what is the importance of covid 19 vaccine essay

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Benefits of Getting Vaccinated

What to know.

There are many benefits of getting vaccinated against COVID-19.

COVID-19 vaccines protect your health

COVID 19-vaccines are effective at protecting people from getting seriously ill, being hospitalized, and dying. Vaccination remains the safest strategy for avoiding hospitalizations, long-term health outcomes, and death.

• Prevents serious illness: COVID-19 vaccines available in the United States are safe and effective at protecting people from getting seriously ill, being hospitalized, and dying.
• A safer way to build protection: Getting a COVID-19 vaccine is a safer, more reliable way to build protection than getting sick with COVID-19.
• Offers added protection: COVID-19 vaccines can offer added protection to people who had COVID-19, including protection against being hospitalized from a new infection.

How to be best protected: As with vaccines for other diseases, people are best protected when they stay up to date .

What you can do now to prevent severe illness, hospitalization, and death

Everyone ages 6 months and older should get a 2024–2025 COVID-19 vaccine. CDC recommends everyone ages 5 years and older get 1 updated 2024–2025 COVID-19 vaccine . Children ages 6 months–4 years may need more than 1 dose of updated COVID-19 to stay up to date .

Note: The 2023–2024 Novavax COVID-19 Vaccine remains authorized but is no longer available in the United States, as all doses have expired. Accordingly, at this time, CDC recommendations for use of Novavax COVID-19 Vaccine have been removed. This page will be updated if FDA approves or authorizes additional 2024–2025 COVID-19 vaccines.

Severe illness

COVID-19 vaccines are highly effective in preventing the most severe outcomes from a COVID-19 infection.

Myocarditis is a condition where the heart becomes inflamed in response to an infection or some other trigger. Myocarditis after COVID-19 vaccination is rare. This study shows that patients with COVID-19 had nearly 16 times the risk for myocarditis compared with patients who did not have COVID-19 .

Hospitalization

COVID-19 vaccines can help prevent you from becoming hospitalized if you do get infected with COVID-19.

COVID-19 vaccines can help prevent you from dying if you do get infected with COVID-19.

COVID-19 vaccination is a safer, more reliable way to build protection

Getting a covid-19 vaccine is safer and more reliable‎, getting sick.

• Getting sick with COVID-19 can cause severe illness or death, even in children, but it is not possible to determine who will experience mild or severe illness from COVID-19 infection.
• People may have long-term health issues after having COVID-19. Even people who do not have symptoms when they are first infected with COVID-19 can experience long-term health problems, also known as long COVID or post-COVID conditions.
• Complications can appear after mild or severe COVID-19, or after multisystem inflammatory syndrome in children (MIS-C) .

Protection from COVID-19

While people can get some protection from having COVID-19, the level and length of that protection varies, especially as COVID-19 variants continue to emerge.

• Immunity (protection) from infection can vary depending on how mild or severe someone’s illness was and their age.
• Immunity from infection decreases over time.

Importantly, there is no antibody test available that can reliably determine if a person is protected from further infection.

After Vaccination‎

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

For Everyone

Health care providers, public health.

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Effectiveness of COVID‐19 vaccines: findings from real world studies

David a henry.

1 Institute for Evidence-Based Healthcare, Bond University, Gold Coast QLD

2 Gold Coast University Hospital and Health Service, Gold Coast QLD

Mark A Jones

3 University of Queensland, Brisbane QLD

Paulina Stehlik

Paul p glasziou.

Community‐based studies in five countries show consistent strong benefits from early rollouts of COVID‐19 vaccines

By the beginning of June 2021, almost 11% of the world’s population had received at least one dose of a coronavirus disease 2019 (COVID‐19) vaccine. 1 This represents an extraordinary scientific and logistic achievement — in 18 months, researchers, manufacturers and governments collaborated to produce and distribute vaccines that appear effective and acceptably safe in preventing COVID‐19 and its complications. 2 , 3

The initial randomised trials confirmed immunological responses and generated unbiased evidence of vaccine efficacy. They were conducted in selected populations with limited numbers of participants in high risk groups, such as older people and those with serious underlying medical conditions. 2 , 3 They provided sparse information on the impact of vaccination on transmission of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), were too small to quantify rare but serious harms, and did not take account of the logistic obstacles encountered during the community‐wide rollout of new vaccines. While large cluster randomised trials could address some of these concerns, 4 large observational studies have used large linked routinely collected population datasets in five countries to address important knowledge gaps. 5 , 6 , 7 , 8 , 9

This article reviews findings from the initial real world studies and stresses that researchers in Australia currently do not have timely access to the linked Commonwealth and state datasets needed to perform such analyses.

Real world studies

In five countries (Israel, England, Scotland, Sweden and the United States) researchers have analysed routinely collected data to report the early outcomes of community‐wide vaccination programs with three of the first vaccines to reach market: the BNT162b2 mRNA (Pfizer–BioNTech), mRNA‐1273 (Moderna) and ChAdOx1 adenoviral vector (Oxford–AstraZeneca) vaccines. 5 , 6 , 7 , 8 , 9

At the time of writing, two of the articles (from the US and Sweden ) have not yet been peer reviewed, so details reported here may change after revisions to these reports. 8 , 9 There is a rapidly growing literature on the community impact of COVID‐19 and it has provided very consistent evidence of substantial vaccine effectiveness with the original (Wuhan) viral strain and the Alpha variant. An important focus of future work will be the effectiveness of existing vaccines against emerging viral variants.

The vaccination programs against COVID‐19 commenced in December 2020 in the study countries, so follow‐up is limited. Most of the investigators used rigorous designs and statistical methods to analyse linked routinely collected person‐level data from large community‐wide databases that tracked outcomes in vaccinated and unvaccinated individuals ( Box ). Importantly, allocation to vaccines was not by randomisation, and vaccinated and unvaccinated populations differed in respect of factors that were associated with both the probability of vaccination and with the severe outcomes of COVID‐19. Information that featured in most studies included demographic details, a vaccine register, results of laboratory polymerase chain reaction (PCR) testing, records of hospitalisation and death, and some geographic measures of social deprivation. In addition, the Israeli, US and Scottish studies included linkage to clinical records from which to quantify comorbidities. 5 , 6 , 8 The Israeli study included information on previous adherence to influenza vaccination schedules. 5

Characteristics of five real world community‐based studies of effectiveness of SARS‐CoV‐2 vaccines

BNT162b2 =Pfizer–BioNTech mRNA vaccine; ChAdOx1 = Oxford–AstraZeneca adenoviral vector vaccine; mRNA‐1273 = Moderna mRNA vaccine; NHS = National Health Service; PCR = polymerase chain reaction.

Study designs and adjustments for confounding

The studies used different approaches to adjust for confounding ( Box ). The most advanced design was used to analyse the linked data from members of the Clalit Health Services integrated health care organisation in Israel, which covers around 4.7 million people. 5 The investigators extracted data on matched cohorts of vaccinees and non‐vaccinated controls and analysed study endpoints using rules that emulated the steps taken in a randomised trial. 10 These steps minimised selection or measurement biases and controlled for potential confounders through precise 1:1 matching of vaccinated and non‐vaccinated subjects across seven domains. The investigators took the additional step of calibrating their statistical model against the results of the pivotal phase 3 randomised trial, which found no benefit during the first 2 weeks after vaccination. 2 In contrast, this observational study found lower rates of infection in the first 2 weeks after vaccination, which remained after matching for age and sex — illustrating the potential for confounding. Only after full matching on seven factors was this source of bias eliminated. 5

In England, investigators linked data from a national vaccine register to laboratory PCR swab results, emergency department admissions, demographic and ethnicity data, care home status, and deaths in participants aged 70 years and over ( Box ). 7 The first part was a test‐negative case–control design, which compared vaccination status in those who received a positive PCR swab result with contemporaneous controls who returned a negative result. That both cases and controls had been tested for SARS‐CoV‐2 should have controlled for clinical and behavioural factors that influence the probability of having a test. The second part of the study followed participants aged 80 years and over with a positive PCR test result and analysed them according to vaccination status. The investigators calculated adjusted hazard ratios for death up to and beyond 14 days from the first vaccine dose.

A study in Scotland used an unmatched cohort design comparing hospital admission for COVID‐19 in people who received either the Pfizer–BioNTech or Oxford–AstraZeneca vaccines with an unvaccinated control group. 6 The Oxford–AstraZeneca vaccine was given later to an older population. The study adjusted for age and sex, frequency of prior PCR tests and clinical risk groups extracted from linked health records. The statistical model generated unexpectedly strong protective effects of the vaccines on hospitalisation rates in the first 2 weeks after vaccination, indicating possible bias due to a healthy vaccinee effect.

In the US, researchers working within the Mayo Clinic health system used postcode and propensity scores (based on age, sex, race, ethnicity and records of PCR testing) to match a cohort of individuals who received the Pfizer–BioNTech or Moderna mRNA vaccine with unvaccinated controls, to measure impact on infections and hospitalisations. 8

A simple unmatched cohort design using linkage of routinely collected administrative data measured infection rates in a cohort who received the Pfizer–BioNTech vaccine in a single county in Sweden. 9 The unvaccinated population acted as controls ( Box ). Confounding adjustments in this study were limited to age and sex.

The Box summarises the results of these studies. All included at least one mRNA vaccine and the reductions in infections and hospitalisations were consistent and large. Two studies reported on mortality and the reductions were substantial, although based on small numbers of deaths in Israel. 5 , 7 The studies did not directly compare vaccines, but the Oxford–AstraZeneca vaccine appeared to perform as well as the mRNA vaccines in reducing hospitalisations.

Other approaches to estimating vaccine effectiveness

In the UK, over 600 000 volunteers using a COVID‐19 symptom mobile phone app recorded adverse events after vaccination with either the Pfizer–BioNTech or Oxford–AstraZeneca vaccine. 11 Based on post‐vaccination self‐reports of infections and after adjustment for age, sex, obesity and comorbidities, they estimated effectiveness rates of 60–70% beyond 21 days after administration of either vaccine.

Three studies measured the effectiveness of COVID‐19 vaccines in care home, health care and other frontline workers in the UK, Israel and the US. 12 , 13 , 14 These projects enrolled smaller numbers of participants than the community‐based studies but used similar designs and adjustment techniques. Importantly, workers in these settings undergo routine PCR testing for SARS‐CoV‐2, which enabled detection of asymptomatic infections. These studies also found large protective effects and a potential to reduce viral transmission. The latter possibility has been investigated directly in a study conducted in Scotland that showed that 14 days or more after health care workers received a second dose of vaccine, their household members had a 54% lower rate of COVID‐19 than individuals who shared households with non‐vaccinated health care workers. 15

Conclusions

We can draw important conclusions from these non‐randomised studies of vaccine effectiveness. Most importantly, the currently available COVID‐19 vaccines appear to be very effective in preventing severe complications and deaths from COVID‐19 in adults of all ages. Recent real world studies confirm that substantial protection extends to the Delta variant of SARS‐CoV‐2, although this requires two vaccine doses. 16 , 17 Follow‐up periods in all studies are relatively short, and these reports do not provide information on rare but serious adverse events, such as cerebral venous thrombosis. The use of sophisticated trial emulation methods in the Israeli study 5 replicated some key features of the pivotal randomised trial of the Pfizer–BioNTech vaccine, 2 particularly by controlling for an early healthy cohort effect that confounded the incompletely adjusted endpoint analyses. This design should prove useful in enabling direct head‐to‐head comparisons of effectiveness and safety of vaccines, the duration of their protective effects, the degree to which vaccines prevent transmission of viral variants, and the impact of vaccines on so‐called long COVID.

