (rVE) to estimate the incremental benefit associated with receiving an additional vaccine dose when recommended. rVE was estimated by comparing individuals who had recently received 1 or 2 booster doses with those who were eligible for but had not received the respective booster dose, ie, persons who had received a third dose within the last 7 to 119 days vs persons who had received a second dose 150 or more days prior and persons who had received a fourth dose within the last 7 to 119 days vs persons who had received a third dose 120 or more days prior.

VEs were estimated separately among ED or UC encounters and hospitalizations for any combination of mRNA vaccine products and stratified by age group (18-49, 50-64, and ≥65 years). Two additional sensitivity analyses were conducted: stratified by vaccine product received and restricted to patients without a prior SARS-CoV-2 infection documented in electronic medical records.

All models included covariates for age, geographic region, calendar time, and level of local SARS-CoV-2 circulation (7-day moving mean of percentage of RT-PCR tests that were positive for SARS-CoV-2 within the medical facility’s geographic region). Age, calendar time, and SARS-CoV-2 circulation level covariates were specified as natural cubic spline functions with knots at quartiles. For models estimating the absolute OR, cases and controls were propensity score–weighted using the inverse probability of being vaccinated (if vaccinated) or unvaccinated (if not vaccinated). For models estimating relative ORs, a similar method was used based on patients’ inverse propensity to be 3-dose vs 2-dose vaccinated or 4-dose vs 3-dose vaccinated. Generalized boosted regression trees were used to estimate the propensity score for being vaccinated based on demographics, underlying medical conditions, and facility characteristics. Separate weights were calculated for each model and were truncated at the 99th percentile of the distribution of weights. After weighting, an absolute standardized mean difference (SMD) of 0.20 or less was taken to indicate a negligible difference in distributions of covariates by vaccination status. Any covariates with an SMD greater than 0.20 after weighting were also included in the model in addition to the a priori variables for the respective OR estimate to minimize residual confounding (eTable 3 in Supplement 1 ). Two-sided 95% CIs were calculated for each VE estimate, with 95% CIs that excluded 0 considered statistically significant. Nonoverlapping CIs were interpreted as statistically different VEs.

To describe outcomes of patients hospitalized with COVID-19 during the BA.4- and BA.5-predominant period compared with earlier sublineage periods, we restricted to hospitalized patients during BA.1, BA.2 and BA.2.12.1, and BA.4 and BA.5 periods who met aforementioned inclusion criteria. Baseline demographic, clinical, and vaccination characteristics and in-hospital outcomes were compared between patients with COVID-19 during BA.4 and BA.5 periods and those during other sublineage periods using SMDs.

Analyses were performed using R software version 4.1.2 (R Project for Statistical Computing) and SAS software version 9.4 (SAS Institute). Detailed methods are included in the eAppendix, eTable 1, and eTable 2 in Supplement 1 . Data were analyzed from August 2 to September 21, 2022.

Among 253 367 ED and UC encounters during the BA.4 and BA.5 period, there were 82 229 eligible ED or UC encounters related to COVID-19–like illness (median [IQR] patient age, 51 [33-70] years; 49 682 [60.4%] female patients) (eFigure 1 in Supplement 1 ); 19 114 encounters (23.2%) included a positive SARS-CoV-2 test result. Among eligible encounters, 12 872 (15.7%) were Hispanic patients, 10 300 (12.5%) were non-Hispanic Black patients, and 48 753 (59.3%) were non-Hispanic White patients ( Table 1 ). A total of 171 138 ED and UC encounters were excluded from analysis.

Among included ED and UC encounters, patients with COVID-19 were less likely to have received at least 1 booster dose compared with controls (6181 patients [32.3%] vs 26 437 patients [41.9%]) but were similar in age to controls (median [IQR] age, 50 [33-69] years vs 52 [30-70] years) ( Table 1 ). Among patients aged at least 50 years, 1097 patients with COVID-19 (11.4%) with ED or UC encounters had received a second booster (fourth dose) compared with 6565 patients without COVID-19 (19.6%).

Among 56 471 hospitalizations during the BA.4 and BA.5 period, there were 21 007 eligible hospitalizations (median [IQR] patient age, 71 [58-81] years; 11 209 [53.4%] female patients) included in the analysis ( Figure 1 ). A total of 3583 patients (17.1%) had a positive SARS-CoV-2 test result. There were 2370 Hispanic patients (11.3%), 2362 non-Hispanic Black patients (11.2%), and 13 620 non-Hispanic White patients (64.8%) ( Table 2 ). A total of 35 464 hospitalizations were excluded from analysis.

Hospitalized patients with COVID-19 were less likely to have received at least 1 booster dose compared with controls (1475 patients [41.2%] vs 8209 patients [47.1%]) and more likely to be older (median [IQR] age, 75 [62-83] vs 70 [57-80] years) ( Table 2 ). Among hospitalized patients aged 50 years or older, 324 patients with COVID-19 (10.3%) had received a second booster (fourth dose) compared with 2275 patients without COVID-19 (15.8%).

Among all 82 229 included ED and UC encounters, the estimated VE for prior receipt of 2 vaccine doses at least 150 days earlier (median [IQR], 424 [326-470] days) compared with unvaccinated was 28% (95% CI, 24%-31%) for all adults (eFigure 2 in Supplement 1 ). The estimated VE for a third dose 7 to 119 days earlier was 62% (95% CI, 54%-68%), but the estimated VE for the third dose at least 120 days earlier (median [IQR], 228 [197-257] days) was 32% (95% CI, 29%-36%), similar to that observed with the second dose at least 150 days earlier. Among patients aged 50 years or older eligible for a fourth dose, a fourth dose in the prior 7 to 59 days was associated with higher protection but associated protection also began to decline at 60 days, with a VE closer to null (ie, 0) ( Figure 2 ).

Among hospitalizations, the estimated VE for prior receipt of 2 vaccine doses at least 150 days earlier vs unvaccinated was 25% (95% CI, 17%-32%) (eFigure 2 in Supplement 1 ). A recent third dose was associated with higher protection (estimated VE, 68% [95% CI, 50%-80%]), but the estimated VE was closer to 0 at 120 days or longer after receipt of vaccine (estimated VE, 36% [95% CI, 29%-42%]), suggestive of waning effectiveness. Among adults aged 65 years or older, a fourth dose was associated with greater protection compared with a late third dose that was similar at 7 to 59 days (estimated VE, 66% [95% CI, 53%-75%]) and 60 days or longer (estimated VE, 57% [95% CI, 44%-66%]) after receipt of the fourth dose ( Figure 2 ). Estimated VEs were similar or higher against COVID-19–related ICU admission or in-hospital death and among patients aged 65 years or older who received a fourth dose (eFigure 3 in Supplement 1 ). In sensitivity analyses, findings were generally similar and with overlapping CIs between BNT162b2 and mRNA-1273 recipients (eFigures 4-6 in Supplement 1 ) and when restricted to patients without a documented laboratory-confirmed history of prior SARS-CoV-2 infection (eFigures 7-9 in Supplement 1 ).

Receipt of a third dose within the previous 7 to 119 days was associated with greater protection compared with completing 2 doses 150 or more days after receipt among all ED and UC encounters (estimated rVE, 49% [95% CI, 39%-58%]) and hospitalizations (estimated rVE, 57% [95% CI, 35%-72%]) (eTable 4 and eTable 5 in Supplement 1 ). Likewise, in adults aged 65 years or older, a recent fourth dose was associated with greater protection than a distant third dose among ED and UC encounters (estimated rVE, 35% [95% CI, 28%-41%]) and hospitalizations (estimated rVE, 37% [95% CI, 25%-46%]). There was not enough statistical power to calculate precise estimates for ICU admission or in-hospital death.

In addition to the 3547 hospitalized patients with COVID-19 included during the BA.4 and BA.5 period, there were 12 127 hospitalized patients with COVID-19 during the BA.1 period and 2698 hospitalized patients with COVID-19 during the BA.2 and BA.2.12.1 period ( Table 3 ). Baseline characteristics and outcomes of hospitalized patients with COVID-19 during the BA.4 and BA.5 and BA.2 and BA.2.12.1 periods were similar. However, compared with the BA.1 period, patients hospitalized with COVID-19 during the BA.4 and BA.5 period were older (median [IQR] age, 75 [62-83] vs 67 [54-78] years; SMD, 0.36) and more likely to be vaccinated (2284 patients [64.4%] vs 4349 patients [35.9%]; SMD across vaccination exposure groups, 1.19). The severity of cases during the BA.4 and BA.5 period was lower compared with the BA.1 period, with ICU admission occurring in 459 patients (12.9%) during the BA.4 and BA.5 period vs 2131 patients (17.6%) during the BA.1 period (SMD, 0.13), in-hospital death in 126 patients (3.6%) during the BA.4 and BA.5 period vs 1019 patients (8.4%) during the BA.1 period (SMD, 0.21), and shorter length of stay (median [IQR], 4 [2-7] vs 5 [3-9] days; SMD, 0.31).

In this case-control study using a multistate sample during Omicron BA.4 and BA.5 predominant circulation, first-generation COVID-19 vaccines were associated with effective protection against COVID-19, including for COVID-19–associated hospitalization and ICU admission or in-hospital death. However, protection associated with vaccination declined within several months of the most recent vaccine dose. For hospitalization, estimated VE of 3 doses for all adults and 4 doses for adults aged 50 years or older using an unvaccinated reference group was similar to that reported during BA.2 and BA.2.12.1 predominance. 18 In addition, changes in the epidemiology of hospitalized patients with COVID-19 were observed; 64% of patients hospitalized with COVID-19 during the BA.4- and BA.5-predominant period had received at least a primary vaccine series, compared with 36% of hospitalized patients during the earlier BA.1-predominant period, aligning with VE findings of lower effectiveness during the BA.4 and BA.5 period. Patients hospitalized during the recent BA.4- and BA.5-predominant period tended to have less severe illness compared with the earlier BA.1 period despite being older. These findings provide an important baseline for bivalent VE analyses. 19 , 20

Estimated VE was similar across outcomes, contradicting many past VE studies, including previous studies from the VISION Network, which have tended to show higher vaccine-associated protection for more severe outcomes. This could be due to changes in baseline population immunity (eg, most adults now have evidence of prior infection), changes in behavior (eg, decreased use of social distancing and masks during recent months), or residual confounding. 3 , 4 , 21 - 23 Across all outcomes, estimated VE in this analysis was lower than reported VE when the Delta variant and Omicron BA.1 sublineage predominated. 18 , 24 However, the relative contribution of immune evasion from newer variants vs other factors, such as influence of prior infections, on VE is unclear. 25 A 2022 report from South Africa 26 found that estimated VE against COVID-19–related hospitalization after receipt of 2 or 3 doses of BNT162b2 waned substantially within several months of vaccine receipt during BA.5-predominant circulation, which is similar to findings in this study. While this analysis did not find waning after the fourth dose, median time from fourth dose to the included encounter in our analysis was less than 3 months (compared with approximately 8 months after the third dose), so VE waning may become evident with increased follow-up time. Approved bivalent booster doses, which include the ancestral strain as well as an additional component targeting BA.4 and BA.5 variants, might provide greater protection against currently circulating variants, although data on VE for bivalent boosters are limited to date, and ongoing surveillance is warranted to guide public health practice and vaccine policy decisions. 19 , 20 The implications of these findings on potential vaccine protection for other emerging sublineages, such as XBB sublineages, which carry additional mutations in the spike protein, are unclear.

