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

Reviewed and current on 10 August 2021.

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

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

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

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

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

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

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

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

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

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

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January 12, 2021

Experimental coronavirus vaccine highly effective

At a glance.

• Clinical trial results showed that the investigational vaccine known as mRNA-1273 is 94.1% effective in preventing symptomatic COVID-19.
• The findings suggest that the vaccine, which has now been FDA-approved for emergency use, is safe and effective.

Researchers have been working to develop a safe and effective vaccine against SARS-CoV-2, the coronavirus that causes COVID-19. One vaccine candidate, called mRNA-1273, is being developed by researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the biotech company Moderna, Inc. Early results showed it can trigger an immune response against the virus without serious side effects.

To further investigate the safety and efficacy of this vaccine, a research team led by Dr. Lindsey R. Baden of Brigham and Women’s Hospital in Boston, Dr. Hana M. El-Sahly of Baylor College of Medicine, and Dr. Brandon Essink of Meridian Clinical Research carried out a clinical trial with more than 30,000 adult volunteers nationwide. Participants were 18 years of age or older with no known previous SARS-CoV-2 infection. Results were published on December 30, 2020 in the New England Journal of Medicine.

Volunteers were randomly assigned to receive either two doses of the investigational vaccine (100 micrograms each) or two shots of a saline placebo. They received the first injection between July 27 and October 23, 2020. The second shot was given 28 days after.

The investigators recorded 196 cases of symptomatic COVID-19 among participants at least 14 days after they received their second shot. Only 11 of these cases were in the group that received the vaccine, with none severe. In contrast, 185 of the cases occurred in the placebo group, 30 of which were severe. The incidence of symptomatic COVID-19 was thus 94.1% lower in participants who received mRNA-1273 compared to those receiving placebo. For participants 65 years or older, the efficacy was 86.4%.

There were no concerning safety issues with vaccination. Local reactions to the vaccine were generally mild. About half the participants receiving mRNA-1273 experienced moderate to severe side effects—such as fatigue, muscle aches, joint pain and headache—after the second dose. In most volunteers, these resolved within two days.

One potential concern about COVID-19 vaccines is an unusual phenomenon called vaccine-associated enhanced respiratory disease, or VAERD. VAERD can occur when a vaccine induces an immune response that causes the disease the vaccine is supposed to protect against to be more severe if you’re exposed to the virus. However, the team found no evidence of VAERD among those who received mRNA-1273.

“There is much we still do not know about SARS-CoV-2 and COVID-19. However, we do know that this vaccine is safe and can prevent symptomatic COVID-19 and severe disease,” says NIAID Director Dr. Anthony S. Fauci. “It is my hope that all Americans will protect themselves by getting vaccinated when the vaccine becomes available to them. That is how our country will begin to heal and move forward.”

The FDA issued an Emergency Use Authorization for Moderna to make the vaccine available for the prevention of COVID-19 in adults on December 18, 2020.

Although mRNA-1273 can prevent symptomatic COVID-19, more study is needed to determine whether it protects against SARS-CoV-2 transmission. Additional analyses are also underway to understand the vaccine’s impact on asymptomatic infections.

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References:  Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine . Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Kehtan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group. N Engl J Med . 2020 Dec 30. doi: 10.1056/NEJMoa2035389. Online ahead of print. PMID: 33378609.

Funding:  NIH’S National Institute of Allergy and Infectious Diseases (NIAID); Office of the Assistant Secretary for Preparedness and Response.

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FDA approved and authorized the 2024-2025 mRNA COVID-19 vaccines on August 22, 2024. FDA authorized Novavax COVID-19 Vaccine, Adjuvanted (2024 – 2025 Formula) under Emergency Use Authorization on August 30, 2024. Learn how you can stay up to date with your COVID-19 vaccine: Staying Up to Date with COVID-19 Vaccines

COVID-19 Vaccine Effectiveness

What to know.

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

What CDC is doing

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

The overall goal of CDC’s vaccine effectiveness program is to generate the comprehensive evidence needed to inform COVID-19  vaccine policy  decisions and CDC guidance on other prevention measures.

To accomplish this, CDC in collaboration with public health and academic partners, conducts  observational studies  to evaluate the real-world effectiveness of authorized and licensed COVID-19 vaccines in the United States.

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

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

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

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

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

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

Guiding principles for monitoring vaccine effectiveness

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

• Assessing COVID-19 vaccine effectiveness in key populations and against key outcomes (see below)
• Providing timely data to evaluate effectiveness of new vaccine recommendations
• Detecting changes in COVID-19 vaccine effectiveness due to waning of vaccine-induced protection and emergence of new variants
• Including populations at high risk for severe COVID-19
• Communicating findings to policy makers, the scientific community, the public, and other stakeholders
• Vaccine Effectiveness Studies
• COVID Data Tracker
• National Center for Immunization and Respiratory Diseases (NCIRD), Coronavirus and Other Respiratory Viruses Division

COVID-19 (coronavirus disease 2019) is a disease caused by a virus named SARS-CoV-2. It can be very contagious and spreads quickly.

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FDA Approves and Authorizes Updated mRNA COVID-19 Vaccines to Better Protect Against Currently Circulating Variants

FDA News Release

Today, the U.S. Food and Drug Administration approved and granted emergency use authorization (EUA) for updated mRNA COVID-19 vaccines (2024-2025 formula) to include a monovalent (single) component that corresponds to the Omicron variant KP.2 strain of SARS-CoV-2. The mRNA COVID-19 vaccines have been updated with this formula to more closely target currently circulating variants and provide better protection against serious consequences of COVID-19, including hospitalization and death. Today’s actions relate to updated mRNA COVID-19 vaccines manufactured by ModernaTX Inc. and Pfizer Inc.

In early June, the FDA advised manufacturers of licensed and authorized COVID-19 vaccines that the COVID-19 vaccines (2024-2025 formula) should be monovalent JN.1 vaccines. Based on the further evolution of SARS-CoV-2 and a rise in cases of COVID-19, the agency subsequently determined and advised manufacturers that the preferred JN.1-lineage for the COVID-19 vaccines (2024-2025 formula) is the KP.2 strain, if feasible.

“Vaccination continues to be the cornerstone of COVID-19 prevention,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “These updated vaccines meet the agency’s rigorous, scientific standards for safety, effectiveness, and manufacturing quality. Given waning immunity of the population from previous exposure to the virus and from prior vaccination, we strongly encourage those who are eligible to consider receiving an updated COVID-19 vaccine to provide better protection against currently circulating variants.”

The updated mRNA COVID-19 vaccines include Comirnaty and Spikevax, both of which are approved for individuals 12 years of age and older, and the Moderna COVID-19 Vaccine and Pfizer-BioNTech COVID-19 Vaccine, both of which are authorized for emergency use for individuals 6 months through 11 years of age.

What You Need to Know

• 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.
• 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 the updated, authorized Moderna or Pfizer-BioNTech COVID-19 vaccines (timing and number of doses to administer depends on the previous COVID-19 vaccine received).
• Individuals 5 years through 11 years of age regardless of previous vaccination are eligible to receive a single dose of the updated, authorized Moderna or Pfizer-BioNTech COVID-19 vaccines; if previously vaccinated, the dose is administered at least 2 months after the last dose of any COVID-19 vaccine.
• Individuals 12 years of age and older are eligible to receive a single dose of the updated, approved Comirnaty or the updated, approved Spikevax; if previously vaccinated, the dose is administered at least 2 months since the last dose of any COVID-19 vaccine.
• Additional doses are authorized for certain immunocompromised individuals ages 6 months through 11 years of age as described in the Moderna COVID-19 Vaccine and Pfizer-BioNTech COVID-19 Vaccine fact sheets.

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 and as described in the respective prescribing information or fact sheets. The updated vaccines are expected to provide protection against COVID-19 caused by the currently circulating variants. Barring the emergence of a markedly more infectious variant of SARS-CoV-2, the FDA anticipates that the composition of COVID-19 vaccines will need to be assessed annually, as occurs for seasonal influenza vaccines.

For today’s approvals and authorizations of the mRNA COVID-19 vaccines, the FDA assessed manufacturing and nonclinical data to support the change to include the 2024-2025 formula in the mRNA COVID-19 vaccines. The updated mRNA vaccines are manufactured using a similar process as previous formulas of these vaccines. The mRNA COVID-19 vaccines have been administered to hundreds of millions of people in the U.S., and the benefits of these vaccines continue to outweigh their risks.

On an ongoing basis, the FDA will review any additional COVID-19 vaccine applications submitted to the agency and take appropriate regulatory action.

The approval of Comirnaty (COVID-19 Vaccine, mRNA) (2024-2025 Formula) was granted to BioNTech Manufacturing GmbH. The EUA amendment for the Pfizer-BioNTech COVID-19 Vaccine (2024-2025 Formula) was issued to Pfizer Inc.

The approval of Spikevax (COVID-19 Vaccine, mRNA) (2024-2025 Formula) was granted to ModernaTX Inc. and the EUA amendment for the Moderna COVID-19 Vaccine (2024-2025 Formula) was issued to ModernaTX Inc.

Related Information

• Comirnaty (COVID-19 Vaccine, mRNA) (2024-2025 Formula)
• Spikevax (COVID-19 Vaccine, mRNA) (2024-2025 Formula)
• Moderna COVID-19 Vaccine (2024-2025 Formula)
• Pfizer-BioNTech COVID-19 Vaccine (2024-2025 Formula)
• FDA Resources for the Fall Respiratory Illness Season
• Updated COVID-19 Vaccines for Use in the United States Beginning in Fall 2024
• June 5, 2024, 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, radiation-emitting electronic products, and for regulating tobacco products.

Decades in the Making: mRNA COVID-19 Vaccines

Two U.S. Food and Drug Administration (FDA)–approved mRNA vaccines for COVID-19 have saved millions of lives. These vaccines were developed with NIH support and research on a protein found on SARS-CoV-2, the virus that causes COVID-19. Clinical trials for the COVID-19 vaccines in people were established in what seemed like record time. But in reality, more than 50 years of public and private laboratory research laid the groundwork for the rapid development of these life-saving vaccines.

Studies of viruses, including other coronaviruses, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV); advances in general vaccine technology; and the breakthrough in using fatty, oil-like particles called lipid nanoparticles to deliver vaccines to cells were just some of the efforts that made the mRNA COVID-19 vaccines possible. For decades, NIH has supported the research that led to these vaccines — and this timeline provides some of the best examples.

Knowledge of mRNA and Viruses Grows

1961 to 1990.

Scientists discover mRNA and how it can either activate or block protein production in cells. They start to study its use in medicine. Source 1 , Source 2

NIH launches the HIV/AIDS Clinical Trials Networks. The flexibility and rapid-response design of these networks acts as a framework for future responses to other viruses and infectious diseases, including SARS-CoV-2.

Early 1990s

Congress and NIH set aside 10% of NIH’s yearly budget for HIV/AIDS research, funding that continues through 2016 and supports discoveries about the virus, that help in understanding other viruses.

Studies of Other Viruses and mRNA Breakthroughs Advance Vaccine Science

Early 2000s.

NIH scientists lay the foundation for structure-based vaccine design by finding that the structure of a protein on the surface of the human immunodeficiency virus allows it to enter human cells. Source

A laboratory breakthrough shows that modified mRNA can safely deliver instructions to cells without over-activating the body’s immune system. Source

2005 to 2016

Scientists investigate the use of lipids as envelopes to deliver information to the cells of the body. These studies eventually lead to the creation of the lipid nanoparticles used as the outer envelopes for mRNA vaccines against COVID-19. Source

 NIH scientists discover the structure of virus proteins that let viruses invade cells. This finding leads scientists to create the first stabilized proteins for use in vaccines that provoke a strong immune response to viruses such as RSV, a major cause of severe disease in infants and older adults. Source  

2014 to 2018

NIH’s response to the Ebola epidemic in the Democratic Republic of Congo helps establish pathways to streamline and speed up regulatory review and emergency  use of investigational treatments  during critical disease outbreaks. Source

By stabilizing the coronavirus “spike protein” that lets HKU1, a form of the common cold, invade cells, NIH scientists are able to better understand coronavirus immunity. Source

Scientists from NIH and Moderna begin to collaborate on a general vaccine design that uses viral mRNA. This design can be quickly adapted to protect people from emerging viruses such as Nipah virus and the Middle East respiratory syndrome (MERS) coronavirus. Source

NIH scientists stabilize the spike protein that MERS uses to invade cells, allowing researchers to better understand how to build an effective vaccine against coronaviruses. Source

Through study of a Zika virus DNA-based vaccine, NIH scientists discover that gene-based vaccines, such as those using mRNA, are safe and effective, paving the way for development of mRNA vaccines. Source

NIH and Moderna scientists plan for Phase 1 clinical trials to test the safety of mRNA vaccines for Nipah virus; the trials began in 2022. Source 1 , Source 2

COVID-19 Pandemic Begins

December 31, 2019 .

The first cluster of people sick with what is now called COVID-19 is reported in Wuhan, China. Global response begins almost right away. The U.S. government comes together with private, non-governmental, and academic organizations to begin work on COVID-19 vaccines. Source

January 2020

Chinese scientists share the first genetic sequence of SARS-CoV-2 with the NIH database GenBank. Scientists from NIH and Moderna quickly pivot from studies of other viral vaccines to focus on a vaccine candidate for COVID-19, mRNA-1273, to respond to the outbreak.  Source 1 , Source 2

March 11, 2020

The World Health Organization (WHO) declares COVID-19 a pandemic. Source

March 16, 2020 

NIH clinical trials for the Moderna mRNA vaccine begin. Source

April 17, 2020

NIH launches Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a first-of-its-kind public-private partnership for developing COVID-19 treatments and vaccines. Source

May 15, 2020

Operation Warp Speed launches to coordinate federal government efforts that speed up the approval and production of reliable COVID-19 diagnostics, vaccines, and treatments. Source 1 ,  Source 2

July 8, 2020

NIH launches the COVID-19 Prevention Network (CoVPN), which uses the existing structure of NIH clinical trial networks to support trials of COVID-19 vaccines and other prevention tools. Source

November 16, 2020

A large-scale Phase 3 clinical trial of the Moderna mRNA vaccine shows promising interim results. Source

mRNA Vaccines for COVID-19 Ready for People

December 11, 2020.

The FDA grants an emergency use authorization (EUA) to the Pfizer-BioNTech mRNA vaccine for people age 16 and older. Source

December 18, 2020

The FDA grants an EUA to the Moderna mRNA vaccine for people age 18 and older. Source

August 23, 2021

The FDA grants full approval to the Pfizer-BioNTech mRNA vaccine for people age 16 and older. Source

October 29, 2021

The FDA grants an EUA to the Pfizer-BioNTech mRNA vaccine for children age 5 to 11. Source

January 31, 2022

The FDA grants full approval to the Moderna mRNA vaccine for people age 18 and older. Source

March 14, 2022

NIH launches Phase 1 clinical trials for three mRNA HIV vaccines. These vaccines apply lessons learned from the development of mRNA vaccines for COVID-19. Source

Data show that the U.S. COVID-19 vaccination program is estimated to have prevented 2 million deaths, 17 million hospitalizations, and 66 million infections through March 2022. Vaccination is also estimated to have saved nearly $900 billion in health care costs. Source

June 17, 2022

The FDA grants an EUA to the Pfizer-BioNTech and Moderna mRNA vaccines for children age 6 months or older. Source

July 11, 2022

NIH launches a Phase 1 clinical trial for an mRNA Nipah virus vaccine. Source

August 31, 2022

The FDA grants an EUA of the Moderna and Pfizer-BioNTech COVID-19 vaccines to authorize bivalent formulations for use as a booster dose. These updated boosters contain mRNA components for both the original strain of SARS-CoV-2 and its Omicron variant. Source

December 8, 2022

The FDA grants an EUA to the Pfizer-BioNTech and Moderna bivalent COVID-19 vaccines for children age 6 months or older. Source

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Inside the story about the research and development of COVID-19 vaccines

Shrina p. patel.

Ramanbhai Patel College of Pharmacy, Charusat University, Anand, India.

Gayatri S. Patel

Jalpa v. suthar.

The ongoing coronavirus threat from China has spread rapidly to other nations and has been declared a global health emergency by the World Health Organization (WHO). The pandemic has resulted in over half of the world's population living under conditions of lockdown. Several academic institutions and pharmaceutical companies that are in different stages of development have plunged into the vaccine development race against coronavirus disease 2019 (COVID-19). The demand for immediate therapy and potential prevention of COVID-19 is growing with the increase in the number of individuals affected due to the seriousness of the disease, global dissemination, lack of prophylactics, and therapeutics. The challenging part is a need for vigorous testing for immunogenicity, safety, efficacy, and level of protection conferred in the hosts for the vaccines. As the world responds to the COVID-19 pandemic, we face the challenge of an overabundance of information related to the virus. Inaccurate information and myths spread widely and at speed, making it more difficult for the public to identify verified facts and advice from trusted sources, such as their local health authority or WHO. This review focuses on types of vaccine candidates against COVID-19 in clinical as well as in the preclinical development platform.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in Hubei Province, China, in December 2019 (and possibly earlier, though unrecognized), as a pneumonia-causing disorder [ 1 ], most likely the result of natural selection in animal hosts (bats, pangolins) before the zoonotic transition [ 2 ]. Seven members of this viral family are now known to infect humans, three of whom have the potential to cause severe respiratory diseases [ 3 ]. Coronaviruses (CoVs) are positive-sense, single-stranded Coronaviridae family (subfamily Coronavirinae) RNA viruses that infect a broad range of hosts to produce diseases ranging from the common cold to severe/fatal diseases [ 4 ]. The novel virus was initially named “2019-nCoV” by the International Committee on Virus Taxonomy. It was changed to “SARS-CoV-2” since it was found to be the sister virus of an extreme acute respiratory syndrome (SARS-CoV) [ 5 ]. The ongoing threat of coronavirus emerging in China has spread rapidly to other countries and has been declared by the World Health Organization (WHO) as a global health emergency [ 6 ].