These studies exemplify the value of advanced analyses of large multiply linked routinely collected community datasets. This resource is not yet readily available to researchers in Australia due to continued lack of agreement on the governance of linked state and Commonwealth datasets. 18 While Australia’s current low rates of community transmission of SARS‐CoV‐2 reduce the feasibility of observational studies of vaccine effectiveness, the available data can provide important information on potential harms of vaccines. With continuing questions about the comparative safety of vaccines, the emergence of viral variants, the long term effects of COVID‐19 and the likelihood of future epidemics, it is essential that Australia urgently removes barriers to allowing prequalified researchers to safely access the linked de‐identified population datasets that are needed to expeditiously conduct the types of studies reviewed here.

Competing interests

No relevant disclosures.

Not commissioned; externally peer reviewed.

The unedited version of this article was published as a preprint on mja.com.au on 20 May 2021.

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Personal Health

The Importance of Getting Fully Vaccinated

Covid remains a mortal threat not just for people like me in the upper decades of life but for almost anyone, no matter how young and healthy.

• Share full article

By Jane E. Brody

Too many Americans don’t seem to realize just how easily the novel coronavirus spreads and how awful Covid-19 can be. It is prompting far too many either to a) avoid getting any vaccine, b) skip the second dose if their first was Pfizer or Moderna or c) assume that the vaccine they got means they are now free to gather in any way they choose without taking any public health precautions.

Covid remains a mortal threat not just for people like me in the upper decades of life but also for almost anyone, no matter how young and healthy. Like the 37-year-old pregnant woman in Illinois who was put on life support after her baby was delivered by emergency C-section. Or the 26-year-old man in Maryland who was hospitalized on oxygen for five days and now tells everyone “ how bad it was and how scary it is. ” Although infections, hospitalizations and deaths are down from their dreadful peaks in 2020, we are still a long way from herd immunity — if we ever get there .

Sixty-one percent of people live in counties where the risk of infection right now is very high or extremely high, and whenever someone gets infected with the coronavirus, a mutation to an even more dangerous variant could arise.

After months of uncertainty about whether any vaccine that emerged from Operation Warp Speed would be safe and effective, the final highly reassuring results from the vaccine trials late last year were almost beyond belief. The members of the vaccine advisory committee who endorsed the Food and Drug Administration’s emergency use authorization of the vaccines are nongovernment experts with integrity and independent judgment. Had the government delayed the vaccine release until fully licensed, both the population and the economy likely would have been irreparably devastated.

I waited with bated breath for my turn to get immunized last winter and then for my two sons and daughters-in-law and four grandsons to become eligible this spring. All will be fully vaccinated by the end of the month when we gather for the first time in nearly two years to celebrate my 80th birthday. And all of us will continue to wear masks and maintain appropriate distance from others when we’re outdoors in close settings or indoors in public venues with people we don’t know.

In its advisory issued April 27 , the Centers for Disease Control and Prevention said that fully vaccinated people can visit indoors with others who are fully vaccinated without wearing a mask or physically distancing and can travel domestically without getting tested or self-quarantining. They can also now “gather or conduct activities outdoors without wearing a mask, except in certain crowded settings or venues” like a live performance, parade or sporting event.

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Quantifying the Importance of COVID-19 Vaccination to Our Future Outlook

Affiliations.

• 1 Department of Health Sciences Research, Mayo Clinic, Rochester, MN. Electronic address: [email protected].
• 2 Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
• 3 Department of Health Sciences Research, Mayo Clinic, Rochester, MN; Robert D. Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.
• 4 Division of Health Care Policy and Research, Mayo Clinic, Rochester, MN; Robert D. Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.
• 5 Department of Anesthesiology, Mayo Clinic, Rochester, MN; Division of Critical Care Medicine, Mayo Clinic, Rochester, MN.
• 6 Biostatistics, Mayo Clinic, Phoenix, AZ.
• 7 Department of Pulmonary and Critical Care Medicine.
• 8 Department of Neurology.
• 9 Department of Neurologic Surgery, Mayo Clinic, Rochester, MN.
• 10 Department of Transplant Critical Care Medicine, Mayo Clinic, Rochester, MN.
• 11 Division of Infectious Diseases, Mayo Clinic, Rochester, MN.
• 12 Department of Health Sciences Research, Mayo Clinic, Rochester, MN; Department of Medicine, Mayo Clinic, Rochester, MN.
• 13 Department of Gynecologic Surgery, Mayo Clinic College of Medicine, Rochester, MN.
• 14 Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.
• PMID: 34218862
• PMCID: PMC8075811
• DOI: 10.1016/j.mayocp.2021.04.012

Predictive models have played a critical role in local, national, and international response to the COVID-19 pandemic. In the United States, health care systems and governmental agencies have relied on several models, such as the Institute for Health Metrics and Evaluation, Youyang Gu (YYG), Massachusetts Institute of Technology, and Centers for Disease Control and Prevention ensemble, to predict short- and long-term trends in disease activity. The Mayo Clinic Bayesian SIR model, recently made publicly available, has informed Mayo Clinic practice leadership at all sites across the United States and has been shared with Minnesota governmental leadership to help inform critical decisions during the past year. One key to the accuracy of the Mayo Clinic model is its ability to adapt to the constantly changing dynamics of the pandemic and uncertainties of human behavior, such as changes in the rate of contact among the population over time and by geographic location and now new virus variants. The Mayo Clinic model can also be used to forecast COVID-19 trends in different hypothetical worlds in which no vaccine is available, vaccinations are no longer being accepted from this point forward, and 75% of the population is already vaccinated. Surveys indicate that half of American adults are hesitant to receive a COVID-19 vaccine, and lack of understanding of the benefits of vaccination is an important barrier to use. The focus of this paper is to illustrate the stark contrast between these 3 scenarios and to demonstrate, mathematically, the benefit of high vaccine uptake on the future course of the pandemic.

Copyright © 2021. Published by Elsevier Inc.

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What are the benefits and risks of vaccines for preventing COVID-19?

Key messages

– Most vaccines reduce, or probably reduce, the number of people who get COVID-19 disease and severe COVID-19 disease.

– Many vaccines likely increase number of people experiencing events such as fever or headache compared to placebo (sham vaccine that contains no medicine but looks identical to the vaccine being tested). This is expected because these events are mainly due to the body's response to the vaccine; they are usually mild and short-term.

– Many vaccines have little or no difference in the incidence of serious adverse events compared to placebo. 

– There is insufficient evidence to determine whether there was a difference between the vaccine and placebo in terms of death because the numbers of deaths were low in the trials.

– Most trials assessed vaccine efficacy over a short time, and did not evaluate efficacy to the COVID variants of concern. 

What is SARS-CoV-2 and COVID-19?

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the virus that causes COVID-19 disease. Not everyone infected with SARS-CoV-2 will develop symptoms of COVID-19. Symptoms can be mild (e.g. fever and headaches) to life-threatening (e.g. difficulty breathing), or death.

How do vaccines prevent COVID-19?

While vaccines work slightly differently, they all prepare the body's immune system to prevent people from getting infected with SARS-CoV-2 or, if they do get infected, to prevent severe disease.

What did we want to find out?

We wanted to find out how well each vaccine works in reducing SARS-CoV-2 infection, COVID-19 disease with symptoms, severe COVID-19 disease, and total number of deaths (including any death, not only those related to COVID-19).

We wanted to find out about serious adverse events that might require hospitalization, be life-threatening, or both; systemic reactogenicity events (immediate short-term reactions to vaccines mainly due to immunological responses; e.g. fever, headache, body aches, fatigue); and any adverse events (which include non-serious adverse events).

What did we do? 

We searched for studies that examined any COVID-19 vaccine compared to placebo, no vaccine, or another COVID-19 vaccine.

We selected only randomized trials (a study design that provides the most robust evidence because they evaluate interventions under ideal conditions among participants assigned by chance to one of two or more groups). We compared and summarized the results of the studies, and rated our confidence in the evidence based on factors such as how the study was conducted.

What did we find? 

We found 41 worldwide studies involving 433,838 people assessing 12 different vaccines. Thirty-five studies included only healthy people who had never had COVID-19. Thirty-six studies included only adults, two only adolescents, two children and adolescents, and one included adolescents and adults. Three studied people with weakened immune systems, and none studied pregnant women.

Most cases assessed results less than six months after the primary vaccination. Most received co-funding from academic institutions and pharmaceutical companies. Most studies compared a COVID-19 vaccine with placebo. Five evaluated the addition of a 'mix and match' booster dose.

Main results 

We report below results for three main outcomes and for 10 World Health Organization (WHO)-approved vaccines (for the remaining outcomes and vaccines, see main text). There is insufficient evidence regarding deaths between vaccines and placebo (mainly because the number of deaths was low), except for the Janssen vaccine, which probably reduces the risk of all-cause deaths. 

People with symptoms

The Pfizer, Moderna, AstraZeneca, Sinopharm-Beijing, and Bharat vaccines produce a large reduction in the number of people with symptomatic COVID-19.

The Janssen vaccine reduces the number of people with symptomatic COVID-19.

The Novavax vaccine probably has a large reduction in the number of people with symptomatic COVID-19.

There is insufficient evidence to determine whether CoronaVac vaccine affects the number of people with symptomatic COVID-19 because results differed between the two studies (one involved only healthcare workers with a higher risk of exposure).

Severe disease

The Pfizer, Moderna, Janssen, and Bharat vaccines produce a large reduction in the number of people with severe disease.

There is insufficient evidence about CoronaVac vaccine on severe disease because results differed between the two studies (one involved only healthcare workers with a higher risk of exposure).

Serious adverse events

For the Pfizer, CoronaVac, Sinopharm-Beijing, and Novavax vaccines, there is insufficient evidence to determine whether there was a difference between the vaccine and placebo mainly because the number of serious adverse events was low.

Moderna, AstraZeneca, Janssen, and Bharat vaccines probably result in no or little difference in the number of serious adverse events. 

What are the limitations of the evidence?

Most studies assessed the vaccine for a short time after injection, and it is unclear if and how vaccine protection wanes over time. Due to the exclusion criteria of COVID-19 vaccine trials, results cannot be generalized to pregnant women, people with a history of SARS-CoV-2 infection, or people with weakened immune systems. More research is needed comparing vaccines and vaccine schedules, and effectiveness and safety in specific populations and outcomes (e.g. preventing long COVID-19). Further, most studies were conducted before the emergence of variants of concerns.

How up to date is this evidence?

The evidence is up to date to November 2021. This is a living systematic review. Our results are available and updated bi-weekly on the COVID-NMA platform at covid-nma.com.

Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform ( covid-nma.com ).

Implications for practice

Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern.

Implications for research

Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital. 

Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally. 

To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2.

We searched the Cochrane COVID-19 Study Register and the COVID-19 L·OVE platform (last search date 5 November 2021). We also searched the WHO International Clinical Trials Registry Platform, regulatory agency websites, and Retraction Watch.

We included randomized controlled trials (RCTs) comparing COVID-19 vaccines to placebo, no vaccine, other active vaccines, or other vaccine schedules.

We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for all except immunogenicity outcomes. 

We synthesized data for each vaccine separately and presented summary effect estimates with 95% confidence intervals (CIs). 

We included and analyzed 41 RCTs assessing 12 different vaccines, including homologous and heterologous vaccine schedules and the effect of booster doses. Thirty-two RCTs were multicentre and five were multinational. The sample sizes of RCTs were 60 to 44,325 participants. Participants were aged: 18 years or older in 36 RCTs; 12 years or older in one RCT; 12 to 17 years in two RCTs; and three to 17 years in two RCTs. Twenty-nine RCTs provided results for individuals aged over 60 years, and three RCTs included immunocompromized patients. No trials included pregnant women. Sixteen RCTs had two-month follow-up or less, 20 RCTs had two to six months, and five RCTs had greater than six to 12 months or less. Eighteen reports were based on preplanned interim analyses.

Overall risk of bias was low for all outcomes in eight RCTs, while 33 had concerns for at least one outcome.

We identified 343 registered RCTs with results not yet available. 