The finding of less severe disease during BA.4 and BA.5 predominance compared with earlier Omicron sublineage periods has important implications for interpretation of VE over time. Between December 2021 and February 2022, prevalence of infection-induced antibodies among clinical samples tested at commercial laboratories increased from 33.5% to 57.7%, indicating widespread infection-induced immunity by the end of the BA.1 predominant period. 8 Although VE against infection was substantially lower during Omicron compared with earlier periods, some protection remained, especially individuals who received booster doses, indicating that unvaccinated or unboosted individuals may have higher infection-induced protection compared with individuals who received recommended vaccinations. This increased infection-induced protection in unvaccinated and unboosted individuals, sometimes termed depletion of susceptibles , may bias VE estimates, accentuating waning. 27 VE estimates during BA.4 and BA.5 predominance should therefore be interpreted in the context of population immunity due to prior infection; measured VE is likely blunted by high infection-induced immunity in the unvaccinated and undervaccinated comparison groups, and waning may not be as substantial as estimated.

This analysis has several limitations. First, patient samples were not available for genomic characterization directly. Local prevalence estimates of BA.4 and BA.5, combined with date of testing, were used ecologically to determine inclusion in the analysis periods; however, as estimates of VE during BA.2 and BA.2.12.1 predominance are similar to this analysis, misclassifying some early cases as BA.4 and BA.5 should not have impacted VE estimates substantially. Second, because prior infection was likely underascertained, the primary analysis included all individuals, regardless of documented prior infection or time since documented prior infection, which may have biased results toward the null if prior infection is associated with some protection against reinfection or attenuation of severity if reinfected. Third, although inverse propensity-to-be-vaccinated weights were used to balance vaccinated and unvaccinated medical encounters, residual confounding in VE estimates due to other factors is possible. Fourth, this analysis combined estimated VE against ICU admission and death, which may have obscured differences in VE for these individual outcomes; other severe sequelae of COVID-19, such as postacute sequelae or post–COVID-19 condition were not included.

This case-control study among immunocompetent adults found that, compared with unvaccinated adults, the estimated VE of recently received third or fourth doses of an mRNA vaccine against ED or UC visits, hospitalization, and ICU admission or death was higher compared with 2 doses but waned during BA.4 and BA.5 variant predominance. Hospitalized patients with COVID-19 were less likely to be admitted to the ICU or experience in-hospital death and had shorter length of stay during BA.4 and BA.5 predominance compared with earlier Omicron sublineage periods.

Accepted for Publication: January 24, 2023.

Published: March 15, 2023. doi:10.1001/jamanetworkopen.2023.2598

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 Link-Gelles R et al. JAMA Network Open .

Corresponding Author: Ruth Link-Gelles, PhD, MPH, Centers for Disease Control and Prevention COVID-19 Response Team, 1600 Clifton Rd, Mailstop H24-5, Atlanta, GA 30329 ( [email protected] ).

Author Contributions: Drs Levy and Reese had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Link-Gelles, Levy, Naleway, Dascomb, Uhlemann, Fadel, Valvi, Embí, Tenforde.

Acquisition, analysis, or interpretation of data: Link-Gelles, Levy, Natarajan, Reese, Naleway, Grannis, Klein, DeSilva, Ong, Gaglani, Hartmann, Dickerson, Stenehjem, Kharbanda, Han, Spark, Irving, Dixon, Zerbo, McEvoy, Rao, Raiyani, Sloan, Patel, Dascomb, Dunne, Fadel, Lewis, Barron, Murthy, Nanez, Griggs, Grisel, Annavajhala, Akinseye, Goddard, Mamawala, Arndorfer, Yang, Embí, Fireman, Ball, Tenforde.

Drafting of the manuscript: Link-Gelles, Levy, Han, Spark, McEvoy, Yang, Tenforde.

Critical revision of the manuscript for important intellectual content: Link-Gelles, Levy, Natarajan, Reese, Naleway, Grannis, Klein, DeSilva, Ong, Gaglani, Hartmann, Dickerson, Stenehjem, Kharbanda, Irving, Dixon, Zerbo, McEvoy, Rao, Raiyani, Sloan, Patel, Dascomb, Uhlemann, Dunne, Fadel, Lewis, Barron, Murthy, Nanez, Griggs, Grisel, Annavajhala, Akinseye, Valvi, Goddard, Mamawala, Arndorfer, Embí, Fireman, Ball, Tenforde.

Statistical analysis: Link-Gelles, Levy, Reese, Han, Spark, Raiyani, Fadel, Murthy, Mamawala, Yang, Fireman.

Obtained funding: Klein, Ong, Irving, Goddard.

Administrative, technical, or material support: Link-Gelles, Levy, Natarajan, Grannis, Dickerson, Stenehjem, Irving, Dixon, Sloan, Patel, Dascomb, Dunne, Barron, Nanez, Griggs, Grisel, Goddard, Mamawala, Arndorfer, Embí, Ball, Tenforde.

Supervision: Link-Gelles, Levy, Grannis, Klein, Ong, Gaglani, Stenehjem, Dixon, McEvoy, Dascomb, Uhlemann, Embí, Tenforde.

Conflict of Interest Disclosures: Dr Natarajan reported receiving grants from Janssen during the conduct of the study. Dr Naleway reported receiving grants from Pfizer and Vir Biotechnology outside the submitted work. Dr Klein reported receiving grants from Pfizer, Merck, GSK, and Sanofi Pasteur outside the submitted work. Dr Gaglani reported receiving grants directly from the Centers for Disease Control and Prevention (CDC) and from the CDC via subcontracts from Abt Associates and Vanderbilt University Medical Center to her institution outside the submitted work. Dr Hartmann reported receiving personal fees from Westat outside the submitted work. Dr Dixon reported receiving grants from the CDC, National Institutes of Health, Agency for Healthcare Research and Quality, and the US Department of Veterans Affairs to his institution; personal fees from Elsevier and Springer Nature; and consulting fees from Merck outside the submitted work. Dr McEvoy reported receiving grants from AstraZeneca outside the submitted work. Dr Rao reported receiving grants from GSK and serving as a consultant for Sequiris outside the submitted work. Dr Uhlemann reported receiving grants from Merck outside the submitted work. Dr Irving reported receiving grants from the CDC to her institution outside the submitted work. Dr Murthy reported receiving grants from the CDC to his institution outside the submitted work. During the conduct of the study, all Westat- and Kaiser Permanente Northern California Division of Research–affiliated authors reported receiving contractual support from the CDC via payments made to their respective institutions. Additionally, all authors affiliated with Baylor Scott & White Health, Children’s Minnesota, Columbia University Irving Medical Center, HealthPartners Institute, Intermountain Healthcare, Kaiser Permanente Center for Health Research, Regenstrief Institute, University of Colorado Anschutz Medical Campus, Paso del Norte Health Information Exchange, and Vanderbilt University Medical Center reported receiving contractual support from the CDC during the conduct of the study, via subcontracts from Westat, with payments made to their respective institutions.

Funding/Support: This study was supported by the CDC through contract No. 75D30120C07986 to Westat and contract No. 75d30120c07765to Kaiser Foundation Hospitals.

Role of the Funder/Sponsor: The VISION Network Steering Committee and study staff designed the VISION Network. The analysis plan for this study was drafted by Westat in conjunction with CDC and VISION Network Steering Committee input. Data were exported from existing electronic health care records and managed by VISION Network staff at sites and transmitted to Westat. Data were stored centrally on secure Westat and CDC servers; the funder did not have access to personally identifiable information. Data management and statistical analyses were performed by Westat. Drs Link-Gelles, Levy, and Tenforde wrote the draft manuscript with revisions based on comments from the VISION Network Steering Committee and other coauthors.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: The VISION Network includes Westat: Elizabeth Bassett, BA; Bria Berry, MPH; Rebecca Birch, MPH; Kevin Cheng, BS; Sumathi Croos, BA; Jonathan Davis, PhD; Maria Demarco, PhD; Rebecca Fink, MPH; Carly Hallowell, MPH; Nina Hamburg, MBA; Alex Hughes, PhD; Jean Keller, MS; Salome Kiduko, MPH; Lindsey Kirshner, MPH; Magdalene Kish, BS; Victoria Lazariu, PhD; Yong Lee, BSEE; Vanessa Masick, MS; Thomas Mienk, MPA; Patrick Mitchell, ScD; Jean Opsomer, PhD; Weijia Ren, PhD; John Riddles, PhD; Elizabeth Rowley, DrPH; Anna Rukhlya; MA, Kristin Schrader, MA; Patricia Shifflett, MS; Brenda Sun, MS; Zachary Weber, PhD; and Yan Zhuang, PhD; Baylor Scott and White Health: Deepika Konatham, BS; I-Chia Liao, MPH; Deborah Hendricks; Jason Ettlinger, MA; Joel Blais, BTh; Elisa Priest, DrPH; Michael Smith, BS; Spencer Rose, BS; Natalie Settele, PA; Jennifer Thomas, MS; Muralidhar Jatla, MD; Madhava Beeram, MD; Javed Butler, MD; and Alejandro Arroliga, MD; School of Medicine, University of Colorado Anschutz Medical Campus, Health Data Compass: David Mayer, BS; Bryant Doyle; Briana Kille, PhD; and Catia Chavez, MPH; Regenstrief Institute: Ashley Wiensch, MPH, and Amy Hancock, MPA; Kaiser Permanente Center for Health Research: Padma Dandamudi, MPH; HealthPartners Institute: Inih Essien, OD; Sunita Thapa, MPH; and Sheryl Kane, BS; and Intermountain Healthcare: Bert Lopansri, MD.

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COVID-19 vaccines: Get the facts

Looking to get the facts about COVID-19 vaccines? Here's what you need to know about the different vaccines and the benefits of getting vaccinated.

As the coronavirus disease 2019 (COVID-19) continues to cause illness, you might have questions about COVID-19 vaccines. Find out about the different types of COVID-19 vaccines, how they work, the possible side effects, and the benefits for you and your family.

COVID-19 vaccine benefits

What are the benefits of getting a covid-19 vaccine.

