latest research covid vaccine

Two years after Covid vaccines rolled out, researchers are calling for newer, better options

Two years after the first Covid shots went into arms, a growing chorus of researchers is calling for a new generation of vaccines that provide broader and more long-term protection against the disease.

The U.S. is currently recording around 430 Covid deaths per day, on average, according to NBC News’ tally . That includes many people who received at least two Covid shots: Six in 10 adults who died of Covid in August were vaccinated or boosted, according to a report by KFF , a nonprofit health think tank. And for the most part, vaccinated people don’t avoid infections or reinfections anymore.

“Coming up with a vaccine that’s going to last longer and cover a wider range of the Covid family of viruses is a life and death problem,” said Dr. Tom Frieden, who directed the Centers for Disease Control and Prevention until 2017 and is now president of the public health organization Resolve to Save Lives.

Many people thought the solution to that problem had arrived two years ago, on December 14, 2020, when Sandra Lindsay became the first person in the U.S. to get a Covid vaccine outside of a clinical trial.

“My whole life just changed tremendously in that one moment in time,” said Lindsay, who is now the vice president of public health advocacy at Northwell Health.

“What was going through my mind is, ‘I cannot wait for this needle to pierce my arm,’” she said.

Millions of people shared her impatience, for good reason: Adults who are up to date on their shots are 15 times less likely to die from Covid than those who are unvaccinated. Covid vaccines prevented more than 3.2 million deaths and 18.5 million hospitalizations in the U.S. from December 2020 through November 2022, according to an analysis published Tuesday by the Commonwealth Fund and Yale School of Public Health.

But at first, the shots were perceived to be even more powerful than that — a shield against mild symptoms and a ticket back to pre-pandemic life. The reality proved more complicated and, in certain ways, disappointing.

Many experts maintain that we can — and must — do better.

In particular, researchers think sprays or drops given through the nose or mouth could do a better job of stopping transmission. They also hope that vaccines that target multiple parts of the virus or several variants at once could reduce the need for continuous boosters.

“It’s sometimes easy to forget what a tremendous achievement it was to get a brand new vaccine against a brand new class of viruses. … It was pragmatic, and it was tremendously successful. But it’s certainly not the panacea,” said Matthew Miller, scientific director of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster University. “We can certainly improve on what we know now.”

The promises and shortcomings of mRNA

Vaccine researchers generally agree that mRNA technology was suited to the needs of this pandemic, since it allowed scientists to develop a vaccine quickly at a time when each day meant more lives lost. Scientists then updated the shots relatively easily to target new variants.

“If it wasn’t mRNA, it wouldn’t have gotten done so fast,” said Dr. Barney Graham, former deputy director of the National Institutes of Health’s Vaccine Research Center, now a senior adviser for global health equity at Morehouse School of Medicine. 

To date, he added, the Covid vaccine is “one of our simplest, safest vaccines that we’ve ever made.”

When Lindsay got her vaccine in 2020, she was dealing with severely ill Covid patients every day as director of nursing critical care at Long Island Jewish Medical Center.

“It felt like you were just walking into a burning building, but it’s your job,” she said. “It’s what I love doing: taking care of people. So I was going in there no matter what, and just praying every day that I don’t fall ill.”

Despite the odds, Lindsay still hasn’t gotten Covid, as far as she knows. But the majority of Americans have, according to CDC estimates — a situation most of the public did not anticipate when clinical trial results showed 95% efficacy against symptomatic disease.

“It may be that the vaccines were their own worst enemies in some ways, because they were so good initially that people had an expectation that went beyond reason,” Graham said.

Experts agree now, though, that protection from Covid shots fades too fast. Plus, a lack of access to vaccines in many countries allowed the virus to spread rampantly and mutate over time, which has undermined vaccines and treatments.

“If we had immunized the whole world in six months, we may not be having all the problems with the variants because we would have constrained [the] virus’ spread earlier,” Graham said.

The future of Covid vaccines: No needles

When Lindsay volunteered to get her vaccine on day one, she wasn’t aware that she was the country’s very first recipient — despite the cameras.

Now, she said, she still gets recognized.

“I was in TJ Maxx the other day and this man who I didn’t expect was basically bowing down at my feet, [saying] that through my one action, I saved his life, his family’s lives, and so many more,” Lindsay said. “Those are the stories that just solidify for me that what I did on that day made a big difference.”

But others see Lindsay as the face of a promise that fell short. 

“You get this on social media, when you post anything: ‘Well, how do you feel now that this thing was all a lie? People are not supposed to get Covid and you got the shots and it’s a big letdown,’” she said.

Researchers still hope that in the future, nasal spray vaccines could inspire more confidence by offering more protection against illness, reducing side effects and removing needles from the equation. 

Because Covid seems to infect most people through the nasal passages first, administering a vaccine in the nose could vanquish the virus before it has a chance to spread, the thinking goes.

“It’s sort of akin to having guards placed outside the door in the mucus layer, versus waiting for the invaders to come in,” said Dr. Akiko Iwasaki, an immunobiology professor at Yale University who is developing an intranasal Covid vaccine.

Globally, 117 intranasal Covid vaccines are in development or have been rolled out, according to an analysis provided to NBC News by Airfinity , a health analytics company. Five have been approved in at least one country — two in China and one each in India, Iran and Russia — and 20 more have entered clinical trials. The majority rely on traditional vaccine platforms, not mRNA.

“There’s probably a number of advantages to the intranasal route that will be realized once that route is fully exploited. People can administer it themselves. You can use it in a developing world setting. You can use lower doses,” said Dr. David Curiel, a professor of radiation oncology at Washington University School of Medicine in St. Louis. “There may even be a safety gain, and you get sterilizing immunity and possibly block transmission.”

Curiel developed the technology for the nasal vaccine approved in India. But the vaccine hasn’t entered trials in the U.S., and trial results from India haven’t been published in a peer-reviewed journal.

Other researchers are betting on inhaled vaccines, which come in the form of aerosolized mists administered through a nebulizer into the lungs, where the virus tends to wreak the most havoc.

In September, China approved an inhaled version of a previously authorized Covid shot, called Convidecia. A small trial showed that the inhaled booster dose produced a stronger antibody response than a booster of the intramuscular shot.

Miller and his McMaster colleagues are testing two inhaled vaccines in phase 1 human trials. The more effective candidate will likely advance to phase 2, he said.

Those vaccines might offer an additional advantage, according to Miller: They target three parts of the coronavirus, whereas the current shots target just the spike protein, which mutates faster than the virus’ other components.

Still, some researchers worry that protection from nasal or inhaled vaccines could also wane quickly.

“If we can give a vaccine at the site where infection typically occurs, we would always love to do it that way. The challenge, of course, is that sometimes it doesn’t generate the same type of bloodstream immunity that we really want,” said Dr. Buddy Creech, director of the Vanderbilt Vaccine Research Program.

Creech said future versions of mRNA shots could potentially be tweaked to target three or more coronavirus strains. (The new bivalent boosters target two.)

“It will not be surprising if at some point we need something like a trivalent vaccine or some other permutation of what we have now,” he said. “It could very well mirror what we do with influenza.”

Then there’s the idea of targeting several different coronaviruses at once. The National Institute of Allergy and Infectious Diseases has allocated more than $62 million for research and development of pan-coronavirus vaccines. 

In July, researchers at the California Institute of Technology showed that their candidate protected mice and monkeys from the viruses that cause both Covid and SARS. In October, researchers at Duke University School of Medicine similarly showed that their pan-coronavirus vaccine protected animals from multiple SARS-related viruses.

But unlike in 2020, the federal government’s motivation to fund Covid-related innovations is drying up. Whatever Covid vaccine comes next is likely three to five years off, Miller estimated — or perhaps longer, according to other experts. 

“The mRNA technology is remarkably successful — these vaccines work better than we had the right to expect,” Frieden said. “But the virus is adapting. And as the virus adapts, we need to adapt.”

Aria Bendix is the breaking health reporter for NBC News Digital.

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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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FDA Takes Action on Updated mRNA COVID-19 Vaccines to Better Protect Against Currently Circulating Variants

FDA News Release

Today, the U.S. Food and Drug Administration took action approving and authorizing for emergency use updated COVID-19 vaccines formulated to more closely target currently circulating variants and to provide better protection against serious consequences of COVID-19, including hospitalization and death. Today’s actions relate to updated mRNA vaccines for 2023-2024 manufactured by ModernaTX Inc. and Pfizer Inc. Consistent with the totality of the evidence and input from the FDA’s expert advisors, these vaccines have been updated to include a monovalent (single) component that corresponds to the Omicron variant XBB.1.5.

What You Need to Know

• Individuals 5 years of age and older regardless of previous vaccination are eligible to receive a single dose of an updated mRNA COVID-19 vaccine at least 2 months since the last dose of any COVID-19 vaccine. 
• Individuals 6 months through 4 years of age who have previously been vaccinated against COVID-19 are eligible to receive one or two doses of an updated mRNA COVID-19 vaccine (timing and number of doses to administer depends on the previous COVID-19 vaccine received). 
• Unvaccinated individuals 6 months through 4 years of age are eligible to receive three doses of the updated authorized Pfizer-BioNTech COVID-19 Vaccine or two doses of the updated authorized Moderna COVID-19 Vaccine.
• The FDA is confident in the safety and effectiveness of these updated vaccines and the agency’s benefit-risk assessment demonstrates that the benefits of these vaccines for individuals 6 months of age and older outweigh their risks.
• Individuals who receive an updated mRNA COVID-19 vaccine may experience similar side effects as those reported by individuals who previously received mRNA COVID-19 vaccines as described in the respective prescribing information or fact sheets.
• The updated vaccines are expected to provide good protection against COVID-19 from the currently circulating variants. Barring the emergence of a markedly more virulent variant, the FDA anticipates that the composition of COVID-19 vaccines may need to be updated annually, as is done for the seasonal influenza vaccine. 
• The U.S. Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices will meet tomorrow (Sept. 12), to discuss clinical recommendations on who should receive an updated vaccine, as well as further considerations for specific populations such as immunocompromised and older individuals. 
• Manufacturers have publicly announced that the updated vaccines would be ready this fall, and the FDA anticipates that the updated vaccines will be available in the near future.