Virus genetic sequencing shows that it is a beta coronavirus that is closely related to the SARS virus [ 7 ]. Currently, immunization prevents 2–3 million deaths from more than 20 life-threatening diseases that are now being controlled by vaccinations, and work is underway at an unprecedented pace to make coronavirus disease 2019 (COVID-19) a vaccine-preventable illness [ 8 ]. To accelerate the research and development process and to establish new standards and standards to prevent the spread of the coronavirus pandemic and care for those affected, WHO brings together the world's scientists and public health practitioners [ 7 ]. In human medical intervention, vaccines are one of the monumental achievements in mitigating the dispersion and effects of infectious diseases [ 9 ]. Vaccines are the most useful method for contagious disease prevention because they are more cost-effective than treatment and reduce morbidity and mortality without long-lasting effects [ 10 ]. Preventive and therapeutic vaccines will be of fundamental significance as the most obvious way to safeguard public health [ 11 ]. Since the coronavirus shares substantial sequence homology with two other lethal coronaviruses, SARS and Middle East respiratory syndrome (MERS), the vaccines identified could potentially promote the design of anti-SARS-CoV-2 vaccines. It is essential to establish safe and effective vaccines to contain the COVID-19 pandemic, eradicate its spread, and eventually prevent its future recurrence [ 12 ]. By exposing individuals to antigens, vaccination can produce long-lasting immunity to drive the production of immunological memory before meeting live pathogens. Thus the resulting immunity can be mediated by the activation of humoral antibodies and the effector function of cellular T-cells [ 13 ]. The full development path for an effective SARS-CoV-2 vaccine will involve th e cooperation of industry, government, and academia in unprecedented ways, each contributing its strengths [ 14 ].

It is a difficult task to develop a SARS-CoV-2 vaccine to control its spread and help remove it from the human population since there is a lack of knowledge on its biological properties, epidemiology, individual immune responses to it, and so forth [ 15 ]. The S protein is the critical target of vaccine production since it includes a receptor-binding domain (RBD) and viral functions. It will be essential to confirm the clinical significance of the SARS-CoV-2 binding and neutralizing antibody titers and their ability to predict efficacy [ 16 ]. Only in a significant clinical efficacy study would it be possible to confirm the association between antibody titers and defense against COVID-19 [ 17 ]. For any frequently used vaccine, there is a theoretical risk that vaccination could cause subsequent infection with SARS-CoV-2 more severe. This has been confirmed in feline coronaviruses and has been observed in some SARS-CoV-1 animal vaccine challenge models [ 18 ].

The key benefit of next-generation vaccines is that they can be produced based on sequence data alone [ 19 ]. If the viral protein(s) that are essential for the defense against infection or disease and therefore for inclusion in the vaccine is established, the availability of coding sequences for the viral protein(s) is sufficient to start the production of the vaccine rather than to rely on the ability to grow the virus [ 20 ]. This makes these platforms extremely adaptable and dramatically accelerates the production of vaccines, as is evident from the fact that the majority of currently underway clinical trials of COVID-19 vaccines include a next-generation platform [ 19 ]. A prospective pharmaceutical manufacturer must send an application to a regulatory authority such as the Food and Drug Administration (FDA) to examine the new vaccine after a possible vaccine has been announced by a researcher [ 21 ].

The demand for immediate therapy and potential prevention of COVID-19 is growing [ 22 ] with the increase in the number of individuals affected due to the seriousness of the disease, global dissemination, lack of prophylactics, and therapeutics [ 23 ]. Attempts are being made to establish secure and successful methods for prophylactics [ 24 , 25 ]. Several vaccines are in different phases of clinical trials [ 6 ], but there is a lack of prophylactics in the present scenario [ 26 ]. Several attempts have been made to create COVID-19 vaccines to avoid the pandemic condition as well as the S-protein SARS-CoV-2 has been used for most of the emerging vaccine candidates. In Fig. 1 , the overview of vaccine candidates in their respective ongoing clinical phases depicts the percentage of vaccine candidates amongst which the majority of developing vaccines is in phase 1/2. The data shown below in the graph is assessed until 15 October 2020, in the pipeline of vaccine development and registered clinical trials globally.

In Fig. 2 , the overview of the global COVID-19 vaccine landscape in clinical development depicts that there are seven major types of vaccine candidates for COVID-19 is illustrated as (inactivated, non-replicating viral vectors, replicating viral vectors, protein subunit, nucleic acid-based, and virus-like particles [VLP]), showing the percentage of candidate vaccines that are currently under clinical development. The nucleic acid-based platform includes both RNA vaccines and DNA vaccines. Among the seven types of vaccine candidates, protein subunit-based vaccines constitute the highest 31% in clinical development. In contrast, VLP-based vaccine and replicating viral vectors comprises the lowest as 5% in the clinical development.

In Fig. 3 , the overview of global COVID-19 vaccine landscape in preclinical development depicts that there are 10 significant types of vaccine candidates for COVID-19 is illustrated as (inactivated, replicating bacteria vector, DNA, live attenuated virus, non-replicating viral vectors, protein subunit, t-cell based, replicating viral vectors, RNA, and VLP), showing the percentage of candidate vaccines that are currently under preclinical development. Among the 10 types of vaccine candidates, protein subunit-based vaccines constitute the highest 36% in clinical development whereas T-cell based vaccine and replicating bacteria vector comprises the lowest at 1% in the preclinical development globally.

RNA-Based Vaccine

As a result of considerable developments in biotechnology, due to their higher potency, short development cycles, low-cost product, and safe administration, mRNA vaccines represent a substantial improvement over traditional vaccine strategies [ 27 ]. The mRNA is an evolving platform that is non-infectious and non-integrated and has almost no possible risk of insertional mutagenesis. Antigen discovery, sequence analysis, and optimization, screening of modified nucleotides, delivery system discovery, and immune response and safety assessment tests are the sequential events in the mRNA vaccine production process [ 28 ]. In vaccines, two primary forms of RNA are investigated: virally derived, RNA self-replicating, and mRNA non-replicating. The antigen and the necessary viral replication machinery are typically self-replicating RNAs, whereas conventional mRNA-based vaccines encode only the antigen of interest with 50 and 30 untranslated regions (UTRs) [ 27 ].

The immunogenicity of mRNA can be decreased, and changes can be made to enhance the stability of these vaccines [ 29 ]. Furthermore, anti-vector immunity is also resisted as mRNA is the minimally immunogenic genetic vector, allowing repeated administration of the vaccine [ 30 ]. This platform has empowered the rapid vaccine development program due to its flexibility and ability to reproduce the structure and expression of the antigen as seen in the course of natural infection [ 31 ]. A possible benefit of mRNA vaccines is the convenient availability of a portable mRNA “printing” facility for large-scale production of mRNA [ 32 ].

mRNA-1273 (Moderna TX Inc.)

It is a vaccine composed of lipid nanoparticle (LNP) encapsulated synthetic mRNA that codes for SARS-CoV-2 full-length, pre-fusion stabilized spike protein (S) [ 33 ]. It has the potential to induce an antiviral response that is highly S-protein specific. Also, it is known to be relatively harmless since it is neither composed of the inactivated pathogen nor of the live pathogen sub-units [ 34 ]. To perform the phase II trials, the vaccine has received FDA fast-track approval. The company published the interim antibody data for phase I of eight participants who received different levels of dose [ 33 ]. For the participants receiving 100 µg dose, neutralizing antibody levels were significantly higher than those observed in convalescent sera. In the 25 µg and 100 µg dose cohorts, the vaccine was found to be primarily safe and well-tolerated. In comparison, three participants reported systemic symptoms of grade 3 following administration of the second 250 µg dose level [ 26 ]. The possible benefits of a prophylactic vaccine mRNA strategy include the ability to replicate natural infection to induce a more effective immune response and the ability to incorporate multiple mRNAs into a single vaccine [ 12 ].

On 24 February 2020, Moderna declared that it had released the first batch of mRNA-1273 against SARS-CoV-2 for human use, prepared using the methods and strategies outlined in its previous patents. mRNA-1273 vials have been shipped to the National Institute of Allergy and Infectious Diseases (NIAID), a division of the National Institutes of Health (NIH), to be used in the United States in the proposed phase 1 study [ 35 ]. In collaboration with researchers at the NIAID Vaccine Research Centre, Moderna reports that mRNA-1273 is an mRNA vaccine targeting a prefusion stabilized form of the S protein associated with SARS-CoV-2, which was chosen by Moderna [ 32 ]. Patent application WO2018115527 describes vaccines consisting of mRNA encoding at least one MERS coronavirus antigen, preferably an S protein or an S protein fragment (S1), an envelope protein (E), a membrane protein (M), or a nucleocapsid protein (N), all of which have been successful in inducing an immune response unique to the antigen [ 33 ]. Intradermal administration of a LNP-encapsulated mRNA mixture encoding MERS-CoV S proteins into mice has been shown to result in vivo translation and humoral immune response induction [ 12 ].

BNT162b1 (BioNTech, Fosun Pharma, Pfizer)

BNT162b1 is a codon-optimized mRNA vaccine that codes for the essential target of the neutralizing antibody virus, trimerized SARS-CoV-2 RBD [ 29 ]. The vaccine shows improved immunogenicity due to the addition of the foldon trimerization domain of T4 fibrin-derived to the RBD antigen. In 80 nm ionizable cationic LNPs, the mRNA is encapsulated, which guarantees its efficient delivery [ 31 ]. In phase 1/2 clinical trials, elevated levels of RBD-specific immunoglobulin G (IgG) antibodies with a geometric mean concentration were found to be 8 to 46.3 times the convalescent serum titer. Whereas, the SARS-CoV-2 neutralizing antibody geometric mean titers were found to be 1.8 to 2.8 times the convalescent serum panel [ 29 ]. With no adverse effects, mild and transient local reactions and systemic events were observed. The data review did not, however, assess the protection and immune response beyond 2 weeks after the second dose administration [ 31 ].

Report of available effectiveness, tolerability, and immunogenicity results from an ongoing placebo-controlled, observer-blinded dose-escalation study in healthy adults 18–55 years of age, randomized to receive two 21-day separate doses of 10 µg, 30 µg, or 100 µg of BNT162b1, a nucleoside-modified LNP mRNA vaccine encoding trimerized SARS-CoV-2 spike glycoprotein dose-dependent, usually mild to moderate, and temporary, was the local reactions and systemic events [ 29 ]. The BNT162b1 vaccine candidate now being clinically studied integrates such nucleoside modified RNA and encodes the SARS-CoV-2 spike protein RBD, a primary target of virus-neutralizing antibodies [ 31 ]. Sera's RBD-binding IgG and SARS-CoV-2 neutralizing titers increased both at the dose level and after the second dose. Geometric mean neutralizing titers were 1.8 to 2.8 times those of a panel of human sera convalescent COVID-19. These findings help further evaluation of this candidate for the mRNA vaccine [ 33 ]. By adding a T4 fibritin-derived “foldon” trimerization domain, the RBD antigen expressed by BNT162b1 is modified to improve its immunogenicity by a multivalent display. The RNA vaccine is formulated in LNPs for more effective delivery to cells after intramuscular injection [ 31 ]. In Table 1 , potential RNA-based vaccine candidates are listed below for COVID-19 which are in the clinical development phase and registered globally [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; LNP, lipid nanoparticle; NIAID, National Institute of Allergy and Infectious Diseases; P/B, prime/boost; RBD, receptor-binding domain.

Viral Vector-Based Vaccines

Viral vector-based vaccines have a high degree of protein expression and long-term stability, inducing strong immune responses [ 46 ]. These include vaccines focused on chemically weakened viruses used to bear antigens or pathogens of concern for immune response induction [ 47 ]. A possible prophylactic strategy against a pathogen is a viral vector-based vaccine. These vaccines are highly selective in transmitting genes to the target cells, are highly effective in gene transduction, and are useful in inducing immune responses [ 48 ]. They have a long-term and high level of antigenic protein expression and thus have an excellent potential for prophylactic use as these vaccines activate and facilitate cytotoxic T cells, eventually contributing to the elimination of infected virus cells [ 46 ]. The generation of immunity to the vector is an essential consideration for the development of virus vectored vaccines, which could impede the antigen-specific response to boost vaccination [ 49 ]. Reports from preclinical and clinical trials suggested that adequate safety can be obtained from a single dose [ 50 ].

Ad5-nCoV (CanSino Biologics Inc., Beijing Institute of Biotechnology)

A four-fold increase in RBD and S protein-specific neutralizing antibodies was observed within 14 days [ 51 ]. Ad5-nCoV is a recombinant type-5 adenovirus (Ad5) replication-defective vector expressing the recombinant SARS-CoV-2 spike protein. It was prepared by cloning, together with the plasminogen activator signal peptide gene, an optimized full-length gene of the S protein in the Ad5 vector devoid of genes E1 and E3 [ 29 ]. The vaccine was constructed from the Microbix Biosystem using the Admax system. A positive antibody reaction or seroconversion of immunization was identified in phase I clinical trials and peaked at day 28, post-vaccination. Also, the response of CD4+T cells and CD8+T cells peaked at day 14 post-vaccination. However, the pre-existing anti-Ad5 immunity has partially restricted the reaction of both the antibody and the T cell [ 51 ]. The study would further assess the antibody response in recipients between 18 and 60 years of age who received one of three doses in the study, with follow-up at 3- and 6-months post-vaccination [ 29 ].

Coroflu (University of Wisconsin-Madison, FluGen, Bharat Biotech)

M2SR, a self-limiting variant of the influenza virus that is modified by spike protein sequence insertion of the SARS-CoV-2 gene. Besides, the vaccine expresses the influenza virus' hemagglutinin protein, thereby triggering an immune response to both viruses [ 52 ]. The M2SR is self-limiting and, since it lacks the M2 gene, does not undergo replication. It is capable of entering the cell, thereby causing immunity to the virus [ 32 ]. It is delivered intra-nasally, mimicking the normal viral infection pathway. Compared to intramuscular injections, this route stimulates many immune system modes and has higher immunogenicity [ 52 ].

LV-SMENP-DC (Shenzhen Geno-Immune Medical Institute)

By using SMENP minigenes to engineer dendritic cells (DC) with a lentiviral vector expressing the conserved domains of the structural proteins SARS-CoV-2 and protease [ 29 ], the LV-SMENP-DC vaccine is prepared. Subcutaneous vaccine inoculation introduces antigen-presenting cell antigens, which eventually cause cytotoxic T cells and produce an immune response [ 48 ].

ChAdOx1 (University of Oxford)

The recombinant adenovirus vaccine ChAdOx1 was developed using codon-optimized S glycoprotein and synthesized at the 5 ends with the leading tissue plasminogen activator (tPA) sequence [ 50 ]. The SARS-CoV-2 amino acid coding sequence (2 to 1273) and the tPA leader have been propagated in the shuttle plasmid. This shuttle plasmid is responsible for the coding between the Gateway recombination cloning site of the main immediate-early genes of the human cytomegalovirus (IE CMV) along with tetracycline operator sites and polyadenylation signal from bovine growth hormone (BGH) [ 29 ]. In the bacterial artificial chromosome, the adenovirus vector genome is built by inserting the SARS-CoV-2 S gene into the ChAdOx1 adenovirus genome's E1 locus. In the T-Rex human embryonic kidney 293 (HEK-293) cell lines, the virus was then allowed to replicate and purified by ultracentrifugation of the CsCl gradient [ 53 ]. The absence of any subgenomic RNA from preclinical trials in intra-muscularly vaccinated animals is suggestive of improved immunity to the virus [ 50 ]. Previous studies have proposed that the immune response should be marshalled by a single shot [ 53 ]. In Table 2 , potential viral vector-based vaccine candidates are listed below for COVID-19 which are in the clinical development phase and registered globally [ 45 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ].

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RBD, receptor-binding domain; MVA, modified vaccinia Ankara.

Protein Subunit-Based Vaccines

Subunit vaccines, safer and more straightforward to manufacture, present a host with high immunogenicity with one or few antigens, but need adjuvants to evoke a strong defensive immune response [ 62 ]. A subunit vaccine is a synthetic peptide or recombinant antigenic protein-dependent vaccine which is essential for long-term protection and a therapeutic invigoration of the immune response [ 63 ]. The subunit vaccine exhibits low immunogenicity and requires an adjuvant's additional assistance to potentiate the vaccine-induced immune responses. An adjuvant may improve the biological half-life of the antigenic material, or the immunomodulatory cytokine response may be improved. The use of an adjuvant, therefore, helps to overcome the shortcomings of the protein subunit vaccines [ 64 ]. Subunit vaccines may be designed to concentrate the immune response on the neutralization of epitopes, thus preventing the development of non-neutralizing antibodies that may encourage disease-related antibody-dependent enhancement [ 65 ]. Antigenic proteins thought to cause a defensive immune response are used in protein subunit vaccines. The S protein of SARS-CoV-2 is the most appropriate antigen to induce neutralizing antibodies against the pathogen [ 13 ]. The S protein is comprised of two subunits. In the S1 subunit, the N-terminal domain, RBD, and receptor-binding motif (RBM) domains are found, while the S2 subunit consists of FP, HR 1, and 2 [ 62 ]. The virus reaches the cell by endocytosis using S-protein mediated binding to the human angiotensin-converting enzyme 2 (hACE2) receptor. Therefore, S-protein and its antigenic fragments are key objectives for the establishment of a subunit vaccine [ 63 ]. A complex protein with two conformation states, i.e., a pre-fusion and post-fusion state, is the S glycoprotein [ 62 ]. Therefore, the antigen must maintain its surface chemistry and the profile of the initial pre-fusion spike protein to retain the epitopes for igniting good quality antibody responses. Also, targeting the masked RBM as an antigen, it will increase the neutralizing antibody response and enhance the overall efficacy of the vaccine [ 66 ].