Staying up to date with a COVID-19 vaccine can:

• Help prevent serious illness and death due to COVID-19 for both children and adults.
• Help prevent you from needing to go to the hospital due to COVID-19 .
• Be a less risky way to protect yourself compared to getting sick with the virus that causes COVID-19.
• Lower long-term risk for cardiovascular complications after COVID-19.

Factors that can affect how well you're protected after a vaccine can include your age, if you've had COVID-19 before or if you have medical conditions such as cancer.

How well a COVID-19 vaccine protects you also depends on timing, such as when you got the shot. And your level of protection depends on how the virus that causes COVID-19 changes and what variants the vaccine protects against.

Talk to your healthcare team about how you can stay up to date with COVID-19 vaccines.

Should I get the COVID-19 vaccine even if I've already had COVID-19?

Yes. Catching the virus that causes COVID-19 or getting a COVID-19 vaccination gives you protection, also called immunity, from the virus. But over time, that protection seems to fade. The COVID-19 vaccine can boost your body's protection.

Also, the virus that causes COVID-19 can change, also called mutate. Vaccination with the most up-to-date variant that is spreading or expected to spread helps keep you from getting sick again.

Researchers continue to study what happens when someone has COVID-19 a second time. Later infections are generally milder than the first infection. But severe illness can still happen. Serious illness is more likely among people older than age 65, people with more than four medical conditions and people with weakened immune systems.

Safety and side effects of COVID-19 vaccines

What covid-19 vaccines have been authorized or approved.

The COVID-19 vaccines available in the United States are:

• 2023-2024 Pfizer-BioNTech COVID-19 vaccine, available for people age 6 months and older.
• 2023-2024 Moderna COVID-19 vaccine, available for people age 6 months and older.
• 2023-2024 Novavax COVID-19 vaccine, available for people age 12 years and older.

These vaccines have U.S. Food and Drug Administration (FDA) emergency use authorization or approval.

In December 2020, the Pfizer-BioNTech COVID-19 vaccine two-dose series was found to be both safe and effective in preventing COVID-19 infection in people age 18 and older. This data helped predict how well the vaccines would work for younger people. The effectiveness varied by age.

The Pfizer-BioNTech vaccine is approved under the name Comirnaty for people age 12 and older. The FDA authorized the vaccine for people age 6 months to 11 years. The number of shots in this vaccination series varies based on a person's age and COVID-19 vaccination history.

In December 2020, the Moderna COVID-19 vaccine was found to be both safe and effective in preventing infection and serious illness among people age 18 or older. The vaccine's ability to protect younger people was predicted based on that clinical trial data.

The FDA approved the vaccine under the name Spikevax for people age 12 and older. The FDA authorized use of the vaccine in people age 6 months to 11 years. The number of shots needed varies based on a person's age and COVID-19 vaccination history.

In July 2022, this vaccine was found to be safe and effective and became available under an emergency use authorization for people age 18 and older.

In August 2022, the FDA authorized the vaccine for people age 12 and older. The number of shots in this vaccination series varies based on a person's age and COVID-19 vaccination history.

In August 2022, the FDA authorized an update to the Moderna and the Pfizer-BioNTech COVID-19 vaccines. Both included the original and omicron variants of the virus that causes COVID-19. In June 2023, the FDA directed vaccine makers to update COVID-19 vaccines. The vaccines were changed to target a strain of the virus that causes COVID-19 called XBB.1.5. In September and October 2023, the FDA authorized the use of the updated 2023-2024 COVID-19 vaccines made by Novavax, Moderna and Pfizer-BioNTech.

How do the COVID-19 vaccines work?

COVID-19 vaccines help the body get ready to clear out infection with the virus that causes COVID-19.

Both the Pfizer-BioNTech and the Moderna COVID-19 vaccines use genetically engineered messenger RNA (mRNA). The mRNA in the vaccine tells your cells how to make a harmless piece of virus that causes COVID-19.

After you get an mRNA COVID-19 vaccine, your muscle cells begin making the protein pieces and displaying them on cell surfaces. The immune system recognizes the protein and begins building an immune response and making antibodies. After delivering instructions, the mRNA is immediately broken down. It never enters the nucleus of your cells, where your DNA is kept.

The Novavax COVID-19 adjuvanted vaccine is a protein subunit vaccine. These vaccines include only protein pieces of a virus that cause your immune system to react the most. The Novavax COVID-19 vaccine also has an ingredient called an adjuvant that helps raise your immune system response.

With a protein subunit vaccine, the body reacts to the proteins and creates antibodies and defensive white blood cells. If you later become infected with the COVID-19 virus, the antibodies will fight the virus. Protein subunit COVID-19 vaccines don't use any live virus and can't cause you to become infected with the COVID-19 virus. The protein pieces also don't enter the nucleus of your cells, where your DNA is kept.

Can a COVID-19 vaccine give you COVID-19?

No. The COVID-19 vaccines available in the U.S. don't use the live virus that causes COVID-19. Because of this, the COVID-19 vaccines can't cause you to become sick with COVID-19.

It can take a few weeks for your body to build immunity after getting a COVID-19 vaccination. As a result, it's possible that you could become infected with the virus that causes COVID-19 just before or after being vaccinated.

What are the possible general side effects of a COVID-19 vaccine?

Some people have no side effects from the COVID-19 vaccine. For those who get them, most side effects go away in a few days.

A COVID-19 vaccine can cause mild side effects after the first or second dose. Pain and swelling where people got the shot is a common side effect. That area also may look reddish on white skin. Other side effects include:

• Fever or chills.
• Muscle pain or joint pain.
• Tiredness, called fatigue.
• Upset stomach or vomiting.
• Swollen lymph nodes.

For younger children up to age 4, symptoms may include crying or fussiness, sleepiness, loss of appetite, or, less often, a fever.

In rare cases, getting a COVID-19 vaccine can cause an allergic reaction. Symptoms of a life-threatening allergic reaction can include:

• Breathing problems.
• Fast heartbeat, dizziness or weakness.
• Swelling in the throat.

If you or a person you're caring for has any life-threatening symptoms, get emergency care.

Less serious allergic reactions include a general rash other than where you got the vaccine, or swelling of the lips, face or skin other than where you got the shot. Contact your healthcare professional if you have any of these symptoms.

You may be asked to stay where you got the vaccine for about 15 minutes after the shot. This allows the healthcare team to help you if you have an allergic reaction. The healthcare team may ask you to wait for longer if you had an allergic reaction from a previous shot that wasn't serious.

Contact a healthcare professional if the area where you got the shot gets worse after 24 hours. And if you're worried about any side effects, contact your healthcare team.

Are there any long-term side effects of the COVID-19 vaccines?

The vaccines that help protect against COVID-19 are safe and effective. Clinical trials tested the vaccines to make sure of those facts. Healthcare professionals, researchers and health agencies continue to watch for rare side effects, even after hundreds of millions of doses have been given in the United States.

Side effects that don't go away after a few days are thought of as long term. Vaccines rarely cause any long-term side effects.

If you're concerned about side effects, safety data on COVID-19 vaccines is reported to a national program called the Vaccine Adverse Event Reporting System in the U.S. This data is available to the public. The U.S. Centers for Disease Control and Protection (CDC) also has created v-safe, a smartphone-based tool that allows users to report COVID-19 vaccine side effects.

If you have other questions or concerns about your symptoms, talk to your healthcare professional.

Can COVID-19 vaccines affect the heart?

In some people, COVID-19 vaccines can lead to heart complications called myocarditis and pericarditis. Myocarditis is the swelling, also called inflammation, of the heart muscle. Pericarditis is the swelling, also called inflammation, of the lining outside the heart.

Symptoms to watch for include:

• Chest pain.
• Shortness of breath.
• Feelings of having a fast-beating, fluttering or pounding heart.

If you or your child has any of these symptoms within a week of getting a COVID-19 vaccine, seek medical care.

The risk of myocarditis or pericarditis after a COVID-19 vaccine is rare. These conditions have been reported after COVID-19 vaccination with any of the vaccines offered in the United States. Most cases have been reported in males ages 12 to 39.

These conditions happened more often after the second dose of the COVID-19 vaccine and typically within one week of COVID-19 vaccination. Most of the people who got care felt better after receiving medicine and resting.

These complications are rare and also may happen after getting sick with the virus that causes COVID-19. In general, research on the effects of the most used COVID-19 vaccines in the United States suggests the vaccines lower the risk of complications such as blood clots or other types of damage to the heart.

If you have concerns, your healthcare professional can help you review the risks and benefits based on your health condition.

Things to know before a COVID-19 vaccine

Are covid-19 vaccines free.

In the U.S., COVID-19 vaccines may be offered at no cost through insurance coverage. For people whose vaccines aren't covered or for those who don't have health insurance, options are available. Anyone younger than 18 years old can get no-cost vaccines through the Vaccines for Children program. Adults can get no-cost COVID-19 vaccines through the temporary Bridges to Access program, which is scheduled to end in December 2024.

Can I get a COVID-19 vaccine if I have an existing health condition?

Yes, COVID-19 vaccines are safe for people who have existing health conditions, including conditions that have a higher risk of getting serious illness with COVID-19.

The COVID-19 vaccine can lower the risk of death or serious illness caused by COVID-19. Your healthcare team may suggest that you get added doses of a COVID-19 vaccine if you have a moderately or severely weakened immune system.

Cancer treatments and other therapies that affect some immune cells also may affect your COVID-19 vaccine. Talk to your healthcare professional about timing additional shots and getting vaccinated after immunosuppressive treatment.

Talk to your healthcare team if you have any questions about when to get a COVID-19 vaccine.

Is it OK to take an over-the-counter pain medicine before or after getting a COVID-19 vaccine?

Don't take medicine before getting a COVID-19 vaccine to prevent possible discomfort. It's not clear how these medicines might impact the effectiveness of the vaccines. It is OK to take this kind of medicine after getting a COVID-19 vaccine, as long as you have no other medical reason that would prevent you from taking it.

Allergic reactions and COVID-19 vaccines

What are the signs of an allergic reaction to a covid-19 vaccine.

Symptoms of a life-threatening allergic reaction can include:

If you or a person you're caring for has any life-threatening symptoms, get emergency care right away.

Less serious allergic reactions include a general rash other than where you got the vaccine, or swelling of the lips, face or skin other than where the shot was given. Contact your healthcare professional if you have any of these symptoms.

Tell your healthcare professional about your reaction, even if it went away on its own or you didn't get emergency care. This reaction might mean that you are allergic to the vaccine. You might not be able to get a second dose of the same vaccine. But you might be able to get a different vaccine for your second dose.

Can I get a COVID-19 vaccine if I have a history of allergic reactions?

If you have a history of severe allergic reactions not related to vaccines or injectable medicines, you may still get a COVID-19 vaccine. You're typically monitored for 30 minutes after getting the vaccine.