“Vaccination remains critical to public health and continued protection against serious consequences of COVID-19, including hospitalization and death,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “The public can be assured that these updated vaccines have met the agency’s rigorous scientific standards for safety, effectiveness, and manufacturing quality. We very much encourage those who are eligible to consider getting vaccinated.”

The updated mRNA vaccines are each approved for individuals 12 years of age and older and are authorized under emergency use for individuals 6 months through 11 years of age. As part of today’s actions, the bivalent Moderna and Pfizer-BioNTech COVID-19 vaccines are no longer authorized for use in the United States.

Data Supporting the Updated mRNA COVID-19 Vaccines (2023-2024 Formula)

The mRNA COVID-19 vaccines approved and authorized today are supported by the FDA’s evaluation of manufacturing data to support the change to the 2023-2024 formula and non-clinical immune response data on the updated formulations including the XBB.1.5 component. 

• The updated mRNA vaccines are manufactured using a similar process as previous formulations. In studies that have been recently conducted, the extent of neutralization observed by the updated vaccines against currently circulating viral variants causing COVID-19, including EG.5 and BA.2.86, appears to be of a similar magnitude to the extent of neutralization observed with prior versions of the vaccines against corresponding prior variants against which they had been developed to provide protection. This suggests that the vaccines are a good match for protecting against the currently circulating COVID-19 variants.
• The benefit-risk profile of previously authorized and approved mRNA COVID-19 vaccines is well understood as these vaccines have been administered to hundreds of millions of people in the United States. 

Based on an evaluation of the totality of the evidence, the benefit-risk profile is favorable for individuals 6 months of age and older to receive an updated COVID-19 mRNA vaccine. Although serious outcomes from COVID-19 are less common in younger individuals, they do occur, and it has been demonstrated that recently receiving a COVID-19 vaccine reduces the risk of such serious outcomes.

Additional Details on Today’s Actions

Specifically, today’s actions include:

• Approval of Comirnaty (COVID-19 Vaccine, mRNA) to include the 2023-2024 formula, and a change to a single dose for individuals 12 years of age and older. Comirnaty was previously approved as a two-dose series for individuals 12 years of age and older. 
• Approval of Spikevax (COVID-19 Vaccine, mRNA) to include the 2023-2024 formula, a change to a single dose for individuals 18 years of age and older, and approval of a single dose for individuals 12 through 17 years of age. Spikevax was previously approved as a two-dose series for individuals 18 years of age and older. 
• Authorization of Moderna COVID-19 Vaccine for emergency use in individuals 6 months through 11 years of age to include the 2023-2024 formula and lower the age eligibility for receipt of a single dose from 6 years to 5 years of age. Additional doses are also authorized for certain immunocompromised individuals ages 6 months through 11 years, as described in the fact sheets.
• Authorization of Pfizer-BioNTech COVID-19 Vaccine for emergency use in individuals 6 months through 11 years of age to include the 2023-2024 formula. Additional doses are also authorized for certain immunocompromised individuals ages 6 months through 11 years, as described in the fact sheets.

The approval of Comirnaty (COVID-19 Vaccine, mRNA) (2023-2024 Formula) was granted to BioNTech Manufacturing GmbH. The EUA amendment for the Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) was issued to Pfizer Inc.

The approval of Spikevax (COVID-19 Vaccine, mRNA) (2023-2024 Formula) was granted to ModernaTX Inc. and the EUA amendment for the Moderna COVID-19 Vaccine (2023-2024 Formula) was issued to ModernaTX Inc.

Related Information

• Comirnaty (COVID-19 Vaccine, mRNA) (2023-2024 Formula)
• Spikevax (COVID-19 Vaccine, mRNA) (2023-2024 Formula)
• Moderna COVID-19 Vaccine (2023-2024 Formula)
• FDA Resources for the Fall Respiratory Illness Season
• Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) 
• Updated COVID-19 Vaccines for Use in the United States Beginning in Fall 2023
• June 15, 2023, Meeting of the Vaccines and Related Biological Products Advisory Committee

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

The Updated COVID Vaccines Are Here: 9 Things to Know

BY KATHY KATELLA February 29, 2024

[Originally published: Oct. 2, 2023. Updated: Feb. 29, 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-19 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, with more than 200,000 reported deaths since January 2022. That figure includes more than 600 deaths in adolescents and children ages 19 and younger.

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 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 new 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-19 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-19 vaccine (and who have not already been vaccinated with a recently updated mRNA COVID-19 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-19, 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-19. 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-19 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-19 may consider delaying their vaccine by 3 months.

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) are brand new this fall, 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-19 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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Study Largely Confirms Known, Rare COVID-19 Vaccine Side Effects

By Kate Yandell

Posted on February 27, 2024

SciCheck Digest

An international study of around 99 million people confirmed known serious side effects of COVID-19 vaccination. It also identified a possible relationship between the first dose of the Moderna vaccine and a small risk of a neurological condition. Social media posts about the study left out information on the vaccines’ benefits and the rarity of the side effects.

More than  half a billion doses of COVID-19 vaccines have now been administered in the U.S. and only a few, very rare, safety concerns have emerged. The vast majority of people experience only minor, temporary side effects such as pain at the injection site, fatigue, headache, or muscle pain — or no side effects at all. As the Centers for Disease Control and Prevention has said , these vaccines “have undergone and will continue to undergo the most intensive safety monitoring in U.S. history.”

A small number of severe allergic reactions known as anaphylaxis, which are expected with any vaccine, have occurred with the authorized and approved COVID-19 vaccines. Fortunately, these reactions are rare, typically occur within minutes of inoculation and can be treated. Approximately 5 per million people vaccinated have experienced anaphylaxis after a COVID-19 vaccine, according  to the CDC.

To make sure serious allergic reactions can be identified and treated, all people receiving a vaccine should be observed for 15 minutes after getting a shot, and anyone who has experienced anaphylaxis or had any kind of immediate allergic reaction to any vaccine or injection in the past should be monitored for a half hour. People who have had a serious allergic reaction to a previous dose or one of the vaccine ingredients should not be immunized. Also, those who shouldn’t receive one type of COVID-19 vaccine should be monitored for 30 minutes after receiving a different type of vaccine.

There is evidence that the Pfizer/BioNTech and Moderna mRNA vaccines may rarely cause inflammation of the heart muscle (myocarditis) or of the surrounding lining (pericarditis), particularly in male adolescents and young adults .

Based on data collected through August 2021, the reporting rates of either condition in the U.S. are highest in males 16 to 17 years old after the second dose (105.9 cases per million doses of the Pfizer/BioNTech vaccine), followed by 12- to 15-year-old males (70.7 cases per million). The rate for 18- to 24-year-old males was 52.4 cases and 56.3 cases per million doses of Pfizer/BioNTech and Moderna vaccines, respectively.

Health officials have emphasized that vaccine-related myocarditis and pericarditis cases are rare and the benefits of vaccination still outweigh the risks. Early evidence suggests these myocarditis cases are less severe than typical ones. The CDC has also noted that most patients who were treated “responded well to medicine and rest and felt better quickly.”

The Johnson & Johnson vaccine has been linked to an  increased risk of rare blood clots combined with low levels of blood platelets, especially in women ages 30 to 49 . Early symptoms of the condition, which is known as thrombosis with thrombocytopenia syndrome, or TTS, can appear as late as three weeks after vaccination and  include  severe or persistent headaches or blurred vision, leg swelling, and easy bruising or tiny blood spots under the skin outside of the injection site.

According to the CDC, TTS has occurred in around 4 people per million doses administered. As of early April ,  the syndrome has been confirmed in 60 cases, including nine deaths, after more than 18.6 million doses of the J&J vaccine. Although TTS remains rare, because of the availability of mRNA vaccines, which are not associated with this serious side effect, the FDA on May 5 limited authorized use of the J&J vaccine to adults who either couldn’t get one of the other authorized or approved COVID-19 vaccines because of medical or access reasons, or only wanted a J&J vaccine for protection against the disease. Several months earlier, on Dec. 16, 2021 ,  the CDC had recommended the Pfizer/BioNTech and Moderna shots over J&J’s.

The J&J vaccine has also been linked to an increased risk of Guillain-Barré Syndrome, a rare disorder in which the immune system attacks nerve cells.  Most people  who develop GBS fully recover, although some have permanent nerve damage and the condition can be fatal.

Safety surveillance data suggest that compared with the mRNA vaccines, which have not been linked to GBS, the J&J vaccine is associated with 15.5 additional GBS cases per million doses of vaccine in the three weeks following vaccination. Most reported cases following J&J vaccination have occurred in men 50 years old and older.

Link to this

COVID-19 vaccines — like all  vaccines  and other medical products — come with side effects, including  serious side effects  in rare cases. The vaccines were rolled out to protect people from a novel virus that has  killed  millions of people globally and would likely have killed millions more without the arrival of the vaccines. There is a broad consensus from experts and governmental health agencies that the benefits of COVID-19 vaccination outweigh the risks.

Researchers have  scrutinized  the COVID-19 vaccines’ safety and continue to do so. A  study  published Feb. 12 in the journal Vaccine reported on an international group of more than 99 million people who received COVID-19 vaccines, primarily finding links to known rare side effects. The study largely focused on the Pfizer/BioNTech and Moderna vaccines, which have been  widely given  in the U.S., as well as the AstraZeneca vaccine, which was  never authorized  in the U.S.