NVX-CoV2373 (Novavax Inc., Emergent BioSolutions)

NVX-CoV2373 is a nano-particle-mediated immunogenic vaccine-mediated on coronavirus S-protein, the recombinant expression of stable pre-fusion [ 67 ]. In the baculovirus system, the protein has been stably expressed. By inducing high levels of neutralizing antibodies, the company aims to use the matrix-M adjuvant to strengthen the immune response against the SARS-CoV-2 spike protein [ 35 ]. A single immunization in animal models resulted in a high level of anti-spike protein antibodies that blocked the binding domain of the hACE2 receptor and could elicit SARS-CoV-2 wild-type virus-neutralizing antibodies [ 68 ].

Molecular clamp stabilized spike protein vaccine candidate

It is being developed in partnership with GSK and Dynavax by the University of Queensland [ 29 ]. The University will have access to the vaccine adjuvant (AS03 Adjuvant) platform technology, which is believed to enhance the response of the vaccine and reduce the amount of vaccine needed per dose [ 69 ]. The University is developing a stabilized pre-fusion, recombinant viral protein subunit vaccine based on the molecular clamp technology. It has been established that this technology induces the development of neutralizing antibodies [ 34 ].

PittCoVacc (University of Pittsburgh)

It is a recombinant SARS-CoV-2 vaccine based on the micro-needle array (MNA) that involves administering rSARS-CoV-2 S1 and rSARS-CoV-2-S1fRS09 (recombinant immunogens) [ 70 ]. A significant increase in statistically significant antigen-specific antibodies was found in the mice models in preclinical studies at the end of 2 weeks [ 29 ]. Furthermore, even after sterilization using gamma rays, the immunogenicity of the vaccine was maintained. Statistically, relevant antibody titers confirm the feasibility of the MNA-SARS-CoV-2 vaccine at the early stage and even before boosting [ 70 ].

Triple antigen vaccine (Premas Biotech, India)

It is a multi-antigenic VLP vaccine prototype in which an engineered Saccharomyces cerevisiae expression platform (D-CryptTM) co-expresses the recombinant spike, membrane, and envelope protein of SARS-CoV-2 [ 71 ]. The proteins then, like the VLP, undergo self-assembly. The biophysical characterization of the VLP was simultaneously given by the transmission electron microscopy and allied analytical data [ 29 ]. After more research and development, this prototype has the potential to engage in preclinical trials as a vaccine candidate. Besides, cost-effectively, it is assumed to be safe and easy to produce on a mass scale [ 71 ]. In Table 3 , potential protein subunit-based vaccine candidates are listed below for COVID-19 which are in the clinical development phase and registered globally [ 45 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ].

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; HIV, human immunodeficiency virus; RBD, receptor-binding domain; FIH, first-in-human; FDA, U.S. Food and Drug Administration.

DNA-Based Vaccines

A typical DNA vaccine is a plasmid DNA molecule that codes for the host immune system to be presented with one or more antigens [ 62 ]. They have the advantages of stability and successful delivery over mRNA vaccines [ 84 ]. Still, since they are needed to reach the nucleus, they have the risk of vector mutations and incorporation into the host genome [ 85 ]. DNA vaccines reflect a revolutionary approach, followed by a wide variety of immune responses, by the direct injection of plasmids encoding antigens [ 86 ]. The most groundbreaking approach to vaccination is the introduction of the DNA vaccine that codes for the antigen and an adjuvant that stimulates the adaptive immune response [ 87 ]. The transfected cells express the transgene, which gives a steady supply of transgene-specific proteins very similar to the live virus [ 84 ]. Also, immature DCs, which eventually present the antigen on the cell surface to the CD4 + and CD8 + T cells in combination with the major histocompatibility complex (MHC) 2 and MHC 1 antigens, endocytose the antigen material, thereby stimulating both successful humoral and cell-mediated immune systems [ 87 ]. DNA vaccines are considered safe and stable and can be developed easily, but their immunogenicity and immune response efficiency in humans have not yet been demonstrated [ 21 ].

INO-4800 (Inovio Pharmaceuticals)

It is an anti-SARS-CoV-2 prophylactic DNA vaccine. It uses the SARS-CoV-2 codon-optimized S protein sequence to which an immunoglobulin E (IgE) leader sequence is attached [ 29 ]. Using BamHI and XhoI, the SARS-CoV-2 IgE-spike sequence was synthesized and digested. Under the management of IE CMV, and BGH polyadenylation signal, the digested DNA was incorporated into the expression plasmid pGX0001 [ 85 ]. In preclinical studies, the existence of functional antibodies and the response of T cells indicate that the vaccine will produce an efficient immune response within seven days after vaccination [ 88 ]. The vaccine has entered phase I clinical trials (phase I: NCT04336410) and it is anticipated that this phase of clinical trials will be completed by July, with participants receiving 1.0 mg of INO-4800 by electroporation with CELLECTRA 2000 per dosing visit. The research will assess the immunological profile, efficacy, and tolerability of the candidate vaccine in healthy human adults upon intradermal injection and electroporation [ 29 ]. INO-4800 and the previous Inovio vaccine INO-4700 express either SARS-CoV-2-S or MERS-CoV-S inside the same DNA vector, respectively [ 85 ]. The vaccine is delivered by intramuscular injection, accompanied by injection site electroporation. The need for electroporation could restrict INO-4800's ability to be expanded to the scales necessary for a global pandemic and may be difficult to handle globally [ 13 ].

bacTRL (Symvivo Corporation)

Symvivo Corporation's bacTRL platform uses the engineered probiotic Bifidobacterium longum to deliver a SARS-CoV-2-S expressing DNA vaccine into intestinal cells. The first-in-man study of the bacTRL platform will also be a phase I study of the COVID-19 vaccine, so no prior immunological results are available [ 13 ]. In Table 4 , DNA-based vaccine candidates are listed below for COVID-19 which are in the clinical development phase and registered globally [ 89 , 90 , 91 , 92 , 93 , 94 ].

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Virus-Like Particles Vaccine

VLPs are particles that form spontaneously, consisting of many co-expressed or mixed structural viral proteins. Several commercial vaccines are based on VLPs, such as hepatitis B and human papillomavirus vaccines [ 95 ]. Without the need for adjuvants, these vaccines can be constructed and used. Only when antigens with neutralizing epitopes are extensively investigated is the production of such vaccines possible [ 22 ]. A VLP is a self-assembled nanostructure incorporating essential viral structural proteins. VLP is similar to true viruses' molecular and morphological features but is non-infectious and non-replicating due to the absence of genetic materials [ 26 ]. Successful applications of VLP have been proved by vaccinological and virological study [ 95 ]. In the ongoing battle against the COVID-19 pandemic, the development of SARS-CoV-2 VLPs is highly in demand as an accessibly safe and relevant substitute for naturally pathogenic viruses [ 26 ]. A study suggested the possible use of plant biotechnology for the development of low-cost COVID-19 vaccines and plant-made antibodies for diagnosis, prophylaxis, and therapy [ 22 ].

In the current research, we have established SARS-CoV-2 VLPs effectively, using the mammalian expression system [ 47 ], which helps maintain specific patterns of protein glycosylation [ 22 ]. For the efficient formation and release of SARS-CoV2 VLPs among the four SARS-CoV-2 structural proteins, we have shown that membrane protein (M) expression and small envelope protein (E) are essential [ 47 ]. Also, the corona-like structure presented in SARS-CoV-2 VLPs from Vero E6 cells is more stable and unified in comparison with those from HEK-293 T cells. Our data show that the molecular and morphological characteristics of native virion particles in SARS-CoV-2 VLPs make SARS-CoV-2 VLPs a promising candidate vaccine and a powerful tool for research into SARS-CoV-2 [ 96 ]. The immunogenic composition composed of MERS-CoV nanoparticle VLPs containing at least one trimer of S protein formed by baculovirus overexpression in Sf9 cells was disclosed in patent application WO2015042373 by Novavax in 2015 [ 35 ]. When administered along with their patented adjuvant Matrix M, this VLP preparation induced a neutralizing antibody response in mice and transgenic cattle. Sera preparations from vaccinated cattle (SAB-300 or SAB-301) were also injected into Ad5-hDPP4 transduced BALB/c mice before the MERS-CoV challenge [ 22 ]. With a single prophylactic injection, both SAB-300 and SAB-301 were able to protect these mice from MERS-CoV infection [ 96 ]. On 26 February, Novavax announced that due to their prior experience dealing with other coronaviruses, including both MERS and SARS, animal testing of possible COVID-19 vaccine candidates had begun. Using their recombinant nanoparticle vaccine technology along with their proprietary adjuvant matrix-M, their COVID-19 candidate vaccines targeting the S protein of SARS-CoV-2 were created [ 35 ].

UMass Medical School researchers have developed a framework to create vaccines using VLPs, which one scientist claims may be a successful and safer alternative to a COVID-19 vaccine. Trudy Morrison, Ph.D., professor of Microbiology & Physiological Systems, said her work on a VLP-based respiratory syncytial virus vaccine that can be modified to COVID-19 causes severe lower respiratory tract disease in young children and the elderly. And some of the problems inherent in the production of vaccines from inactivated or live viruses will be avoided [ 97 ].

Medicago, a biopharmaceutical company, headquartered in Quebec City, announced the successful development of a coronavirus VLP only 20 days after the SARS-CoV-2 (COVID-19 disease virus) gene was obtained [ 29 ]. The manufacturing of VLP is the first step in the development of the COVID-19 vaccine, which will now undergo preclinical protection and efficacy testing. They plan to negotiate clinical testing of the vaccine with the relevant health authorities by summer (July/August) 2020 once this is done. Medicago uses its technology platform to create antibodies against SARS-CoV-2. These antibodies to SARS-CoV-2 might theoretically be used to treat people who are infected by the virus. In part, this study is sponsored by the Canadian Institutes for Health Research [ 98 ]. In Table 5 , potential VLPs-based vaccine candidates are listed below for COVID-19 which are in the clinical development phase and registered globally [ 81 , 99 ].

VLP, virus-like particle; COVID-19, coronavirus disease 2019; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; HBsAg, Hepatitis B surface antigen.

Current Updates

To bring this pandemic to an end, a large share of the world needs to be immune to the virus. The safest way to achieve this is with a vaccine. Vaccines are a technology that humanity has often relied on in the past to bring down the death toll of infectious diseases. Within less than 12 months after the beginning of the COVID-19 pandemic, several research teams rose to the challenge and developed vaccines that protect from SARS-CoV-2, the virus that causes COVID-19. Now the challenge is to make these vaccines available to people around the world.

To resume a normal lifestyle, free from government lockdowns, and fear of continuing pandemic waves over the coming months, the world is anxiously awaiting a safe, successful vaccine to protect against COVID-19. Innovative ties with both pharmaceutical companies and medical start-ups are joining hands with scientists across the continents to repurpose medications, create vaccines, and devices to hinder the progress of this overwhelming pandemic. A large number of vaccine candidates for COVID-19 based on different platforms have already been identified. Current review shows preclinical as well as in clinical development of vaccine candidates, wherein, five major vaccine platforms for COVID-19 namely RNA, DNA, viral vector, protein subunit, and VLP which constitutes 10, 2, 10, 14, and 2 vaccine candidates globally in clinical development as of 15 October 2020. Among all the vaccine platforms, extensive research and development are going on protein subunit-based vaccine which has the maximum candidates in the clinical development.

A significant amount of hindrance to the rapid production of vaccines is the length of clinical trials. With several phases, including the preclinical stage and clinical development, which is a three-phase process, the vaccine development process is very laborious. However, if adequate data is already available, it has been proposed that a few stages be skipped to accelerate the achievement of a vaccine faster with a rapid regulatory review, approval, development, and quality control. By looking towards pandemic conditions, the scientific fraternity will be ready for any harmful situation to overwhelmed opportunities. Therefore, the current situation has given the world a new perspective to facilitate research in the worst circumstances and hasten the drug development process.

No potential conflict of interest relevant to this article was reported.

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Vaccine Research & Development

How can covid-19 vaccine development be done quickly and safely, typical vaccine development timeline.

• Each clinical trial phase follows completion of the prior phase
• Can take a long time to accumulate cases to assess vaccine efficacy outside pandemic
• Manufacturing capacity is scaled-up after phase III trial and regulatory approval

Accelerated timeline in a pandemic

• Some clinical trial phases are combined
• Cases accumulate rapidly to assess vaccine efficacy because of the pandemic
• Manufacturing capacity is scaled up during the clinical trials but at financial risk

Typical Timeline

A typical vaccine development timeline takes 5 to 10 years, and sometimes longer, to assess whether the vaccine is safe and efficacious in clinical trials, complete the regulatory approval processes, and manufacture sufficient quantity of vaccine doses for widespread distribution.

to the Accelerated Timeline

Preclinical Trials

Preclinical testing of vaccine candidates typically starts in animal models, first in small mammals such as mice or rats and then non-human primates such as monkeys. Preclinical studies are important for eliminating potential vaccines that are either toxic or do not induce protective immune responses. But many vaccines that appear to be safe and induce protective immune responses in animals fail in human studies. Only vaccine candidates that are very promising in preclinical testing move forward into phase I clinical trials.

Phase I Clinical Trials to Assess Safety, Dosing, and Immune Responses

Phase I clinical trials are the first step in assessing vaccines in people. Typically involving one to several dozen healthy volunteers, phase I trials assess short-term safety (e.g., soreness at the site of injection, fever, muscle aches) and immune responses, often with different vaccine dosages. Only if a vaccine candidate is shown to be safe in phase I trials will it move to larger phase II trials.

Phase 1 trials can be completed in two to three months, allowing for two doses of a vaccine three to four weeks apart

Phase II Clinical Trials to Assess Safety and Immune Responses

Phase II clinical trials continue to assess safety and immune responses but in a larger number and more diverse group of volunteers, typically one to several hundred people. Phase II trials may include target populations of a specific age or sex, or those with underlying medical conditions. Vaccines for children start with adult volunteers and move to progressively younger groups of children. Different types of immune responses are often measured, including antibodies and cell-mediated immunity, but phase II trials do not assess how well a vaccine actually works. Only in phase III trials is vaccine efficacy assessed.

Phase 2 trials can be completed in three to four months, allowing for longer follow-up to better assess safety and immunogenicity. This timeline is shortened when phase 1 and phase 2 trials are combined.

Phase III Clinical Trials to Assess Safety and Efficacy

Phase III clinical trials are critical to understanding whether vaccines are safe and effective. Phase III trials often include tens of thousands of volunteers. Participants are chosen at random to receive the vaccine or a placebo. In Phase III, participants and most of the study investigators do not know who has received the vaccine and who received the placebo. Participants are then followed to see how many in each group get the disease. Assessing short- and long-term safety is also a major goal of phase 3 trials.

Phase 3 trials may take six to nine months to allow early assessment of safety and efficacy, particularly if conducted in areas with a high risk of infection, but with follow-up continuing for two years or more to assess long-term safety and efficacy.

Regulatory Approval Process

Each country has a regulatory approval process for vaccines. In the United States, the Food and Drug Administration (FDA) is responsible for regulating vaccines. In situations when there is good scientific reason to believe that a vaccine is safe and is likely to prevent disease, the FDA may authorize its use through an Emergency Use Authorization (EAU) even if definitive proof of the efficacy of the vaccine is not known, especially for diseases that cause high mortality.

Scaling Up Vaccine Manufacturing

Scaling up vaccine manufacturing is typically done near the end of the regulatory process because of the huge financial investment needed. In the United States, the FDA will inspect the manufacturing facilities. The cost of developing a new vaccine can be several billion U.S. dollars prior to the scale up of manufacturing facilities.

Post-Licensure Vaccine Safety Monitoring

After a vaccine is approved and in widespread use, it is critically important to continue to monitor vaccine safety. Some very rare side effects may only be detectable when large numbers of people have been vaccinated. Safety concerns that are discovered at this late stage could lead a licensed vaccine to be withdrawn from use, although this is very rare.

COVID-19 vaccines: Get the facts

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

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

COVID-19 vaccine benefits

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

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

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

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

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

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

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

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

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

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

Safety and side effects of COVID-19 vaccines

What covid-19 vaccines have been authorized or approved.

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

• Pfizer-BioNTech COVID-19 vaccine 2024-2025 formula, available for people age 6 months and older.
• Moderna COVID-19 vaccine 2024-2025 formula, available for people age 6 months and older.
• Novavax COVID-19 vaccine 2024-2025 formula, available for people age 12 years and older.

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

In June 2024, the FDA recommended COVID-19 vaccine updates to target a strain of the COVID-19 virus called JN.1. But JN.1 soon began to fade from the community. Strains that evolved from it began to spread at higher levels. As the virus continued to change, the FDA updated its guidance and asked vaccine makers to focus on a JN.1 strain subtype called KP.2.

The Pfizer-BioNTech and Moderna COVID-19 vaccines for 2024-2025 focus on building protection against the KP.2 virus strain. The Novavax COVID-19 vaccine, adjuvanted 2024-2025 formula will focus on the JN.1 strain.

In December 2020, the Pfizer-BioNTech COVID-19 vaccine two-dose series was found to be both safe and effective in preventing COVID-19 infection in people age 18 and older. This data helped predict how well the vaccines would work for younger people. The effectiveness varied by age. Since 2020, the vaccine has been updated yearly to better protect against the strains of COVID-19 spreading in the community. The currently approved vaccine is Pfizer-BioNTech COVID-19 vaccine 2024-2025 formula.