If you've had an immediate allergic reaction to other vaccines or injectable medicines, ask your healthcare professional about getting a COVID-19 vaccine. If you've ever had an immediate or severe allergic reaction to any ingredient in a COVID-19 vaccine, the CDC recommends not getting that specific vaccine.

If you have an immediate or severe allergic reaction after getting the first dose of a COVID-19 vaccine, don't get the second dose. But you might be able to get a different vaccine for your second dose.

Pregnancy, breastfeeding and fertility with COVID-19 vaccines

Can pregnant or breastfeeding women get the covid-19 vaccine.

The CDC recommends getting a COVID-19 vaccine if:

• You are planning to or trying to get pregnant.
• You are pregnant now.
• You are breastfeeding.

Staying up to date on your COVID-19 vaccine helps prevent severe COVID-19 illness. It also may help a newborn avoid getting COVID-19 if you are vaccinated during pregnancy.

People at higher risk of serious illness can talk to a healthcare professional about additional COVID-19 vaccines or other precautions. It also can help to ask about what to do if you get sick so that you can quickly start treatment.

Children and COVID-19 vaccines

If children don't often experience severe illness with covid-19, why do they need a covid-19 vaccine.

While rare, some children can become seriously ill with COVID-19 after getting the virus that causes COVID-19 .

A COVID-19 vaccine might prevent your child from getting the virus that causes COVID-19 . It also may prevent your child from becoming seriously ill or having to stay in the hospital due to the COVID-19 virus.

After a COVID-19 vaccine

Can i stop taking safety precautions after getting a covid-19 vaccine.

You can more safely return to activities that you might have avoided before your vaccine was up to date. You also may be able to spend time in closer contact with people who are at high risk for serious COVID-19 illness.

But vaccines are not 100% effective. So taking other action to lower your risk of getting COVID-19 still helps protect you and others from the virus. These steps are even more important when you're in an area with a high number of people with COVID-19 in the hospital. Protection also is important as time passes since your last vaccination.

If you are at higher risk for serious COVID-19 illness, basic actions to prevent COVID-19 are even more important. Some examples are:

• Avoid close contact with anyone who is sick or has symptoms, if possible.
• Use fans, open windows or doors, and use filters to move the air and keep any germs from lingering.
• Wash your hands well and often with soap and water for at least 20 seconds. Or use an alcohol-based hand sanitizer with at least 60% alcohol.
• Cough or sneeze into a tissue or your elbow. Then wash your hands.
• Clean and disinfect high-touch surfaces. For example, clean doorknobs, light switches, electronics and counters regularly.
• Spread out in crowded public areas, especially in places with poor airflow. This is important if you have a higher risk of serious illness.
• The CDC recommends that people wear a mask in indoor public spaces if COVID-19 is spreading. This means that if you're in an area with a high number of people with COVID-19 in the hospital a mask can help protect you. The CDC suggests wearing the most protective mask possible that you'll wear regularly, that fits well and is comfortable.

Can I still get COVID-19 after I'm vaccinated?

COVID-19 vaccination will protect most people from getting sick with COVID-19. But some people who are up to date with their vaccines may still get COVID-19. These are called vaccine breakthrough infections.

People with vaccine breakthrough infections can spread COVID-19 to others. However, people who are up to date with their vaccines but who have a breakthrough infection are less likely to have serious illness with COVID-19 than those who are not vaccinated. Even when people who are vaccinated get symptoms, they tend to be less severe than those felt by unvaccinated people.

Researchers continue to study what happens when someone has COVID-19 a second time. Reinfections and breakthrough infections are generally milder than the first infection. But severe illness can still happen. Serious illness is more likely among people older than age 65, people with more than four medical conditions and people with weakened immune systems.

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• Brief Communication
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• Published: 29 April 2024

Influence of COVID-19 on trust in routine immunization, health information sources and pandemic preparedness in 23 countries in 2023

• Jeffrey V. Lazarus   ORCID: orcid.org/0000-0001-9618-2299 1 , 2 , 3 ,
• Trenton M. White 1 , 2 ,
• Katarzyna Wyka 1 ,
• Scott C. Ratzan 1 ,
• Kenneth Rabin 1 ,
• Heidi J. Larson   ORCID: orcid.org/0000-0002-8477-7583 4 , 5 ,
• Federico Martinon-Torres   ORCID: orcid.org/0000-0002-9023-581X 6 ,
• Ernest Kuchar 7 ,
• Salim S. Abdool Karim   ORCID: orcid.org/0000-0002-4986-2133 8 , 9 ,
• Tamara Giles-Vernick 10 ,
• Selina Müller   ORCID: orcid.org/0000-0003-0886-3487 11 ,
• Carolina Batista 12 , 13 ,
• Nellie Myburgh 14 ,
• Beate Kampmann 15 &
• Ayman El-Mohandes 1  

Nature Medicine ( 2024 ) Cite this article

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It is unclear how great a challenge pandemic and vaccine fatigue present to public health. We assessed perspectives on coronavirus disease 2019 (COVID-19) and routine immunization as well as trust in pandemic information sources and future pandemic preparedness in a survey of 23,000 adults in 23 countries in October 2023. The participants reported a lower intent to get a COVID-19 booster vaccine in 2023 (71.6%), compared with 2022 (87.9%). A total of 60.8% expressed being more willing to get vaccinated for diseases other than COVID-19 as a result of their experience during the pandemic, while 23.1% reported being less willing. Trust in 11 selected sources of vaccine information each averaged less than 7 on a 10-point scale with one’s own doctor or nurse and the World Health Organization, averaging a 6.9 and 6.5, respectively. Our findings emphasize that vaccine hesitancy and trust challenges remain for public health practitioners, underscoring the need for targeted, culturally sensitive health communication strategies.

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Infectious disease in an era of global change

The emergence of the severe acute respiratory syndrome coronavirus 2 virus in late 2019 precipitated a global health emergency that contributed to more than 7 million reported deaths globally as of 19 January 2024 (ref. 1 ) and an estimated 18.2 million excess deaths between 1 January 2020 and 31 December 2021 (ref. 2 ). The coronavirus disease 2019 (COVID-19) pandemic, requiring urgent international intervention, led to an accelerated pace of research and development of multiple safe, effective COVID-19 vaccines, which were first authorized for emergency use in December 2020 3 . The expeditious vaccine development and limited availability resulted in serious challenges in the equitable global distribution of vaccines, coupled with vaccine-related misinformation and mistrust of the science behind vaccine safety 4 .

Vaccine hesitancy 5 , pandemic fatigue 6 and vaccine fatigue, defined as the ‘inertia or inaction toward vaccine information or instruction due to perceived burden and burnout’ 7 , continue to present challenges to vaccine uptake in 2023. Although COVID-19 has been deprioritized as a substantial public health threat since 2023, the virus strains continue to circulate and, in some settings, lead to new increases in hospitalization and intensive care unit admission 1 . The potential impact of vaccine hesitancy on confidence in booster doses remains substantial 8 . In addition, documented spillover effects on routine immunization pose a threat for the reemergence of some childhood and adult vaccine-preventable diseases 9 , 10 .

In this Brief Communication, the fourth study in a series of annual global surveys across 23 countries (Brazil, Canada, China, Ecuador, France, Germany, Ghana, India, Italy, Kenya, Mexico, Nigeria, Peru, Poland, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Türkiye, the United Kingdom and the United States) 11 , 12 , 13 , we report perspectives of adults in the general public on COVID-19 and routine immunization in late 2023, trust in pandemic information sources and collective preparedness to address any possible future pandemic. We also compare COVID-19 vaccine acceptance in 2023 to that in previous years to promote a better understanding of the current and future challenges public health authorities may face in encouraging vaccine uptake.

The reported uptake of at least one COVID-19 vaccine dose rose to 87.8% in 2023 across the 23 countries (Fig. 1a ), as compared with 36.9% in 2021 ( P  < 0.001) and 70.4% in 2022 ( P  = 0.002). The reported uptake of at least one COVID-19 vaccine was similar in middle-income countries (MICs; 86.9%) and high-income countries (HICs; 87.5%) ( P  = 0.381). COVID-19 vaccine booster acceptance among those vaccinated decreased from 87.9% in 2022 to 71.6% in 2023 ( P  < 0.001) (Fig. 1b ). This decrease was most profound in HICs (from 85.1% to 63.3%, P  < 0.001), compared with MICs (from 90.5% to 78.9%, P  = 0.010). The perspectives on willingness to get vaccinated against diseases other than COVID-19 (for example, influenza, measles and hepatitis B) indicate that 60.8% of respondents may be more and 23.1% less willing to get vaccinated in 2023, following their experience during the COVID-19 pandemic (Fig. 1c ). Individual country analyses on vaccine acceptance are available in Extended Data Fig. 1 .

a , COVID-19 vaccine acceptance among 23 countries, HICs and MICs. b , COVID-19 booster vaccine acceptance among 23 countries, HICs and MICs. c , Reported pandemic influence toward routine immunization. Four countries (Ghana, Kenya, Peru and Türkiye) were not included in the 2020 global survey. HICs: Canada, France, Germany, Italy, Poland, Singapore, South Korea, Spain, Sweden, the United Kingdom and the United States. ‘Routine immunization’ referrs to ‘other diseases (for example, flu, measles and viral hepatitis B)’ in the survey item.

The COVID-19 pandemic led to widespread disruptions in routine immunization services globally, including for childhood doses, resulting in delayed and reduced vaccine uptake 10 . The results of this study demonstrate that 23.1% of respondents are less likely to accept vaccines for diseases other than COVID-19. Experience from the diversion of healthcare resources during the pandemic, along with lockdown measures and concerns about infection, highlights the need for resilient primary care systems, especially in maintaining access to crucial prevention interventions, such as routine childhood and adult vaccination. Other challenges, including disruptions to vaccine supply chains, underscore the importance of strengthening immunization systems and services to prevent future outbreaks 14 , 15 . Moreover, the extension of COVID-19 vaccine skepticism to other vaccines, including among parents who make vaccination decisions for their children 10 , signals a crucial need for ongoing efforts in vaccine education and trust building. Looking ahead, these insights should inform strategies to fortify healthcare systems against similar challenges to minimize disruptions and ensure continuity of essential health services, including routine vaccinations. Meanwhile, many communities are facing increased vulnerability to vaccine-preventable diseases 10 , highlighting the need for innovative strategies to ensure the continuity of routine immunization and COVID-19 vaccination campaigns to improve vaccine confidence.