This abstract reports results for the critical outcomes of confirmed symptomatic COVID-19, severe and critical COVID-19, and serious adverse events only for the 10 WHO-approved vaccines. For remaining outcomes and vaccines, see main text. The evidence for mortality was generally sparse and of low or very low certainty for all WHO-approved vaccines, except AD26.COV2.S (Janssen), which probably reduces the risk of all-cause mortality (risk ratio (RR) 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; high-certainty evidence).

Confirmed symptomatic COVID-19

High-certainty evidence found that BNT162b2 (BioNtech/Fosun Pharma/Pfizer), mRNA-1273 (ModernaTx), ChAdOx1 (Oxford/AstraZeneca), Ad26.COV2.S, BBIBP-CorV (Sinopharm-Beijing), and BBV152 (Bharat Biotect) reduce the incidence of symptomatic COVID-19 compared to placebo (vaccine efficacy (VE): BNT162b2: 97.84%, 95% CI 44.25% to 99.92%; 2 RCTs, 44,077 participants; mRNA-1273: 93.20%, 95% CI 91.06% to 94.83%; 2 RCTs, 31,632 participants; ChAdOx1: 70.23%, 95% CI 62.10% to 76.62%; 2 RCTs, 43,390 participants; Ad26.COV2.S: 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; BBIBP-CorV: 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; BBV152: 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants).

Moderate-certainty evidence found that NVX-CoV2373 (Novavax) probably reduces the incidence of symptomatic COVID-19 compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; 3 RCTs, 42,175 participants).

There is low-certainty evidence for CoronaVac (Sinovac) for this outcome (VE 69.81%, 95% CI 12.27% to 89.61%; 2 RCTs, 19,852 participants).

Severe or critical COVID-19

High-certainty evidence found that BNT162b2, mRNA-1273, Ad26.COV2.S, and BBV152 result in a large reduction in incidence of severe or critical disease due to COVID-19 compared to placebo (VE: BNT162b2: 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; mRNA-1273: 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; AD26.COV2.S: 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; BBV152: 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants).

Moderate-certainty evidence found that NVX-CoV2373 probably reduces the incidence of severe or critical COVID-19 (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants).

Two trials reported high efficacy of CoronaVac for severe or critical disease with wide CIs, but these results could not be pooled.

Serious adverse events (SAEs)

mRNA-1273, ChAdOx1 (Oxford-AstraZeneca)/SII-ChAdOx1 (Serum Institute of India), Ad26.COV2.S, and BBV152 probably result in little or no difference in SAEs compared to placebo (RR: mRNA-1273: 0.92, 95% CI 0.78 to 1.08; 2 RCTs, 34,072 participants; ChAdOx1/SII-ChAdOx1: 0.88, 95% CI 0.72 to 1.07; 7 RCTs, 58,182 participants; Ad26.COV2.S: 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants); BBV152: 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants). In each of these, the likely absolute difference in effects was fewer than 5/1000 participants.

Evidence for SAEs is uncertain for BNT162b2, CoronaVac, BBIBP-CorV, and NVX-CoV2373 compared to placebo (RR: BNT162b2: 1.30, 95% CI 0.55 to 3.07; 2 RCTs, 46,107 participants; CoronaVac: 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; BBIBP-CorV: 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; NVX-CoV2373: 0.92, 95% CI 0.74 to 1.14; 4 RCTs, 38,802 participants).

For the evaluation of heterologous schedules, booster doses, and efficacy against variants of concern, see main text of review.

COVID-19 vaccines: everything you need to know

No matter which one you take, covid-19 vaccines offer potentially life-saving protection against a disease that has killed millions. read more about how they work below..

Frequently asked questions about COVID-19 vaccines

What are the different types of covid-19 vaccines.

There are four types of vaccines in clinical trials: whole virus, protein subunit, viral vector and nucleic acid (RNA and DNA), each of which protects people, but by producing immunity in a slightly different way.

How safe are COVID-19 vaccines?

Despite the record speed at which they have been developed, COVID-19 vaccines have still been subject to the same checks, balances, and scientific and regulatory rigour as any other vaccine, and shown to be safe.

How did we get COVID-19 vaccines so quickly?

An unprecedented combination of political will, global collaboration and funding have enabled the rapid development of COVID-19 vaccines, without compromising vaccine safety.

Why are fully vaccinated people still catching COVID-19?

No vaccine is perfect, so “breakthrough infections”, where people get sick with an infection even after vaccination, are to be expected with any disease. But just how common are they when it comes to COVID-19, and what should you expect if you test positive for SARS-CoV-2 after being fully vaccinated?

Do kids need a COVID-19 vaccine?

New variants have evolved that seem to be able to affect children more, with low- and middle-income countries worst affected. New research is showing vaccines can be effective in children, but they remain at relatively low risk of the disease. While millions of vulnerable people in low- and middle-income countries have yet to have a single dose, it’s vital that they remain priorities for vaccine rollouts.

Can antibody tests show if a COVID-19 vaccine is working?

Many COVID-19 antibody tests are not designed to specifically detect antibodies that develop as a result of vaccination, and thus cannot show whether antibodies are of the right quantity or quality for protection against infection or illness.

If I’ve had COVID-19, do I really need the vaccine?

Vaccines mimic our body’s natural response to infection. However while a previous infection does give you some immunity against COVID-19, vaccination gives your body a massive immune boost – including against new variants.

Do we need booster doses?

A number of wealthy nations have decided to press ahead with plans to administer COVID-19 vaccine boosters in the coming months, yet with so many in under-resourced countries still without vaccines, we should be prioritising vaccinating all adults first.

Do COVID-19 vaccines affect fertility or periods?

Anecdotal evidence suggests the vaccine could temporarily affect menstruation, but the effects are short-lived and scientists say there is no evidence that vaccines affect fertility.

• Read more: Do COVID-19 vaccines affect menstruation and fertility?
• Read more: Five things you need to know about COVID-19 vaccines and your period

What is the link between COVID-19 vaccines and myocarditis?

Countries that are now vaccinating adolescents and young adults have seen an unexpected, though very rare, side-effect: heart inflammation.

How long after I get COVID-19 will I test positive?

Testing positive for COVID-19 – even without symptoms – can be disruptive to daily life, but how long should we expect to test positive for?

Does a faint line on a COVID-19 test mean I’m no longer infectious?

Rapid antigen or lateral flow tests can help to identify when someone with COVID-19 is most infectious, but even a faint line should be treated as a positive result.

What happens in Long COVID?

Long COVID has altered the lives of millions of people, all living in the limbo of experiencing COVID-19 symptoms weeks or months after their initial infection, yet not knowing how or when they will recover. Published on International Long COVID Awareness Day, here are ten stories about a condition that we still have much to learn about.

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• Review Article
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• Published: 03 May 2022

COVID-19 vaccine development: milestones, lessons and prospects

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

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

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• Infectious diseases

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

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COVID-19 vaccines: where we stand and challenges ahead

Safety, immunogenicity and efficacy of an mRNA-based COVID-19 vaccine, GLB-COV2-043, in preclinical animal models

SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates

Introduction.

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

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

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

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

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

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

Vaccine-induced immunity

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

Vaccine-induced Th1 cell response

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

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

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

Vaccine-induced germinal center response and humoral immune regulation

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

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

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

COVID-19 vaccine-induced memory cell responses

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

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

Existing vaccine platforms for COVID-19 vaccines

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

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

COVID-19 inactivated vaccines

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

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

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

COVID-19 live attenuated vaccines

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

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

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

COVID-19 viral vector vaccines

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

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

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

COVID-19 protein subunit vaccine

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

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

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

COVID-19 DNA vaccines

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

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

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

COVID-19 mRNA vaccines

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

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

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

COVID-19 VLP vaccines

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

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

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

Efficacy of covid-19 vaccines

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

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

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

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

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

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

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

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

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

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

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

Clinical trials of COVID-19 vaccines approved by the WHO

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

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

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

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

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

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

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

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

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

Ad26.COV-2-S

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

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

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

NVX-CoV2373

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

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

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

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

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

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

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

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

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

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

The effectiveness of COVID-19 vaccines in the real world

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

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

Variants of Concern (VOC)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Inactivated vaccines

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

Live attenuated vaccine

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

Viral vector vaccine

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

Protein subunit vaccine

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

DNA and mRNA vaccines

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

Safety of vaccines

Vaccine-induced complications.

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

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

Blood coagulation dysfunction

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

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

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

Heart diseases

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

Immune diseases

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

Allergic reactions

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

Autoimmune diseases

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

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

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

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

Nervous system diseases

Facial paralysis.

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

Functional neurological disorder (FND)

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

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

Lymphatic diseases

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

Other diseases

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

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

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

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

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

Effect of COVID-19 vaccination in different populations

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

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

Pregnant women

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

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

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

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

Elderly individuals

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

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

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

Organ transplant recipients

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

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

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

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

Cancer patients

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

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

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

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

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

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

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

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

Antibody-dependent enhancement (ADE) of vaccines

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

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

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

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

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

Improvement of COVID-19 vaccines

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

Mixed inoculation

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

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

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

Nanoparticle vaccines

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

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

Improvement of immune adjuvants

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

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

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

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

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

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

Change of inoculation route

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

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

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

Prospects and perspectives

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

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

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

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

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

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

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Acknowledgements

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

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

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

Authors and Affiliations

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

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

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

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

Qingkun Yang

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

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

Yigang Tong

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

Corresponding authors

Correspondence to Lihua Song , Yigang Tong or Huahao Fan .

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

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What are the Benefits of Getting the COVID-19 Vaccine?

Although experts are still learning a lot about the COVID-19 vaccines, there are some clear benefits to getting vaccinated.

If you’ve already received the vaccine, great job! Share these facts with others who might be hesitant. If you’re unsure whether the vaccine is right for you, consider these four benefits the vaccine could provide you and your loved ones.

The vaccine reduces your risk of infection.

Once you receive your first shot, your body begins producing antibodies to the coronavirus. These antibodies help your immune system fight the virus if you happen to be exposed, so it reduces your chance of getting the disease. There are four vaccines available for use in the United States, and they are all effective in preventing infection. Learn more about effectiveness .

It’s true that you can still become infected after being vaccinated, but once more of the population is vaccinated, those chances are further reduced thanks to something called herd immunity. So getting vaccinated not only reduces your chance of being infected, it also contributes to community protection, reducing the likelihood of virus transmission.

The vaccine can help your unborn baby or newborn.

Studies have found that expectant mothers who receive the COVID-19 vaccine create antibodies to the virus and pass those to their unborn baby through the placenta. Mothers were also shown to pass antibodies to their newborns through breast milk. This suggests those newborns have some immunity to the virus, which is especially important as young children cannot get the vaccine. Learn more about vaccine considerations for pregnant and nursing women .

The vaccine protects against severe illness.

During studies, the four vaccines — Johnson & Johnson, Moderna, Novavax and Pfizer — have shown to be effective at preventing severe illness from COVID-19. So if you are vaccinated and become infected, you are very unlikely to become severely ill.

The CDC tracks confirmed COVID-19 hospitalizations by vaccination status. For adults 18 and older, unvaccinated people were 3.5 times more likely to be hospitalized than fully vaccinated people. Among adolescents between ages 12-17, unvaccinated people are 2.1 times more likely to be hospitalized than fully vaccinated people.

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Covid-19 vaccination hesitancy

Read our latest coverage of the coronavirus pandemic.