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

In December 2020, the Moderna COVID-19 vaccine was found to be both safe and effective in preventing infection and serious illness among people age 18 or older. The vaccine's ability to protect younger people was predicted based on that clinical trial data. Since 2020, the vaccine has been updated yearly to better protect against the changing strains of COVID-19. The currently approved vaccine is Moderna COVID-19 vaccine 2024-2025 formula.

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

In July 2022, this vaccine was found to be safe and effective and became available under an emergency use authorization for people age 18 and older. In August 2022, the FDA authorized the vaccine for people age 12 and older. Since then, the vaccine has been updated yearly to better protect against the changing strains of COVID-19. The currently approved vaccine is Novavax COVID-19 vaccine, adjuvanted 2024-2025 formula.

How do the COVID-19 vaccines work?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Can COVID-19 vaccines affect the heart?

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

Symptoms to watch for include:

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

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

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

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

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

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

Things to know before a COVID-19 vaccine

Are covid-19 vaccines free.

In the U.S., COVID-19 vaccines may be offered at no cost through insurance coverage. For people whose vaccines aren't covered or for those who don't have health insurance, options are available. Anyone younger than 18 years old can get no-cost vaccines through the Vaccines for Children program.

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

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

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

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

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

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

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

Allergic reactions and COVID-19 vaccines

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

Symptoms of a life-threatening allergic reaction can include:

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

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

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

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

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

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

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

Pregnancy, breastfeeding and fertility with COVID-19 vaccines

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

The CDC recommends getting a COVID-19 vaccine if:

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

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

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

Children and COVID-19 vaccines

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

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

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

After a COVID-19 vaccine

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

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

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

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

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

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

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

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

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

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CDC greenlights two updated COVID-19 vaccines, but how will they fare against the latest variants? 5 questions answered

Professor of Pathology, Microbiology and Immunology, University of South Carolina

Disclosure statement

Prakash Nagarkatti receives funding from the National Institutes of Health and the National Science Foundation.

Mitzi Nagarkatti receives funding from the National Institutes of Health and National Science Foundation.

University of South Carolina provides funding as a member of The Conversation US.

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On Sept. 12, 2023, the Centers for Disease Control and Prevention recommended the newly formulated COVID-19 vaccines for all Americans ages 6 months and up , hours after its expert advisory committee voted 13 to 1 in favor of recommending the vaccines.

The CDC’s broad recommendation comes one day after the Food and Drug Administration approved Moderna’s and Pfizer’s updated mRNA vaccines that target a previously dominant variant of the omicron family called XBB.1.5. The updated shots will be available to the public within days.

The Conversation asked Prakash Nagarkatti and Mitzi Nagarkatti , a husband and wife team of immunologists from the University of South Carolina, to weigh in on how the new vaccines might stand up against the latest COVID-19 variants that are swirling across the globe.

1. How are the new vaccines different from the previous?

When the first vaccine against COVID-19 was rolled out in December 2020, it was designed as a monovalent vaccine, meaning that it was formulated against only the original SARS-CoV-2 virus. That vaccine, as well as the updated ones, target the spike protein, which the virus uses to infect our cells and cause the disease.

That design made sense before the virus began mutating into a complex family tree of variants and sublineages . But as the virus structure shifted over time, the antibodies produced in response to the original vaccine became less effective against the new variants.

This necessitated the development in 2022 of new “bivalent” vaccines that targeted both the original strain of SARS‑CoV‑2 and new viral variants such as the omicron BA.4 and BA.5 lineages that were dominant in mid-2022 .

But, not surprisingly, new variants of the virus continued to emerge.

In June 2023, the FDA asked vaccine developers to formulate new fall shots to target the then-dominant XBB.1.5 subvariant.

The FDA approved that monovalent mRNA-based vaccine based on the overall efficacy data presented by the vaccine manufacturers.

Unfortunately, XBB.1.5 is no longer the dominant strain in the U.S.; it has been displaced by other variants from the XBB lineage, thereby raising concerns about the potential efficacy of the new shot. As of mid-September, the dominant variants nationwide are EG.5, also known as Eris, followed by FL.1.5.1 – called Fornax – and XBB.1.16.6.

Meanwhile, a new highly mutated omicron offshoot, BA.2.86, nicknamed Pirola , is making its way across the globe – albeit so far in small numbers.

2. Who should get a new shot?

The CDC recommended that everyone ages 6 months old and up should get an updated COVID-19 vaccine so that they can be better protected against developing serious outcomes from COVID-19, including hospitalization. The agency noted that people who received the 2022-2023 bivalent COVID-19 shot “saw greater protection against illness and hospitalization than those who did not.”

Most Americans will be able to get the newly formulated vaccine at no cost , according to the CDC.

The FDA approved a single shot of the updated vaccine for anyone ages 5 and older – regardless of whether they were previously vaccinated or not. The agency also approved unvaccinated individuals 6 months to 4 years of age to receive three doses of the updated Pfizer vaccine or two doses of the updated Moderna vaccine.

3. How effective could the updated shot be against the latest variants?

Based on its current assessment, the CDC indicates that the BA.2.86 variant may be able to cause infection even in people who have been previously vaccinated or those who have had COVID-19 infection in the past. But the CDC says it still expects the updated fall 2023 booster shot to be effective at reducing severe disease and hospitalization.

Moderna reported in August 2023 that the new monovalent mRNA COVID-19 vaccine gave a “significant boost” in antibodies that are protective against two of the currently circulating variants: EG.5 – which is responsible for most cases in the U.S. as of mid-September – and FL.1.5.1. Then, in early September, Moderna announced that its most recent data from human trials showed an 8.7-fold increase in neutralizing antibodies against the newest variant, BA.2.86, following vaccination with the updated shot.

Similarly, new pre-clinical data from Pfizer shows that its version of the new mRNA vaccine produced antibodies that were effective at neutralizing the XBB.1.5, BA.2.86 and EG.5.1 variants.

This early research suggests that the new mRNA vaccines – although developed specifically against XBB.1.5 – are still effective against some of the most prevalent variants.

Novavax, which specializes in traditional protein-based vaccines, also announced in August that its updated COVID-19 vaccine directed against the XBB variant produced a broad neutralizing antibody response against key variants in animal studies. However, the company does not yet have data on its vaccine’s performance against two other key variants, FL.1.5.1 and BA.2.86. The Novavax vaccine has not yet gone up for FDA review, but its approval is also expected within months.

It is important to keep in mind that while all three vaccines have been shown to trigger antibodies that can neutralize most of the currently circulating variants, it is unclear whether the vaccines will be able to effectively prevent COVID-19 infection in humans. Such clinical studies are time-consuming, so given the urgency and speed needed to develop vaccines against the ever-changing COVID-19 variants, vaccine manufacturers rely on antibody levels as an indicator of protection.

4. Is there a ‘right’ time to get the new vaccine?

Antibodies produced after a COVID-19 infection or vaccination last for about six months, and then their levels start declining . This is called “waning immunity.”

About a year after getting a COVID-19 infection or vaccination, only a small fraction of antibodies can be detected. This is why health care providers recommend getting another shot if a year has passed since you were vaccinated or had an active infection.

It has become very clear that vaccines against COVID-19 do not provide 100% protection against catching a new COVID-19 infection , but they can make illness from the infection milder, shorter or both .

In addition, vaccines provide significant protection from hospitalization and death and may help protect against developing long COVID .

Viral infections normally peak in the winter, which is why experts advise getting both COVID-19 and flu vaccine shots in the months of September and October . For convenience, the two shots can be safely taken at the same time . This is because the immune cells that produce antibodies against one vaccine agent are distinct from those that produce antibodies against the other vaccine agent.

However, taking two different vaccines at the same time could cause more side effects , such as fever, aches and pain. This is especially the case for people who have experienced such side effects in the past after taking the COVID-19 and flu vaccines separately.

In addition, a newly approved vaccine against the respiratory syncytial virus, or RSV, is now recommended for people ages 60 and up .

5. Should some people wait for the updated Novavax vaccine?

The Moderna and Pfizer vaccines use the more recent vaccine technology based on mRNA, which instructs the body to produce a protein from a small portion of the SARS-CoV-2 virus. The immune system responds by producing antibodies.

In contrast, the Novavax vaccine relies on a more traditional approach to vaccine production, injecting the viral protein directly into the body to stimulate antibody production. So while the two vaccine types use different pathways to trigger antibodies against the virus, the end result is the same.

The CDC has reported rare cases of myocarditis , which is inflammation of the heart muscle, following vaccination with the Moderna and Pfizer mRNA vaccines. However, the same is true of the Novavax vaccine . So all three vaccines carry this very rare risk.

It is noteworthy that myocarditis is most frequently seen in adolescent and young adult males .

Although some people may have a preference for the traditional protein-based vaccine by Novavax, those who are at higher risk of catching COVID-19 should not wait for the approval of the Novavax vaccine to get their shot.

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• Published: 14 September 2024

Understanding the rationales and information environments for early, late, and nonadopters of the COVID-19 vaccine

• Lisa Singh 1 ,
• Leticia Bode 1 ,
• Ceren Budak   ORCID: orcid.org/0000-0002-7767-3217 2 ,
• Josh Pasek   ORCID: orcid.org/0000-0001-6099-6119 2 ,
• Trivellore Raghunathan 2 ,
• Michael Traugott 2 ,
• Yanchen Wang 1 &
• Nathan Wycoff 1  

npj Vaccines volume  9 , Article number:  168 ( 2024 ) Cite this article

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Anti-vaccine sentiment during the COVID-19 pandemic grew at an alarming rate, leaving much to understand about the relationship between people’s vaccination status and the information they were exposed to. This study investigated the relationship between vaccine behavior, decision rationales, and information exposure on social media over time. Using a cohort study that consisted of a nationally representative survey of American adults, three subpopulations (early adopters, late adopters, and nonadopters) were analyzed through a combination of statistical analysis, network analysis, and semi-supervised topic modeling. The main reasons Americans reported choosing to get vaccinated were safety and health. However, work requirements and travel were more important for late adopters than early adopters (95% CI on OR of [0.121, 0.453]). While late adopters’ and nonadopters’ primary reason for not getting vaccinated was it being too early, late adopters also mentioned safety issues more often and nonadopters mentioned government distrust (95% CI on OR of [0.125, 0.763]). Among those who shared Twitter/X accounts, early adopters and nonadopters followed a larger fraction of highly partisan political accounts compared to late adopters, and late adopters were exposed to more neutral and pro-vaccine messaging than nonadopters. Together, these findings suggest that the decision-making process and the information environments of these subpopulations have notable differences, and any online vaccination campaigns need to consider these differences when attempting to provide accurate vaccine information to all three subpopulations.

Introduction

COVID-19 remains an ongoing public health concern, and all indications suggest that the virus will persist for the foreseeable future 1 . Vaccines have been crucial in mitigating COVID-19, and their uptake as new boosters develop will remain an important element of a public health strategy to manage the continued presence of this virus 2 . Most Americans (81% according to the CDC) have received at least one dose of a COVID-19 vaccine since the shots became widely available in early 2021. While many were initially eager to roll up their sleeves, a moderate portion of the country expressed hesitancy 3 , with some waiting months before getting vaccinated. Around one in five Americans remained unvaccinated two years later 4 , and only one quarter of those who received the original vaccine received the latest recommended booster 5 . Compared to other countries, Americans had lower COVID-19 vaccine acceptance rates (57%) during the initial rollout phase at the end of 2020 6 .

COVID-19 vaccine hesitancy has been associated with political and social divides, questions around safety of vaccines, declining public trust in government and science, and misinformation more broadly 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . In general, online information consumption has been linked to offline behaviors 17 , and there is also evidence that misinformation on the internet, particularly on social media and YouTube, is associated with hesitancy 18 . This presence of online misinformation can be more impactful because it exists against a backdrop of low health literacy with respect to COVID-19 19 . Some research also raised the potential that these sources of misinformation may be associated with partisanship 20 , 21 , 22 . Misinformation about COVID-19 is not limited to the United States; it is a global phenomenon 23 with false information disseminating worldwide on social media platforms 15 , 24 , 25 , 26 , 27 , 28 , 29 .

Despite the considerable body of research on vaccine acceptance and hesitancy, there is a gap in our understanding of the more nuanced nature of individual perceptions and decisions about vaccination. Existing work sheds light on two components of this process—the types of people that report hesitancy 30 , 31 , 32 and the extent to which various message streams contain problematic information 33 , 34 , 35 —but it does not directly link these components, meaning that it is unclear whether certain types of beliefs and attitudes undergird hesitancy or whether both just happen to be present (perhaps because hesitant individuals bolster their rejection of the vaccination by accepting misinformation 36 ). To the extent that digital platforms have been acknowledged as a significant source of vaccine information 37 , 38 , 39 , 40 , there is a need for a more in-depth examination of how individuals engage with these channels and whether this is related to how they subsequently form their perceptions about vaccination.

This article is an important step toward understanding this relationship. We first determined what factors are associated with decisions to obtain the COVID-19 vaccine. Using the subpopulation categorization presented by Kang et al. 41 , we then compared rationalizations of those who vaccinated early (early adopters), those who initially expressed skepticism about getting vaccinated but later change their minds (late adopters), and those who chose not to get vaccinated during our study period (nonadopters). One important part of understanding vaccine hesitancy is identifying the types of information different subpopulations are exposed to and how that may have influenced their behavior. A number of studies documented high levels of ideological segregation of political information on social media 42 , 43 , 44 , 45 . Given this, our final analysis investigated differences in the information environments of these three subpopulations on Twitter/X. This line of inquiry allowed us to better understand any distinguishing features of each of these subpopulations, including the vaccine messaging received and prominent accounts followed.

While previous research investigated the reasons why some people chose to vaccinate and others chose not to 11 , 46 , 47 , these studies focused primarily on one particular group (e.g., late adopters 46 , 47 or nonadopters 11 ). In this longitudinal study, we compared the reasons why early adopters and late adopters chose to get vaccinated, as well as the reasons why the late adopters initially hesitated and nonadopters did not. While investigating all three subgroups, we focused more on those who initially chose not to get vaccinated, but eventually did, in order to gain insight into what the people who changed their minds were thinking and how their rationale aligned with (or deviated from) the other subgroups. This line of research is important because persuasion of initially hesitant individuals constitutes a primary goal for public health officials, and insights into the thought processes and information environments of those who have already undergone this change directly supports this goal. Also, decisions to delay or refuse vaccines have important implications beyond their ability to save lives during the pandemic 48 , including the tendency to stay up to date on subsequent COVID-19 shots and vaccines for other diseases 49 .

We begin by investigating the rate and time of vaccinations by demographics. Despite various efforts to incentivize vaccination, both the rate and timing of vaccinations varied by partisanship and socioeconomic factors (see Fig. 1 ). Based on our survey demographics, partisanship explained the most variation, with Democrats getting vaccinated faster than the average CDC reported percentages. Democrats also had significantly higher percentages of vaccination when compared to Republicans and Independents. Within our sample, vaccine percentages were lowest among Black Americans, those with lower incomes (less than $30,000), and those with less education (a high school education or less). All these subgroups also vaccinated at percentages slower than the CDC overall vaccination percentages. Our results also suggested that female, Black, and Hispanic respondents were less likely to get vaccinated early (late adopters), while people in the 45–65 age group, with a postgraduate degree, and Independents and Democrats (compared to Republicans) were more likely to be early adopters. Focusing on those who were initially hesitant (late adopters), we found that they were more likely to have a college degree (OR 1.869 with 95% CI [0.909, 3.945]) and less likely to be parents (OR 0.393 with 95% CI [0.177, 0.846]). (See Supplementary Table 1 for detailed sociodemographic information.) Finally, we found that the median difference in timing between early adopters and late adopters was three and a half months. These findings are consistent with previous literature 20 , 50 , 51 .

Each subfigure highlights a different demographic subgroup. The x-axis shows the date of vaccination, and the y-axis shows the overall percent vaccinated for the subgroup. The dark gray dotted line represents the estimates of population vaccination percentages based on our overall survey population. The light gray dashed line represents the vaccination percentages (population 18 and above) based on CDC data. The two vertical lines in the top left subfigure indicate the median vaccination timing for early adopters (left vertical line) and late adopters (right vertical line).

Why people do and do not get vaccinated

In addition to the partisan and demographic differences, we are interested in understanding the rationales of the early and the late adopters for getting vaccinated, and the rationales of the late adopters and the nonadopters for not getting vaccinated when the vaccines first became available.

The top two reasons people chose to get vaccinated were their personal safety and health, and protecting others/stopping the spread of COVID-19 (see Fig. 2 ). In general, when late adopters did get vaccinated, their top five reasons for doing so were similar to early adopters. However, a smaller proportion of late adopters (32%) cited personal safety and health as their reason for vaccination compared to early adopters (54%); a larger percentage indicated that they chose to get vaccinated because of work/job requirements (21%) and travel (12%), in contrast to early adopters, for whom these reasons were less prevalent at 6% and 2%, respectively. We note that the wave 1 survey occurred when vaccine mandates were being implemented in the federal government and some schools 52 .

The x-axis shows the percentage of responses associated with a specific topic for early adopters (left subfigure) and late adopters (right subfigure). * p  < 0.05, ** p  < 0.01, *** p  < 0.001 indicates the topic is statistically significant as a predictor of vaccine status. These topic data are limited to responses from wave 1, as this was the period when both early adopters and late adopters provided their main reasons for getting vaccinated. We focus here on the top 5 out of 10 topics as they make up over 95% of the responses. See Supplemental Materials for exact survey question, full results, and sample topic words.