“What we take away, is that the Covid-19 vaccination campaigns have been very effective in preventing severe disease,” study co-author  Anders Hviid , head of the department of epidemiology research at the Statens Serum Institut in Denmark, told us in an email. “The few serious side effects that we have observed in this and other studies have been rare.”

Many popular posts on social media have shared results from the study, some lacking the context that the identified  health problems are rare , that most aren’t new and that the vaccines have proven benefits. Various posts made unfounded claims, stating or implying that people should not have received the vaccines , that the risks outweigh the benefits or that the  risk of the rare side effects is greater than was reported in the study.

“Hundreds of millions of people were used as lab rats and now the truth that WE ALL ALREADY KNEW can no longer be denied,” said one popular  post , referring to the vaccines as “experimental” and “UNTESTED.” The post shared a screenshot of the headline of a New York Post  article  about the new study, which read, “COVID vaccines linked to slight increases in heart, brain, blood disorders: study.”

“This thing was forced on people who faced almost no risk from Covid,” said another widely read post . “It is completely unacceptable.” The post shared statistics from the paper without making it clear that serious health problems after vaccination were rare and that risk varied by vaccine type and dose.

The Vaccine study confirmed that the Moderna and Pfizer/BioNTech vaccines are linked in rare cases to myocarditis and pericarditis, conditions involving inflammation of the heart muscle and lining. The rate of myocarditis was most elevated after the second dose of the Moderna vaccine. Myocarditis risk — which is greatest in men in their late teens and early twenties — was  identified via vaccine safety monitoring and first reported in 2021. Based on the current evidence, the  CDC says, the benefit of vaccination outweighs the risk of these conditions, which improve for most people after medical treatment and rest.

The study confirmed neurological and blood clotting conditions associated with the AstraZeneca vaccine. In the U.S., these  problems  were  linked  to the Johnson & Johnson vaccine, contributing to this vaccine no longer being recommended or available.

The study also identified a new possible safety signal indicating a potential link between the first dose of the Moderna and AstraZeneca vaccines and rare neurological conditions. This included an association between the first doses of the vaccines and acute disseminated encephalomyelitis, or ADEM, an autoimmune condition that causes inflammation of the brain and spinal cord.

Hviid emphasized that the researchers only saw these neurological events after first doses of the two vaccines. “We did not see these signals following further doses of these two Covid-19 vaccines, nor did we see them after any dose of the Pfizer/BioNTech vaccine which has been more widely used,” he said.

“We are also talking about very rare events,” Hviid continued. “As an example, the association between the first dose of Moderna and acute inflammation of the brain and spine would, if causal, correspond to 1 case per 1.75 million vaccinated. It is only due to the sheer scale of our study, that we have been able to identify this minute potential risk.”

Study Bolsters the Evidence Serious COVID-19 Vaccine Side Effects Are Rare

The Vaccine  study  drew on national or regional health records from eight countries with institutions participating in the  Global Vaccine Data Network , an international group that studies vaccine safety. The researchers analyzed health outcomes after around 184 million doses of the Pfizer/BioNTech vaccine, 36 million doses of the Moderna vaccine and 23 million doses of the AstraZeneca vaccine. 

The researchers focused on 13 health problems that either had a known association with vaccination or for which there was some rationale to investigate whether there was an association. To determine whether the health problems were associated with vaccination, they compared the expected rates of the health problems — or the number of health events that should occur based on background rates in the regions studied — with the number of events they observed in the 42 days after vaccination.

“This study confirms the primary already detected and validated side effects established by previous literature,”  Jeffrey S. Morris , director of the division of biostatistics at the University of Pennsylvania’s Perelman School of Medicine, told us via email, referring to the rare heart conditions associated with the Moderna and Pfizer/BioNTech vaccines, as well as the rare conditions associated with the AstraZeneca and Johnson & Johnson vaccines. 

Morris said that findings on ADEM — the rare autoimmune neurological condition linked to first doses of the Moderna and AstraZeneca vaccines — “might be a new safety signal.” 

ADEM  involves  inflammation to the brain and spinal cord, arising most often in children following an infectious illness. It has a  sudden onset  and typically eventually improves, with a full recovery in many, although not all, cases.

After the first dose of the Moderna vaccine, researchers observed seven ADEM cases, when they expected two. As we’ve said, Hviid calculated the rate of this side effect — if ultimately shown to be related to vaccination — to be 1 in 1.75 million following the first dose of the Moderna vaccine. 

The data show “this was indeed an EXTREMELY rare adverse event,” Morris said, referring to ADEM. “It is understandable at this incidence rate why it may not have been detected before now, and why a study with 99 million participants like this is important to find even the most rare serious adverse events that are potential minority harm risks of these vaccines.”

The authors of the study wrote that more research is needed into ADEM following COVID-19 vaccination, saying that “the number of cases of this rare event were small and the confidence interval wide, so results should be interpreted with caution and confirmed in future studies.” The authors also wrote that neurological  events  have been found to occur at a much higher rate after COVID-19 than after COVID-19 vaccination.

The study means that “early warning systems are solid,” said  Marc Veldhoen , an immunologist at the Instituto de Medicina Molecular João Lobo Antunes in Portugal, in a  post  on X, formerly known as Twitter. “To avoid any adverse reaction is not possible, but, identifying those at higher risk may be possible.”

Identifying those at greater risk of side effects can help guide decisions on which vaccines to recommend and what problems doctors should watch for in their patients.

Editor’s note: SciCheck’s articles providing accurate health information and correcting health misinformation are made possible by a grant from the Robert Wood Johnson Foundation. The foundation has no control over FactCheck.org’s editorial decisions, and the views expressed in our articles do not necessarily reflect the views of the foundation.

“ How do we know vaccines are safe? ” FactCheck.org. Updated 8 Jul 2021.

“ Selected Adverse Events Reported after COVID-19 Vaccination .” CDC website. Updated 12 Sep 2023.

Yandell, Kate. “ Tucker Carlson Video Spreads Falsehoods on COVID-19 Vaccines, WHO Accord .” FactCheck.org. 13 Jan 2024.

“ Safety of COVID-19 Vaccines .” CDC website. 3 Nov 2023.

“ How safe are the COVID-19 vaccines? ” FactCheck.org. Updated 17 May 2022.

Faksova, K. et al. “ COVID-19 Vaccines and Adverse Events of Special Interest: A Multinational Global Vaccine Data Network (GVDN) Cohort Study of 99 Million Vaccinated Individuals .” Vaccine. 12 Feb 2024.

COVID Data Tracker. “ COVID-19 Vaccinations in the United States .” CDC website. Updated 11 May 2023.

Liu, Angus. “ AstraZeneca withdraws US COVID vaccine application, shifts focus to antibody treatments .” Fierce Pharma. 10 Nov 2022.

Hviid, Anders. Email with FactCheck.org. 22 Feb 2024.

TheBlaze. “ Blood clots, neurological disorders, and swollen hearts: Multinational study on COVID vaccines paints a damning picture .” Facebook. 20 Feb 2024.

Dr. Anthony G. Jay (@anthonygjay). “ I post a lot of vids but rarely PLUG them WATCH my YouTube vid on this – it’s 6 minutes – before it gets taken down 🤐 .” Instagram. 20 Feb 2024.

bikinibottom_fish 🐟 (@bikinibottom_fish). “ Global Study Links COVID-19 Vaccines to Heart and Brain Issues! ” Instagram. 20 Feb 2024.

PatrioticBabe 🇺🇸 (@babedoesthenews). “ ❗️ .” Instagram. 20 Feb 2024.

RASPY RAWLS (@raspy_rawls2). “ … We told yall not to take that shyt but hey wat dew we know 🤷🏾‍♂️ …  .” Instagram. 20 Feb 2024.

Jaimee Michell (@thegaywhostrayed). “ I want to know if you think Trump holds any blame, and if not, why not? COMMENT your thoughts BELOW! ” Instagram. 20 Feb 2024.

Liberty Counsel (@libertycounsel). “ …  “Based on ‘conservative assumptions,’ the estimated harms of the COVID-19 mRNA vaccines ‘greatly outweigh the rewards,’ the article stated, noting that ‘for every life saved, there were nearly 14 times more deaths caused by the modified mRNA injections.’” … ” Instagram. 20 Feb 2024.

Shemeka Michelle (@ theshemekamichelle ). “ Remember when they called them “rare” breakthrough cases? Yeah, me too. #slight .” Instagram. 20 Feb 2024.

Mal’aki (@awake.the.mind). “ ‘Slight’ will turn to ‘significant’ soon enough. We tried to warn you all but we’re just crazy conspiracy theorists .” Instagram. 20 Feb 2024.

Steinbuch, Yaron. “ COVID vaccines linked to slight increases in heart, brain, blood disorders: study .” New York Post. 20 Feb 2024.

Vogel, Gretchen and Couzin-Frankel, Jennifer. “ Israel reports link between rare cases of heart inflammation and COVID-19 vaccination in young men .” Science. 1 Jun 2021.

Robertson, Lori and Kiely, Eugene. “ Q&A on the Rare Clotting Events That Caused the J&J Pause .” FactCheck.org. Updated 6 May 2022.

Kahn, Ilana. “ Acute Transverse Myelitis and Acute Disseminated Encephalomyelitis .” Pediatrics in Review. 1 Jul 2020.

Morgan, Hannah J. et al. “ Acute Disseminated Encephalomyelitis and Transverse Myelitis Following COVID-19 Vaccination – A Self-Controlled Case Series Analysis .” Vaccine. 12 Feb 2024. 

“ Global COVID Vaccine Safety (GCoVS) .” Global Vaccine Data Network website. Accessed 23 Feb 2024.

Morris, Jeffrey S. Email with FactCheck.org. 22 Feb 2024.