The survey responses on trust in sources that provide information or guidance on pandemic interventions revealed generally high levels of trust in those close to the individual, although all 11 studied sources averaged less than seven points on a ten-point scale. For example, ‘my doctor or nurse’ ranked highest at 6.9 and ‘my family and friends’ ranked at 6.4 (Extended Data Fig. 2d ). Similarly, established health institutions such as the World Health Organization (WHO) (6.5) and the US Centers for Disease Control and Prevention (6.4) ranked high. Social media platforms (5.0) and religious leaders (5.0) each ranked neutrally (Extended Data Fig. 2d ). There was variability across countries, for example, ‘religious leaders’ ranked 3.16 in Sweden and 3.19 in Germany but 6.57 in Nigeria and 6.72 in India, whereas ‘my doctor or nurse’ ranked 4.95 in Russia and 7.70 in Kenya (Extended Data Fig. 2e ). Trust in health authorities that recommended COVID-19 vaccination was higher than trust in governments’ management of the COVID-19 pandemic at 65.4% and 56.4%, respectively (Extended Data Fig. 3 ). General trust in health authorities was 66.8% and 63.9% in MICs and HICs, respectively ( P  = 0.542), while general trust in government was 60.7% and 51.7% in MICs and HICs, respectively ( P  = 0.073). A decrease in perceived trust in science as a result of COVID-19 vaccine development was reported by 13.9% of respondents (MICs 13.4% and HICs 14.3%, P  = 0.674). A decrease in perceived trust in the pharmaceutical industry as a result of COVID-19 vaccine development was reported by 18.7% of respondents (MICs 18.4% and HICs 19.1%, respectively, P  = 0.772) (Extended Data Fig. 3 ). Trust in the science behind available COVID-19 vaccines was reported by 71.6% of respondents on average, with this value being 74.5% and 68.4% among MICs and HICs, respectively ( P  = 0.115) (Extended Data Fig. 3 ). The unprecedented speed of development, the novel application of mRNA technology and the proliferation of misinformation, particularly on social media, raised concerns among some about the thoroughness of testing and long-term safety of COVID-19 vaccines and contributed to increased skepticism regarding science generally, as well as its application to preventive and therapeutic applications in particular 16 , 17 , 18 . Moreover, factors such as prepandemic vaccine-related controversies and mistrust in pharmaceutical companies, governments and health institutions, sometimes the result of cultural beliefs or past negative experiences, have further complicated public health communication 16 , 19 .

Perspectives on future pandemic preparedness reveal a mixed picture of confidence and trust among global populations. Approximately three-quarters (74.9%) of respondents are confident that society collectively will manage the next health crisis better than the COVID-19 pandemic, yet only 63.3% reported trusting a hypothetical WHO recommendation to vaccinate if such a crisis was announced (Fig. 2 ). Approximately a quarter of respondents in Russia (26.6%) and the United States (25.5%) express low trust in the WHO as a reliable source of information to announce a new pandemic threat (Extended Data Fig. 2a ). Approximately half of respondents in Ghana (51.5%), India (51.3%) and Kenya (49.2%) report a high level of confidence in our collective ability to better manage the next potential health crisis (Extended Data Fig. 2c ). A 2023 analysis in Kenya reporting 49.6% of respondents rating their own government’s management of the pandemic as very good or excellent may inform public confidence in future management capabilities 20 . Confidence in Ghana may be attributable to the government’s approach in preparing early readiness assessments, strategic and substantial investments in response planning and the effective use of surveillance technology 21 . India’s confidence in pandemic preparedness might be higher due to vaccine production capacity and public health investments in massive awareness campaigns and the rapid expansion of testing and contact tracing capabilities, despite having a large population and fragmented health system 22 . By contrast, 30.2% of respondents to our survey in France and 28.9% of respondents in Poland are ‘not at all confident’ in our collective ability, the highest percentages among the countries studied. These findings are comparable to panel data in France and Poland demonstrating low and decreasing trust in scientists among these populations during COVID-19 23 . Trust in the collective scientific and health communities to respond effectively to pandemic threats will require country-specific approaches that consider relevant sociocultural factors. How much individuals trust scientists and governments, respectively, has been observed as weakly related in Brazil and the United States, suggesting populations in these countries distinguish between these two health communicator groups, whereas the relationship was stronger in France, and populations view them as more closely aligned 23 . For example, in the United States and Brazil, a trend toward privatization and the erosion of the government’s role in mitigating public health threats exacerbated racial inequities and contributed to a fragmented response to the COVID-19 pandemic 24 , 25 . Ongoing global efforts to prepare for future global health threats promote a comprehensive ‘vaccines plus’ approach that incorporates social and behavioral preventive measures alongside rigorous testing and treatment 26 . Heightened vaccine hesitancy relative to COVID-19, pandemic fatigue and concerted disinformation campaigns have strong implications for plans to prevent or manage future pandemics, as well as a degree of spillover effect on our collective ability to control other vaccine-preventable diseases 27 . This may be particularly important as it pertains to routine childhood immunizations.

MICs: Brazil, China, Ecuador, Ghana, India, Kenya, Mexico, Nigeria, Peru, Russia, South Africa and Türkiye. Four countries (Ghana, Kenya, Peru and Türkiye) were not included in the 2020 global survey. HICs: Canada, France, Germany, Italy, Poland, Singapore, South Korea, Spain, Sweden, the United Kingdom and the United States.

A vocal minority of vaccine-resistant populations continue to believe inaccurate and disproven claims, such as the effectiveness of ivermectin as a treatment for COVID-19 and some conspiracy theories, that drive resistance to vaccination 28 , 29 . Disinformation aiming to influence public opinion poses major challenges for communication campaigns that require heterogeneous data-driven precision public health approaches 30 , 31 . These strategies should focus on delivering clear, accurate and culturally sensitive information to specific communities through their preferred information channels and via trusted sources and on exposing the motivation of those behind disinformation. It is important to acknowledge that individuals often show a preference for information that aligns with their existing beliefs and perceive such information as more credible 32 . This biased selection and perception is more pronounced among those with higher health literacy 32 , which is a factor that health communication professionals must consider.

The critical need to catch up on routine immunizations and prepare for potential new pandemic threats, coupled with the continued spread of COVID-19, requires maintaining vigilance in addressing vaccine hesitancy globally. The varying degrees of hesitancy observed across different demographic groups and countries emphasize the importance of culturally and contextually relevant strategies that include the selection of welcomed credible sources as primary conduits of information to address and mitigate vaccine hesitancy. The findings of this study demonstrate that the WHO and the US Centers for Disease Control and Prevention, as well as the respondents’ personal doctor, were more highly trusted as sources of pandemic information. The communication of accurate and timely information, as well as countering misinformation, are pivotal in guiding public perception and behavior toward COVID-19 vaccination acceptance.

Furthermore, whole-of-society action has been recommended by pandemic researchers to address the thus far fragmented approaches seen in relation to pandemic preparedness and response 33 , 34 . Such an approach involves various sectors and actors in decision-making processes to build resilient systems and takes life risks other than health, such as employment, housing and food security status, into consideration. A proposed pandemic agreement is currently being debated in advance of the May 2024 World Health Assembly. It aims to strengthen global collaboration between countries and global health organizations, including the WHO, around improving One Health data monitoring and sharing, toward ensuring equitable access to preventive and therapeutic measures and strengthening health systems 35 . The intent of such an agreement would signal to Member States and their populations that pandemic preparedness to address the shortcomings of the COVID-19 pandemic response is being taken seriously, including the rapid, real-time country collaboration on surveillance and the equitable distribution of vaccines and other mitigation and elimination efforts.

Limitations to interpreting these data include the recognition of a fundamental discrepancy that may exist between the respondents’ reported willingness to receive the vaccine and their actual vaccination behavior. What people express in surveys can differ meaningfully from their actions 27 . Therefore, the findings regarding vaccine acceptance and hesitancy should not be directly equated with actual vaccine uptake; rather, the reported responses reflect attitudes and opinions at a specific point in time. As public perceptions of the COVID-19 pandemic and vaccination evolves, so too might their willingness to be vaccinated. This temporal aspect suggests that the acceptance levels reported in our study are subject to change due to a variety of factors, including new information about the virus and the vaccine, changes in public health recommendations and shifts in societal norms and attitudes toward vaccination. While our study assessed individuals’ perceptions of trust in sources of pandemic information, including governments and health authorities, we did not investigate the quality of country responses to the pandemic, which may be an important determinant of such trust, given its independent association with COVID-19 vaccination 20 . Our study’s design did not allow for a detailed analysis of the nuanced relationship between language, trust and cultural context, while early research on the impact of health communication language on vaccine hesitancy in bilingual settings may be mediated by cultural factors regarding trust in health and governing institutions 36 . We permitted participants to respond using their preferred language within their country.

This study reveals that a substantial proportion of individuals express resistance to vaccination and that concerns about COVID-19 vaccination appear to have spilled over to affect other vaccine-preventable diseases. This underscores the increasingly urgent necessity for sustained vaccine education and trust-building efforts. Moreover, although we found that people were generally confident that society will handle future health crises better, there remains a notable lack of trust and potential adherence to the recommendations of public health authorities. Health system preparedness for future outbreaks and global health threats should include improving vaccine accessibility and vaccine demand through effective, culturally and contextually relevant public communication strategies and innovative use of digital and social media in health education employing infodemic countermeasures.

Study design and sample

This study employed random stratified sampling in a 23-panel cross-sectional design (Extended Data Table 1 and Reporting Summary). A target quota was established for four strata (that is, age, gender, country-specific statistical regions and country-specific levels of education) according to the latest available country data for these strata and with a minimum quota of 50 participants per strata 37 , 38 , 39 , 40 , 41 . There were 23,000 participants, 1,000 from each country, the populations for which collectively represent nearly 60% of the world’s population 42 . MICs consisted of Brazil, China, Ecuador, Ghana, India, Kenya, Mexico, Nigeria, Peru, Russia, South Africa and Türkiye and HICs consisted of Canada, France, Germany, Italy, Poland, Singapore, South Korea, Spain, Sweden, the United Kingdom and the United States 43 . The details on participant recruitment are described in Reporting Summary.

Survey instrument

The instrument ( Supplementary Information ) included 30 items from previous study iterations, 9 new items on misinformation and pandemic preparedness and 11 items on trusted sources of information selected by the authors following a scoping review of peer-reviewed primary research that used survey methodologies to assess these topics 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 . The selected items aimed to cover a broad spectrum of information channels that people might rely on for pandemic-related information. They include formal and informal sources, spanning from international health organizations to personal acquaintances, attempting to capture a comprehensive view of trust in different information environments and applicable for a global sample. The questionnaire was cross-culturally translated from English to the two most widely spoken lanugages in each country.