While most of the respondents who did not plan to get vaccinated in March 2021 continued to remain unvaccinated throughout the study period, some respondents changed their mind, getting the recommended shots (between survey waves 0 and 1). Figure 3 shows that the main reason for both late adopters and nonadopters not initially getting vaccinated was because they considered it too early to get the vaccine. This reason was reported by 36% of late adopters, compared to 24% of nonadopters. There were also differences in the percentages of respondents statinglack of institutional distrust and having already had COVID-19 as the reason for not getting vaccinated. Only 9% of the late adopters cited lack of institutional trust as their reason for not getting vaccinated, while it was more prevalent among nonadopters at 17%. In addition, a previous COVID-19 infection was a reason for 8% of late adopters not getting vaccinated compared to 11% of nonadopters. We also found that those who initially mention institutional trust and having natural immunity as reasons for not getting vaccinated were also less likely to get vaccinated later (OR 0.322 with 95% CI [0.125,0.763] and OR 0.281 with CI [0.094,0.760], respectively). (See Supplementary Table 2 for more details.)

We compare the nonadopters (left side of figure) to the late adopters (right side of figure). These are the top five reasons based on the open-ended responses as to why they chose not to get vaccinated. * p  < 0.05, ** p  < 0.01, *** p  < 0.001 indicates the topic is statistically significant at the respective level as a predictor of vaccine status. The topic data are limited to responses from wave 0, as this was the period when both nonadopters and late adopters provided their main reasons for not getting a coronavirus vaccine. We focus on the top 5 out of 14 topics since they make up nearly 80% of the responses. See Supplementary Materials for exact survey question, full results, and sample topic words.

When comparing the late adopters and early adopters to explain the timing of vaccine uptake, those who mention personal safety and health as their reasons for getting vaccinated were also more likely to be early adopters; and those mentioning the topic work/job reasons were less likely to get the vaccine early. (See Supplementary Table 3 for more details.)

Information exposure of Twitter/X users

To consider how information flows might play a role, we turn to participants’ social media, in particular Twitter/X. Among survey respondents who shared Twitter/X accounts, we compared who early adopters, late adopters, and nonadopters each follow on Twitter/X, focusing on prominent accounts –the 25 Twitter/X accounts that were followed by the most users in each group (See Fig. 4 ). We found that there was little overlap in the accounts most frequently followed across all three groups (5% of accounts overlap). Donald Trump, Elon Musk, and Ellen DeGeneres were the only prominent individuals in the top-25 followed accounts who overlapped across all three groups. There was a strong following of mostly Democratic political elites accounts among early adopters and entirely-Republican elites accounts among nonadopters. In general, following politicians’ accounts were the most commonly identified statistically significant factor for predicting vaccine status among early adopters and nonadopters. In contrast, late adopters followed fewer Democratic leaning political accounts than early adopters and fewer Republican leaning political accounts than nonadopters. The political accounts they followed belonged to national leaders of both parties (Trump, Obama, Clinton, Sanders are all in the top 10). Generally, they followed a more diverse set of account types than the early adopters and the nonadopters. The accounts that were most statistically significant predictors of eventual vaccine status among those who were initially skeptical were, for example, an economist’s account (Paul Krugman), a social media platform (Instagram), an educational account (TED Talks), a conspiracy figure’s account (Snowden), and a sports figure’s account (Victor Cruz). In contrast, the best predictors of eventual vaccine status among early adopters were overwhelmingly political accounts.

The x-axis shows the proportion of consented Twitter/X respondents in that group following each of the prominent accounts listed on the y-axis. The colors of bars show the groups of respondents with different types of vaccine behavior who follow the prominent account. The colors of the labels on the y-axis represent the partisanship of the accounts (blue: Democrats, red: Republicans, purple: apolitical). * p  < 0.05, ** p  < 0.01, *** p  < 0.001 indicates the account is statistically significant at the respective level as a predictor of vaccine status.

When we broadened our analysis to the top 100 accounts followed by each group, we obtained a little more nuanced picture. The largest account type followed by our consented Twitter/X respondents was entertainment with nonadopters following them at the highest percentage (52%) comparing to early adopters (39%) and late adopters (45%). Early adopters follow more political and news accounts (43%) compared to the other two groups (31% for late adopters and 30% for nonadopters), and late adopters tended to follow slightly more science/tech accounts (12%) compared to early adopters (7.5%) and nonadopters (6%). (See Supplementary Fig. 5 for details about the types of accounts being followed by out three groups).

Next, we looked only at the vaccine-related content of the previously identified prominent accounts. Figure 5 shows the distribution of different message types for our set of prominent accounts. We see that the prominent accounts followed by early adopters shared a high amount of pro-vaccination messaging (72% of accounts), while the prominent accounts followed by late adopters shared a more modest level of pro-vaccination messaging (36% of accounts). In contrast, based on the accounts they followed, nonadopters heard anti-vaccination or anti-vaccine mandate messaging significantly more than the other two groups combined (36% of accounts as opposed to 8%) and pro-vaccination messaging less than each of the other two groups (12% as opposed to 72% for early adopter and 52% for late adopters). Early adopters were over five times more likely than nonadopters to have heard pro-vaccination messaging from prominent accounts, while late adopters were three times more likely.

The x-axis shows the proportion of consented Twitter/X respondents in a specific group exposed to different vaccine-related messaging. Green represents the proportion of prominent accounts that shared pro-vaccination messaging (Pro). Red represents the proportion of prominent accounts that shared anti-vaccination or anti-vaccine mandate messaging (Anti Vax/Mandate). Yellow represents the proportion of prominent accounts that shared neutral vaccination messaging or no vaccination messaging (Neutral + No Mentions). There are no prominent accounts that shared both pro and anti-vaccine messaging.

Evidence that individuals with certain beliefs and behaviors followed particular sets of accounts could be a product either of the specific information those accounts share or the kinds of networks in which those accounts are embedded. Although we found suggestive evidence that the vaccine content of the individuals being followed differed across groups, it is still important to understand what those information networks looked like on an individual level. To better understand the connections across accounts that were followed, Fig. 6 shows a network that highlights the relationship between prominent accounts followed by our respondents in the consented Twitter/X population (See Supplementary Fig. 1 for the labeled version of network). The average degree and weighted degree of the network were 5.18 and 78.14, respectively. There were three connected components and the largest had a diameter of 9. We found that there are clear distinct clusters for each vaccine status group, particularly the nonadopters and the early adopters. The modularity was 0.18 and the average clustering coefficient was 0.41, confirming the network’s clear group structure. The highest degree (largest) nodes in the purple cluster (early adopters) were the handles BarackObama, POTUS, and JoeBiden. The highest degree nodes in the red cluster (nonadopters) were the handles realDonaldTrump and ElonMusk. The green cluster (late adopters) did not contain nodes with as high a degree as the other clusters. Its highest degree node was handle CFBPlayoffs.

Nodes represent prominent accounts followed by consented Twitter/X respondents. An edge indicates that at least two respondents follow the pair of accounts. The thickness of the edge is based on the number of respondents following different pairs of nodes. The edge color shows the respondents vaccine status (purple = early adopter, green = late adopter, red = nonadopter). In cases where multiple edges exist between a pair of nodes, we show a single edge with an edge coloring determined using edge weight. There are only four cases when multiple edges occur between a pair of nodes. The four nodes with 2 edges between them are the following (DonaldJTrumpJr, realDonaldTrump), (DrBiden, BarackObama), (DrBiden, JoeBiden), and (elonMusk, realDonaldTrump). See Supplementary Fig. 1 for a labeled version of the network.

Our late adopters shared more network nodes with both groups than the two groups shared with each other. They shared 18 edges with early adopters and 13 edges with nonadopters. Among those not intending to vaccinate or unsure in the first wave, when predicting eventual vaccination status based on high-ranking Twitter/X followers, demographics, and survey response topics, a combination of Twitter/X follows and demographics was most informative, with a predictive cross entropy of approximately 0.45 on average compared to a predictive cross entropy of 0.5 for demographics alone or Twitter/X follows alone ( p  < 0.001, See Supplementary Fig. 2 ).

We also found that across all network metrics except the number of connected components, differences in the metrics determined from our graph compared to those generated using random graphs were statistically significant. For example, the clustering coefficient has 95% CI [0.0252, 0.0682] and the largest diameter has 95% CI 5 , 7 (see Supplementary Table 4 for more details). In other words, the connectivity structure and clustering behavior were not random.

Our demographic results about vaccine hesitancy are consistent with previous research 20 , 50 , 51 . The panel design of our study and the coupling of social media and survey analysis allows us to investigate what factors lead initially hesitant respondents to eventually vaccinate (late adopters), and gives insight into prominent information sources they follow on Twitter/X. This leads to our unique findings differentiating this group from early adopters and nonadopters (differences in rationales and in Twitter/X information they are exposed to). While the reasons that people are initially hesitant overlap, our results suggest that vaccine mandates are an important strategy for persuading late adopters to get vaccinated, in addition to the desire to travel and return to a more normal lifestyle. While these matter to early adopters, they are less important. When comparing late adopters and nonadopters, the primary reason of it being too early was the same for both subgroups. However, the differences in the proportion of respondents stating institutional distrust as a reason for not getting vaccinated was significant with nonadopters mentioning it almost twice as often. While these top reasons align with the previous findings indicating that lack of government trust is a primary reason against vaccination 11 , as well as echoes of tropes anti-vaxxers use 53 , the divergence between nonadopters and late adopters is crucial, with the latter group reporting rationales that are more temporal in nature. This implies that they may have always been more open to changing their stance on vaccination once safety concerns were alleviated.

In addition, the vaccine-related information obtained on Twitter/X by our three subpopulations differed. Early adopters follow a large number of prominent politicians who are Democrats, and also see a large percentage of pro-vaccine messages. The nonadopters in our sample, on the other hand, follow a large number of prominent politicians who are Republican, and were potentially exposed to five times more anti-vaccine and/or anti-vaccine mandate messaging than the other two groups. The late adopters are in the middle of these two extremes - while they are exposed to some anti-vaccination messaging, they also follow prominent politicians who share pro-vaccine messages and follow many prominent non-politicians, most of whom either do not post about vaccines at all, or post support for them. In general, they follow a diverse set of accounts, many of which post support for vaccinations. From our network analysis, we see that clear clusters emerge based on who respondents in different vaccination groups follow. Similar to Johnson and colleagues’ study of Facebook users, we find that late adopters are connected to prominent accounts that are both pro-vaccine and anti-vaccine, creating messaging competition 54 . However, in our sample, the proportion of pro-vaccination messaging is significantly higher than anti-vaccination messaging within both the early adopter and late adopter groups.

Both the demographic results and the Twitter/X followers analysis descriptively support our statistical analysis. In both cases a combination of demographic factors and Twitter/X follows is most informative for predicting the likelihood of vaccinating. Our research design does not allow us to determine whether social media information environments led to changes in vaccine attitude or whether this rich information is simply a correlate. But the value of social media data is clear. Whether a cause or correlate, such data can help us identify vaccine attitudes more accurately than is possible using only demographics data alone. In short, what seems to be the primary difference between those who eventually choose to be vaccinated and those who remain unvaccinated are 1) the reinforcement of anti-vaccination messaging from prominent individuals and 2) a general distrust in government.

Social media platforms have increasingly become the primary source of news and information for many people. Although it is not the modal experience 55 , individuals on these platforms can exist in echo chambers , where they predominantly follow, consume, trust, and share content that mirrors their existing beliefs 56 , 57 , 58 , 59 . This reinforcement loop means users are more likely to interact with, and perhaps be influenced by, content and individuals that affirm their pre-existing views. This trend can be amplified during times of uncertainty, e.g., during a pandemic. Prior research has shown that social media can impact beliefs and outcomes related to vaccination 40 , and this impact is more pronounced when individuals receive information from trusted in-group sources 60 , 61 . Both early adopters and nonadopters on Twitter/X seem to have more significant exposure to prominent accounts that already align with their existing political stands. In contrast, even though late adopters follow political accounts, they generally follow a more diverse range of prominent accounts on social media and are likely exposed to a wider array of high- and low-quality information. If we view early adopters and nonadopters as firmly locked in their political camps and respective views on vaccination, the late adopters represent the “ambiguous public” -- a middle group potentially open to persuasion 62 , 63 . This highlights the importance of both trust and information quality in the age of misinformation. The role of trusted political and non-political figures in setting the initial position and subsequently impacting people’s behavior is evident and crucial. While our experimental frame does not allow us to establish causality, the existence of a relationship between online messaging and behavior is clear.

Finally, our analysis further confirms previous studies that highlight how prevalent and problematic a growing lack of trust in government may be 9 , 11 , 64 , 65 , 66 , 67 , 68 . In this sample, nonadopters cited distrust as one of the major reasons for not getting vaccinated. This was an important difference between those who eventually received the vaccine and those who did not. However, when we look at our Twitter/X sample, we see that both early adopters and nonadopters follow a similar number of prominent politicians, with early adopters following more Democrats and nonadopters following more Republicans. We conjecture that the decline of public trust in government is associated with the growing anti-establishment sentiment. This trend is particularly pronounced with the rise of anti-establishment politicians in the United States like Donald Trump and Rand Paul, and opinion leaders such as Elon Musk. Studies find that anti-establishmentarianism is associated with antisocial psychological traits, the acceptance of political violence, time spent on extremist social media platforms, support for populist politicians, and belief in misinformation and conspiracy theories 69 , 70 . Ultimately, if anti-establishment leaders (political and otherwise) advocate an anti-vaccination campaign online, it will continue to impact vaccine acceptance rates.

The primary limitation of this study is its observational nature: it is not possible to disentangle two scenarios related to social media. The first possible scenario is that individuals are being influenced by the content of their Twitter/X feeds and are being moved to change their vaccination behavior as a result. The second possible scenario is that, having already solidified their vaccination intentions, individuals then follow accounts on Twitter/X that reinforce their existing viewpoints and validate their previously made decisions. We expect reality to be somewhere in the middle. This makes it difficult to estimate with certainty the effectiveness of an intervention deployed via social media. But regardless of the extent of these two effects, knowing which accounts are associated with vaccination hesitancy is a useful barometer of public sentiment, as information about who follows which accounts is easily accessible.

Additionally, due to individual differences in platform usage and to the nature of social media algorithmic curation we do not know how often the respondents access Twitter/X, or what specific information they see when they do. We only know how often they post or repost content. Furthermore, Twitter/X is only one of many sources of information respondents are exposed to. Other sources include traditional media and personal networks. Any given individual may be more or less reliant on Twitter/X as a source of information, and the persuasiveness of the information they encounter there also likely varies on an individual basis.

There are also the standard limitations associated with any survey-based study that requires additional consent. Namely, there can be bias associated with survey non-response, as well as associated with consenting to share and link the Twitter/X account information 71 . As we have seen, a lack of trust in institutions is associated with vaccine hesitancy, and it is plausible that this may also be associated with a reduced willingness to participate in research in general and to share social media profiles more specifically 72 . Additionally, there is a risk that some respondents may misreport their vaccination status as a function of social desirability and that their responses to the open-ended questions may not reflect the true reasons that individuals behaved the way they do – if indeed they can even identify such reasons.

Moving forward, these findings highlight the importance of using both social media and traditional media to inform the public about the need to vaccinate and the safety of vaccines. Reinforcement of the need to obtain vaccinations by prominent social media accounts (including those of entertainment, news, science, and sports figures) could be important for those who are hesitant but persuadable because prominent accounts may be viewed by the public as trusted surrogates when information is hard to access or polluted by misinformation. New strategies should be explored to engage different types of social media influencers and personalities in vaccine messaging. The recent campaign featuring Travis Kelce encouraging the public to get COVID-19 and flu vaccines simultaneously is a great example of a cross-media campaign that could be effective in persuading skeptics 73 . Vaccine messaging that is more randomly shared through advertising may be useful for those who are already likely to get vaccinated (early adopters), but posts shared by influencers may be more beneficial for those who are less inclined to get vaccinated (late adopters). We also suggest regular public announcements on different social media and traditional media platforms that focus on vaccine safety more broadly, as well as announcing the importance of vaccinations through stories of how vaccines have saved lives. Storytelling is a particularly effective persuasive device 74 . Continual exposure to pro-vaccine messaging is vital to decreasing the impact of poor-quality vaccine-related information and increasing health literacy. Recall our finding that individuals who are initially skeptical but eventually received a vaccine (late adopters) are most concerned about side effects of the vaccine, suggesting that messaging about the safety of the vaccine may help alleviate some of these concerns and lead to higher rates of vaccinations. If public health officials do not actively share and reinforce the health benefits of vaccinations and how effective and safe they are, the information pollution generated by anti-vaxxers will likely continue to increase vaccine hesitancy.

Conversely, our finding that the greatest concern among those who remain unvaccinated is trust in institutions implies that trust-building efforts to date have not had their desired effects. Trust-building is also not a quick process that can be undertaken in response to a crisis. Increasing trust in government and reducing the politicization of vaccinations will require persistent effort if we want better outcomes during the next public health emergency.

The primary question left open by this article is that of causality between social media exposure and vaccination, but this study makes it easier to tackle that question in future work. The most robust research design would involve a controlled experiment where subjects modify their social media behavior. Some such studies ask the user not to use social media at all (see e.g., ref. 75 ). Another avenue of experimentation consists of exposing subjects to particular social media posts 76 , and then asking the subjects attitudinal questions and comparing the responses with those of a control group. Some previous research has even used platform-based manipulations to assess social media impacts 77 . Our results motivate such an experiment, exposing subjects to messaging from political elites, both Republican and Democratic, and measuring whether this hardens attitudes on vaccines relative to a control group. Similarly, one can ask subjects to subscribe to these same accounts and rely on the social media platform to expose them to the messaging 78 or, in collaboration with the platform, alter the extent to which certain users receive messages from certain accounts 79 .