Frontera, Jennifer A. et al. “ Neurological Events Reported after COVID-19 Vaccines: An Analysis of VAERS .” Annals of Neurology. 2 Mar 2022.

Marc Veldhoen (@Marc_Veld). “ COVID-19 vaccines and adverse events of special interest: A multinational Global Vaccine Data Network (GVDN) cohort study of 99 million vaccinated individuals Anything in those anti-vax stories about large scale damage and deaths due to vaccines? No. … ” X. 19 Feb 2024.

Older Adults Now Able to Receive Additional Dose of Updated COVID-19 Vaccine

For Immediate Release: Wednesday, February 28, 2024 Contact: Media Relations (404) 639-3286

Today, CDC Director Mandy Cohen endorsed the CDC Advisory Committee on Immunization Practices’ (ACIP) recommendation for adults ages 65 years and older to receive an additional updated 2023-2024 COVID-19 vaccine dose. The recommendation acknowledges the increased risk of severe disease from COVID-19 in older adults, along with the currently available data on vaccine effectiveness.

Previous CDC recommendations ensured that people who are immunocompromised are already eligible for additional doses of the  COVID-19 vaccine.

Data continues to show the importance of vaccination to protect those most at risk for severe outcomes of COVID-19. An additional dose of the updated COVID-19 vaccine may restore protection that has waned since a fall vaccine dose, providing increased protection to adults ages 65 years and older.

Adults 65 years and older are disproportionately impacted by COVID-19, with more than half of COVID-19 hospitalizations during October 2023 to December 2023 occurring in this age group.

CDC and ACIP will continue to monitor COVID-19 vaccine safety and effectiveness. CDC continues to recommend that everyone  stay up to date on their COVID-19 vaccines , especially  people with weakened immune systems .

The following is attributable to Dr. Mandy Cohen:

“Today’s recommendation allows older adults to receive an additional dose of this season’s COVID-19 vaccine to provide added protection,” said Mandy Cohen, M.D., M.P.H. “Most COVID-19 deaths and hospitalizations last year were among people 65 years and older. An additional vaccine dose can provide added protection that may have decreased over time for those at highest risk.”

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New Research Supports an Annual COVID Vaccine Plan

Key takeaways.

• New research suggests that most people will benefit from an annual COVID-19 vaccine.
• Certain groups may need two vaccines a year.
• Doctors said more needs to be done to encourage people to get vaccinated.

There have been a lot of changes in recommendations around COVID-19 vaccines over the past few years, making it difficult to know whether you need another shot and how often you should get one. Now, new research from the Yale School of Public Health has recommendations for a vaccine cadence moving forward.

The study, which was published in the Annals of Internal Medicine , used computer simulations to compare five annual vaccination strategies and predict outcomes. The researchers discovered that getting an annual COVID vaccine with a second dose for adults over 50 and children under 2 was linked to fewer hospitalizations, fewer deaths, and less healthcare spending each year.

This isn’t revolutionary: The Centers for Disease Control and Prevention (CDC) already proposed similar interim guidelines, although they’re slightly different. But it backs up existing recommendations around COVID vaccines.

Is an Annual COVID Shot Realistic?

While the COVID vaccine was relatively popular when it first rolled out, many people haven’t gotten the most recent 2023-2024 updated version . Current data show that less than 23% of the adult population in the U.S. has gotten the updated vaccine. The numbers are even lower in children; less than 14% of children aged 6 months to 17 years have received the updated vaccine.  

Current recommendations from the CDC say that people 65 and up should receive an additional dose of the COVID-19 vaccine, but the new Yale study suggests it would be more effective if people did this starting at age 50.

Given how few people have gotten the updated vaccine to begin with, do doctors actually think the public will embrace this?

“This sounds familiar and it rather mirrors what, by and large, is happening to date,” William Schaffner, MD , an infectious disease specialist and professor at the Vanderbilt University School of Medicine, told Verywell. While older people have been the most likely to follow recommendations around COVID vaccines, Schaffner said it’s been tricky to get parents on board.

“The vast majority of parents have not taken their child in to be vaccinated with even their first dose,” he said. “Pediatricians are going to have to do a lot of friendly persuasion to get that group vaccinated. Parents just do not see the current Omicron variants distinctly impacting children.”

If a new concerning COVID-19 variant emerges, though, recommendations could change, Schaffner said.

What About People Who Are Immunocompromised?

The study didn’t address the ideal vaccine cadence for people who are immunocompromised. If you have a condition that causes you to be immunocompromised, it’s important to consult your doctor, said infectious disease expert  Amesh A. Adalja, MD , senior scholar at the Johns Hopkins Center for Health Security.

“Immunocompromised individuals may have to have individualized vaccination schedules dependent upon their net state of immunosuppression,” Adalja told Verywell. He noted that the word ‘immunosuppression’ is used very generally, “but it is a phenomenon that has degrees.”

The CDC has COVID vaccine recommendations for immunocompromised people, but it’s very specific to age, type of vaccine, and current level of vaccination.

“The standing recommendation is that these individuals can get repeated doses if they are moderately or severely immunocompromised and at least two months have passed since their last dose,” Schaffner said.

How Doctors Can Increase Vaccination Rates

Doctors suggest coupling your COVID vaccine with your flu shot. The convenience of a combined appointment increases the odds people will get both vaccines.

“The annual rate of people getting the flu shot is about 50% of the population, but that’s better than it is for the COVID vaccine,” Timothy Murphy, MD, senior associate dean for clinical and translational research at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences, told Verywell. “Pairing the COVID vaccine with the flu vaccine might increase the likelihood of people getting it.”

Schaffner agrees.

“We have to promote this as a circumstance where in the fall, you roll up both your sleeves,” he said. While it’s not available yet, a combination flu and COVID-19 vaccine would likely increase use of both vaccines even more. “It would also make life easier,” Schaffner said.

What This Means For You

COVID-19 vaccine can lower your risk of being hospitalized and dying from the virus, so you should make sure you have the latest shot available every year. If you’re unsure what your personal needs are regarding the vaccine, consult with your primary care physician for more information.

The information in this article is current as of the date listed, which means newer information may be available when you read this. For the most recent updates on COVID-19, visit our  coronavirus news page .

Read the original article on Verywell Health .

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August 26, 2021

Largest real-world study of COVID-19 vaccine safety published

by Clalit Research Institute

The Clalit Research Institute, in collaboration with researchers from Harvard University, analyzed one of the world's largest integrated health record databases to examine the safety of the Pfizer/BioNTech BNT162B2 vaccine against COVID-19. The study provides the largest peer-reviewed evaluation of the safety of a COVID-19 vaccine in a nationwide mass-vaccination setting. The study was conducted in Israel, an early global leader in COVID-19 vaccination rates.

Previous efforts to characterize vaccine safety have relied on voluntary active reporting by vaccinated individuals, which is known to be incomplete. The present study relies on the analysis of millions of anonymized electronic medical records, which are far more comprehensive.

Furthermore, in order to provide the necessary context for interpreting vaccine safety findings, this study is the first to examine a wide range of adverse events both among vaccinated individuals and among unvaccinated individuals who were infected with the coronavirus. Thus, two separate analyses were conducted:

• Vaccination Outcomes Analysis: 884,828 vaccinated individuals aged 16 and over were carefully matched with 884,828 unvaccinated individuals based on an extensive set of sociodemographic, geographic and health-related attributes. Individuals were assigned to each group dynamically based on their changing vaccination status (235,541 individuals moved from the unvaccinated cohort into the vaccinated cohort during the study). Rates of the 25 potential adverse events within three weeks following either vaccine dose were compared between the two groups. This analysis took place from December 20, 2020, the launch of Israel's national vaccination campaign, through May 24, 2021.
• Infection Outcomes Analysis: To provide context for the vaccine safety findings above, a separate analysis was conducted that estimated the rates of the same 25 potential adverse events among 173,106 unvaccinated individuals who were infected with the coronavirus, compared to 173,106 carefully matched controls who were not infected with the coronavirus. This analysis took place from March 1, 2020 (the beginning of the COVID-19 pandemic in Israel) through May 24, 2021.

The vaccine was found to be safe: Out of 25 potential side effects examined, 4 were found to have a strong association with the vaccine.

Myocarditis was found to be associated with the vaccine, but rarely—2.7 excess cases per 100,000 vaccinated individuals. (The myocarditis events observed after vaccination were concentrated in males between 20 and 34.) In contrast, coronavirus infection in unvaccinated individuals was associated with 11 excess cases of myocarditis per 100,000 infected individuals.

Other adverse events moderately associated with vaccination were swelling of the lymph nodes, a mild side effect that is part of a standard immune response to vaccination, with 78 excess cases per 100,000, appendicitis with 5 excess cases per 100,000 (potentially as a result of swelling of lymph nodes around the appendix), and herpes zoster with 16 excess cases per 100,000.

In contrast to the relatively small number of adverse effects associated with the vaccine, high rates of multiple serious adverse events were associated with coronavirus infection among unvaccinated patients, including: Cardiac arrhythmias (a 3.8-fold increase to an increase of 166 cases per 100,000 infected patients), kidney damage (14.8-fold increase; 125 excess cases per 100,000), pericarditis (5.4-fold increase; 11 excess cases per 100,000), pulmonary embolism (12.1-fold increase; 62 excess cases per 100,000), deep vein thrombosis (3.8-fold increase; 43 excess cases per 100,000), myocardial infarction (4.5-fold increase; 25 excess cases per 100,000), and stroke (2.1-fold increase; 14 excess cases per 100,000).

The research was conducted by Dr. Noam Barda, Dr. Noa Dagan, Yair Ben-Shlomo, Dr. Eldad Kepten, Dr. Jacob Waxman, Reut Ohana and Prof. Ran Balicer from the Clalit Research Institute, Dr. Doron Netzer of Clalit Health Services, as well as Prof. Miguel Hernán and Prof. Marc Lipsitch of the Harvard T.H. Chan School of Public Health, Prof. Isaac Kohane of the Department of Biomedical Informatics at Harvard Medical School, and Prof. Ben Reis of Boston Children's Hospital and Harvard Medical School.