Statistical analysis

Descriptive statistics were used to report COVID-19 vaccine uptake and booster acceptance. In 2022, COVID-19 booster acceptance was defined as having received at least one dose of a booster and if not, willingness to take the booster when it is available (answer options ‘strongly agree’ or ‘somewhat agree’ to question ‘I will take the COVID-19 booster dose(s) when it is available to me’). We also report the descriptive statistics for items related to reported attitudes toward routine immunization, trusted sources of information and future pandemic preparedness. The participants ranked the trustworthiness of these sources on a scale of 1 to 10, where 1 indicated ‘no trust at all’ and 10 represented ‘complete trust’. For each source of information, individual scores from participants within a country were aggregated to produce a single mean score for that source in that country. This method allowed for a concise representation of the collective trust level in each information source per country. The country-specific weighted estimates were used to compute 23-country average as well as averages for MIC and HIC country groupings. Independent sample t -tests were used to compare average estimates over time as well as for HIC and MIC country groups. All the analyses were conducted in SAS version 9.4 software. All the estimates reported in the paper have a maximum credibility interval of error of ±3.1 percentage points. The country-specific standard errors for each estimate are provided in Extended Data Table 2 .

Ethics and inclusion statement

This study was approved and the survey administered by Emerson College, Boston, USA under institutional review board protocol no. 20–023-F-E-6/12, which employed online data collection panels not requiring local review. Informed consent was obtained from participants after describing the study purpose and expected risks and benefits before participants were permitted to advance to the study questionnaire. We fully endorse the Nature Portfolio journals’ guidance on MIC authorship and inclusion. In this fourth-round study, the author list has expanded from 8 to 12 with stronger regional and gender balances. These authors (two authors from South Africa, one from Brazil, three from Spain, four from the United States and four from Poland, Germany and France) provided insights into the translation of the survey to local languages and interpretation and discussion of the results for their respective countries. We reviewed relevant studies from among the 23 studied countries in preparing the survey instrument and manuscript.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Data availability

The raw data generated in this study are available for download via Zenodo at https://doi.org/10.5281/zenodo.10568581 (ref. 58 ). All authors had access to the raw data.

Code availability

All code for data analysis associated with the paper is available for download via Zenodo at https://doi.org/10.5281/zenodo.10568594 (ref. 59 ).

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Acknowledgements

J.V.L. and T.M.W. acknowledge support to ISGlobal from the Spanish Ministry of Science, Innovation and Universities through the ‘Centro de Excelencia Severo Ochoa 2019–2023’ program (CEX2018-000806-S) funded by MCIN/AEI/10.13039/501100011033 and from the ‘Generalitat de Catalunya’ through the CERCA program.

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J.V.L., A.E.-M. and T.M.W. conceived of the study. K.W. was responsible for coding and data analyses, with input from T.M.W. J.V.L. and T.M.W. A.E.-M. wrote the first draft of the paper. T.M.W., K.W., K.R., J.V.L., A.E.-M., S.C.R., H.J.L., F.M-T., E.K., S.A.K., T.G.-V., S.M., C.B., N.M. and B.K. edited subsequent revisions of the draft and approved the final paper.

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Correspondence to Jeffrey V. Lazarus .

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Study funding was provided by Moderna, to the City University of New York Research Foundation. The authors retained full autonomy in the design of the study; the development of the survey instrument; the collection, analysis and interpretation of data; the presentation of results; and the decision to submit the article for publication. J.V.L. has received speaker fees from Echosens, Gilead Sciences, Moderna, Novo Nordisk, Novovax, Pfizer and ViiV and grants from Gilead Sciences, GSK, Madrigal Pharmaceuticals and Roche Diagnostics outside the submitted work. The other authors declare no competing interests.

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Extended data

Extended data fig. 1 reported willingness for routineimmunization, covid-19 vaccine and booster acceptance and hesitancy in october 2023 by country..

Sample size for each individual country n = 1,000. Middle-Income Countries (MIC): Brazil, China, Ecuador, Ghana, India, Kenya, Mexico, Nigeria, Peru, Russia, South Africa, Turkiye. High-Income Countries (HIC): Canada, France, Germany, Italy, Poland, Singapore, South Korea, Spain, Sweden, United Kingdom, United States. ( a )“I am more willing to get vaccinated against other disease (e g, flu, measles,viral hepatitis B)”, ( b ) COVID-19 vaccine acceptance and hesitancy, October 2023, COVID-19 vaccine acceptance was defined as having received at least one dose of a COVID-19 vaccine. COVID-19 vaccine hesitancy was defined as not having received at least one dose of a COVID-19 vaccine. ( c ) COVID-19 booster acceptance and hesitancy among vaccinated respondents, October 2023. COVID-19 booster acceptance among vaccinated respondents was defined as willingness to take future recommended boosters (answer options “strongly agree” or “somewhat agree” to question “I will take the recommended COVID-19 booster”. COVID-19 booster hesitancy among vaccinated respondents was defined as having reportedeither “unsure/ no opinion” or “somewhat disagree” or “strongly disagree” to the same question.

Extended Data Fig. 2 Reportedattitudes about future potential pandemic preparedness.

Sample size for each individual country n = 1,000. Middle-Income Countries (MIC): Brazil, China, Ecuador, Ghana, India, Kenya, Mexico, Nigeria, Peru, Russia, South Africa, Turkiye. High-Income Countries (HIC): Canada, France, Germany, Italy, Poland, Singapore, South Korea, Spain, Sweden, United Kingdom, United States. ( a ) “If the World Health Organization (WHO) announced a new pandemic threat, would you trust thisinformation?”, ( b ) “If the World Health Organization (WHO) announced a newpandemic threat and advised getting vaccinated, would you?”, ( c ) “How confidentare you that we will manage the next health crisis better than the COVID-19 pandemic?”, ( d ) Reported trust in the sources of information about COVID-19 vaccines, ( e ) Reported trustin the sources of information about COVID-19 vaccines by country.

Extended Data Fig. 3 Trust in science, health authorities, government and pharmaceutical industry.

Sample size for each individual country n = 1,000. Middle- Income Countries (MIC): Brazil, China, Ecuador, Ghana, India, Kenya, Mexico, Nigeria, Peru, Russia, South Africa, Turkiye. High-Income Countries (HIC): Canada, France, Germany, Italy, Poland, Singapore, South Korea, Spain, Sweden, United Kingdom, United States. Survey items: ( a ) ‘I trust the science behind the COVID-19 vaccines available to me,’ ( b ) ‘How much do you trust the health authorities that recommended you get a COVID-19 vaccine?,’ ( c ) ‘How much did you trust your government’s management of the COVID-19 pandemic in your country?,’ ( d ) ‘Did the development of COVID-19 vaccines affect your trust in science generally?,’ ( e ) ‘Did the development of the COVID-19 vaccines affect your trust in the pharmaceutical industry?’.

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Lazarus, J.V., White, T.M., Wyka, K. et al. Influence of COVID-19 on trust in routine immunization, health information sources and pandemic preparedness in 23 countries in 2023. Nat Med (2024). https://doi.org/10.1038/s41591-024-02939-2

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DOI : https://doi.org/10.1038/s41591-024-02939-2

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Impact of SARS-CoV-2 vaccines on Covid-19 incidence and mortality in the United States

Roles Formal analysis, Methodology, Writing – original draft

Affiliation Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), Los Angeles, CA, United States of America

Roles Writing – review & editing

Affiliations Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), Los Angeles, CA, United States of America, International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh, International Vaccination Institute (IVI), Seoul, the Republic of Korea

Roles Conceptualization, Methodology, Supervision, Writing – review & editing

* E-mail: [email protected] (Z-FZ); [email protected] (TFB)

Affiliations Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), Los Angeles, CA, United States of America, Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, United States of America, Department of Medicine, Center for Human Nutrition, UCLA David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, CA, United States of America

Affiliations Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), Los Angeles, CA, United States of America, Division of Infectious Diseases, UCLA David Geffen School of Medicine, Los Angeles, CA, United States of America

• Fang Fang, 
• John David Clemens, 
• Zuo-Feng Zhang, 
• Timothy F. Brewer

• Published: April 24, 2024
• https://doi.org/10.1371/journal.pone.0301830
• Reader Comments

Given the waning of vaccine effectiveness and the shifting of the most dominant strains in the U.S., it is imperative to understand the association between vaccination coverage and Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) disease and mortality at the community levels and whether that association might vary according to the dominant SARS-CoV-2 strains in the U.S.

Generalized estimating equations were used to estimate associations between U.S. county-level cumulative vaccination rates and booster distribution and the daily change in county-wide Coronavirus 2019 disease (COVID-19) risks and mortality during Alpha, Delta and Omicron predominance. Models were adjusted for potential confounders at both county and state level. A 2-week lag and a 4-week lag were introduced to assess vaccination rate impact on incidence and mortality, respectively.

Among 3,073 counties in 48 states, the average county population complete vaccination rate of all age groups was 50.79% as of March 11 th , 2022. Each percentage increase in vaccination rates was associated with reduction of 4% (relative risk (RR) 0.9607 (95% confidence interval (CI): 0.9553, 0.9661)) and 3% (RR 0.9694 (95% CI: 0.9653, 0.9736)) in county-wide COVID-19 cases and mortality, respectively, when Alpha was the dominant variant. The associations between county-level vaccine rates and COVID-19 incidence diminished during the Delta and Omicron predominance. However, each percent increase in people receiving a booster shot was associated with reduction of 6% (RR 0.9356 (95% CI: 0.9235, 0.9479)) and 4% (RR 0.9595 (95% CI: 0.9431, 0.9761)) in COVID-19 incidence and mortality in the community, respectively, during the Omicron predominance.

Conclusions

Associations between complete vaccination rates and COVID-19 incidence and mortality appeared to vary with shifts in the dominant variant, perhaps due to variations in vaccine efficacy by variant or to waning vaccine immunity over time. Vaccine boosters were associated with notable protection against Omicron disease and mortality.

Citation: Fang F, Clemens JD, Zhang Z-F, Brewer TF (2024) Impact of SARS-CoV-2 vaccines on Covid-19 incidence and mortality in the United States. PLoS ONE 19(4): e0301830. https://doi.org/10.1371/journal.pone.0301830

Editor: Olatunji Matthew Kolawole, University of Ilorin, NIGERIA

Received: August 8, 2022; Accepted: March 19, 2024; Published: April 24, 2024

Copyright: © 2024 Fang et al. 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 publicly accessible from the data sources listed in Table 1 . All pooled data are available on a public repository via https://github.com/Clairyff/COVID_Vaccine .

Funding: FF is supported by the NIH/NCI T32 CA009142. The funding source had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: FF and TB held stocks in Pfizer. All other authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction

Since being recognized in December, 2019, the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused more than 479 million cases and six million deaths worldwide [ 1 ]. The United States has been particularly affected, with almost 80 million Coronavirus 2019 (COVID-19) infections and 972 thousand deaths reported as of March 25 th , 2022 [ 2 ]. Though a number of non-pharmacologic prevention initiatives (NPIs) have been introduced to slow SARS-CoV-2 transmission [ 3 ], vaccines are now recognized as among the most effective means for preventing COVID-19 cases and deaths [ 4 ].