There are also many other important future directions. One direction is to investigate other social media platforms, and ideally, to simultaneously look at multiple platforms. Additionally, communications from employers or health insurance companies and government entities may have played a role in decision making. Capturing that information in a survey or from health providers is also a fruitful direction. Furthermore, personal offline networks are likely to play a moderating role in vaccination behavior. To investigate this, we could imagine either simply adding questions about personal networks in a survey much like the one conducted in this study, or even using a more sophisticated survey design, such as snowball sampling, which would allow researchers to collect information from respondents who know one another personally to investigate correlations in behavior not explained by social media activity. Finally, all of the information on social media occurs against the backdrop of traditional media, government messaging, and other sources of information. Future work could incorporate both traditional and non-traditional information sources.

In conclusion, we find that the self-reported rationalizations for vaccine hesitancy differs among those who eventually decide to be vaccinated and those who choose not to. There is also a difference in terms of the types of accounts followed by each group and the amount of pro- versus anti-vaccine messaging our Twitter/X subsample was exposed to. It is also important to note that nonadopters tend to follow prominent Republican political accounts and express a lack of trust in institutions. By contrast, late adopters are less likely to follow only prominent political accounts and are more motivated by a desire to return to normal life and work requirements to be vaccinated. Our findings also suggest that we must engage in strategies to increase trust in government. Addressing the fundamental issues that cause a lack of trust in institutions is a whole-of-society problem. Research has noted that Americans’ trust in government, in particular the national government, has declined over the past half century 80 . Especially in the age of misinformation and during critical times like pandemics, trust in government becomes even more vital for cohesive societal responses. Other important strategies include improving the digital experience for those who engage with government, increasing capacity to effectively deliver public services, and sharing success stories and narratives of public servants on social media and other platforms. Ultimately, the battle for increasing vaccination uptick includes a secondary battle to improve trust in government.

We used micro-linked data from a panel survey and Twitter/X (i.e., closed-ended survey response, open-ended text data, social media post text data, and network data) and implemented a series of analytical techniques, including topic modeling, statistical models, and network analysis to gain a more comprehensive and nuanced understanding of respondents’ attitudes toward COVID-19 vaccines.

All survey participants consented to participation in the research via online forms. More details in Section IV.1.

Ethical approvals

This study obtained IRB approval. The study was approved via Georgetown University IRB under protocol STUDY00003571.

Micro-linked data sample

We leveraged the SSRS Opinion Panel for survey recruitment ( N  = 9544), a probability-based panel of U.S. adults ages 18 or older and recruited randomly based on a nationally representative ABS (Address Based Sample) probability design (including Hawaii and Alaska) 81 . Survey recruitment was conducted via the web in three waves (Wave 0: March 1 to June 15, 2021; Wave 1: October 11 to October 20, 2021; Wave 2: January 27 to February 9, 2022) and included survey questions on the SSRS Opinion Panel registration survey for new panelists as well as survey questions on demographic refreshment surveys conducted among existing SSRS Opinion Panel members. The overall cumulative response rate (AAPOR – RR3) was 4% for wave 0, the full panel sample. Among a recruited sample of 9544 panelists, 9468 were interviewed in English and 76 in Spanish. Data were weighted to adjust for ABS recruitment, and raking weights were produced to represent the U.S. adult population.

Wave 1 and 2 were samples of Wave 0. For Wave 1, a subset of the SSRS Opinion Panel participated in new data collection via the web from October 11 – 20, 2021, resulting in a sample of 1003 participants. For Wave 2, a subset of the SSRS Opinion Panel participated in new data collection via the web from January 27- February 9, 2022, resulting in a sample of 1000 participants. In each wave, data were weighted to represent the target U.S. adult population. These weighted survey responses were used to generate descriptive and statistical results. Respondents were asked via multiple choice questions to self-report their vaccination intentions (Wave 0) or behavior (Waves 1 and 2), as well as for the date during which they received their vaccination if applicable. Our statistical analyses primarily focused on respondents who participated in both Wave 0 and Wave 1 of the study. This is to maximize the number of respondents included in the analysis, for whom we can consistently track observed behavioral changes and topic mentions within the same time period. Wave 2 was primarily used to determine vaccine uptick percentages through time for different demographic groups. Among 1532 respondents who participated in at least one follow-up wave of surveys, 9 respondents mentioned they planned to get vaccinated but never did by the time of their final survey response. We excluded this group from the analysis.

Among 9544 survey participants in Wave 1, 3140 were Twitter/X users, and among these, 735 were willing to provide their handle. For a detailed assessment of potential consent bias, Supplementary Figs. 4 and 5 provide systematic comparisons between Twitter/X users and consenting survey respondents. We looked at posts shared by respondents between March 1, 2021, and February 28, 2022. We also collected the accounts that the consented Twitter/X respondents were following and used these accounts as proxies for information exposure and sources. We selected Twitter/X as our primary platform for several reasons. First, the Twitter/X posts are expected to be visible publicly, aligning with our considerations of privacy and ethics. Second, its wide use in the U.S. with over 20% of Americans actively using the platform at the time of our study means that a reasonable portion of the population or at least an important subpopulation consume information and communicate online through this platform. Additionally, the process of collecting Twitter handles from survey respondents proved to be relatively straightforward (compared to other platforms), as users typically recall their handles easily when completing surveys.

Topic modeling

In order to quantitatively evaluate the open-ended question responses, the exact responses to open-ended questions were transcribed by interviewers and coded using a semi-supervised guided topic model, GTM 82 . Preprocessing steps included capitalization standardization, punctuation removal, and stopword removal. Frequently occurring words and phrases were identified by counting the frequency with which respondents used different unigrams, bigrams, and trigrams. In order to generate an initial set of topics for each open-ended response, researchers on our team looked through the list of frequently occurring words and phrases to identify those that could be combined to form specific topics. These initial topics were inputs into GTM 82 . The model produced additional words for each identified topic and produced new topics. The research team reviewed all the added words and new topics. Topics were manually adjusted and added when at least two out of three researchers agreed on the change. This process was conducted iteratively at least three times for each open-ended question, until the researchers were satisfied with the resulting topic list. Responses were then labeled. This full human-in-the-loop process was repeated until at least 85% of responses were labeled for each open-ended question.

Statistical analysis

In order to compare the predictive ability of demographic factors, survey responses and Twitter/X follows, we conducted out-of-sample analysis. Specifically, for each of 100 iterations, we randomly held out 20% of the respondents who had consented to Twitter/X linking and used the remaining 80% of such respondents to fit a logistic regression model. We used the following variable groups in our analysis: only demographic information, only Twitter/X follows, only survey data, and a combination of all the variable groups. We then used these models to predict the vaccination status of the remaining 20%. In the first analysis, the response variable is given as one of the three vaccination classes (early adopter, late adopters, or nonadopters) a respondent belongs to, and the model is specified as a multiclass logistic regression (see Supplementary Fig. 3 ).

We additionally conducted two-class logistic regressions in order to contrast the characteristics of nonadopters from late adopters (Supplementary Table 2 ), as well as late adopters from early adopters (Supplementary Table 3 ). In each case, we conducted a regression based only on sociodemographic factors (left column of coefficients), as well as one using both sociodemographics and survey topics (right column).

Twitter follow and network analysis

We used the Twitter4J software package to access the Twitter/X Timeline API and collected 24,076 accounts followed by at least two consented survey respondents who used Twitter/X. This collection occurred after wave 2. Within the descriptive network analysis, we identified the top 100 commonly followed pairs of accounts for each of our three vaccination status groups. Using the statistical analysis described in the previous subsection, we included the top 25 accounts followed by each of the three outcome groups when estimating the effects of following the account on predicting the vaccination status. For Figs. 4 and 5 , we focused only on the most-followed, prominent accounts to identify the common information exposure for each group. For Fig. 5 , we considered all vaccine-related content, and then classified it as pro-vaccine, anti-vaccine (including posts against vaccine mandates), or neutral on vaccines. For the analysis of Supplementary Fig. 5 , researchers on our team manually classified each of the top 100 accounts into the following categories: Entertainment, Politics (Democratic, Republican, or Nonpartisan), News, Science/Technology, Sports and Others. Each account was classified by at least two researchers and disagreements were discussed among all three.

We also created a uni-modal, multi-edge, weighted network. Nodes represented prominent accounts, and an edge was added between two nodes if at least 2 respondents followed both nodes (accounts). The edge was colored by vaccine status of the respondents following the pair and the width of the edge was based on the number of respondents following the pair. There were only four cases when multiple edges occurred between a pair of nodes. Along with measuring network metrics (weighted degree, betweenness, clustering coefficient, and eigenvector centrality), we determined whether our network was random. We accomplished this by simulating random networks with the same number of nodes and edges as our prominent accounts network. We conducted this simulation 1000 times, determined the network metrics for each constructed network, and reported the average metric value and the confidence intervals.

Data availability

The survey data for conducting the analysis are available from the authors upon reasonable request. The study protocols and designs are described in the Supplementary Appendices.

Code availability

The Guided Topic Model (GTM) code can be accessed from Github ( https://github.com/GU-DataLab/topic-modeling ). The statistical analysis code can also be accessed from Github ( https://github.com/georgetown-mdi/vax_adoption ).

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Acknowledgements

This work was supported by National Science Foundation grant numbers #1934925 and #1934494. We also acknowledge infrastructure and technical team support from the Massive Data Institute at Georgetown University. Finally, we acknowledge the survey support and collaboration with SSRS.

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L.S. is the principal investigator of the research, leading the research effort. L.S., L.B.2, C.B., J.P., T.R., and M.T. contributed to conceptualization of the project design, and survey design. L.S. and Y.W. contributed to the data collection. L.S., L.B.1, Y.W., and N.W. performed the data analysis. All authors contributed to the manuscript design, writing, and revisions.

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Singh, L., Bao, L., Bode, L. et al. Understanding the rationales and information environments for early, late, and nonadopters of the COVID-19 vaccine. npj Vaccines 9 , 168 (2024). https://doi.org/10.1038/s41541-024-00962-5

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The reports to the Vaccine Adverse Event Reporting System met the case definition of myocarditis (reported cases). Among individuals older than 40 years of age, there were no more than 8 reports of myocarditis for any individual age after receiving either vaccine. For the BNT162b2 vaccine, there were 114 246 837 first vaccination doses and 95 532 396 second vaccination doses; and for the mRNA-1273 vaccine, there were 78 158 611 and 66 163 001, respectively. The y-axis range differs between panels A and B.

The reports to the Vaccine Adverse Event Reporting System met the case definition of myocarditis (reported cases). Among recipients of either vaccine, there were only 13 reports or less of myocarditis beyond 10 days for any individual time from vaccination to symptom onset. The y-axis range differs between panels A and B.

A, For the BNT162b2 vaccine, there were 138 reported cases of myocarditis with known date for symptom onset and dose after 114 246 837 first vaccination doses and 888 reported cases after 95 532 396 second vaccination doses.

B, For the mRNA-1273 vaccine, there were 116 reported cases of myocarditis with known date for symptom onset and dose after 78 158 611 first vaccination doses and 311 reported cases after 66 163 001 second vaccination doses.

eMethods. Medical Dictionary for Regulatory Activities Preferred Terms, Definitions of Myocarditis and Pericarditis, Myocarditis medical review form

eFigure. Flow diagram of cases of myocarditis and pericarditis reported to Vaccine Adverse Event Reporting System (VAERS) after receiving mRNA-based COVID-19 vaccine, United States, December 14, 2020-August 31, 2021.

eTable 1. Characteristics of all myocarditis cases reported to Vaccine Adverse Event Reporting System (VAERS) after mRNA-based COVID-19 vaccination, United States, December 14, 2020–August 31, 2021.

eTable 2. Characteristics of all pericarditis cases reported to Vaccine Adverse Event Reporting System (VAERS) after mRNA-based COVID-19 vaccination, United States, December 14, 2020–August 31, 2021.

eTable 3. Characteristics of myocarditis cases reported to Vaccine Adverse Event Reporting System after mRNA-based COVID-19 vaccination by case definition status.

• Myocarditis and Pericarditis After Vaccination for COVID-19 JAMA Research Letter September 28, 2021 This study investigates the incidence of myocarditis and pericarditis emergency department or inpatient hospital encounters before COVID-19 vaccine availability (January 2019–January 2021) and during a COVID-19 vaccination period (February-May 2021) in a large US health care system. George A. Diaz, MD; Guilford T. Parsons, MD, MS; Sara K. Gering, BS, BSN; Audrey R. Meier, MPH; Ian V. Hutchinson, PhD, DSc; Ari Robicsek, MD
• Myocarditis Following a Third BNT162b2 Vaccination Dose in Military Recruits in Israel JAMA Research Letter April 26, 2022 This study assessed whether a third vaccine dose was associated with the risk of myocarditis among military personnel in Israel. Limor Friedensohn, MD; Dan Levin, MD; Maggie Fadlon-Derai, MHA; Liron Gershovitz, MD; Noam Fink, MD; Elon Glassberg, MD; Barak Gordon, MD
• Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US—Reply JAMA Comment & Response May 24, 2022 Matthew E. Oster, MD, MPH; David K. Shay, MD, MPH; Tom T. Shimabukuro, MD, MPH, MBA
• Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US JAMA Comment & Response May 24, 2022 Sheila R. Weiss, PhD
• JAMA Network Articles of the Year 2022 JAMA Medical News & Perspectives December 27, 2022 This Medical News article is our annual roundup of the top-viewed articles from all JAMA Network journals. Melissa Suran, PhD, MSJ
• Diagnosis and Treatment of Acute Myocarditis—A Review JAMA Review April 4, 2023 This Review summarizes current evidence regarding the diagnosis and treatment of acute myocarditis. Enrico Ammirati, MD, PhD; Javid J. Moslehi, MD
• Patient Information: Acute Myocarditis JAMA JAMA Patient Page August 8, 2023 This JAMA Patient Page describes acute myocarditis and its symptoms, causes, diagnosis, and treatment. Kristin Walter, MD, MS
• Prognosis of Myocarditis Attributed to COVID-19 mRNA Vaccination, SARS-CoV-2, or Conventional Etiologies JAMA Original Investigation August 26, 2024 This cohort study examines cardiovascular complications of postvaccine and other types of myocarditis (ie, post–COVID-19 and conventional myocarditis) during 18-month follow-up. Laura Semenzato, MSc; Stéphane Le Vu, PhD; Jérémie Botton, PhD, PharmD, MPH; Marion Bertrand, MSc; Marie-Joelle Jabagi, PhD, PharmD, MPH; Jérôme Drouin, MSc; François Cuenot, PhD; Florian Zores, MD; Rosemary Dray-Spira, PhD, MD; Alain Weill, MD; Mahmoud Zureik, PhD, MD
• Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military JAMA Cardiology Brief Report October 1, 2021 This case series describes myocarditis presenting after COVID-19 vaccination within the Military Health System. Jay Montgomery, MD; Margaret Ryan, MD, MPH; Renata Engler, MD; Donna Hoffman, MSN; Bruce McClenathan, MD; Limone Collins, MD; David Loran, DNP; David Hrncir, MD; Kelsie Herring, MD; Michael Platzer, MD; Nehkonti Adams, MD; Aliye Sanou, MD; Leslie T. Cooper Jr, MD
• Patients With Acute Myocarditis Following mRNA COVID-19 Vaccination JAMA Cardiology Brief Report October 1, 2021 This study describes 4 patients who presented with acute myocarditis after mRNA COVID-19 vaccination. Han W. Kim, MD; Elizabeth R. Jenista, PhD; David C. Wendell, PhD; Clerio F. Azevedo, MD; Michael J. Campbell, MD; Stephen N. Darty, BS; Michele A. Parker, MS; Raymond J. Kim, MD
• Association of Myocarditis With BNT162b2 Vaccination in Children JAMA Cardiology Brief Report December 1, 2021 This case series reviews comprehensive cardiac imaging in children with myocarditis after COVID-19 vaccine. Audrey Dionne, MD; Francesca Sperotto, MD; Stephanie Chamberlain; Annette L. Baker, MSN, CPNP; Andrew J. Powell, MD; Ashwin Prakash, MD; Daniel A. Castellanos, MD; Susan F. Saleeb, MD; Sarah D. de Ferranti, MD, MPH; Jane W. Newburger, MD, MPH; Kevin G. Friedman, MD

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Oster ME , Shay DK , Su JR, et al. Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021. JAMA. 2022;327(4):331–340. doi:10.1001/jama.2021.24110

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Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021

• 1 US Centers for Disease Control and Prevention, Atlanta, Georgia
• 2 School of Medicine, Emory University, Atlanta, Georgia
• 3 Children’s Healthcare of Atlanta, Atlanta, Georgia
• 4 Vanderbilt University Medical Center, Nashville, Tennessee
• 5 Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
• 6 Boston Medical Center, Boston, Massachusetts
• 7 Duke University, Durham, North Carolina
• 8 US Food and Drug Administration, Silver Spring, Maryland
• Research Letter Myocarditis and Pericarditis After Vaccination for COVID-19 George A. Diaz, MD; Guilford T. Parsons, MD, MS; Sara K. Gering, BS, BSN; Audrey R. Meier, MPH; Ian V. Hutchinson, PhD, DSc; Ari Robicsek, MD JAMA
• Research Letter Myocarditis Following a Third BNT162b2 Vaccination Dose in Military Recruits in Israel Limor Friedensohn, MD; Dan Levin, MD; Maggie Fadlon-Derai, MHA; Liron Gershovitz, MD; Noam Fink, MD; Elon Glassberg, MD; Barak Gordon, MD JAMA
• Comment & Response Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US—Reply Matthew E. Oster, MD, MPH; David K. Shay, MD, MPH; Tom T. Shimabukuro, MD, MPH, MBA JAMA
• Comment & Response Myocarditis Cases After mRNA-Based COVID-19 Vaccination in the US Sheila R. Weiss, PhD JAMA
• Medical News & Perspectives JAMA Network Articles of the Year 2022 Melissa Suran, PhD, MSJ JAMA
• Review Diagnosis and Treatment of Acute Myocarditis—A Review Enrico Ammirati, MD, PhD; Javid J. Moslehi, MD JAMA
• JAMA Patient Page Patient Information: Acute Myocarditis Kristin Walter, MD, MS JAMA
• Original Investigation Prognosis of Myocarditis Attributed to COVID-19 mRNA Vaccination, SARS-CoV-2, or Conventional Etiologies Laura Semenzato, MSc; Stéphane Le Vu, PhD; Jérémie Botton, PhD, PharmD, MPH; Marion Bertrand, MSc; Marie-Joelle Jabagi, PhD, PharmD, MPH; Jérôme Drouin, MSc; François Cuenot, PhD; Florian Zores, MD; Rosemary Dray-Spira, PhD, MD; Alain Weill, MD; Mahmoud Zureik, PhD, MD JAMA
• Brief Report Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military Jay Montgomery, MD; Margaret Ryan, MD, MPH; Renata Engler, MD; Donna Hoffman, MSN; Bruce McClenathan, MD; Limone Collins, MD; David Loran, DNP; David Hrncir, MD; Kelsie Herring, MD; Michael Platzer, MD; Nehkonti Adams, MD; Aliye Sanou, MD; Leslie T. Cooper Jr, MD JAMA Cardiology
• Brief Report Patients With Acute Myocarditis Following mRNA COVID-19 Vaccination Han W. Kim, MD; Elizabeth R. Jenista, PhD; David C. Wendell, PhD; Clerio F. Azevedo, MD; Michael J. Campbell, MD; Stephen N. Darty, BS; Michele A. Parker, MS; Raymond J. Kim, MD JAMA Cardiology
• Brief Report Association of Myocarditis With BNT162b2 Vaccination in Children Audrey Dionne, MD; Francesca Sperotto, MD; Stephanie Chamberlain; Annette L. Baker, MSN, CPNP; Andrew J. Powell, MD; Ashwin Prakash, MD; Daniel A. Castellanos, MD; Susan F. Saleeb, MD; Sarah D. de Ferranti, MD, MPH; Jane W. Newburger, MD, MPH; Kevin G. Friedman, MD JAMA Cardiology

Question   What is the risk of myocarditis after mRNA-based COVID-19 vaccination in the US?