This study focused on adverse events that may develop in the short to medium term after vaccination, and those with clinical significance. The study did not focus on common immediate symptoms such as redness and discomfort at the injection site or fever. Symptoms that occurred within 6 weeks of the vaccine (three weeks after each vaccine dose) were defined as an adverse event of the vaccine if they occurred more frequently among the vaccinated group compared to the control group.

The results of this study validate and complement the previously reported findings of the Pfizer/BioNTech Phase-III randomized clinical trial, which, with 21,720 vaccinated individuals, could not precisely and comprehensively assess vaccine safety. The present study's large size allows a more detailed assessment of the vaccine's safety across a wider range of adverse events.

"The extensive nationwide rollout of Israel's COVID-19 vaccination campaign provided the Clalit Research Institute with a unique opportunity to assess, through its rich and comprehensive digital datasets, the safety of the vaccine in a real-world setting, without needing to rely on individual-driven active reporting of side-effects" said Prof. Ran Balicer, senior author of the study, Director of the Clalit Research Institute and Chief Innovation Officer for Clalit. "These results show convincingly that this mRNA vaccine is very safe and that the alternative of 'natural' morbidity caused by the coronavirus puts a person at significant, higher and much more common risk of serious adverse events. These data should facilitate informed individual risk-benefit decision-making, and, in our view, make a strong argument in favor of opting-in to get vaccinated, especially in countries where the virus is currently widespread," added Prof. Balicer, who also serves as Chairman of Israel's National Expert Advisory Team on COVID-19 response.

"This study sheds light for the first time on the significant side effects of the coronavirus vaccine. Since this is a more comprehensive analysis based on electronic medical records , these are more reliable assessments than those published to date which have relied on voluntary active reporting systems," explains Doron Netzer, Chief Medical Officer of Clalit's Community Health Division.

Prof. Ben Reis, Director of the Predictive Medicine Group at the Boston Children's Hospital Computational Health Informatics Program and Harvard Medical School, said, "To date, one of the main drivers of vaccine hesitancy has been a lack of information regarding potential side effects of the vaccine. This careful epidemiological study provides reliable information on vaccine safety, which we hope will be helpful to those who have not yet decided about vaccination." He continued, "Those who have hesitated until now to get vaccinated due to concerns about very rare side effects—such as myocarditis—should be aware that the risks for this very same side effect are actually higher among unvaccinated infected individuals."

Prof. Miguel Hernán, Director of the CAUSALab and Professor at the Harvard T.H. Chan School of Public Health, said, "This research is a perfect example of how randomized trials and observational healthcare databases complement each other. The original trial of the Pfizer/BioNTech vaccine provided evidence of its safety, but the estimates were too imprecise given the small sample size. This analysis of Clalit's high-quality database emulates the design of the original trial, uses its findings as a benchmark, and expands upon them to confirm the vaccine's safety on a wide range of adverse events. This combination of evidence from randomized trials and observational studies is a model for efficient medical research, something which is especially important in COVID times."

Prof. Marc Lipsitch, Director of the Center for Communicable Disease Dynamics and Professor at the Harvard T.H. Chan School of Public Health, said, "In all studies of vaccine safety, a major challenge is to ensure that those we are comparing to identify the vaccine's side effects are similar in the other characteristics that may predict whether they will experience these side effects. This is especially hard in the context of a rapidly growing, age-targeted vaccine campaign. Clalit's extraordinary database made it possible to design a study that addressed these challenges in a way that provides tremendous confidence in the inferences that come out of the study."

The research was funded in part by the newly announced Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute. "The strengthening of the scientific collaboration between Harvard and Clalit made possible by the Berkowitz Living Laboratory Collaboration is already bearing fruit and giving us a foretaste of the value of healthcare systems instrumented for research," said Prof. Isaac Kohane, Chair of the Department of Biomedical Informatics at Harvard Medical School and co-Director of the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration along with Professor Balicer. "Israel offers a unique environment in which to study the vaccine and its effects, and this study is an excellent example of what can be accomplished through such close scientific collaborations."

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SARS-CoV-2 articles from across Nature Portfolio

SARS-CoV-2 is a positive-sense single-stranded RNA virus. It is contagious in humans and is the cause of the coronavirus disease 2019 (COVID-19).

Mobile delivery of COVID-19 vaccines improved uptake in rural Sierra Leone

A trial that took mobile health services to rural Sierra Leone finds that this initiative increased COVID-19 vaccine uptake. But more must be done to expand the coverage of health services in low-income countries.

• Alison Buttenheim
• Harsha Thirumurthy

Latest Research and Reviews

Incident allergic diseases in post-COVID-19 condition: multinational cohort studies from South Korea, Japan and the UK

SARS-CoV-2 infection has been linked to various persistent or new-onset health consequences, including disruption of the immune system. Here, the authors investigate the risk of new-onset allergic diseases following SARS-CoV-2 infection using data from South Korea, Japan, and the UK.

• Myeongcheol Lee
• Dong Keon Yon

Faster detection of asymptomatic COVID-19 cases among care home staff in England through the combination of SARS-CoV-2 testing technologies

• Finola Ryan
• Joanna Cole-Hamilton

The SARS-CoV-2 neutralizing antibody response to SD1 and its evasion by BA.2.86

Due to the focus of vaccination on the SARS CoV-2 spike protein, spike has been associated with high levels of viral mutation and subsequent immune escape. Here the authors study a conserved epitope in SARS CoV-2 sub-domain-1 and characterise the neutralising antibody response and evasion in contemporary SARS COV-2 viral strains.

• Daming Zhou
• Piyada Supasa
• Gavin R. Screaton

Stability, homogeneity and measurement uncertainty estimation of PVP-I solutions for the application on oro and nasopharynx against SARS-CoV-2

• Md. Moniruzzaman
• Mamudul Hasan Razu

Long-term effects of Omicron BA.2 breakthrough infection on immunity-metabolism balance: a 6-month prospective study

Here the authors study recovery from mild to moderate Omicron breakthrough infection at six months post infection. Serum proteomics, PBMC single-cell transcriptomics and clinical parameters indicate slow recovery with coagulation abnormalities and an imbalance of the immune response and metabolism remaining.

• George Fu Gao

Aesculus hippocastanum extract and the main bioactive constituent β-escin as antivirals agents against coronaviruses, including SARS-CoV-2

• Freddy Armando Peñaranda Figueredo
• Josefina Vicente
• Carlos Alberto Bueno

News and Comment

Google AI could soon use a person’s cough to diagnose disease

Machine-learning system trained on millions of human audio clips shows promise for detecting COVID-19 and tuberculosis.

• Mariana Lenharo

COVID’s toll on the brain: new clues emerge

A leaky blood–brain barrier and inflammation might account for some of the cognitive symptoms of COVID-19.

• Claudia López Lloreda

Massive public-health experiment sends vaccination rates soaring

The rate of vaccination against COVID-19 rose sharply in villages in Sierra Leone where health officials held mobile vaccination clinics.

Speed up relief for long COVID through grassroots clinical trials

• Marc Jamoulle
• Elena Louazon
• Johan Van Weyenbergh

Save lives in the next pandemic: ensure vaccine equity now

The proposed Pandemic Agreement must ensure that COVID-19 vaccine nationalism is never repeated; 290 scientists call for action.

• Colin Carlson
• Daniel Becker
• Alexandra Phelan

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Cardiovascular risks and COVID-19 : New research confirms the benefits of vaccination

Member, IMPART (Initiative on Medication Management, Policy Analysis, Research & Training), Dalhousie University

Disclosure statement

Glen Pyle receives funding from the Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the Natural Sciences and Engineering Research Council of Canada. He is a on the advisory board of "Royal City Science" and "Science Up First".

Dalhousie University provides funding as a founding partner of The Conversation CA.

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COVID-19 is a respiratory disease. Yet, from the earliest days of the pandemic, the cardiovascular risks associated with SARS-CoV-2 infection were clear: individuals with severe cases of COVID-19 often died from cardiovascular complications, and those with pre-existing cardiovascular disease were more likely to have severe illness or die.

In short, the cardiovascular system has played a central role in COVID-19 since the beginning.

It is not surprising that as debate over COVID-19 and vaccines flared that cardiovascular disease was a central issue . Those opposed to vaccination often make claims of cardiovascular risks that exceed any benefits. But when data on COVID-19, vaccines and cardiovascular health are reviewed, the conclusions are clear: vaccines are safe and effective at reducing the cardiovascular complications that are a hallmark of COVID-19.

Hot off the presses

A new study of 20.5 million people in the United Kingdom, Spain and Estonia used electronic health records to determine how COVID-19 vaccines affect cardiovascular complications following SARS-CoV-2 infection. Roughly the same number of vaccinated and unvaccinated subjects were included, and the vaccinated group consisted of people who received at least one of the AstraZeneca, Pfizer, Moderna or Janssen vaccines.

The study found that common cardiovascular complications of COVID-19 — including blood clots, stroke, arrhythmias and heart attacks — were substantially reduced in the vaccinated group, with protective effects lasting up to a year after vaccination.

Bigger picture

While this most recent study represents one of the most comprehensive investigations into the cardiovascular benefits of COVID-19 vaccination, its findings are consistent with earlier, smaller studies.

A 2022 study of 231,037 people found two doses of COVID-19 vaccines reduced the risk of stroke and heart attack up to four months after a breakthrough infection.

A subsequent study of 1.9 million people found that while two doses of the mRNA vaccines or one dose of the Johnson & Johnson vaccine protected against major cardiovascular events following COVID-19, even a single dose of the mRNA vaccines offered some benefit in reducing the risk of cardiovascular complications.