As of March 25, 2022, three vaccine preparations were authorized for use in the U.S. The BNT162b2 vaccine (Pfizer, Inc. and BioNTech) and the mRNA-1273 (Moderna) vaccine have full U.S. Food and Drug Administration (FDA) approval [ 5 , 6 ], while JNJ-78436735 (Janssen Pharmaceuticals) is available under an emergency use authorization. All three vaccines are effective in preventing SARS-CoV-2 infections and COVID-19 associated diseases, hospitalizations, and deaths [ 7 – 9 ], though vaccine effectiveness wanes over time and breakthrough infections occur [ 4 , 10 ].

Numerous studies have demonstrated that SARS-CoV-2 vaccines are effective in preventing COVID-19 infections and disease in individuals outside of clinical trials, including among health care workers, first responders, individuals attending ambulatory clinics, veterans, and in nursing homes [ 11 – 13 ]. However, vaccine waning has been reported, especially after 6 months being fully vaccinated [ 14 – 16 ]. Vaccine effectiveness also varies by SARS-CoV-2 variant. Omicron, the most recent predominant variant, evades infection- or vaccination-induced immunity more effectively than Delta variant, and correspondingly has higher rates of breakthrough infections or disease reported compared with other variants [ 14 , 16 – 18 ]. With the previous recognition of waning vaccine immunity and the rise of Delta as the predominant SARS-CoV-2 variant in the U.S., the FDA authorized the emergency use of one or two boosters for COVID-19 vaccines, including the use of a heterologous booster [ 19 – 21 ]. Studies showed the effectiveness of vaccines improved after a booster dose, including against Omicron [ 16 , 22 , 23 ].

Despite the proven safety and effectiveness of these vaccines, a substantial minority of the adult U.S. population remains resistant to getting vaccinated [ 24 ]. To understand the impact of SARS-CoV-2 vaccines, it is imperative to evaluate the impact of vaccination on community-wide SARS-CoV-2 cases and COVID-19 disease, not just among those vaccinated—a concept popularly referred to as “herd immunity” [ 25 ]. Moreover, it is worth examining whether and by how much such an impact might differ corresponding to different dominant strains in the community. To investigate the impact of population percentages of SARS-CoV-2 vaccination on community-wide COVID-19 case and mortality rates, we undertook an ecological analysis of U.S. county vaccination rates on reported county COVID-19 cases and deaths, controlling for socioeconomic, demographic, comorbid conditions, rural/urban, air pollution, hospital capacity, and related factors, the introduction of NPIs and the presence of most prevalent strain in the U.S.

Materials and methods

Poisson distribution with generalized linear models [ 26 ] were used to estimate associations between cumulative U.S. county-level vaccination rates of all age groups and the daily change in county-wide COVID-19 incidence and mortality between April 23 rd , 2021, and March 25 th , 2022. The dates represent when Delta was first recognized in the U.S. to the end of the study period. The analyses were divided into three periods to account for the most dominant strain in the U.S. during each period. The first period was from April 23 rd to July 2 nd , 2021 before the Delta predominance and when Alpha was the most prevalent strain. Delta was responsible for the majority of reported U.S. COVID-19 cases from July 3 rd to December 1 st , 2021. Between December 2 nd , 2021 and March 25 th , 2022, Omicron began circulating in the U.S. and replaced Delta to become the dominant strain.

All models were adjusted for the following potential confounders: annual average of ambient atmospheric particulate matter <2.5 μm in diameter (PM 2.5 ) between 2000 and 2018, population density, poverty, education, proportions of White, proportions of male, proportion of population older than 65 years old, owner-occupied property, median house value, median household income, percentage of people without health insurance, proportion of people living in rural area, prevalence of tobacco smoking, and obesity. All covariates were measured at the county level. State-level variables for NPIs policies (facemask mandates, stay home orders) also were included in models. Table 1 summarizes data sources utilized in this study.

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https://doi.org/10.1371/journal.pone.0301830.t001

County-level COVID-19 incidence and mortality data were obtained from the Johns Hopkins University, Center for Systems Science and Engineering Coronavirus Resource Center (CSSE). CSSE collects county-level confirmed numbers of cases and deaths of 3,342 counties across the U.S. from the U.S. Centers for Disease Control and Prevention (CDC) as well as state departments of health since January 21 st , 2020 [ 2 ].

County-level vaccine data were obtained from Covid Act Now. These data are derived from the U.S. Department of Health and Human Services, the CDC, the New York Times, and official state and county dashboards. Data on vaccinations initiated, vaccination regimens completed and booster shots received were available for all 50 states [ 27 ]. To allow for the development of protective immunity after vaccination, a two-week lag was introduced after people were completely vaccinated (a person vaccinated on June 18 th was considered fully protected by July 2 nd ). The two-week lag also was used to account for time between exposure and development of COVID-19 disease. To assess the impact of vaccination on COVID-19 mortality, a four-week lag was used (vaccinated by September 2 nd to assess the impact on mortality on September 30 th ). In order to capture the immunity gained from the previous natural infection, county-level cumulative incidence was multiplied by the proportion of unvaccinated people among total infection during different stages of pandemic estimated by CDC [ 31 ]. A two-week and a four-week lags were applied to the cumulative incidence when assessing incidence and mortality outcomes, respectively. This was added to the fully vaccination rate and to the coverage of booster to estimate the holistic immunity in each county, by accounting for the immunity gained from both vaccination and from natural infection.

Covariates were selected based on previous publications [ 3 , 32 ] and availability of publicly accessible data. Fig 1 shows the directed acyclic graph applied in this study. County-level annual average of PM 2.5 between the years 2000 and 2018, as well as county-level covariates, were available from the Atmospheric Composition Analysis Group [ 28 ]. County-level socioeconomic and demographic variables for 2020 were available from the US Census/American Community Survey. 2020 data on the prevalence of adult tobacco smoking and adult obesity and the proportion of people living in rural area were accessible through the County Health Rankings & Roadmaps program [ 29 ]. State averages were used to replace missing values for county-level prevalence for smoking and obesity. State-wide non-pharmacologic prevention policies, including facemask use and stay home orders, were obtained from the Boston University School of Public Health [ 30 ].

County characteristics include annual PM2.5 concentration between 2000 and 2018, percentage of adults smokers, percentage of obese adults, percentage of people living under poverty, population density, percentage of owner occupied properties, percentage of adults with less than high school education, percentage of White population, median household income, median house value, percentage of population over 65 years old, percentage of male, percentage of population without an insurance, and percentage of population living in rural area. State policies include stay home orders and facemask mandates.

https://doi.org/10.1371/journal.pone.0301830.g001

Counties with invalid Federal Information Processing Standards (n = 10), missing covariates (n = 98), missing vaccination status with a 2-week (n = 113) or a 4-week (n = 122) lag, and negative change in incidence (n = 48) or in mortality (n = 70) possibly due to data entry error were excluded. As a result, data from 3,073 counties in 48 states (excluding District of Columbia, Hawaii, and New Hampshire) were available to investigate the association between population vaccination rates and county-wide COVID-19 incidence and 3,042 counties in 48 states to investigate the association between vaccination rates and COVID-19 mortality. Among these eligible counties, 2,906 counties in 46 states and 2,876 counties in 46 states also reported percentage of people receiving a booster shot during the Omicron predominance and were utilized to assess the association between booster coverage and COVID-19 incidence and mortality, respectively. To assess the potential effect modification due to metropolitan status, stratified analyses by metropolitan status defined by Department of Agriculture [ 33 ] were performed. Relative risks (RR) and 95% confidence intervals (CI) are reported. Analyses were performed in SAS 9.4 (Cary, NC).

Among the 3,073 counties across 48 states, the average county total population complete vaccination rate was 50.79% as of March 11 th , 2022. Counties with complete vaccination rates above the national median (49.8%) had higher median house values, higher median household incomes, higher population density, and less population living in rural area compared with counties with vaccination rates below 49.8%. These counties also were more likely to be located in states where a facemask policy or a stay-home order was ever issued before July 2 nd , 2021 ( Table 2 ).

https://doi.org/10.1371/journal.pone.0301830.t002

When Alpha was the dominant strain in the U.S., each percentage increase in a county’s total population complete vaccination rate was associated with a 4% decrease in county-wide COVID-19 cases (relative risk (RR) 0.9607 (95% confidence interval (CI): 0.9553, 0.9661)) and with a 3% reduction in COVID-19 mortality (RR 0.9694 (95% CI: 0.9653, 0.9736)). However, county-level complete vaccine coverage was not associated with decreases in COVID-19 cases during the Delta (RR 0.9988 (95% CI: 0.9964, 1.0011)) and Omicron (RR 0.9969 (95% CI: 0.9919, 1.0019)) predominance. The association between complete vaccination rates and COVID-19 mortality declined to less than 0.1% (RR 0.9934 (95% CI: 0.9889, 0.9980)) when Delta accounted for the majority of reported cases in the U.S. between July 3 rd and December 1 st , 2021. When Omicron began circulating, complete vaccination rate was associated with a slight increase of 0.6% in county-level COVID-19 mortality (RR 1.0061 (95% CI: 1.0022, 1.0101)). In contrast to the associations between complete vaccination rates and COVID-19 outcomes during the Omicron predominance, a 6% reduction in COVID-19 incidence (RR 0.9356 (95% CI: 0.9235, 0.9479)) and a 4% reduction in COVID-19 mortality (RR 0.9595 (95% CI: 0.9431, 0.9761)) were observed with each percentage increase in people receiving a booster shot at the county level. After accounting for the immunity gained from natural infection, the results remained similar ( Table 3 ). Moreover, metropolitan status seems not to modify the association between vaccination and COVID-19 outcomes ( Table 4 ).

https://doi.org/10.1371/journal.pone.0301830.t003

https://doi.org/10.1371/journal.pone.0301830.t004

Data from 3,073 counties across 48 states demonstrates that the associations between county-level complete vaccination rate and COVID-19 incidence and mortality varied based on the most prevalent SARS-CoV-2 variant circulating in the U.S. between April 23 rd , 2021 and March 25 th , 2022 after adjusting for potential confounders. The protective associations between county-level complete vaccination rate and COVID-19 incidence and mortality were observed during the Alpha predominance, but such associations attenuated later when Delta or Omicron was the most prevalent strain in the U.S. However, after booster shots were available, the increase in the county percentage of people receiving a booster shot was associated with reduction in both COVID-19 incidence and mortality between December 2 nd , 2021 and March 25 th , 2022.