• Related content
• Peer review
• Mohammad S Razai , academic clinical fellow in primary care 1 ,
• Umar A R Chaudhry , clinical teaching fellow 1 ,
• Katja Doerholt , paediatric infectious diseases consultant 2 ,
• Linda Bauld , professor of public health 3 ,
• Azeem Majeed , professor of primary care and public health 4
• 1 Population Health Research Institute, St George University of London, London, UK
• 2 St George’s University Hospitals NHS Foundation Trust, London, UK
• 3 Usher Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
• 4 Department of Primary Care and Public Health, Imperial College London, London, UK
• Correspondence to M Razai mrazai{at}sgul.ac.uk

What you need to know

Lack of confidence in vaccines for covid-19 poses direct and indirect threats to health, and could derail efforts to end the current pandemic

Concerns about unknown future effects, side effects, and a lack of trust are common reasons given by people who say they are unlikely to have a covid-19 vaccine

No single intervention is likely to be able to address vaccine hesitancy

Consider barriers to uptake of vaccination at a population level and in groups who have lower rates of vaccine uptake

Develop local approaches by engaging members of the community and co-producing communications and materials that meet population needs

Rollout of covid-19 vaccination is well underway, with more than 700 million doses given worldwide as of April 2021. 1 Vaccination is highly effective at reducing severe illness and death from covid-19. Vaccines for covid-19 are also safe, with extremely low risks of severe adverse events. 2 3 4 A major threat to the impact of vaccination in preventing disease and death from covid-19 is low uptake of vaccines. In this practice pointer we offer on overview of vaccine hesitancy and some approaches that clinicians and policymakers can adopt at the individual and community levels to help people make informed decisions about covid-19 vaccination.

What is vaccine hesitancy?

The World Health Organization defines vaccine hesitancy as a “delay in acceptance or refusal of safe vaccines despite availability of vaccine services.” 5 It is caused by complex, context specific factors that vary across time, place, and different vaccines, and is influenced by issues such as complacency, convenience, confidence, and sociodemographic contexts. 6 Vaccine hesitancy may also be related to misinformation and conspiracy theories which are often spread online, including through social media. 7 8 In addition, structural factors such as health inequalities, socioeconomic disadvantages, systemic racism, and barriers to access are key drivers of low confidence in vaccines and poor uptake. 5 9 10 11 The term vaccine hesitancy, although widely used, may not adequately convey these wider determinants that influence decisions to delay or refuse vaccination.

How common is vaccine hesitancy?

Vaccine hesitancy is a global problem. Surveys in 2021 report that between 50% and 60% of all respondents worldwide would be willing to receive a covid-19 vaccine, with wide variations across countries. 12 13 In the UK, surveys have found variation in willingness to have a vaccine between ethnic groups. The UK Household Longitudinal survey asked 12 035 participants (in November 2020) “how likely or unlikely would you be to take the vaccine?” Overall only 18% of respondents were hesitant (answering unlikely or very unlikely), in contrast with high levels of hesitancy in people of Black ethnicity (72%) followed by South Asians of Pakistani and Bangladeshi heritage (both 42%), and mixed ethnicities (32%), though levels of vaccine hesitancy were comparable with White people in respondents of Chinese ethnicity. 14 UK data (as of 11 March 2021) show lower vaccination rates (among those eligible for vaccination) in Black African and Black Caribbean (58.8% and 68.7%, respectively), Bangladeshi (72.7%), and Pakistani (74%) ethnic groups compared with White British (91.3%), and lower vaccination rates in people who live in more deprived areas (most deprived 87%, least deprived 92.1%). 15

Higher vaccine hesitancy is also reported among women (women 21%, men 15%), younger age groups (28% in 25-34 years, versus 14% in 55-64 years), and in people with a lower education level (24% in secondary school graduates; 13% in university graduates). 14 These data follow a historical trend in the UK of lower uptake of pneumococcal, influenza, rotavirus, and shingles vaccines among socioeconomically disadvantaged individuals 16 17 18 and ethnic minorities. 11 19 Similarly, a lower uptake has been observed with childhood immunisations in ethnic minority populations. 11 Variation in covid-19 vaccination rates is also seen between religious groups. Vaccination rates have been lower in Muslim (72.3%), Buddhist (78.1%), Sikh (87%), and Hindu (87.1%) groups compared with Christian (91.1%). 15

Vaccine hesitancy among healthcare workers (HCWs) is an area of concern because of HCWs’ roles as trusted sources of health information, and because of their greater personal exposure to infections acquired in a healthcare setting. This is particularly the case in HCWs of ethnic minorities, who comprise a high proportion of NHS workers in the UK. Data from one NHS trust show lower rates of covid-19 vaccination in ethnic minority HCWs (70.9% in White workers versus 58.5% in South Asian and 36.8% in Black workers; P<0.001 for both). 2 20

What are the causes of covid-19 vaccine hesitancy?

Confidence in the importance of vaccines has the strongest association with vaccine uptake; however, confidence in the importance (necessity and value), safety, and effectiveness of vaccines fell in many countries between 2015 and 2019. 21 WHO listed vaccine hesitancy among the top 10 global threats to health in 2019. 22 Drivers of low confidence in covid-19 vaccination are listed in box 1 . The ‘Understanding Society’ UK Household Longitudinal survey highlighted that the main reason for hesitancy was concerns about future unknown effects, with 42.7% of respondents specifying this. 14 Less common reasons included those under the bracket of “other” (12.2%), worries about side effects (11.4%), concern that others are in more urgent need of the vaccine (7.7%), and lack of trust in vaccines (7.6%). 14 However, the survey found that people of Black ethnicities were more likely to state that they “don’t trust vaccines” compared with White people (29.2% v 5.7%), and people of Pakistani and Bangladeshi ethnicities often cited concerns about vaccine side effects (35.4% v 8.6%). 14 Some reports indicate a rise in vaccine hesitancy following the AstraZeneca vaccine safety scare across Europe and Africa. 24 25 Historical precedents show that widely publicised safety scares can have profound and long-lasting effects on vaccine confidence. 26

Causes and drivers of low confidence in covid-19 vaccines 5 7 9 11 23

Socioeconomic and healthcare inequalities and inequities

Structural racism and previously unethical research involving some ethnic minority groups

Social disadvantages including lower levels of education and poor access to accurate information

Misinformation, disinformation, rumours, and conspiracy theories, in particular through social media

Lack of effective public health messages or targeted campaigns

Barriers to access, including vaccine delivery time, location, and cost related to socioeconomic inequalities and marginalisation

How to approach covid-19 vaccine hesitancy

Approaching vaccine hesitancy is complex, and therefore no single intervention can address this entirely, especially in the context of covid-19 where evidence for effective strategies to address it is currently limited. 27 When considering the most effective methods to increase vaccine uptake, we advocate comprehensive multi-component approaches tailored to the local population, combined with good communication at an individual level. 27 At a broader national level, a multifaceted, non-stigmatising approach is needed to share communication (in a variety of mediums) from trusted sources. 11 This includes traditional media channels (for example, television, radio, public transport advertising, and internet) to engage different groups regarding public health policies and counter any misinformation. 28 29

Recognising barriers to uptake ( box 2 ) helps to inform appropriate interventions to address them ( box 3 ). The key is to build confidence, particularly listening to people’s concerns, being respectful of different religious or cultural beliefs, and being aware of historically rooted understandable mistrust, as well as other ethical considerations around clinical interventions. 11 They will usually be open to engage in dialogue about vaccine safety, efficacy, and importance, and discuss the risks and benefits of vaccination.

Stated reasons for low uptake of covid-19 vaccines among the public 21 30 31

Concerns about long term effects, side effects, and unknown future effects on health

Previous side effects to other routine vaccines such as influenza vaccine

Low confidence in vaccines, including their importance, safety, and efficacy

Lack of trust in the manufacturing and country of production of vaccines, vaccine technology, the pharmaceutical industry, government, and public health bodies

Concerns about the speed of development of covid-19 vaccines

Concerns about vaccines’ incompatibility with religious beliefs

Previously negative experiences of healthcare, including racial discrimination

Lower risk and perception of lower risk of covid-19 (especially among younger age groups)

Lack of communication from trusted providers and community leaders

Practical concerns such as inconvenient vaccine delivery time and location

Not offered vaccine because of inaccurate patient contact information

Direct and indirect costs of vaccine (in some low and middle income countries)

Apprehensions surrounding fertility, pregnancy, and breastfeeding

Belief in conspiracy theories such as covid-19 not being real, or that vaccines modify DNA

Recent covid-19 infection

Summary of strategies for interventions to increase vaccination uptake 11 27 32

Offer tailored communication from trusted sources such as community representatives, healthcare providers, and local authorities that is culturally relevant and accessible in multiple languages.

Improve access to vaccines. This may include flexible delivery models in the community, such as GP practices and outreach programmes with good transportation links.

. Community engagement. Work with community champions, youth ambassadors, faith leaders, and healthcare workers to raise knowledge and awareness on vaccinations; celebrate household members, friends, relatives, and role models being vaccinated; foster an approach of community immunity and helping others; and create locally developed action plans and a continuous, open, and transparent dialogue.

Training and education of those involved with engagement activities at a local level: use relevant educational materials (eg, eLearning modules) in presentations and communication skills training.

HCWs are a trusted source of information on vaccination and can influence local vaccination rates in individuals and at a population level. HCWs working alongside local authority members, faith leaders, and “community champions” can facilitate engagement, guide household decision makers, and make vaccine recommendations. 11 33

Improving access and removing barriers

Historically, interventions based on reminder/recall notifications have improved vaccination uptake in several groups and settings, although limited evidence supports their use specifically for addressing hesitancy. 23 34

Offering appointments in the evenings or weekends may improve accessibility for some. People with disabilities or those who have been shielding may find it particularly hard to attend a vaccination appointment. Considering an individual’s distance from the vaccination site, offering to arrange appropriate transportation, or using home visiting facilities can maximise access for these patients. 11 Vaccination sites away from formal healthcare settings, such as places of worship and work based environments, can offer a degree of familiarity and enable reach within communities that distrust government or medical sources. 33 They also offer the opportunity for peer support from friends, family members, and colleagues who have agreed to be vaccinated.

Community engagement and local interventions

Religious or traditional community leaders can engage key audiences through open discussion, advocacy, and integrated community activities. 23 Where appropriate, this could be alongside group discussions with HCWs in local settings to improve awareness, reinforce messages, and promote consistency. 23 27 28 Having readily available online material for HCWs and vaccine recipients—such as eLearning modules—will reinforce messaging for vaccine safety and effectiveness. 28

Consider engaging local health, political, community, legal, and academic representatives to help authorities understand relevant issues and build trust with community partners. 35 Written, audio, or visual information might be translated into a range of suitable languages or produced in a more accessible format ( box 4 ). 32 35 36 37 38

Online resources

NHS Choices. Coronavirus vaccine. https://www.nhs.uk/conditions/vaccinations/

NHS England Coronavirus (covid-19) Resource Centre. https://coronavirusresources.phe.gov.uk/covid-19-vaccine/resources/

Vaccine Knowledge Project. https://vk.ovg.ox.ac.uk/vk/

Video by Gavi the Vaccine Alliance. Four types of vaccines and how they work. https://www.youtube.com/watch?v=lFjIVIIcCvc

WHO Global Vaccine Safety. https://www.who.int/vaccine_safety/en/

US Centers for Disease Control and Prevention: Vaccines and Immunisations. https://www.cdc.gov/vaccines/covid-19/index.html

The covid-19 vaccine communication handbook. https://hackmd.io/@scibehC19vax/home

Johns Hopkins Medicine. https://www.hopkinsmedicine.org/health/conditions-and-diseases/coronavirus/is-the-covid19-vaccine-safe

British Medical Association. Covid-19: how to communicate with different groups about the vaccine. https://www.bma.org.uk/advice-and-support/covid-19/vaccines/covid-19-how-to-communicate-with-different-groups-about-the-vaccine

Regular reporting of vaccine uptake at a local level by different population demographics, including ethnicity, can help to monitor the overall vaccine coverage and identify where resources need to be further targeted. 11

Discussing vaccination with a patient

Discussion and engagement with patients who are vaccine hesitant should be conducted in an open, honest, and non-judgmental manner ( boxes 5, 6 ). 39 HCWs are well placed to have these conversations given their expertise in communication skills and biomedical training, although evidence is lacking to say whether vaccination uptake is greater if HCWs discuss vaccinations, versus staff in administrative roles. Various approaches have been studied, 23 from calling patients who have not received a vaccine to supplying online or paper based resources to inform patients of benefits and safety issues. One simple example is the “elicit-share-elicit” approach. 32 The HCW asks open ended questions to identify concerns and then offers to share their expertise about this concern. Tailored education based on specific attitudes, and previous experiences have also been shown to be beneficial. 39 This approach maintains an empathetic relationship, and provides an opportunity to communicate risk and support for decision making. For example, if a patient tells you they are concerned about the speed of the vaccine rollout, you might highlight the accelerated collaborative international drive that has taken place, which has occurred without compromising on scientific rigour to establish safety and efficacy including through ethics approval and expert peer review and will be continuously monitored by regulators. Recent concerns over a possible link between coronavirus vaccines and rare blood clots show that this monitoring is taking place, and can even detect serious side effects as rare as one in 250 000 people vaccinated. 40

Individual level interventions for healthcare workers 39

Educational online or written material

Specialist immunisation clinics

Tailored education

“Elicit-share-elicit” approach

Active listening

Motivational interviewing

Top tips for HCWs communicating with vaccine-hesitant patients 36

Be aware of cultural and emotional differences

Recognise the unique contexts, such as difficulties in accessing healthcare and adhering to public health guidance

Provide clear and up-to-date guidance

Repeatedly check understanding

Adjust styles for differing literacy, education, and language levels

Have reliable, up-to-date, and accessible sources of information on hand

Avoid using jargon and stigmatising language

Support equity by identifying and targeting vulnerable groups

Exploring the person’s priorities—what they have looked forward to, or missed most during the current pandemic—can help to contextualise the importance of the vaccination programme as a collective effort to enable society to come out of lockdown, reverse restrictions, and minimise economic hardships.