Health-care decisions require a weighing of the risk and benefits of treatments, and for COVID-19 vaccines the low cardiovascular risks favour vaccination. A study of over four million vaccinated Australians found no increase in sudden cardiac death. Even patients with pre-existing heart failure do not have an increased risk of worsening heart failure, myocarditis, or blood clots following vaccination.

Weighing the risks

Although the safety of COVID-19 vaccines is well-established, it does not mean there are no risks. A review of 99 million individuals in the Global Vaccine Data Network confirmed earlier studies that found an increased risk of myocarditis and pericarditis, which is seen primarily in young males — historically the group most at risk for myocarditis before COVID-19 emerged.

While individuals at higher risk for these complications should consult with their health-care providers in making decisions about vaccination, it should be noted that the risk for myocarditis and pericarditis is generally higher with COVID-19, even in this cohort.

Read more: Myocarditis: COVID-19 is a much bigger risk to the heart than vaccination

Studies have also found that extending the time between first and second doses of the COVID-19 mRNA vaccines beyond the initially recommended three-week interval decreases the risk of myocarditis . Furthermore, post-vaccine myocarditis tends to be transient with very good recovery and is less severe than that associated with COVID-19.

The risk of myocarditis in young people has led some to claim that the benefits of COVID-19 vaccines are negated when stacked up against the chance of heart inflammation. A statement from the American Heart Association confirms that the risks of cardiovascular complications in young people with more mild cases of COVID-19 (symptoms lasting less than four days) are low, but notes that there are concerning signs for those who experience more severe illness with infection.

Furthermore, other cardiovascular risks associated with infection must be considered in weighing risks and benefits. These include multisystem inflammatory syndrome or “MIS-C” and cardiac arrhythmias — a far more common risk of COVID-19 than myocarditis.

Finally, the claim that COVID-19 is harmless in children is not true: in Canada COVID-19 is the sixth leading cause of death for children aged one to 14 years, and tenth for people 15 to 19 years old. Overall, studies find that even in young people the benefits of vaccination exceed the risks , particularly when it comes to cardiovascular disease.

Take to heart

There are individuals whose health conditions preclude COVID-19 vaccination , and others for whom health risks may outweigh the benefits. But, for the vast majority of people — including young and otherwise healthy people — COVID-19 vaccination is not only safe, but the cardiovascular protection it offers could be life-saving.

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Do you need a spring COVID-19 vaccine? Research backs extra round for high-risk groups

Recent studies suggest staying up-to-date on covid shots helps protect high-risk groups from severe illness.

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New guidelines suggest certain high-risk groups could benefit from having another dose of a COVID-19 vaccine this spring — and more frequent shots in general — while the broader population could be entering once-a-year territory, much like an annual flu shot.

Medical experts told CBC News that falling behind on the latest shots can come with health risks, particularly for individuals who are older or immunocompromised.

"Even when the risk of infection starts to increase, the vaccines still do a really good job at decreasing risk of severe disease," said McMaster University researcher and immunologist Matthew Miller.

Who needs another COVID shot?

Back in January, Canada's national vaccine advisory body set the stage for another round of spring vaccinations. In a statement , the National Advisory Committee on Immunization (NACI) stated that starting in spring 2024, individuals at an increased risk of severe COVID may get an extra dose of the latest XBB.1.5-based vaccines, which better protect against circulating virus variants.

That means:

• Adults aged 65 and up.
• Adult residents of long-term care homes and other congregate living settings for seniors.
• Anyone six months of age or older who is moderately to severely immunocompromised.

The various spring recommendations don't focus on pregnancy, despite research showing clear links between a COVID infection while pregnant, and increased health risks. However, federal guidance does note that getting vaccinated during pregnancy can protect against serious outcomes.

"Vaccinated people can also pass antibodies to their baby through the placenta and through breastmilk," that guidance states .

What do the provinces now recommend?

Multiple provinces have started rolling out their own regional guidance based on those early recommendations — with a focus on allowing similar high-risk groups to get another round of vaccinations.

B.C. is set to announce guidance on spring COVID vaccines in early April, officials told CBC News, and those recommendations are expected to align with NACI's guidance. 

In Manitoba , high-risk individuals are already eligible for another dose, provided it's been at least three months since their latest COVID vaccine.

• Older P.E.I. residents, others at risk, urged to get spring COVID vaccine booster
• High-risk groups can now book spring COVID-19 vaccination in Nova Scotia

Meanwhile Ontario's latest guidance , released on March 21, stresses that high-risk individuals may get an extra dose during a vaccine campaign set to run between April and June. Eligibility will involve waiting six months after someone's last dose or COVID infection.

Having a spring dose "is particularly important for individuals at increased risk of severe illness from COVID-19 who did not receive a dose during the Fall 2023 program," the guidance notes. 

And in Nova Scotia , the spring campaign will run from March 25 to May 31, also allowing high-risk individuals to get another dose.

Specific eligibility criteria vary slightly from province-to-province, so Canadians should check with their primary care provider, pharmacist or local public health team for exact guidelines in each area.

Age still best determines when to get COVID vaccines, new research suggests

Why do the guidelines focus so much on age.

The rationale behind the latest spring guidelines, Miller said, is that someone's age remains one of the greatest risk factors associated with severe COVID outcomes, including hospitalization, intensive care admission and death. 

"So that risk starts to shoot up at about 50, but really takes off in individuals over the age of 75," he noted.

Canadian data suggests the overwhelming majority of COVID deaths have been among older adults, with nearly 60 per cent of deaths among those aged 80 or older, and roughly 20 per cent among those aged 70 to 79.

People with compromised immune systems or serious medical conditions are also more vulnerable, Miller added.

Will people always need regular COVID shots?

While the general population may not require shots as frequently as higher-risk groups, Miller said it's unlikely there will be recommendations any time soon to have a COVID shot less than once a year, given ongoing uncertainty about COVID's trajectory.

"Going forward, I suspect for pragmatic reasons, [COVID vaccinations] will dovetail with seasonal flu vaccine campaigns, just because it makes the implementation much more straightforward," Miller said.

• Just 15% of Canadians got updated COVID vaccines this fall, new figures show
• Spring COVID-19 vaccines available April 2 in N.B. for those at high-risk

"And although we haven't seen really strong seasonal trends with SARS-CoV-2 now, I suspect we'll get to a place where it's more seasonal than it has been."

In the meantime, the guidance around COVID shots remains simple at its core: Whenever you're eligible to get another dose — whether that's once or twice a year — you might as well do it.

What does research say?

One analysis, published in early March in the medical journal Lancet Infectious Diseases , studied more than 27,000 U.S. patients who tested positive for SARS-CoV-2, the virus behind COVID, between September and December 2023. 

The team found individuals who had an updated vaccine reduced their risk of severe illness by close to a third — and the difference was more noticeable in older and immunocompromised individuals.

Another American research team from Stanford University recently shared the results from a modelling simulation looking at the ideal frequency for COVID vaccines. 

• Elderly Canadians remain at higher risk of serious COVID from first infections, study suggests
• Spring vaccine dose suggested to protect seniors in Canada from severe COVID

The study in Nature Communications suggests that for individuals aged 75 and up, having an annual COVID shot could reduce severe infections from an estimated 1,400 cases per 100,000 people to around 1,200 cases — while bumping to twice a year could cut those cases even further, down to 1,000.

For younger, healthier populations, however, the benefit of regular shots against severe illness was more modest.

The outcome wasn't a surprise to Stanford researcher Dr. Nathan Lo, an infectious diseases specialist, since old age has consistently been a risk factor for severe COVID.

"It's almost the same pattern that's been present the entire pandemic," he said. "And I think that's quite striking."

More frequent vaccination won't prevent all serious infections, he added, or perhaps even a majority of those infections, which highlights the need for ongoing mitigation efforts.

ABOUT THE AUTHOR

Senior Health & Medical Reporter

Lauren Pelley covers health and medical science for CBC News, including the global spread of infectious diseases, Canadian health policy, pandemic preparedness, and the crucial intersection between human health and climate change. Two-time RNAO Media Award winner for in-depth health reporting in 2020 and 2022. Contact her at: [email protected]

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Cardiovascular risks and COVID‑19: New research confirms the benefits of vaccination

Glen Pyle - April 1, 2024

Glen Pyle , Member, IMPART (Initiative on Medication Management, Policy Analysis, Research & Training),  Dalhousie University

COVID-19 is a respiratory disease. Yet, from the earliest days of the pandemic, the cardiovascular risks associated with SARS-CoV-2 infection were clear: individuals with severe cases of COVID-19 often died from cardiovascular complications, and those with pre-existing cardiovascular disease were more likely to have severe illness or die.

In short, the cardiovascular system has played a central role in COVID-19 since the beginning.

It is not surprising that as debate over COVID-19 and vaccines flared that cardiovascular disease was a central issue . Those opposed to vaccination often make claims of cardiovascular risks that exceed any benefits. But when data on COVID-19, vaccines and cardiovascular health are reviewed, the conclusions are clear: vaccines are safe and effective at reducing the cardiovascular complications that are a hallmark of COVID-19.

Hot off the presses

A new study of 20.5 million people in the United Kingdom, Spain and Estonia used electronic health records to determine how COVID-19 vaccines affect cardiovascular complications following SARS-CoV-2 infection. Roughly the same number of vaccinated and unvaccinated subjects were included, and the vaccinated group consisted of people who received at least one of the AstraZeneca, Pfizer, Moderna or Janssen vaccines.

The study found that common cardiovascular complications of COVID-19 — including blood clots, stroke, arrhythmias and heart attacks — were substantially reduced in the vaccinated group, with protective effects lasting up to a year after vaccination.