This study is among the first to show the population-wide association between SARS-CoV-2 vaccination rate and COVID-19 incidence and mortality stratified by the predominant strain circulating in the country. The results show that county-level vaccination rate has different associations with COVID-19 incidence and mortality during different periods in the U.S. The protection was highest shortly after COVID-19 vaccines became widely available while Alpha was the predominant circulating strain and declined in later periods. This pattern might be due to the waning effect of the vaccines against infection over time within the community. A meta-analysis showed that though vaccine effectiveness against SARS-CoV-2 infections was reduced, vaccine remained highly efficient in protecting people from severe diseases due to COVID-19 [ 15 ]. In addition, as vaccine uptake increased and cases declined, most states lifted their NPIs orders [ 30 ]. Without the protection of NPIs and given the waning of vaccine effectiveness, people became more susceptible to COVID-19 infection even when fully vaccinated. Besides the waning vaccine effectiveness, our results also suggest the association of vaccine coverage and COVID-19 incidence might depend on the most prevalent strain in the community. The protection of increased vaccination coverage against county-level COVID-19 incidence or mortality was not observed when Omicron circulation predominated, which has been shown to evade previous immunity more than Alpha or Delta [ 17 ]. However, the majority of COVID mortality occurred among unvaccinated people in the U.S. throughout our study period [ 34 ]. In the light of the waning vaccine effectiveness and breakthrough cases, a booster shot has been recommended. Individual-level and experimental data demonstrate that a third dose of mRNA COVID-19 vaccines increases vaccine efficacy [ 16 , 17 ]. Similarly, our results also suggest that the increasing uptake of a booster shot is associated with the reduction in community COVID-19 cases and deaths. Moreover, this study considers the holistic immunity, not only gained from vaccination but also gained from the natural infection.

The study was subject to several limitations. First, ecologic study designs are vulnerable to the ecologic fallacy. Therefore, caution is required when interpreting the study results, especially when extrapolating population findings to the individual level. In addition, we cannot rule out the possibility of residual confounding even after controlling for numerous county-level and state-level covariates. Using COVID-19 reported cases may underestimate of the number of actual infections due to under-testing of asymptomatic patients, especially when self-tests became widely available. However, alternative estimates for cumulative incidence, such as seroprevalence [ 35 ], also have limitations including sampling bias, test sensitivity and specificity, and the progress of the pandemic [ 36 ]. Our analysis was not able to assess the impact of the three different vaccines currently available in the U.S. due to data availability, which likely had different efficacies. Although a detailed distribution of different variants in the U.S. was not available, we examined the associations stratified by the most dominant strain. Therefore, our results represent the associations between vaccine rates overall and COVID-19 incidence and mortality in the U.S. for vaccines as actually deployed and SARS-CoV-2 variants as they circulated during the period of our analysis.

Nevertheless, this study is the first to estimate the association between complete vaccination rates and COVID-19 incidence and mortality in the U.S. general population using county-level data. This nation-wide study covers 3,073 counties in 48 states across the entire country, showing the population-based impact of increasing complete vaccination rates, as well as increasing percentage of those receiving a booster shot. Our results agree with the observation of waning effectiveness over time and higher infection breakthrough rates due to the Omicron variant. However, increasing the coverage of booster shot appear to be an effective way to protect individuals in the community and to potentially to achieve herd immunity.

Acknowledgments

We acknowledged all organizations and groups collecting and maintaining the data sources listed in Table 1 and utilized in this study.

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• 34. Centers for Disease Control and Prevention. Rates of COVID-19 Cases and Deaths by Vaccination Status Atlanta, GA2022 [updated May 20, 2022; cited 2022 June 3, 2022]. Available from: https://covid.cdc.gov/covid-data-tracker/#rates-by-vaccine-status .

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This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility:

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COVID-19 vaccine effectiveness and fewer common side effects most important factors in whether adults choose vaccination

by European Society of Clinical Microbiology and Infectious Diseases

Concerns about the common side effects of COVID-19 vaccines and their effectiveness are key to determining whether adults in Germany and the UK choose to get vaccinated against the virus, according to new research being presented at this year's ESCMID Global Congress (formerly ECCMID) in Barcelona, Spain (27-30 April).

In contrast, timing of COVID-19 and influenza vaccines and their type have little influence on people's willingness to get vaccinated in both countries.

The survey and discrete choice experiment involved 1,000 adults (500 from Germany and 500 from the UK, with 250 who were fully vaccinated and 250 who were willing to receive a COVID-19 vaccine but were not up to date on their vaccine in each country. These "vaccine-hesitant" people included 230/250 participants from the UK who were partially vaccinated, and 20 who were unvaccinated, respectively; and 226/250 from Germany who were partially vaccinated, and 24 who were unvaccinated, respectively. Fully vaccinated was defined as participants who believed they were fully vaccinated, having received the initial primary series and additional COVID-19 booster doses. Un/partially vaccinated consisted of those who did not receive all primary series or booster doses available to them.

The study by Professor Jeffrey Lazarus from the Barcelona Institute for Global Health in Spain and international colleagues offers important insights into the drivers of behavior that might boost COVID-19 vaccine uptake, especially in those who are vaccine-hesitant.

"With vaccination fatigue growing alongside vaccine disinformation and hesitancy, our research suggests that educating the public about the benefits of vaccines, with messaging focusing largely on vaccine safety and efficacy, will get more people to roll up their sleeves," says Professor Lazarus. "What's more, a better understanding of the importance of the perceptions of possible vaccine side effects will be essential to developing more appropriate messaging to reduce vaccine hesitancy."

Despite medical evidence of the importance and safety of COVID-19 vaccines, some of the public is hesitant and/or opposed to COVID-19 vaccination. Understanding the public's preferences for different COVID-19 vaccines and drivers of vaccine hesitancy is critical for implementing effective strategies to increase vaccine uptake.

To identify the most important factors when choosing to be vaccinated against COVID-19, the researchers first conducted an online survey of 1,000 adults in Germany (average age 47 years; 50% women) and the UK (average age 50 years; 49% women) between July and August 2023, to find out their preferences and experiences with SARS-CoV-2 infections and COVID-19 vaccines.

Participants were recruited using a specialist patient recruitment agency called Global Perspectives (GP). GP identified eligible participants through their panel databases, as well as through support groups , word of mouth, internet advertising, email blasts, and social media. Recruitment messages were used to support this process. The sample was stratified by country, vaccination status, and disease risk status.

Then the study went a step further to examine which of six attributes of a COVID-19 vaccine were the most important in making a decision to be vaccinated or not—vaccine type (mRNA or protein), level of protection against COVID infection, level of protection against severe COVID-19 disease, chance of experiencing common side effects (i.e., reactogenicity events), risk of serious side effects (i.e., myocarditis/pericarditis), or joint and separate administration of influenza and COVID-19 vaccines.

This was done by giving each participant an illustrative choice task in which they viewed 11 unique vaccine profiles with a different combination of the six vaccine attributes. Participants were asked to choose between two different vaccine profiles at a time, and to pick which vaccine they would choose if there were only those two vaccine options, or they could select that they would prefer neither of the two options. Using this approach, researchers were able to understand the relative importance of each attribute to each participant.

In the baseline survey that asked participants how they felt about different attributes individually, 59% of German and 46% of UK respondents reported being moderately to extremely worried about COVID-19. More than three-quarters of those surveyed in both countries considered that being able to choose a COVID-19 vaccine to be moderately to extremely important. Additionally, around two-thirds of German and around half (45%) of UK participants reported that they were moderately to extremely worried about serious vaccine side effects.

The survey results differed substantially between the vaccinated and unvaccinated/partially vaccinated groups (based on ranking moderately to severely combined)—while concerns about COVID-19 were higher in the vaccinated group, having a choice of vaccine, vaccine type and concerns of side effects were all rated higher in the unvaccinated/partially vaccinated groups, with the trend followed in both countries.

However, when these attributes were put together in a combined profile in the discrete choice experiment (i.e., when considered together with efficacy, side effects, timing, etc.), the results showed that the most important considerations when deciding whether to be vaccinated in respondents from both countries were vaccine effectiveness against COVID-19 infection and severe disease, followed by common side effects.

Interestingly, the relative importance of common side effects was nearly 10% higher among Germany participants than their UK counterparts, while the importance of serious side effects was less than half as important as common side effects in both countries.

The researchers' next steps involve examining the rate at which participants experience common side effects and the impact on individuals' activities.

The authors note several limitations, including that the study used self-reported/stated preferences that might not always match preferences/decision-making in real-world situations.

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New Covid-19 publications from PharmaSafe

PharmaSafe Research Group Contributes to Research on COVID-19 Vaccine Effectiveness in Preventing Long COVID

The PharmaSafe research group is proud to announce its involvement in new groundbreaking publications that explore the effectiveness of COVID-19 vaccines in preventing long COVID. These publications were published in Lancet Respiratory Medicine, a world-leading respiratory medicine and critical care journal with an impressive Impact Factor of 76·2.

The latest publication, led by Nhung Trinh and other collaborators, draws on extensive data from Norway to examine the effectiveness of COVID-19 vaccines in mitigating long-term symptoms of the virus. This publication builds upon a prior study carried out by an international consortium of researchers, which explored the effectiveness of COVID-19 vaccines in preventing long COVID symptoms in the UK, Spain, and Estonia. The collaborative effort not only underscores the global relevance of the research findings but also contributes to a growing body of evidence on the potential protective effects of vaccination against long COVID. 

Interpreting these studies, the authors find consistent evidence that vaccination against COVID-19 reduces the risk of long COVID symptoms. These findings emphasize the importance of vaccination in preventing persistent COVID-19 symptoms, particularly in adults.

The PharmaSafe research group is proud to have played a role in this collective effort, furthering our commitment to advancing public health and pharmaceutical research. By applying scientific rigor and innovative approaches, our researchers have made significant contributions to the understanding of COVID-19 vaccine effectiveness and long-term health outcomes.

The PharmaSafe research group extends its gratitude to all the collaborators and researchers involved in these publications, as well as the Lancet Respiratory Medicine for providing an exceptional platform to share these impactful findings with the global medical community.

For further details, the publications can be accessed via the following links:

Nhung TH Trinh , Annika M Jödicke, Martí Català, Núria Mercadé-Besora, Saeed Hayati, Angela Lupattelli , Daniel Prieto-Alhambra, Hedvig ME Nordeng.  Effectiveness of COVID-19 vaccines to prevent long COVID: data from Norway. The Lancet Respiratory Medicine, 2024, ISSN 2213-2600, https://doi.org/10.1016/S2213-2600(24)00082-1 .

Martí Català, Núria Mercadé-Besora, Raivo Kolde, Nhung T H Trinh , Elena Roel, Edward Burn, Trishna Rathod-Mistry, Kristin Kostka, Wai Yi Man, Antonella Delmestri, Hedvig M E Nordeng , Anneli Uusküla, Talita Duarte-Salles, Daniel Prieto-Alhambra, Annika M Jödicke. The effectiveness of COVID-19 vaccines to prevent long COVID symptoms: staggered cohort study of data from the UK, Spain, and Estonia. The Lancet Respiratory Medicine, Volume 12, Issue 3, 2024, Pages 225-236, ISSN 2213-2600, https://doi.org/10.1016/S2213-2600(23)00414-9 .

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