Findings   In this descriptive study of 1626 cases of myocarditis in a national passive reporting system, the crude reporting rates within 7 days after vaccination exceeded the expected rates across multiple age and sex strata. The rates of myocarditis cases were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.7 per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.9 per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.4 and 56.3 per million doses of the BNT162b2 vaccine and the mRNA-1273 vaccine, respectively).

Meaning   Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men.

Importance   Vaccination against COVID-19 provides clear public health benefits, but vaccination also carries potential risks. The risks and outcomes of myocarditis after COVID-19 vaccination are unclear.

Objective   To describe reports of myocarditis and the reporting rates after mRNA-based COVID-19 vaccination in the US.

Design, Setting, and Participants   Descriptive study of reports of myocarditis to the Vaccine Adverse Event Reporting System (VAERS) that occurred after mRNA-based COVID-19 vaccine administration between December 2020 and August 2021 in 192 405 448 individuals older than 12 years of age in the US; data were processed by VAERS as of September 30, 2021.

Exposures   Vaccination with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna).

Main Outcomes and Measures   Reports of myocarditis to VAERS were adjudicated and summarized for all age groups. Crude reporting rates were calculated across age and sex strata. Expected rates of myocarditis by age and sex were calculated using 2017-2019 claims data. For persons younger than 30 years of age, medical record reviews and clinician interviews were conducted to describe clinical presentation, diagnostic test results, treatment, and early outcomes.

Results   Among 192 405 448 persons receiving a total of 354 100 845 mRNA-based COVID-19 vaccines during the study period, there were 1991 reports of myocarditis to VAERS and 1626 of these reports met the case definition of myocarditis. Of those with myocarditis, the median age was 21 years (IQR, 16-31 years) and the median time to symptom onset was 2 days (IQR, 1-3 days). Males comprised 82% of the myocarditis cases for whom sex was reported. The crude reporting rates for cases of myocarditis within 7 days after COVID-19 vaccination exceeded the expected rates of myocarditis across multiple age and sex strata. The rates of myocarditis were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.7 per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.9 per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.4 and 56.3 per million doses of the BNT162b2 vaccine and the mRNA-1273 vaccine, respectively). There were 826 cases of myocarditis among those younger than 30 years of age who had detailed clinical information available; of these cases, 792 of 809 (98%) had elevated troponin levels, 569 of 794 (72%) had abnormal electrocardiogram results, and 223 of 312 (72%) had abnormal cardiac magnetic resonance imaging results. Approximately 96% of persons (784/813) were hospitalized and 87% (577/661) of these had resolution of presenting symptoms by hospital discharge. The most common treatment was nonsteroidal anti-inflammatory drugs (589/676; 87%).

Conclusions and Relevance   Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men. This risk should be considered in the context of the benefits of COVID-19 vaccination.

Myocarditis is an inflammatory condition of the heart muscle that has a bimodal peak incidence during infancy and adolescence or young adulthood. 1 - 4 The clinical presentation and course of myocarditis is variable, with some patients not requiring treatment and others experiencing severe heart failure that requires subsequent heart transplantation or leads to death. 5 Onset of myocarditis typically follows an inciting process, often a viral illness; however, no antecedent cause is identified in many cases. 6 It has been hypothesized that vaccination can serve as a trigger for myocarditis; however, only the smallpox vaccine has previously been causally associated with myocarditis based on reports among US military personnel, with cases typically occurring 7 to 12 days after vaccination. 7

With the implementation of a large-scale, national COVID-19 vaccination program starting in December 2020, the US Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration began monitoring for a number of adverse events of special interest, including myocarditis and pericarditis, in the Vaccine Adverse Event Reporting System (VAERS), a long-standing national spontaneous reporting (passive surveillance) system. 8 As the reports of myocarditis after COVID-19 vaccination were reported to VAERS, the Clinical Immunization Safety Assessment Project, 9 a collaboration between the CDC and medical research centers, which includes physicians treating infectious diseases and other specialists (eg, cardiologists), consulted on several of the cases. In addition, reports from several countries raised concerns that mRNA-based COVID-19 vaccines may be associated with acute myocarditis. 10 - 15

Given this concern, the aims were to describe reports and confirmed cases of myocarditis initially reported to VAERS after mRNA-based COVID-19 vaccination and to provide estimates of the risk of myocarditis after mRNA-based COVID-19 vaccination based on age, sex, and vaccine type.

VAERS is a US spontaneous reporting (passive surveillance) system that functions as an early warning system for potential vaccine adverse events. 8 Co-administered by the CDC and the US Food and Drug Administration, VAERS accepts reports of all adverse events after vaccination from patients, parents, clinicians, vaccine manufacturers, and others regardless of whether the events could plausibly be associated with receipt of the vaccine. Reports to VAERS include information about the vaccinated person, the vaccine or vaccines administered, and the adverse events experienced by the vaccinated person. The reports to VAERS are then reviewed by third-party professional coders who have been trained in the assignment of Medical Dictionary for Regulatory Activities preferred terms. 16 The coders then assign appropriate terms based on the information available in the reports.

This activity was reviewed by the CDC and was conducted to be consistent with applicable federal law and CDC policy. The activities herein were confirmed to be nonresearch under the Common Rule in accordance with institutional procedures and therefore were not subject to institutional review board requirements. Informed consent was not obtained for this secondary use of existing information; see 45 CFR part 46.102(l)(2), 21 CFR part 56, 42 USC §241(d), 5 USC §552a, and 44 USC §3501 et seq.

The exposure of concern was vaccination with one of the mRNA-based COVID-19 vaccines: the BNT162b2 vaccine (Pfizer-BioNTech) or the mRNA-1273 vaccine (Moderna). During the analytic period, persons aged 12 years or older were eligible for the BNT162b2 vaccine and persons aged 18 years or older were eligible for the mRNA-1273 vaccine. The number of COVID-19 vaccine doses administered during the analytic period was obtained through the CDC’s COVID-19 Data Tracker. 17

The primary outcome was the occurrence of myocarditis and the secondary outcome was pericarditis. Reports to VAERS with these outcomes were initially characterized using the Medical Dictionary for Regulatory Activities preferred terms of myocarditis or pericarditis (specific terms are listed in the eMethods in the Supplement ). After initial review of reports of myocarditis to VAERS and review of the patient’s medical records (when available), the reports were further reviewed by CDC physicians and public health professionals to verify that they met the CDC’s case definition for probable or confirmed myocarditis (descriptions previously published and included in the eMethods in the Supplement ). 18 The CDC’s case definition of probable myocarditis requires the presence of new concerning symptoms, abnormal cardiac test results, and no other identifiable cause of the symptoms and findings. Confirmed cases of myocarditis further require histopathological confirmation of myocarditis or cardiac magnetic resonance imaging (MRI) findings consistent with myocarditis.

Deaths were included only if the individual had met the case definition for confirmed myocarditis and there was no other identifiable cause of death. Individual cases not involving death were included only if the person had met the case definition for probable myocarditis or confirmed myocarditis.

We characterized reports of myocarditis or pericarditis after COVID-19 vaccination that met the CDC’s case definition and were received by VAERS between December 14, 2020 (when COVID-19 vaccines were first publicly available in the US), and August 31, 2021, by age, sex, race, ethnicity, and vaccine type; data were processed by VAERS as of September 30, 2021. Race and ethnicity were optional fixed categories available by self-identification at the time of vaccination or by the individual filing a VAERS report. Race and ethnicity were included to provide the most complete baseline description possible for individual reports; however, further analyses were not stratified by race and ethnicity due to the high percentage of missing data. Reports of pericarditis with evidence of potential myocardial involvement were included in the review of reports of myocarditis. The eFigure in the Supplement outlines the categorization of the reports of myocarditis and pericarditis reviewed.

Further analyses were conducted only for myocarditis because of the preponderance of those reports to VAERS, in Clinical Immunization Safety Assessment Project consultations, and in published articles. 10 - 12 , 19 - 21 Crude reporting rates for myocarditis during a 7-day risk interval were calculated using the number of reports of myocarditis to VAERS per million doses of COVID-19 vaccine administered during the analytic period and stratified by age, sex, vaccination dose (first, second, or unknown), and vaccine type. Expected rates of myocarditis by age and sex were calculated using 2017-2019 data from the IBM MarketScan Commercial Research Database. This database contains individual-level, deidentified, inpatient and outpatient medical and prescription drug claims, and enrollment information submitted to IBM Watson Health by large employers and health plans. The data were accessed using version 4.0 of the IBM MarketScan Treatment Pathways analytic platform. Age- and sex-specific rates were calculated by determining the number of individuals with myocarditis ( International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes B33.20, B33.22, B33.24, I40.0, I40.1, I40.8, I40.9, or I51.4) 22 identified during an inpatient encounter in 2017-2019 relative to the number of individuals of similar age and sex who were continually enrolled during the year in which the myocarditis-related hospitalization occurred; individuals with any diagnosis of myocarditis prior to that year were excluded. Given the limitations of the IBM MarketScan Commercial Research Database to capture enrollees aged 65 years or older, an expected rate for myocarditis was not calculated for this population. A 95% CI was calculated using Poisson distribution in SAS version 9.4 (SAS Institute Inc) for each expected rate of myocarditis and for each observed rate in a strata with at least 1 case.

In cases of probable or confirmed myocarditis among those younger than 30 years of age, their clinical course was then summarized to the extent possible based on medical review and clinician interviews. This clinical course included presenting symptoms, diagnostic test results, treatment, and early outcomes (abstraction form appears in the eMethods in the Supplement ). 23

When applicable, missing data were delineated in the results or the numbers with complete data were listed. No assumptions or imputations were made regarding missing data. Any percentages that were calculated included only those cases of myocarditis with adequate data to calculate the percentages.

Between December 14, 2020, and August 31, 2021, 192 405 448 individuals older than 12 years of age received a total of 354 100 845 mRNA-based COVID-19 vaccines. VAERS received 1991 reports of myocarditis (391 of which also included pericarditis) after receipt of at least 1 dose of mRNA-based COVID-19 vaccine (eTable 1 in the Supplement ) and 684 reports of pericarditis without the presence of myocarditis (eTable 2 in the Supplement ).

Of the 1991 reports of myocarditis, 1626 met the CDC’s case definition for probable or confirmed myocarditis ( Table 1 ). There were 208 reports that did not meet the CDC’s case definition for myocarditis and 157 reports that required more information to perform adjudication (eTable 3 in the Supplement ). Of the 1626 reports that met the CDC’s case definition for myocarditis, 1195 (73%) were younger than 30 years of age, 543 (33%) were younger than 18 years of age, and the median age was 21 years (IQR, 16-31 years) ( Figure 1 ). Of the reports of myocarditis with dose information, 82% (1265/1538) occurred after the second vaccination dose. Of those with a reported dose and time to symptom onset, the median time from vaccination to symptom onset was 3 days (IQR, 1-8 days) after the first vaccination dose and 74% (187/254) of myocarditis events occurred within 7 days. After the second vaccination dose, the median time to symptom onset was 2 days (IQR, 1-3 days) and 90% (1081/1199) of myocarditis events occurred within 7 days ( Figure 2 ).

Males comprised 82% (1334/1625) of the cases of myocarditis for whom sex was reported. The largest proportions of cases of myocarditis were among White persons (non-Hispanic or ethnicity not reported; 69% [914/1330]) and Hispanic persons (of all races; 17% [228/1330]). Among persons younger than 30 years of age, there were no confirmed cases of myocarditis in those who died after mRNA-based COVID-19 vaccination without another identifiable cause and there was 1 probable case of myocarditis but there was insufficient information available for a thorough investigation. At the time of data review, there were 2 reports of death in persons younger than 30 years of age with potential myocarditis that remain under investigation and are not included in the case counts.

Symptom onset of myocarditis was within 7 days after vaccination for 947 reports of individuals who received the BNT162b2 vaccine and for 382 reports of individuals who received the mRNA-1273 vaccine. The rates of myocarditis varied by vaccine type, sex, age, and first or second vaccination dose ( Table 2 ). The reporting rates of myocarditis were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.73 [95% CI, 61.68-81.11] per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.86 [95% CI, 91.65-122.27] per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.43 [95% CI, 45.56-60.33] per million doses of the BNT162b2 vaccine and 56.31 [95% CI, 47.08-67.34] per million doses of the mRNA-1273 vaccine). The lower estimate of the 95% CI for reporting rates of myocarditis in adolescent males and young men exceeded the upper bound of the expected rates after the first vaccination dose with the BNT162b2 vaccine in those aged 12 to 24 years, after the second vaccination dose with the BNT162b2 vaccine in those aged 12 to 49 years, after the first vaccination dose with the mRNA-1273 vaccine in those aged 18 to 39 years, and after the second vaccination dose with the mRNA-1273 vaccine in those aged 18 to 49 years.

The reporting rates of myocarditis in females were lower than those in males across all age strata younger than 50 years of age. The reporting rates of myocarditis were highest after the second vaccination dose in adolescent females aged 12 to 15 years (6.35 [95% CI, 4.05-9.96] per million doses of the BNT162b2 vaccine), in adolescent females aged 16 to 17 years (10.98 [95% CI, 7.16-16.84] per million doses of the BNT162b2 vaccine), in young women aged 18 to 24 years (6.87 [95% CI, 4.27-11.05] per million doses of the mRNA-1273 vaccine), and in women aged 25 to 29 years (8.22 [95% CI, 5.03-13.41] per million doses of the mRNA-1273 vaccine). The lower estimate of the 95% CI for reporting rates of myocarditis in females exceeded the upper bound of the expected rates after the second vaccination dose with the BNT162b2 vaccine in those aged 12 to 29 years and after the second vaccination dose with the mRNA-1273 vaccine in those aged 18 to 29 years.

Among the 1372 reports of myocarditis in persons younger than 30 years of age, 1305 were able to be adjudicated, with 92% (1195/1305) meeting the CDC’s case definition. Of these, chart abstractions or medical interviews were completed for 69% (826/1195) ( Table 3 ). The symptoms commonly reported in the verified cases of myocarditis in persons younger than 30 years of age included chest pain, pressure, or discomfort (727/817; 89%) and dyspnea or shortness of breath (242/817; 30%). Troponin levels were elevated in 98% (792/809) of the cases of myocarditis. The electrocardiogram result was abnormal in 72% (569/794) of cases of myocarditis. Of the patients who had received a cardiac MRI, 72% (223/312) had abnormal findings consistent with myocarditis. The echocardiogram results were available for 721 cases of myocarditis; of these, 84 (12%) demonstrated a notable decreased left ventricular ejection fraction (<50%). Among the 676 cases for whom treatment data were available, 589 (87%) received nonsteroidal anti-inflammatory drugs. Intravenous immunoglobulin and glucocorticoids were each used in 12% of the cases of myocarditis (78/676 and 81/676, respectively). Intensive therapies such as vasoactive medications (12 cases of myocarditis) and intubation or mechanical ventilation (2 cases) were rare. There were no verified cases of myocarditis requiring a heart transplant, extracorporeal membrane oxygenation, or a ventricular assist device. Of the 96% (784/813) of cases of myocarditis who were hospitalized, 98% (747/762) were discharged from the hospital at time of review. In 87% (577/661) of discharged cases of myocarditis, there was resolution of the presenting symptoms by hospital discharge.