One of the key difficulties can be communicating risk, for example, the risk of developing severe infection from covid-19 versus the risk of developing symptoms following vaccination. Understanding a patient’s perceptions of risk and health beliefs is key to establishing a shared dialogue through which HCWs can discuss data clearly, using simplified language where appropriate. Engaging with patients on the dynamic, evolving, and at times uncertain nature of scientific evidence is also imperative, especially in the context of covid-19 and vaccines.

Education into practice

Do you have a local policy for identifying and engaging patients who are vaccine hesitant in general, and specifically for covid-19 vaccine hesitancy?

What strategies have you used to increase vaccine uptake in your facility and how have you monitored their impact?

What online and community resources do you have access to for increasing vaccine confidence?

How this article was made

This article uses best available evidence, recent research papers, the latest advice from the World Health Organization, and expert opinion. We searched systematic reviews, other relevant published research, and latest guidelines using MEDLINE, EMBASE, and Google Scholar in March and April 2021. Additional resources were drawn from our personal datasets.

How patients were involved in the creation of this article

A patient read the manuscript and provided feedback on the relevance and usefulness of the recommendations. The patient specifically requested that we also discuss the root causes of low take up of vaccine among ethnic minorities, including wider determinants of health.

Competing interests: none declared. Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests

Provenance and peer review: commissioned, based on an idea from the author; externally peer reviewed.

This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

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• ↵ World Health Organization. Ten threats to global health in 2019. 2019. https://www.who.int/news-room/spotlight/ten-threats-to-global-health-in-2019
• ↵ World Health Organization. Strategies for addressing vaccine hesitancy — a systematic review: WHO SAGE working group dealing with vaccine hesitancy. 2014. https://www.who.int/immunization/sage/meetings/2014/october/3_SAGE_WG_Strategies_addressing_vaccine_hesitancy_2014.pdf
• ↵ YouGov. Europeans now see AstraZeneca vaccine as unsafe, following blood clots scare. YouGov 2021. https://yougov.co.uk/topics/international/articles-reports/2021/03/22/europeans-now-see-astrazeneca-vaccine-unsafe-follo
• ↵ Dahir AL. Vaccine hesitancy runs high in some African countries, in some cases leaving unused doses to expire. New York Times 2021. https://www.nytimes.com/2021/04/16/world/vaccine-hesitancy-africa.html
• ↵ Razai MS, Osama T, Majeed A. Covid-19 vaccine adverse events: balancing monitoring with confidence in vaccines. BMJ Opinion 2021. https://blogs.bmj.com/bmj/2021/03/19/covid-19-vaccine-adverse-events-balancing-monitoring-with-confidence-in-vaccines/
• O’Leary M ,
• ↵ Tull K. K4D Helpdesk Report 672. Vaccine hesitancy: guidance and interventions. Institute of Development Studies. 2014. https://opendocs.ids.ac.uk/opendocs/handle/20.500.12413/14747
• Bravo-Araya M ,
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• ↵ Robertson E, Reeve KS, Niedzwiedz CL, et al. Predictors of COVID-19 vaccine hesitancy in the UK Household Longitudinal Study. medRxiv 2021 [preprint] doi: 10.1101/2020.12.27.20248899 OpenUrl Abstract / FREE Full Text
• ↵ Office for National Statistics. Coronavirus and the social impacts on Great Britain: 29 January 2021. 2021. https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthandwellbeing/bulletins/coronavirusandthesocialimpactsongreatbritain/29january2021
• ↵ Lewandowsky S, Cook J, Schmid P, et al. The COVID-19 Vaccine Communication Handbook. A practical guide for improving vaccine communication and fighting misinformation: SciBeh, 2021.
• Peterson P ,
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• ↵ UK Government. Public health messaging for communities from different cultural backgrounds: Scientific Pandemic Influenza Group on Behaviours (SPI-B), 2020. https://www.gov.uk/government/publications/spi-b-consensus-on-bame-communication-22-july-2020
• ↵ British Medical Association. COVID-19: how to communicate with different groups about the vaccine. 2021. https://www.bma.org.uk/advice-and-support/covid-19/vaccines/covid-19-how-to-communicate-with-different-groups-about-the-vaccine
• ↵ UK Government. UK COVID-19 vaccine uptake plan. 2021. https://www.gov.uk/government/publications/covid-19-vaccination-uptake-plan/uk-covid-19-vaccine-uptake-plan
• ↵ NHS England. COVID-19 vaccine programme. Maximising vaccine uptake in underserved communities: a framework for systems, sites and local authorities leading vaccination delivery, 2021. https://www.england.nhs.uk/coronavirus/publication/maximising-vaccine-uptake-in-underserved-communities-a-framework/
• ↵ European Centre for Disease Prevention and Control. Catalogue of interventions addressing vaccine hesitancy. 2017. https://www.ecdc.europa.eu/en/publications-data/catalogue-interventions-addressing-vaccine-hesitancy
• ↵ Public Health England. COVID-19: the green book, chapter 14a. 2021. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/978508/Green_book_chapter_16April2021.pdf

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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.

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The importance and benefits of getting vaccinated against COVID-19

The pandemic has been one of the greatest health crises in recorded history. Thanks to rapid advances in science and technology, the light at the end of the tunnel is getting closer. Major vaccination efforts are currently underway to immunize the world's population. According to data from health authorities compiled by Our World in Data , 39.7% of the world's population has received at least one dose, while, as of today, almost 2.1 billion people across the globe are fully vaccinated.

There are many theories surrounding Covid-19 vaccination. However, the World Health Organization (WHO) and expert health authorities around the world are urging people to get vaccinated as the best solution to end the pandemic. The sooner people are immunized, the faster it will be possible not only to slow the spread of the disease, but also to limit its impact on the economy.

The benefits of vaccination

According to the WHO, vaccination is a simple, safe and effective way to protect against harmful diseases before coming into contact with them, as it activates the body's natural defenses to learn to resist specific infections and strengthen the immune system.

In this sense, vaccination against COVID-19 will reduce the risk of becoming seriously ill and dying, since the person will be better protected. Immunity will not be 100%, since a vaccinated person can still catch the disease; however, the consequences for the body are expected to be much less.

The main benefits are:

• COVID-19 vaccines can also prevent you from becoming seriously ill even if you contract the virus.
• TAll Covid-19 vaccines are safe and effective.
• By getting vaccinated yourself, you also protect the people around you.
• It is a safer way to develop immunity.

Accordingly, leading organizations such as the Centers for Disease Control and Prevention (CDC) of the United States state on their website that the vaccines are safe . They highlight three main points:

• Vaccines were developed based on scientific knowledge used for decades.
• They are not experimental. They went through all the required stages of clinical trials. Extensive testing and monitoring have shown these vaccines to be safe and effective.
• COVID-19 vaccines have undergone, and will continue to undergo, the most intensive safety monitoring in history..

Vaccination around the world

Worldwide, more than 3.19 billion doses of coronavirus vaccine have been administered so far, according to figures compiled by Our World in Data . According to these figures, almost 27% of the world's population has had both doses (approximately 2.1 billion people).

By country, China leads the global tally with more than two billion vaccines, followed by India, with more than 632 million doses administered. These countries are followed by Western nations such as the United States, which has administered 368 million injections; Brazil, with more than 187 million; and Turkey, with 93 million.

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It’s that time of year again – vaccine season. While most people can appreciate that vaccination is an amazing achievement, their enthusiasm might falter when it comes time to schedule and receive their own. And new research suggests that might influence how the vaccine affects them. 

Recently, researchers at Stanford University, Miami University, and the University of California, San Francisco, studied the effects of different types of positive and negative mindsets regarding the COVID-19 vaccine. Their work, published in the journal Brain, Behavior & Immunity – Health , suggests that a positive mindset is associated with more positive outcomes, such as less stress and side effects, better mood, and possibly even better immune response. 

Details of the findings include:

All positive vaccine-related mindsets predict lower anxiety on the day of the appointment, and lower stress and sadness – and more happiness – in the days around vaccination. 

A positive mindset about the efficacy of the vaccine and how the body will respond to vaccination were linked to fewer negative physical side effects.

The vaccine mindset that side effects indicate “ the vaccine is working!”  was associated with better immune response – specifically, higher antibodies six months later.

“Many people will be surprised by these findings, but they shouldn’t be,” said the authors. “Our brains are connected to every physiological system in our bodies, and we know from decades of previous research on placebo effects and psychoneuroimmunology that our mindsets can influence physiological outcomes, including the immune system.” 

Below, study authors Darwin Guevarra of Miami University and UCSF, Alia Crum of Stanford, and Elissa Epel, BA ’90, of UCSF describe some of the most important takeaways from their study and share how people can apply this science to try to improve their own vaccines experiences.  

1. What is the #1 lesson you’d want people to take away from this study? 

Mindsets are beliefs and assumptions about how the world works that can impact what people experience, feel, and do. The main lesson from the study is that your mindsets about vaccines can impact your post-vaccination experience in terms of how you feel, the side effects you experience, and, in some cases, your immune response.

In this study, we were specifically interested in a number of different mindsets, including the mindset that the vaccine will work, the mindset that your body will be responsive to the vaccine, and the mindset that side effects are signs that the vaccine is working. All the mindsets were associated with more positive experiences with the vaccine to some degree (e.g., less anxiety or fewer side effects). However, the mindset about side effects was most strongly associated with a stronger neutralizing antibody response, a physiological marker of vaccine efficacy. 

This being said, it might be easy to misinterpret the findings as “mindsets about the vaccine directly cause better vaccination outcomes.” However, this study only shows a correlation between mindset and outcomes, meaning we cannot say the link is causal. Additional experiments are needed to claim causality.

2. Why are the results related to side effects important?

The findings regarding side effects mindset are particularly important because fear of side effects is the most common reason for vaccine hesitancy. While we cannot deny the reality of vaccine side effects, we can accurately inform people that many side effects are signs that the vaccine is working to boost your immune response. Common side effects of the vaccines, like muscle soreness, headache, and fever, are encouraging indications that the vaccine is working as it should and the body is building immunity to COVID-19. In fact, in a separate paper  based on this same group of participants, the results showed that greater sickness symptoms – assessed through self-reporting and a bio-sensor – predicted stronger long-term antibody response.