Bigger picture

While this most recent study represents one of the most comprehensive investigations into the cardiovascular benefits of COVID-19 vaccination, its findings are consistent with earlier, smaller studies.

A 2022 study of 231,037 people found two doses of COVID-19 vaccines reduced the risk of stroke and heart attack up to four months after a breakthrough infection.

A subsequent study of 1.9 million people found that while two doses of the mRNA vaccines or one dose of the Johnson & Johnson vaccine protected against major cardiovascular events following COVID-19, even a single dose of the mRNA vaccines offered some benefit in reducing the risk of cardiovascular complications.

Health-care decisions require a weighing of the risk and benefits of treatments, and for COVID-19 vaccines the low cardiovascular risks favour vaccination. A study of over four million vaccinated Australians found no increase in sudden cardiac death. Even patients with pre-existing heart failure do not have an increased risk of worsening heart failure, myocarditis, or blood clots following vaccination.

Weighing the risks

Although the safety of COVID-19 vaccines is well-established, it does not mean there are no risks. A review of 99 million individuals in the Global Vaccine Data Network confirmed earlier studies that found an increased risk of myocarditis and pericarditis, which is seen primarily in young males — historically the group most at risk for myocarditis before COVID-19 emerged.

While individuals at higher risk for these complications should consult with their health-care providers in making decisions about vaccination, it should be noted that the risk for myocarditis and pericarditis is generally higher with COVID-19, even in this cohort.

Studies have also found that extending the time between first and second doses of the COVID-19 mRNA vaccines beyond the initially recommended three-week interval decreases the risk of myocarditis . Furthermore, post-vaccine myocarditis tends to be transient with very good recovery and is less severe than that associated with COVID-19.

The risk of myocarditis in young people has led some to claim that the benefits of COVID-19 vaccines are negated when stacked up against the chance of heart inflammation. A statement from the American Heart Association confirms that the risks of cardiovascular complications in young people with more mild cases of COVID-19 (symptoms lasting less than four days) are low, but notes that there are concerning signs for those who experience more severe illness with infection.

Furthermore, other cardiovascular risks associated with infection must be considered in weighing risks and benefits. These include multisystem inflammatory syndrome or “MIS-C” and cardiac arrhythmias — a far more common risk of COVID-19 than myocarditis.

Finally, the claim that COVID-19 is harmless in children is not true: in Canada COVID-19 is the sixth leading cause of death for children aged one to 14 years, and tenth for people 15 to 19 years old. Overall, studies find that even in young people the benefits of vaccination exceed the risks , particularly when it comes to cardiovascular disease.

Take to heart

This article is republished from The Conversation under a Creative Commons license. Read the original article .

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• v.43; 2022 Dec

Global reports of takotsubo (stress) cardiomyopathy following COVID-19 vaccination: A systematic review and meta-analysis

Sirwan khalid ahmed.

a Department of Emergency, Ranya Teaching Hospital, Ranya, Sulaimani, Kurdistan-region, Iraq

d Raparin Research Group (RRG), Ranya, Sulaimani, Kurdistan-region, Iraq

Mona Gamal Mohamed

b Department of Adult Nursing, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE

Rawand Abdulrahman Essa

Eman abdelaziz ahmed rashad dabou, salar omar abdulqadir.

c Department of Nursing, University of Raparin, Ranya, Sulaimani, Kurdistan-region, Iraq

Rukhsar Muhammad Omar

Concerns have been raised recently about takotsubo cardiomyopathy (TCM) after receiving COVID-19 vaccines, particularly the messenger RNA (mRNA) vaccines. The goal of this study was to compile case reports to provide a comprehensive overview of takotsubo cardiomyopathy (TCM) associated with COVID-19 vaccines. A systematic literature search was conducted in PubMed, Scopus, Embase, Web of Science, and Google Scholar between 2020 and June 1, 2022. The study included individuals who developed cardiac takotsubo cardiomyopathy from receiving COVID-19 vaccinations. Ten studies, including 10 cases, participated in the current systematic review. The mean age was 61.8 years; 90 % were female, while 10 % were male. 80 % of the patients received the mRNA COVID-19 vaccine, while 20 % received other types. In addition, takotsubo cardiomyopathy (TCM) occurred in 50 % of patients receiving the first dose and another 40 % after the second dose of COVID-19 vaccines. Moreover, the mean number of days to the onset of symptoms was 2.62 days. All cases had an elevated troponin test and abnormal ECG findings. The left ventricular ejection fraction (LVEF) was lower than 50 % in 90 % of patients. In terms of the average length of hospital stay, 50 % stayed for 10.2 days, and all cases recovered from their symptoms. In conclusion, takotsubo (stress) cardiomyopathy (TCM) complications associated with COVID-19 vaccination are rare but can be life-threatening. Chest pain should be considered an alarming symptom, especially in those who have received the first and second doses of the COVID-19 vaccine.

1. Introduction

The coronavirus (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has hurt millions of people worldwide. The FDA granted emergency approval to Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) COVID-19 vaccines in December 2020. SARS-CoV-2 vaccines are still the best hope for combating the global pandemic.

Takotsubo cardiomyopathy (TCM) is a type of heart disease frequently triggered by excessive physical and emotional stress. Although the pathophysiology of this condition is not fully understood, studies have suggested that it may be caused by the activation of central autonomic neurons expressing estrogen receptors. In addition, coronary vasospasm increases sensitivity to a surge in circulating catecholamines and metabolic dysfunction [1] . Catecholamine levels are higher in TCM than in STEMI [2] , [3] . As a result of the COVID-19 pandemic, TCM cases have risen from 1.5 % to 7.8 % [4] . TCM has already been linked to a 'cytokine storm' of interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNFa), which causes hyper inflammation in COVID-19 patients [5] , [6] . Individuals who presented without COVID-19 infection or other notable risk factors may have been infected with TCM due to the psychological stress of living in a pandemic [1] . TCM is more likely to occur in people with a history of mental illness before the pandemic outbreak [5] , [7] , [8] , [9] . The mRNA1273 and BNT1626b2 (COVID-19 mRNA vaccines) induce innate immunity, cytotoxic and helper T cell responses, and, in particular, B cell responses [10] . Pain, erythema, swelling, fever, headache, and myalgia were reported as the most common systemic or local reactions [11] . However, acute myocardial infarction, pulmonary embolism, stroke, and venous thromboembolism are all possible complications of mRNA-based COVID-19 vaccines [12] , [13] , [14] . There have been reports of takotsubo cardiomyopathy following the COVID-19 vaccination, particularly following the messenger RNA (mRNA) vaccines [1] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] .

We are aware of no systematic review that has been conducted specifically for COVID-19 vaccine induced TCM. Given the rarity of adverse takotsubo syndrome associated with COVID19 vaccination, most of the peer-reviewed papers are case reports. The goal of this study was to compile case reports to provide a comprehensive overview of takotsubo cardiomyopathy (TCM) associated with COVID-19 vaccines.

2.1. Review objectives

This study's primary goal is to clarify the possibility of takotsubo cardiomyopathy (TCM) associated with COVID-19 vaccination. And to elaborate on the demographic and clinical characteristics of COVID-19 vaccinated individuals who develop takotsubo cardiomyopathy (TCM).

2.2. Protocol and registration

The review follows the PRISMA 2020 guidelines for reporting systematic reviews and meta-analyses [24] . The review protocol was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42022316515. Additionally, the AMSTAR-2 checklist was used to assess the quality of this review, which was found to be of high quality [25] . Ethical approval was not required for this review article.

2.3. Search strategy

A comprehensive search of major online databases (PubMed, Scopus, Embase, Web of Science, and Google Scholar) was performed from 2020 until June 1, 2022, to discover all articles that had been published. The search strategy consisted of a combination of the following keywords: “COVID-19 vaccine” AND “takotsubo cardiomyopathy” OR “stress cardiomyopathy.” OR “takotsubo syndrome”. In addition, we checked the references of all relevant papers to ensure the search was complete.

2.4. Eligibility criteria

• 1. All case series and case reports after the COVID-19 vaccine developed takotsubo cardiomyopathy (TCM) in humans, regardless of the type of Vaccine and dose, were included.
• 2. In this review, narrative and systematic reviews, as well as papers with insufficient data, were excluded. Furthermore, articles written in languages other than English were excluded.

2.5. Data extraction and selection process

Every step of the data extraction process from the source was guided by PRISMA 2020. It was used to guide the process. Three independent authors (S.K.A., R.A.E., and M.G.M.) used the Rayyan website to screen abstracts and full-text articles based on inclusion and exclusion criteria [26] . Disagreements between the three independent authors were resolved by discussion. The data extraction process was carried out using predefined forms in Microsoft Office Excel. A total of the following information was extracted from each research study: author names, year of publication, age, gender, type of COVID-19 Vaccine, dose, troponin levels, days to symptom onset, symptoms, length of hospital stay/days, ECG, LVEF < 50 % or LVEF > 50 %, treatment, and their outcomes.

2.6. Critical appraisal

We used the Joanna Briggs Institute's critical appraisal tool for case reports to evaluate all included studies [27] . Three authors evaluated each article independently (S.K.A, M.G.M, and R.A.E). The paper evaluation disagreements were resolved through discussion or by the first author (S.K.A.). The results of our systematic review were evaluated using the AMSTAR 2 criteria [25] . The overall quality of our systematic review was rated “moderate” by the AMSTAR 2 tool.

2.7. Data synthesis and analysis

The data from the articles included in this systematic review were extracted and pooled. This data included (author names, year of publication, age, gender, type of COVID-19 vaccine, dose, troponin levels, days to symptoms onset, symptoms, length of hospital stay/days, ECG, LVEF < 50 % or LVEF > 50 %, treatment, and their outcomes). We collected this information from the findings of eligible studies. Categorical data were expressed as proportions (%), and numerical data were expressed as mean ± standard deviation (SD). Statistical analysis will be performed using the Statistical Package for the Social Sciences (SPSS) 25.0 software program (SPSS Inc., Chicago, IL, USA). We pooled the results of the studies into one table.