In this review of reports to VAERS between December 2020 and August 2021, myocarditis was identified as a rare but serious adverse event that can occur after mRNA-based COVID-19 vaccination, particularly in adolescent males and young men. However, this increased risk must be weighed against the benefits of COVID-19 vaccination. 18

Compared with cases of non–vaccine-associated myocarditis, the reports of myocarditis to VAERS after mRNA-based COVID-19 vaccination were similar in demographic characteristics but different in their acute clinical course. First, the greater frequency noted among vaccine recipients aged 12 to 29 years vs those aged 30 years or older was similar to the age distribution seen in typical cases of myocarditis. 2 , 4 This pattern may explain why cases of myocarditis were not discovered until months after initial Emergency Use Authorization of the vaccines in the US (ie, until the vaccines were widely available to younger persons). Second, the sex distribution in cases of myocarditis after COVID-19 vaccination was similar to that seen in typical cases of myocarditis; there is a strong male predominance for both conditions. 2 , 4

However, the onset of myocarditis symptoms after exposure to a potential immunological trigger was shorter for COVID-19 vaccine–associated cases of myocarditis than is typical for myocarditis cases diagnosed after a viral illness. 24 - 26 Cases of myocarditis reported after COVID-19 vaccination were typically diagnosed within days of vaccination, whereas cases of typical viral myocarditis can often have indolent courses with symptoms sometimes present for weeks to months after a trigger if the cause is ever identified. 1 The major presenting symptoms appeared to resolve faster in cases of myocarditis after COVID-19 vaccination than in typical viral cases of myocarditis. Even though almost all individuals with cases of myocarditis were hospitalized and clinically monitored, they typically experienced symptomatic recovery after receiving only pain management. In contrast, typical viral cases of myocarditis can have a more variable clinical course. For example, up to 6% of typical viral myocarditis cases in adolescents require a heart transplant or result in mortality. 27

In the current study, the initial evaluation and treatment of COVID-19 vaccine–associated myocarditis cases was similar to that of typical myocarditis cases. 28 - 31 Initial evaluation usually included measurement of troponin level, electrocardiography, and echocardiography. 1 Cardiac MRI was often used for diagnostic purposes and also for possible prognostic purposes. 32 , 33 Supportive care was a mainstay of treatment, with specific cardiac or intensive care therapies as indicated by the patient’s clinical status.

Long-term outcome data are not yet available for COVID-19 vaccine–associated myocarditis cases. The CDC has started active follow-up surveillance in adolescents and young adults to assess the health and functional status and cardiac outcomes at 3 to 6 months in probable and confirmed cases of myocarditis reported to VAERS after COVID-19 vaccination. 34 For patients with myocarditis, the American Heart Association and the American College of Cardiology guidelines advise that patients should be instructed to refrain from competitive sports for 3 to 6 months, and that documentation of a normal electrocardiogram result, ambulatory rhythm monitoring, and an exercise test should be obtained prior to resumption of sports. 35 The use of cardiac MRI is unclear, but it may be useful in evaluating the progression or resolution of myocarditis in those with abnormalities on the baseline cardiac MRI. 36 Further doses of mRNA-based COVID-19 vaccines should be deferred, but may be considered in select circumstances. 37

This study has several limitations. First, although clinicians are required to report serious adverse events after COVID-19 vaccination, including all events leading to hospitalization, VAERS is a passive reporting system. As such, the reports of myocarditis to VAERS may be incomplete, and the quality of the information reported is variable. Missing data for sex, vaccination dose number, and race and ethnicity were not uncommon in the reports received; history of prior SARS-CoV-2 infection also was not known. Furthermore, as a passive system, VAERS data are subject to reporting biases in that both underreporting and overreporting are possible. 38 Given the high verification rate of reports of myocarditis to VAERS after mRNA-based COVID-19 vaccination, underreporting is more likely. Therefore, the actual rates of myocarditis per million doses of vaccine are likely higher than estimated.

Second, efforts by CDC investigators to obtain medical records or interview physicians were not always successful despite the special allowance for sharing information with the CDC under the Health Insurance Portability and Accountability Act of 1996. 39 This challenge limited the ability to perform case adjudication and complete investigations for some reports of myocarditis, although efforts are still ongoing when feasible.

Third, the data from vaccination administration were limited to what is reported to the CDC and thus may be incomplete, particularly with regard to demographics.

Fourth, calculation of expected rates from the IBM MarketScan Commercial Research Database relied on administrative data via the use of ICD-10 codes and there was no opportunity for clinical review. Furthermore, these data had limited information regarding the Medicare population; thus expected rates for those older than 65 years of age were not calculated. However, it is expected that the rates in those older than 65 years of age would not be higher than the rates in those aged 50 to 64 years. 4

Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men. This risk should be considered in the context of the benefits of COVID-19 vaccination.

Corresponding Author: Matthew E. Oster, MD, MPH, US Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333 ( [email protected] ).

Correction: This article was corrected March 21, 2022, to change “pericarditis” to “myocarditis” in the first row, first column of eTable 1 in the Supplement.

Accepted for Publication: December 16, 2021.

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

Concept and design: Oster, Shay, Su, Creech, Edwards, Dendy, Schlaudecker, Woo, Shimabukuro.

Acquisition, analysis, or interpretation of data: Oster, Shay, Su, Gee, Creech, Broder, Edwards, Soslow, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, Lopes, Sperling, Baumblatt, Thompson, Marquez, Strid, Woo, Pugsley, Reagan-Steiner, DeStefano, Shimabukuro.

Drafting of the manuscript: Oster, Shay, Su, Gee, Creech, Marquez, Strid, Woo, Shimabukuro.

Critical revision of the manuscript for important intellectual content: Oster, Shay, Su, Creech, Broder, Edwards, Soslow, Dendy, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, Lopes, Sperling, Baumblatt, Thompson, Pugsley, Reagan-Steiner, DeStefano, Shimabukuro.

Statistical analysis: Oster, Su, Marquez, Strid, Woo, Shimabukuro.

Obtained funding: Edwards, DeStefano.

Administrative, technical, or material support: Oster, Gee, Creech, Broder, Edwards, Soslow, Schlaudecker, Smith, Baumblatt, Thompson, Reagan-Steiner, DeStefano.

Supervision: Su, Edwards, Soslow, Dendy, Schlaudecker, Campbell, Sperling, DeStefano, Shimabukuro.

Conflict of Interest Disclosures: Dr Creech reported receiving grants from the National Institutes of Health for the Moderna and Janssen clinical trials and receiving personal fees from Astellas and Horizon. Dr Edwards reported receiving grants from the National Institutes of Health; receiving personal fees from BioNet, IBM, X-4 Pharma, Seqirus, Roche, Pfizer, Merck, Moderna, and Sanofi; and receiving compensation for being the associate editor of Clinical Infectious Diseases . Dr Soslow reported receiving personal fees from Esperare. Dr Schlaudecker reported receiving grants from Pfizer and receiving personal fees from Sanofi Pasteur. Drs Barnett, Ruberg, and Smith reported receiving grants from Pfizer. Dr Lopes reported receiving personal fees from Bayer, Boehringer Ingleheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola, and Sanofi and receiving grants from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. No other disclosures were reported.

Funding/Support: This work was supported by contracts 200-2012-53709 (Boston Medical Center), 200-2012-53661 (Cincinnati Children’s Hospital Medical Center), 200-2012-53663 (Duke University), and 200-2012-50430 (Vanderbilt University Medical Center) with the US Centers for Disease Control and Prevention (CDC) Clinical Immunization Safety Assessment Project.

Role of the Funder/Sponsor: The CDC provided funding via the Clinical Immunization Safety Assessment Project to Drs Creech, Edwards, Soslow, Dendy, Schlaudecker, Lang, Barnett, Ruberg, Smith, Campbell, and Lopes. The authors affiliated with the CDC along with the other coauthors conducted the investigations; performed collection, management, analysis, and interpretation of the data; were involved in the preparation, review, and approval of the manuscript; and made the decision to submit the manuscript for publication.

Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the CDC or the US Food and Drug Administration. Mention of a product or company name is for identification purposes only and does not constitute endorsement by the CDC or the US Food and Drug Administration.

Additional Contributions: We thank the following CDC staff who contributed to this article without compensation outside their normal salaries (in alphabetical order and contribution specified in parenthesis at end of each list of names): Nickolas Agathis, MD, MPH, Stephen R. Benoit, MD, MPH, Beau B. Bruce, MD, PhD, Abigail L. Carlson, MD, MPH, Meredith G. Dixon, MD, Jonathan Duffy, MD, MPH, Charles Duke, MD, MPH, Charles Edge, MSN, MS, Robyn Neblett Fanfair, MD, MPH, Nathan W. Furukawa, MD, MPH, Gavin Grant, MD, MPH, Grace Marx, MD, MPH, Maureen J. Miller, MD, MPH, Pedro Moro, MD, MPH, Meredith Oakley, DVM, MPH, Kia Padgett, MPH, BSN, RN, Janice Perez-Padilla, MPH, BSN, RN, Robert Perry, MD, MPH, Nimia Reyes, MD, MPH, Ernest E. Smith, MD, MPH&TM, David Sniadack, MD, MPH, Pamela Tucker, MD, Edward C. Weiss, MD, MPH, Erin Whitehouse, PhD, MPH, RN, Pascale M. Wortley, MD, MPH, and Rachael Zacks, MD (for clinical investigations and interviews); Amelia Jazwa, MSPH, Tara Johnson, MPH, MS, and Jamila Shields, MPH (for project coordination); Charles Licata, PhD, and Bicheng Zhang, MS (for data acquisition and organization); Charles E. Rose, PhD (for statistical consultation); and Scott D. Grosse, PhD (for calculation of expected rates of myocarditis). We also thank the clinical staff who cared for these patients and reported the adverse events to the Vaccine Adverse Event Reporting System.

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Genomic insights into mRNA COVID-19 vaccines efficacy: Linking genetic polymorphisms to waning immunity

Affiliations.

• 1 Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
• 2 Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
• 3 Big Data Center, Taipei Veterans General Hospital, Taipei, Taiwan.
• 4 Department of Information Management, Taipei Veterans General Hospital, Taipei, Taiwan.
• 5 Department of Statistics, Tamkang University, New Taipei, Taiwan.
• 6 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
• 7 Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
• 8 School of medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
• 9 Biosafety level 3 laboratory, Taipei Veterans General Hospital, Taipei, Taiwan.
• 10 Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan.
• 11 Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei, Taiwan.
• 12 Department of Family Medicine, Taipei Veterans General Hospital Yuli Branch, Hualien, Taiwan.
• PMID: 39254005
• DOI: 10.1080/21645515.2024.2399382

Genetic polymorphisms have been linked to the differential waning of vaccine-induced immunity against COVID-19 following vaccination. Despite this, evidence on the mechanisms behind this waning and its implications for vaccination policy remains limited. We hypothesize that specific gene variants may modulate the development of vaccine-initiated immunity, leading to impaired immune function. This study investigates genetic determinants influencing the sustainability of immunity post-mRNA vaccination through a genome-wide association study (GWAS). Utilizing a hospital-based, test negative case-control design, we enrolled 1,119 participants from the Taiwan Precision Medicine Initiative (TPMI) cohort, all of whom completed a full mRNA COVID-19 vaccination regimen and underwent PCR testing during the Omicron outbreak. Participants were classified into breakthrough and protected groups based on PCR results. Genetic samples were analyzed using SNP arrays with rigorous quality control. Cox regression identified significant single nucleotide polymorphisms (SNPs) associated with breakthrough infections, affecting 743 genes involved in processes such as antigenic protein translation, B cell activation, and T cell function. Key genes identified include CD247, TRPV1, MYH9, CCL16, and RPTOR, which are vital for immune responses. Polygenic risk score (PRS) analysis revealed that individuals with higher PRS are at greater risk of breakthrough infections post-vaccination, demonstrating a high predictability (AUC = 0.787) in validating population. This finding confirms the significant influence of genetic variations on the durability of immune responses and vaccine effectiveness. This study highlights the importance of considering genetic polymorphisms in evaluating vaccine-induced immunity and proposes potential personalized vaccination strategies by tailoring regimens to individual genetic profiles.

Keywords: COVID-19; genetic polymorphisms; long-term memory CD8+ T cells; mRNA-based vaccines; waning immunity.

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When's the best time to get your flu and COVID-19 vaccines?

As temperatures get colder and fall approaches, millions of Americans will start getting their series of vaccines for flu, COVID-19, and respiratory syncytial virus (RSV). Here's how to best time your shots, according to experts.

COVID-19 Vaccine Communications Readiness Assessment

When to get your shots

The consensus among experts is that if you only have the time or inclination to make a single vaccine appointment, it's safe to get your COVID-19, flu, and RSV shots together, if you're eligible.

However, if you're able and inclined to get your shots separately and time them throughout the fall, that may have some benefits. Arnold Monto, co-director of the Michigan Center for Respiratory Virus Research and Response and a professor emeritus of epidemiology at the University of Michigan, said he prefers timing his vaccines to when he'll get the most out of each one, but added that "it's better to get both together than not to get one or the other."

COVID-19 vaccines

COVID-19 vaccines provide fairly durable protection against hospitalization, however, the immunity provided against getting the disease at all is more short-lived, STAT reports. What's more, COVID-19 has not shown to follow a seasonal pattern, and while launching COVID-19 shots in September alongside flu shots may be beneficial from a delivery perspective, it may not provide the best protection, experts said.

"I think it's complicated in general right now because influenza and SARS-CoV-2 behave differently," said Florian Krammer, an influenza virologist at Mount Sinai 's Icahn School of Medicine.

Katelyn Jetelina, an infectious disease epidemiologist, said she tries to time her COVID-19 shots to avoid getting sick at all, rather than just avoiding a severe case of the disease.

"I know that with the vaccines, the primary purpose is [to prevent] severe disease. But I'm using them for their secondary purpose, to help reduce disruptions in my life, even if that's imperfect and short term," she said. "And so I'm thinking of it like: Might as well wait for that winter wave, which will coincide … with fun holiday activities that I don't want to miss."

Jetelina said she plans on getting a COVID-19 and flu shot together around Halloween.

However, a number of experts said getting a COVID-19 shot now, as long as you haven't recently had COVID-19 or another dose of a vaccine, makes sense.

"Right now there's a lot of SARS-CoV-2 cases and so if people didn't have SARS-CoV-2 in a while, it might be good to get a vaccine relatively quickly … because that reduces your chances of getting infected or getting symptomatic disease in the near future," Krammer said.

However, Krammer noted the concern that doing so might leave a person less protected in the winter is "valid."

"It's hard to weigh the risks and say: 'Okay, it would be better to take a risk now and be better protected later versus better protected now, and maybe less well protected later,'" he said. "I think to make these calculations … in a quantitative way, that would be really hard."

Flu vaccines

If you're willing to get your COVID-19 and flu shots at different times, waiting for your flu shot could make sense. CDC recommends people get their flu shots by the end of October.

"You really want to think about getting your appointment or making your plan to get vaccinated sometime around the last half of September through the end of October," said Judith O'Donnell, chief of infectious diseases at Penn Presbyterian Medical Center.

The flu is more seasonally predictable than COVID-19. Flu is typically a winter illness, with cases often peaking between late December and mid-to-late February.

Similar to COVID-19 vaccines, flu shots are better at preventing severe disease than preventing infection entirely, and the immunity provided by the vaccines decline over time.

"What we need to communicate is that these vaccines will keep you from severe illness and death. And they do very well for that," said Kanta Subbarao, a professor of microbiology at Laval University.

"What I think that the public wants, and is fed up with vaccines because they think they're not getting, is protection from infection. And that is true for flu vaccines. It's true for the Covid vaccines," Subbarao said. "So the messaging has to be that you take these vaccines to keep yourself from getting severely ill — ill enough to require hospitalization, or to have complications, and so on."

Subbarao said she will get a COVID-19 shot as soon as she can, but plans on waiting to get a flu shot.

"What I want is protection from November to March. And I think we get six months of protection from flu [shots]," she said. "And so if I want to be protected from November to March, then what I would say is that I think I could get vaccinated in late September or October."

Michael Osterholm, director of the University of Minnesota 's Center for Infectious Disease Research and Policy, recommended holding off on your flu shot until the flu is circulating where you live.

"I urge people to wait until we start seeing flu activity in the community and not just sporadic cases but sustained transmission," he said. "I realize that's a challenge to get scheduled at that point. But at the same time, you don't want to lose the protection you have from the vaccine in its earliest days after administration compared to what may be a 20% to 50% reduction over the winter season from the time you got the vaccine."

Young children, however, will need an initial course of two doses to best protect from the flu. Alicia Budd, team lead of the influenza division at CDC's National Center for Immunization and Respiratory Diseases, said any children who need two doses can get their first shot now.

RSV vaccines

Aside from pregnant people, RSV vaccines are only available for older adults. Two of the three available vaccines — Pfizer 's Abrysvo and Moderna 's mResvia — are available for people ages 60 and older. Meanwhile, GSK 's Arexvy is available for people ages 60 and older and those ages 50 to 59 who are at high risk of serious disease.

Given these vaccines are newer, it's not yet known how often people will need additional doses. However, it's clear that the GSK and Pfizer vaccines don't require annual vaccination, meaning any older adult who's already received an RSV shot isn't eligible for another one.

In a meeting in June, CDC's Advisory Committee on Immunization Practices (ACIP) changed its recommendation on who should get an RSV shot. Previously the policy recommended people ages 60 and older get a shot if they and their doctors agree it's needed. However, doctors argued the approach was too confusing and time-consuming, so ACIP made an adjustment, saying that people 75 and older should get the RSV shot if they haven't yet, as should people ages 60 to 74 who have health conditions increasing their risk of serious illness.

Meanwhile, pregnant people are able to get Pfizer's RSV shot, and CDC recommends pregnant people who will give birth during RSV season, which lasts from September to January in most parts of the United States, receive their shot between week 32 and 36 of each pregnancy. (Branswell, STAT , 9/4; Schmall, New York Times , 9/4; Bendix, NBC News , 9/5)

In March 2020, the   World Health Organization  declared COVID-19 a global pandemic. Here's what we've learned about the virus since then, what we still don't know, and its ongoing impact on both people's health and society at large.    

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Posted on September 10, 2024

Updated on September 10, 2024

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