Yet many people don’t seem to recognize this – and this is a missed opportunity. Helping people to rethink side effects as positive signs can transform them from an unpleasant sensation into a favorable signal. This can improve the vaccine experience and may even lead to a better immune response.  

3. If someone already has a negative or anxious mindset about the vaccine, what can they do to develop a more positive mindset?

People can move to more positive mindsets about the vaccine simply by being more informed about the true effects and mechanisms of the vaccine. In doing this, they should lean on accurate information that educates them about how vaccines work and, in particular, work to understand that side effects are often a sign that the vaccine is doing its job. Side effects are not entirely random. 

Promoting a positive mindset before your vaccination

Positive side effect mindset: Side effects are a good sign. They are part of my immune response. They mean the vaccine is working. My body is working hard to produce antibodies.

Positive body response mindset: My body is capable and will respond well to the vaccine. I trust my body’s natural ability to strengthen its defenses through this vaccination.

Vaccine effectiveness mindset: The vaccine will work and protect me from the virus. The vaccine helps my immune system recognize and fight the virus more effectively if exposed to the COVID-19 virus.

The COVID-19 vaccines give your body a practice run against the virus, teaching it what COVID-19 looks like and helping your body build COVID-19-neutralizing antibodies. This results in immunity because now your body has, within it, what it needs to fight the virus should it encounter it again. Sometimes this process causes side effects. And side effects like muscle stiffness, soreness, aches, headaches, nausea, and generally feeling under the weather, are part of the body’s biological processes promoting vaccine’s efficacy .

4. Is there anything else you want people to understand about this topic?

It’s important to remember that our body’s responses to anything – the medications we take, the foods we eat, and the stress we experience – are influenced by our mindsets as well as the objective properties of those things. And this is also true of the COVID-19 vaccine. Our mindsets about the vaccine can affect not just how we feel afterward but also our experience with side effects. And in some instances, your mindset about the vaccine's side effects can potentially influence your immune response.

For more information

Ethan Dutcher and Aric Prather of UCSF are also co-authors of this study. Crum is an associate professor of psychology in the  School of Humanities and Sciences at Stanford. She is also a member of  Stanford Bio-X , the  Wu Tsai Human Performance Alliance , the  Maternal & Child Health Research Institute (MCHRI) , and the Stanford Cancer Institute .

COVID-19 , flu and RSV shots − an epidemiologist explains why all three matter this fall

Associate Professor of Epidemiology, University of San Francisco

Disclosure statement

Annette Regan receives funding from the National Institutes for Health and the US Centers for Disease Control and Prevention. She has served on a Data Safety Monitoring Board for Moderna Inc.

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The Food and Drug Administration approved and granted emergency use authorization on Aug. 22, 2024, for the newest, updated version of the COVID-19 vaccine . The Centers for Disease Control and Prevention quickly endorsed the new shot to protect against severe illness.

The 2024 summer wave of COVID-19 cases is a good reminder of why people need to stay up to date with their vaccines.

As the fall and winter seasons approach, the usual seasonal respiratory viruses, including flu and respiratory syncytial virus, or RSV , will also be on the rise. Vaccines are now available to help protect against these viruses.

The Conversation asked epidemiologist Annette Regan to explain why officials recommend that people get these shots over the coming months.

What strain is the new COVID-19 shot based on and why?

The COVID-19 vaccine has been updated several times since the original shot in 2020-21 to keep up with how the SARS-CoV-2 virus is changing.

In September 2023, the CDC recommended that all people get the newly updated vaccine that was designed to protect against XBB.1.5 , the variant that had been dominant in the U.S. that summer, regardless of whether they had received all recommended shots in the past.

Now, in August 2024, the XBB.1.5 variant is no longer around and has been replaced by the KP.2 and KP.3 variants , which make up more than 60% of variants currently detected .

Moderna and Pfizer both made updated formulations of the COVID-19 shot that target this new KP.2 variant. It is a monovalent vaccine, which means it includes only the KP.2 strain.

This strain was selected because it was the most common variant at the time the choice was made. Even when new variants such as KP.3 emerge, we researchers expect the updated vaccine to protect against the newer strains. For example, the 2023-24 vaccine was designed to target the XBB.1.5 strain, and studies showed that it continued to protect against the JN.1 variant that later emerged.

The CDC recommends a single shot for everyone 6 months and older, with some exceptions. Children 6 months to 4 years old who have not received any prior shots of COVID-19 vaccine still need two or three shots of the updated 2024-25 vaccine. Adults 65 and older and children and adults with certain health conditions may require an additional shot as well.

People who recently had a SARS-CoV-2 infection may consider delaying their shot for three months after the illness, since risk of reinfection is thought to be low during the months after infection.

How did the 2023 updated vaccine perform?

Recent studies have shown that people who received the 2023-24 vaccine were 54% less likely to develop symptomatic COVID-19 illness , 39% to 51% less likely to visit an emergency department or urgent care with COVID-19 , and 50% to 53% less likely to be hospitalized with COVID-19 compared with unvaccinated people.

The vaccine was most effective among those who had received their shot more recently.

What is the best timing for the shots?

COVID-19 hospitalizations and deaths have been rising since May 2024, with the highest rates seen in adults 65 and older and infants under 6 months old. Therefore, public health experts are recommending that people get the COVID-19 shot as soon as possible to protect against severe illness.

Because infants younger than 6 months are not old enough to be directly vaccinated, COVID-19 vaccination during pregnancy is the best way to protect these babies .

When it comes to the flu, cases and hospitalizations seem to rise steeply between November and December. Some years, however, such as the 2022-23 flu season , they start as early as October.

It’s important to remember that vaccines do not offer immediate protection. You need about two weeks for your body to generate enough antibodies to offer protection. September or early October is a good time to get the flu shot to ensure you are protected in time. However, if you aren’t able to get the shot before November, it’s important to know that it is still helpful to get the shot as long as flu is around.

Is it OK to get both the COVID-19 and flu shots at the same time?

Getting the COVID-19 and flu shots together can certainly make it easier to get up to date with these recommended vaccinations. Data shows that getting the flu shot and the COVID-19 shot together is safe and effective .

Some vaccine companies are working to develop a combined flu/COVID-19 vaccine to reduce the number of shots needed. This vaccine still needs to be approved by the Food and Drug Administration but could become available soon.

Who should get the RSV shot and when?

RSV is another common respiratory virus that can cause severe illness in young children and older adults. There are two groups of people who should get one of the three currently available RSV vaccines: adults 60 years and older and pregnant people. The CDC recommends a single dose of either GSK’s AREXVY, Moderna’s mRESVIA or Pfizer’s ABRYSVO for all adults 75 years and older and adults between the ages of 60 to 74 who are at increased risk of severe RSV disease.

Unlike the COVID-19 and flu shots, additional RSV doses are not currently recommended, because research suggests that the vaccine offers protection for at least two RSV seasons . These vaccines are relatively new, however, and more data will be needed to see how long this protection really lasts. Additional doses may be recommended in the future.

The CDC recommends only Pfizer’s shot for people in weeks 32 to 36 of pregnancy between September and January. The Pfizer vaccine is the only RSV vaccine that has been licensed and approved for use in pregnancy.

These vaccines are different from the antibodies that can be given to infants at or after birth, called Beyfortus (nirsevimab). The CDC recommends one dose of nirsevimab for infants who are younger than 8 months old born during or shortly before their first RSV season. For some children who are 8 to 19 months old and are at increased risk of severe RSV disease, a dose of nirsevimab may also be recommended during their second RSV season.

Both the RSV vaccine and nirsevimab offer safe and effective options for preventing RSV in young babies.

Pregnant people should get advice from their health care professionals about which option is best for them.

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Last Updated August 2023 | This article was created by familydoctor.org editorial staff and reviewed by Deepak S. Patel, MD, FAAFP, FACSM

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Childhood vaccines: what they are and why your child needs them, immunization schedules, preventive services for healthy living.

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There has been confusion and misunderstandings about vaccines. But vaccinations are an important part of family and public health. Vaccines prevent the spread of contagious, dangerous, and deadly diseases. These include measles, polio, mumps, chicken pox, whooping cough, diphtheria, HPV, and COVID-19.

The first vaccine discovered was the smallpox vaccine. Smallpox was a deadly illness. It killed 300 million to 500 million people around the world in the last century. After the vaccine was given to people, the disease was eventually erased. It’s the only disease to be completely destroyed. There are now others close to that point, including polio.

When vaccination rates decline, cases of preventable diseases go up. This has been happening in recent years with measles. As of July 7, 2023, the Centers for Disease Control has been notified of 18 confirmed cases in 12 U.S. jurisdictions. That may not seem like a lot but compare it with just 3 cases during the same time in 2022. By the end of 2022, there were 121 cases. Almost all those cases could have been prevented with vaccines.

What are vaccines?

A vaccine (or immunization) is a way to build your body’s natural immunity to a disease before you get sick. This keeps you from getting and spreading the disease.

For some vaccines, a weakened form of the disease germ is injected into your body. This is usually done with a shot in the leg or arm. Your body detects the invading germs (antigens) and produces antibodies to fight them. Those antibodies then stay in your body for a long time. In many cases, they stay for the rest of your life. If you’re ever exposed to the disease again, your body will fight it off without you ever getting the disease.

Some illnesses, like strains of cold viruses, are fairly mild. But some, like COVID-19, smallpox or polio, can cause life-altering changes. They can even result in death. That’s why preventing your body from contracting these illnesses is very important.

How does immunity work?

Your body builds a defense system to fight foreign germs that could make you sick or hurt you. It’s called your immune system. To build up your immune system, your body must be exposed to different germs. When your body is exposed to a germ for the first time, it produces antibodies to fight it. But that takes time, and you usually get sick before the antibodies have built up. But once you have antibodies, they stay in your body. So, the next time you’re exposed to that germ, the antibodies will attack it, and you won’t get sick.

Path to improved health

Everyone needs vaccines. They are recommended for infants, children, teenagers, and adults. There are widely accepted immunization schedules available. They list what vaccines are needed, and at what age they should be given. Most vaccines are given to children. It’s recommended they receive 12 different vaccines by their 6th birthday. Some of these come in a series of shots. Some vaccines are combined so they can be given together with fewer shots.

The American Academy of Family Physicians (AAFP) believes that immunization is essential to preventing the spread of contagious diseases. Vaccines are especially important for at-risk populations such as young children and older adults. The AAFP offers vaccination recommendations,  immunization schedules , and information on disease-specific vaccines.

Being up to date on vaccines is especially important as children head back to school. During the 2021 school year, state-required vaccines among kindergarteners dropped from 95% to 94%. In the 2021-2022 year it fell again to 93%. Part of this was due to disruptions from the COVID-19 pandemic.

Is there anyone who can’t get vaccines?

Some people with certain immune system diseases should not receive some types of vaccines and should speak with their health care providers first.  There is also a small number of people who don’t respond to a particular vaccine. Because these people can’t be vaccinated, it’s very important everyone else gets vaccinated. This helps preserve the “herd immunity” for the vast majority of people. This means that if most people are immune to a disease because of vaccinations, it will stop spreading.

Are there side effects to vaccines?

There can be side effects after you or your child get a vaccine. They are usually mild. They include redness or swelling at the injection site. Sometimes children develop a low-grade fever. These symptoms usually go away in a day or two. More serious side effects have been reported but are rare.

Typically, it takes years of development and testing before a vaccine is approved as safe and effective. However, in cases affecting a global, public health crisis or pandemic, it is possible to advance research, development, and production of a vaccine for emergency needs. Scientists and doctors at the U.S. Food and Drug Administration (FDA) study the research before approving a vaccine. They also inspect places where the vaccines are produced to make sure all rules are being followed. After the vaccine is released to the public, the FDA continues to monitor its use. It makes sure there are no safety issues.

The benefits of their use far outweigh any risks of side effects.