3.1. Selection of studies

The search was performed on significant databases (PubMed, Scopus, Embase, Web of Science, and Google Scholar) between 2020 and June 1, 2022, and yielded 2371 articles relevant to our search criteria. The references were then organized using a citation manager tool (Mendeley), and 459 articles were automatically eliminated because they were duplicates. Then, a final check was performed on 1912 articles to ensure that their titles, abstracts, and full texts were accurate. One thousand eight hundred ninety-seven articles were rejected because they did not meet the requirements to be included. Aside from that, 15 articles were submitted for retrieval, with five being dismissed because they did not meet our inclusion criteria. Finally, our systematic review included only ten articles ( Fig. 1 ). Case report details are shown in ( Table 1 ).

PRISMA flow diagram.

Characteristics and outcomes of patients with takotsubo cardiomyopathy related to COVID-19 Vaccine.

3.2. Characteristics of the included studies

Table 2 shows an overview of the ten cases. The mean age and SD were 61.8 ± 13.68 years; 90 % were female, while 10 % were male. 80 % of the patients received the mRNA COVID-19 vaccine, either from Pfizer-BioNTech (BNT162b2) or Moderna COVID-19 Vaccine (mRNA-1273), while 20 % of patients received other types, including AstraZeneca COVID-19 vaccine (ChAdOx1 nCoV-19). In addition, takotsubo cardiomyopathy occurred in 50 % of patients receiving the first dose and another 40 % after the second dose of COVID-19 vaccines. Moreover, the mean number of days to onset symptoms was 2.62 ± 2.19 days. All cases had an elevated troponin test and abnormal ECG findings. The left ventricular ejection fraction (LVEF) was lower than 50 % in 90 % of patients. Regarding the average length of hospital stay, 50 % stayed for 10.20 ± 3.96 days, and all cases recovered from their symptoms.

Summary of pooled data from included published research papers have been reported in the literature (n = 10).

4. Discussion

COVID-19 vaccines protect the general public health and restrict viral propagation. Inactivated viral, DNA, mRNA, and protein-based vaccines are the four primary mechanisms that have been examined in this research for COVID-19 vaccines. DNA-based vaccinations use viral vectors to deliver the DNA coding for the SARS-CoV-2 spike protein into cells; mRNA vaccines typically deliver mRNA into cells via a lipid nanoparticle; protein vaccines use the spike proteins or their particles, and certain other vaccinations use inactivated viruses [28] .

The COVID-19 pandemic has recorded the most extensive global vaccination program in history, with over 11.3 billion vaccination doses administered from December 2020 to December 2021. With increasing populations being vaccinated daily, we are seeing increased reports of associated side effects. The most common side effects are pain, swelling, and redness around the injection site. Systemic side effects like fever, tiredness, muscle pain, and headache can also happen to about one in four people. The females have noted a higher prevalence of these systematic effects [29] . Moreover, severe side effects have been reported and are under current monitoring: thrombocytopenic thrombosis, anaphylaxis, Bell's palsy, myocarditis, and capillary leak syndrome [30] , [41] , [50] .

In this systematic review, half of the cases were from the United States, most of the participants were female, and their mean age was 61.6. It was found that the participants received different types of COVID-19 vaccinations, including Pfizer-BioNTech (40 %), Moderna (mRNA-1273) (40 %), and Oxford AstraZeneca ChAdOx1 nCoV-19 (20 %). More than half of the symptoms triggered by the first dose of the COVID-19 vaccine. Another important finding is that the symptoms started to happen after the vaccine dose, with a mean of 2.62 days. In line with the current results, Jani et al. (2021) [31] mentioned that up to now, few cases of TCM have been reported after first or second dose administration of SARS-CoV-2 vaccines, even including different types of vaccines like mRNA-1273, BNT162b2, and ChAdOx1 nCoV-19. Another case report supported that a case of TCM after administration of the second dose of the DNA ChadOX1 nCOV-19 (AZD122) vaccination was reported, and this condition predominantly affects women (90 %) at age 50 and above [1] . Also, Berto et al. (2021) wrote that a healthy 30-year-old Asian woman was brought to the emergency room with sudden chest pain and a cold sweat after receiving the second mRNA COVID-19 vaccine shot (Pfizer, New York City) 2 days prior [32] .

Although the pathophysiology of TCM after COVID-19 vaccination is not well established, the proposed hypotheses are stunning changes in ischemia-induced myocardium. It could be secondary to microvessel or multi-vessel vasospasm and direct myocardial injury due to surge currents. Stress causes more release of catecholamine via excessive activation of sympathetic nervous system through the hypothalamic–pituitary-adrenal axis [33] . The limbic brain regions such as the amygdala, insula, anterior cingulate cortex, prefrontal cortex, and hippocampus have impaired neural networks during stress in TTS patients [34] , [35] , [36] , [37] . In a takotsubo rat model; epinephrin affinity switching from beta2-adrenoreceptors-Gs during low epinephrine amount to Gi when the amount of epinephrin is high causes acute apical cardiac depression, this process is protecting myocardium from toxicity during stress [38] . Scally et al., (2019) [6] has reported elevation of cytokines (serum interleukin-6, chemokine ligand 1, and classic CD14++CD16-) and infiltration of inflammatory myocardial macrophage in TTS patients. Naegele et al., (2016) [39] in his study found serious endothelial dysfunction in TTS patients. Another possible explanation is that the free-floating spike proteins may interact with angiotensin-converting enzyme 2. The imbalance between angiotensin II (overactivity) and angiotensin (deficiency) might play a role in the genesis of acute elevation in blood pressure, and this could be applied as a result of vaccination [45] .

The diagnosis of takotsubo cardiomyopathy (TCM) was based on seven criteria put forward by the European Society of Cardiology [40] . The cardiac signs and symptoms, as well as electrocardiographic and laboratory findings, may be similar in patients who have TCM or myocarditis, which can make it very difficult to differentiate between the two conditions. Despite these difficulties, myocarditis is typically diagnosed with endomyocardial biopsy and cardiac magnetic resonance (CMR) [42] . Additionally, acute emotional or physical stressors induce increased levels of catecholamines and cortisol in the blood. These elevations mediate multiple pathways, including pericardial coronary artery spasms, microvascular dysfunction, and direct muscle cell injury, are all critical findings of transthoracic echocardiography [43] , [44] .

In this systematic review, all cases had elevated troponin levels, the ejection fraction was above 50 %, and the electrocardiogram showed abnormal findings. According to the Mayo Clinic criteria, TCM has left ventricular hypokinesia, akinesia, or dyskinesia. This local wall dyskinesia are specific epicardial vasculature boundaries, with or without apex involvement. It is diagnosed when it expands beyond that. No evidence by angiography of obstructive coronary artery disease or acute plaque rupture, new ST elevation or T wave inversion, or mild cardiac troponin elevation. TCM is triggered by emotional, physical, or unknown causes [31] , [46] .

These findings matched Toida et al. (2021), who reported that patients received the first dose of the Pfizer-BioNTech COVID-19 vaccine. The day after the vaccination, she developed general fatigue and a loss of appetite. A physical examination revealed a systolic murmur of Levine 2/6 at the second left sternal border, clear lung sounds, and no leg edema. On admission, electrocardiography (ECG) revealed atrial fibrillation with a normal axis, negative T -waves in I, aVL, V3-6 leads, and a prolonged QTc interval of 495 ms [47] .

In our review, more than half of the patients stayed in the hospital with a mean ± SD of 10.20 ± 3.96 days, and all recovered without complications. An outcomes study assessing the trends of hospitalized patients with takotsubo cardiomyopathy demonstrated an in-hospital mortality rate of 1.3 %, a hospital discharge rate to the home of 73.6 %, and 1-year mortality of 6.9 % [48] . In addition, Đenić et al. (2022) reported that the patient was clinically improved and had no evidence of high-risk features on ECG or TTE [49] . However, these findings do not support the previous study by Toida et al. (2021), who showed the case report regarding takotsubo cardiomyopathy after the COVID-19 vaccine and found the patient's length of hospital stay was about five days [47] .

5. Limitation

We recognize that our systematic review has some limitations, which include only involving case reports and case series due to the limited numbers of original studies published on the takotsubo cardiomyopathy after taking COVID-19 vaccines, so the results should be interpreted with some caution. Moreover, we do not have any data about the previous history of COVID-19, which may affect the results since COVID-19 can also cause cardiac complications.

6. Conclusion

Takotsubo cardiomyopathy (TCM) complications associated with COVID-19 vaccination are rare but can be life-threatening. Chest pain should be considered an alarming symptom, especially in those who have received a second dose of the vaccine in the last three days. For diagnosis, CK-MB and troponin are better biomarkers to confirm myocarditis than CRP, ESR, and NT‐proBNP. All of the cases had wholly recovered without any irreversible cardiomyopathy changes.

This research did not receive any specific grant from the public, commercial, or not-for-profit funding agencies.

Author Agreement Statement .

We declare that this manuscript is original, has not been published before, and is not currently being considered for publication elsewhere. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We confirm that all have agreed with the order of authors listed in our manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process. He is responsible for communicating with the other authors about progress, submissions of revisions, and final approval of proofs.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Not applicable.

Authors' contributions

Conception and design SKA acquisition of data SKA, RAE analysis and interpretation of data SKA, RAE, MGM, EEA, drafting of the manuscript SKA, RAE, MGM, EAA critical revision of the manuscript for effective intellectual content statistical analysis SKA, SAO and RMO, administrative SKA, RAE, MGM, EAA technical SKA, supervision SKA and all authors approving the final draft.

Provenance and peer review

Not commissioned, externally peer-reviewed