What would happen if we stopped vaccinating children and adults?

If we stopped vaccinating, the diseases would start coming back. Aside from smallpox, all other diseases are still active in some part of the world. If we don’t stay vaccinated, the diseases will come back. There would be epidemics, just like there used to be.

This happened in Japan in the 1970s. They had a good vaccination program for pertussis (whooping cough). Around 80% of Japanese children received a vaccination. In 1974, there were 393 cases of whooping cough and no deaths. Then rumors began that the vaccine was unsafe and wasn’t needed. By 1976, the vaccination rate was 10%. In 1979, there was a pertussis epidemic, with more than 13,000 cases and 41 deaths. Soon after, vaccination rates improved, and the number of cases went back down.

Things to consider

There have been many misunderstandings about vaccines. There are myths and misleading statements that spread on the internet and social media about vaccines. Here are answers to 5 of the most common questions/misconceptions about vaccines.

Vaccines do NOT cause autism.

Though multiple studies have been conducted, none have shown a link between autism and vaccines.  The initial paper that started the rumor has since been discredited.

Vaccines are NOT too much for an infant’s immune system to handle.

Infants’ immune systems can handle much more than what vaccines give them. They are exposed to hundreds of bacteria and viruses every day. Adding a few more with a vaccine doesn’t add to what their immune systems are capable of handling.

Vaccines do NOT contain toxins that will harm you.

Some vaccines contain trace amounts of substances that could be harmful in a large dose. These include formaldehyde, aluminum, and mercury. But the amount used in the vaccines is so small that the vaccines are completely safe. For example, over the course of all vaccinations by the age of 2, a child will take in 4mg of aluminum. A breast-fed baby will take in 10mg in 6 months. Soy-based formula delivers 120mg in 6 months. In addition, infants have 10 times as much formaldehyde naturally occurring in their bodies than what is contained in a vaccine. And the toxic form of mercury has never been used in vaccines.

Vaccines do NOT cause the diseases they are meant to prevent.

This is a common misconception, especially about the flu vaccine. Many people think they get sick after getting a flu shot. But flu shots contain dead viruses—it’s impossible to get sick from the shot but mild symptoms can occur because the vaccine may trigger an immune response, which is normal. Even with vaccines that use weakened live viruses, you could experience mild symptoms similar to the illness. But you don’t actually have the disease.

We DO still need vaccines in the U.S., even though infection rates are low.

Many diseases are uncommon in the U.S. because of our high vaccination rate. But they haven’t been eliminated from other areas of the world. If a traveler from another country brings a disease to the U.S., anyone who isn’t vaccinated is at risk of getting that disease. The only way to keep infection rates low is to keep vaccinating.

Questions to ask your doctor

• Why does my child need to be vaccinated?
• What are the possible side effects of the vaccination?
• What do I do if my child experiences a side effect from the vaccine?
• What happens if my child doesn’t get all doses of the recommended vaccines? Will he or she be able to go to daycare or school?
• We missed a vaccination. Can my child still get it late?
• Are there new vaccines that aren’t on the immunization schedules for kids?
• What should I do if I don’t have health insurance, or my insurance doesn’t cover vaccinations?
• What vaccinations do I need as an adult?
• Why do some people insist they became sick after getting the flu vaccine?

Centers for Disease Control and Prevention: Vaccines & Immunizations

Last Updated: August 10, 2023

This article was contributed by familydoctor.org editorial staff.

Copyright © American Academy of Family Physicians

This information provides a general overview and may not apply to everyone. Talk to your family doctor to find out if this information applies to you and to get more information on this subject.

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What to Know About the Updated COVID Vaccine for Fall, Winter 2024–25

The updated COVID vaccine provides safe, effective protection against current variants for everyone 6 months and older.

Aliza Rosen

Amid an unexpectedly large surge of summer COVID infections in the U.S., and with the fall/winter virus season around the corner, updated COVID vaccines have arrived.

COVID vaccines are one of the best and safest ways to protect against severe illness and hospitalization. Updated COVID vaccines are chosen to target the variants currently circulating and are recommended for everyone 6 months of age and older.

In this Q&A, Andy Pekosz , PhD, a professor in Molecular Microbiology and Immunology , discusses who the updated vaccine is recommended for, when to get yours, whether it’s safe to get it alongside other seasonal vaccines.

What’s new about this year’s updated COVID vaccines?

The updated mRNA COVID vaccines from Moderna and Pfizer are based on the KP.2 strain, one of the FLiRT variants that have been spreading since early spring. These variants and their sub-variants have caused the majority of infections during this summer’s COVID wave.

Who should be getting an updated COVID vaccine?

Everyone 6 months and older should get vaccinated against COVID, according to the CDC’s recommendations .

For children ages 6 months to 4 years: Vaccination is recommended, but the number of vaccinations is based on which vaccine they receive, their age, and whether they’ve received a previous COVID vaccine. Parents and guardians should refer to CDC guidance and check with their pediatrician to see what’s recommended for their child.

For people ages 5 years and up: One dose of the updated COVID vaccine is recommended, regardless of whether they’ve been vaccinated previously. If someone has received a COVID vaccine recently, they should wait at least two months before getting the updated one for this season.

According to updated CDC guidelines, individuals who are immunocompromised may receive additional doses with their health care provider’s guidance.

When is the best time to get vaccinated?

This summer’s surge has been larger and lasted longer than many experts anticipated, making it a little trickier than years past to determine the best time to get vaccinated.

People who have not had COVID in the past few months have a couple options:

• Get the updated COVID vaccine as soon as it’s available  (late August, early September) to protect yourself as the wave of summer infections continues.
• Get the updated COVID vaccine around mid-October to build protection in time for the rise of cases that typically occur around November through January.

People at higher risk of severe illness should consider getting an updated COVID vaccine as soon as possible. Everyone who is eligible should get an updated COVID vaccine by mid-October in order to build immunity ahead of holiday travel and gatherings. Remember, it takes about two weeks to build up immunity following a vaccine, so schedule your vaccination accordingly.

How long does protection last after I'm vaccinated?

Broadly speaking, the COVID vaccine provides strong protection against infection for up to three months and protection against severe disease out to six months. That said, there are a lot of variables that can affect duration and strength of protection, including any new variants that may emerge and how different they are from the vaccine formulation.

If I had COVID recently, when should I get the updated vaccine?

If you’ve had COVID this summer, you’ll have strong infection-based immunity and can wait a few months after your infection before getting the vaccine. According to the CDC, you can wait three months since your symptoms began or, for asymptomatic cases, since you first tested positive.

There’s some evidence to support waiting as long as six months after a COVID infection to receive an updated vaccine. Waiting longer than the CDC’s guidance of three months is not recommended for high-risk groups, but it’s something people can discuss with their doctor.

How should I choose which COVID vaccine to get?

Between the two mRNA vaccines from Moderna and Pfizer, there is no reason to get one over the other. They target the same KP.2 variant, are similarly effective, and elicit similar side effects.

Is the COVID vaccine free?

The COVID vaccine is free under most health insurance plans and Medicare.

If you don’t have insurance to cover the cost of the COVID vaccine, look for vaccination clinics run by your local or state health department. Children under 18 may also be eligible to get a free COVID vaccine through the CDC’s Vaccines for Children Program .

You can find local pharmacies offering COVID vaccines at Vaccines.gov or by contacting your health care provider or local health department.

Are there any side effects to the updated COVID vaccine?

The common side effects are the same as with previous COVID vaccines. Symptoms like soreness at the injection site, achiness or joint pain, fatigue, slight fever, chills, or nausea are normal and not cause for concern. These side effects are a sign that your body is mounting an immune response—exactly what it’s supposed to do following a vaccine. Side effects generally subside within a day or two.

If I haven’t gotten any COVID vaccines yet, can I start with this one?

If you’ve never been vaccinated against COVID, now is a great time to start. People 5 years of age and older are considered up to date on COVID vaccination once they receive one dose of an updated mRNA COVID vaccine.

How well does the vaccine protect against the variants currently circulating?

The vaccine is a close match to variants currently circulating and provides good protection against severe disease, hospitalization, and death. While KP.2 is not causing a significant number of infections, the most prevalent variants circulating right now are very closely related to them. The vaccine will never be a perfect match to the circulating variants because it takes 2-4 months to make the vaccine, and during that time the virus continues to change as it infects people.

Is vaccine-induced immunity better than immunity from infection?

Vaccine-induced immunity is better because it’s safer. When you get infected with COVID, symptoms from the infection wreak havoc on your body. Whether or not you’ve been infected or vaccinated previously, the updated COVID vaccine is going to strengthen your immune responses to high levels and do so in a safe way.

Can I still get COVID if I’m vaccinated?

People who are vaccinated can still get COVID, but it is much more likely they will experience mild symptoms. Vaccinated people are much less likely to experience severe illness or get so sick that they need to be hospitalized. Data continue to show that those who are hospitalized with COVID are largely people who have not received a COVID vaccine within the past 12 months.

Particularly for people at higher risk of severe COVID, vaccination is an essential tool for reducing COVID complications, hospitalization, and death.

Can you get the flu shot and the COVID vaccine at the same time?

Yes! In fact, studies have shown that people who decide to spread out their vaccines into separate appointments often don’t follow through with getting both. We’ve also seen that the immune response generated by each vaccine does not change based on whether they are administered at the same time or separately.

It’s important to remember that many of the same populations at high risk of experiencing severe illness from COVID are also at high risk of severe influenza. Especially for these vulnerable populations, it’s a good idea to time your vaccines together.

When might we see a combined COVID and flu vaccine?

Some vaccine manufacturers have been working on developing a combined vaccine for COVID and flu, but we’re not there yet. We certainly won’t see a combined vaccine this year. It’s possible one will be ready in time for fall 2025, but we won’t know for sure until more clinical trial results are available.  

Aliza Rosen is a digital content strategist in the Office of External Affairs at the Johns Hopkins Bloomberg School of Public Health.

Related Articles:

• Understanding the CDC’s Updated COVID Isolation Guidance
• What to Know About COVID FLiRT Variants
• The Long History of mRNA Vaccines

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FDA approves the new Covid vaccine. Here's the best time to get it.

The Food and Drug Administration on Thursday approved the new Covid vaccines from Pfizer and Moderna.

It’s the third time the vaccines have been updated to match circulating strains since the original series. The shots should be available within days. The agency hasn't yet approved a third vaccine, from drugmaker Novavax.

The timing of the new vaccines — last year's rollout was in mid-September — is significant, since most of the U.S. is still caught in the summer wave of Covid illness. As of Monday, the Centers for Disease Control and Prevention reported, the number of people testing positive for Covid keeps rising and emergency room visits for Covid have been increasing since mid-May. Hospitalizations are rising , too.

Here’s what to know about the updated vaccines.

How are the new Covid vaccines different? 

The new shots from Pfizer and Moderna are designed to target the KP.2 strain, a descendant of the highly contagious JN.1 variant that began circulating widely in the U.S. last winter. The drugmakers started making the new doses in June after the FDA advised them to freshen the formulas to match the version of the virus that was gaining ground in the U.S. 

A third vaccine, from drugmaker Novavax, has been updated to target the JN.1 strain. JN.1 and KP.2 have largely faded from circulation, according to the CDC.

As of Saturday, a sister strain called KP.3.1.1 accounted for about 36% of all new Covid cases, while another sister strain, KP.3, accounted for about 17%. 

It’s unclear exactly how effective the vaccines will be against the newer strains, but experts expect that they will protect against severe illness.

A spokesperson from Pfizer told NBC News that data submitted to the FDA shows that its vaccine generates a “substantially improved” immune response against multiple currently circulating variants, including KP.3, compared to earlier versions of the vaccine. 

There are “very minor sequence differences” between the variants, said John Moore, a professor of microbiology and immunology at Weill Cornell Medical College. 

A paper published this month in the journal Infectious Diseases found that KP.3.1.1 shares similarities with JN.1 and KP.2, although it has a few additional mutations that may help it spread more easily. 

“All these changes are incremental. They do not change the overall big picture,” Moore said. “KP.3.1.1 is just another step in the road that the overall omicron lineage is taking towards greater transmissibility.”

Who should get the new Covid vaccine?

In an earlier interview, Dr. Ashish Jha, dean of the Brown University School of Public Health and a former White House Covid-19 response coordinator, said Covid is most likely endemic in the U.S., meaning the virus is following “a relatively predictable pattern that will last a very long time.” 

That means we’ll be getting a yearly updated Covid vaccine to protect against mutations and waning immunity, just like annual flu shots.

As of May 11, only 22.5% of adults got last year’s updated Covid vaccine, according to data from the CDC . Only 14.4% of children ages 6 months through 17 years got vaccinated.

For this fall, the CDC recommended that all Americans ages 6 months and older get the new shots.

But Dr. Isaac Bogoch, an infectious disease specialist at the University of Toronto, said it’s challenging to make a one-size-fits-all recommendation on who should get the vaccine, especially for healthy, young adults.

“It’s fair to say that the vaccines are still helpful, certainly at an individual level, and to some extent at a community level,” he said.

It’s critically important that people at the highest risk of a severe Covid infection — including people over 65 or with weakened immune systems or underlying health conditions, such as heart disease or obesity — get the vaccine, Bogoch said

“The heavy lifting of the vaccine is really in protecting the most vulnerable people from severe outcomes, like hospitalization and death,” he said. 

When should I get the new Covid vaccine?

Millions of people in the U.S. have had Covid within the last few weeks and months. An advantage of the summer wave is that people who have recently recovered have an immune boost to fight off future infections. 

Because the vaccines will be available earlier this year than last, the question of timing for the most protection through the winter is more urgent. According to CDC guidance, if you’ve recently had Covid , “you may consider delaying your vaccine dose by 3 months.”  

For people at high risk of severe illness, experts say get the vaccine when it becomes available. That's because infection may not provide as much protection as vaccination, said Dr. Ofer Levy, the director of the Precision Vaccines Program at Boston Children’s Hospital. 

Protection from infection can vary based on the severity of infection, the strain, as well as a person’s age and health. 

For the young and healthy, it may not be as beneficial to get the vaccine so close to recovery from infection, said Akiko Iwasaki, professor of immunology at the Yale School of Medicine. High levels of antibodies present from recent infection may prevent the vaccine from stimulating new immune cells.

“If there’s a lot of antibodies already circulating, those antibodies are going to block the [vaccine] from doing its job,” she said. “That’s one reason why it’s not recommended to get the vaccine immediately after you’ve had Covid.”

Dr. Paul Sax, clinical director of the division of infectious diseases at Brigham and Women’s Hospital in Boston, said there’s no harm in getting the vaccine now, although it may make more sense to wait since Covid cases tend to pick up around November.

“Assuming that’s the case again this year, I would say sometime in October when people get their flu shot would be perfect,” Sax said. 

There’s not a risk to getting it right away, but the initial protection from the vaccine may not last through an expected winter wave, Sax said. 

“The good thing is that all of us with our immunity from prior vaccines or getting Covid or both don’t have as much of a risk of severe disease,” he said. “But if you want to really completely avoid getting infected it’s that antibody spike after the vaccine that happens one to three weeks after that’s most protective.” 

Dr. Manisha Juthani, commissioner of the Connecticut Department of Public Health, said that people who recently had Covid can wait a few months before they get their updated vaccine. 

“Immunity does wane from having had Covid or getting the vaccine,” Juthani said Wednesday during a media briefing with the Association of State and Territorial Health Officials ahead of the winter respiratory virus season. “If you don’t feel strongly about getting the vaccine right away, then waiting about three months from when you had Covid, and particularly, so that as we’re approaching the holidays, that you get that shot before the big holidays and when you may be gathering with people.” 

“If you feel strongly that you really want to get the shot as soon as it’s available, even if you had Covid this summer, then of course you can get that,” she added. “There’s nothing to say that you can’t in September or October.”

Data from prior Covid vaccines suggests that the initial protection against infection peaks about a month after the shot and starts to wane over the next several months, even when the vaccine is well matched to the circulating strains. 

Fortunately protection against severe disease remains robust for much longer, Iwasaki said.

Ultimately you never know when you may become infected with the virus, she said.

“It’s kind of a risky calculation because waves just means that there is a large number of infections in the population, but at the individual level you can get infected tomorrow,” she said. “So it’s very difficult to predict what is the best time to get it.” 

Iwasaki plans to get the vaccine herself sooner rather than later since she has not been infected or had a booster in some time. 

Sax recommends that his patients wait two to three months after recovering before getting another shot. 

“The reality is, your infection gives you some boost of your own immunity,” he said.

What are side effects of the new Covid vaccines?

Like other versions of the Covid vaccines and similar to flu shots, the most common reaction is some pain at the injection site. Other side effects include :

• Muscle pain

The CDC says the side effects typically resolve after a few days. Serious side effects , such as the life-threatening allergic reaction called anaphylaxis, are rare.

Pfizer and Moderna’s vaccines have been associated with a small but increased risk of myocarditis , the inflammation of the heart muscle, mostly in young men. Most people make a full recovery.

How much will it cost?

Pfizer, Moderna and Novavax are charging up to $150 per dose for a Covid vaccine , according to data from the Centers for Medicare and Medicaid Services.

The vast majority of people with public and private health insurance should pay nothing out of pocket for the updated Covid vaccines —as long as they stick with an in-network provider, said Jennifer Kates, director of the Global Health & HIV Policy Program.

Medicare and Medicaid require that the vaccines are free for patients. The Affordable Care Act, also known as Obamacare, requires private insurers to cover all vaccines that are recommended by the CDC’s vaccine committee and director.

However, Kates added that the ACA’s requirement does not apply to grandfathered plans — plans that existed before the ACA was signed into law — and short-term health plans. 

“People enrolled in these plans may face cost sharing for the Covid vaccine, or the vaccine may not be covered at all,” she said.

Children without insurance can get free vaccines through the government-run Vaccines for Children Program.

For adults without health insurance, the situation is a bit different. The CDC’s Bridge Access Program — which has been paying for shots for uninsured adults — is expected to shut down in August because of a lack of funding.

Once the funding runs out, uninsured individuals may be able to access free Covid vaccines through community health centers and other safety net providers that participate in the Section 317 vaccine program for adults, Kates said. Section 317 is a federal initiative that gives funding to states to provide vaccines for uninsured and underinsured adults.

“Some state and local health departments may also have a limited supply for people without insurance, but any supply will be very limited,” Kates said.

Berkeley Lovelace Jr. is a health and medical reporter for NBC News. He covers the Food and Drug Administration, with a special focus on Covid vaccines, prescription drug pricing and health care. He previously covered the biotech and pharmaceutical industry with CNBC.

Akshay Syal, M.D., is a medical fellow with the NBC News Health and Medical Unit. 

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The vaccines success story gives us hope for the future

As the world waits for a vaccine to defeat the covid-19 pandemic, we look back to all that vaccines have achieved for humanity..

The World Health Organization (WHO), working in partnership with both public and private sectors, has a proud history of vaccinology.  

By assessing vaccines for global supply, WHO’s groundbreaking Prequalification programme has made possible the deployment of quality-assured, safe and effective vaccines to dozens of countries across the world. This programme gives countries the security and confidence to know that vaccines being purchased meet WHO standards for safety, effectiveness and quality.

The Expanded Programme on Immunization (EPI), created by WHO in the 1970s, has, with the help of UNICEF, Gavi, the Vaccine Alliance, and others, brought lifesaving vaccines to hundreds of millions of children around the world. The immunisation programme is found in every country on the globe.  It has the farthest reach and deepest impact of any public health programme. WHO staff have supported governments and health professionals to deliver vaccines where they are needed on the ground. Its success is measured in millions of lives saved each year.  Through vaccination, smallpox has been eradicated and polio is on the verge of being defeated

On constant alert, every year, WHO studies influenza trends, to work out which strains are emerging and should be included in the next season’s flu vaccine. And it continually monitors potential signals of pandemic threat.

WHO estimates that in 2018 (the latest year for which estimates are available), 25,000 newborns died from neonatal tetanus, an 88% reduction the figure of 200,000 in 2000. 

Global HPV vaccine coverage is increasing. HPV vaccines had been introduced in 106 countries by the end of 2019, representing a third of the global population of girls.

Today, 86% of the world’s children receive essential, lifesaving vaccines, increasing from around 20% back in 1980. This protects them and their communities against a range of infectious diseases, including measles, diphtheria, tetanus, pertussis (whooping cough), hepatitis B and polio. The number of children paralysed by polio has been reduced by 99.9 percent worldwide over the last three decades. 

This level of protection comes through a strong global effort to increase vaccine access and affordability, with support in recent decades from new partnerships like Gavi, the Vaccine Alliance - focussing on expanding vaccine availability in the poorest countries - and the Measles & Rubella Initiative.

Credit: WHO / Mark Nieuwenhof 

Innovative partnerships have also seen WHO help lead major cholera and yellow fever vaccination campaigns, and have also produced effective vaccines against meningitis and pneumonia, diarrhoea, and the world’s first-ever malaria vaccine currently being piloted in Ghana, Kenya and Malawi.

We have known about Ebola since the 1970s, but the disease hit the headlines in 2014–2016 when an epidemic in West Africa killed more than 11 000 people. This epidemic triggered the first human trials of a vaccine against the disease and prompted changes in the way the world responds to outbreaks

To tackle the threat of Ebola, one of the biggest priorities was to fund vaccine discovery, fast-track clinical trials, hasten regulatory approvals and enable manufacturers to produce and roll out an Ebola vaccine. From early testing to trials of the rVSV-ZEBOV Ebola vaccine in Guinea in 2016 took the sum of ten months, a speed unprecedented at the time.

The Government of the Democratic Republic of the Congo (DRC) declared a new outbreak of Ebola virus disease (EVD) in Bikoro in Equateur Province on 8 May 2018. Vaccination began on 21 May.

“I just spent the day out with the vaccination teams in the community, and for the first time in my experience, I saw hope in the face of Ebola and not terror,” said WHO’s Dr Mike Ryan.

When Ebola hit eastern DRCin August 2018 , the vaccine was used just days after the declaration of the outbreak. More than 300 000 people were vaccinated from August 2018 to March 2020, which heped to save lives and slowed the spread of Ebola.

Credit : WHO / Lindsay Mackenzie 

As the rVSV-ZEBOV vaccine was not licensed, it was used under “compassionate use” as part of ongoing research studies. Those who volunteered to take part in the DRC study provided consent, and safety was monitored when they were followed up after vaccination. The results from the DRC vaccine studies confirmed that the vaccine is effective in preventing Ebola. The vaccine was licensed in the United States and Europe in late 2019. Earlier this year after WHO prequalified the vaccine, it was licensed in DRC and five other African countries.

Meningitis vaccine for Africa

Africa has also benefited from another innovative vaccine development. For more than 100 years, countries in sub-Saharan Africa were ravaged by widespread meningitis epidemics. During a severe epidemic 1996-1997 more than 250 000 cases and 2 ,000 deaths were reported across what is known as the “meningitis belt”, stretching from Senegal in the west, to Ethiopia in the east.

With more than 450 million people at risk from meningococcal A disease, African ministers of health challenged public health experts and scientists to seek a new approach.

WHO, the US Centers for Disease Control and Prevention (CDC) and PATH recommended the development of a conjugate meningococcal vaccine for Africa that could meaningfully reduce the disease burden and eventually overcome the epidemics that came in waves. Clinical trials began in 2005 and were carried out in the Gambia, Ghana, India, Mali and Senegal. In June 2010, the vaccine received WHO prequalification. The first countries to introduce the vaccine – Burkina Faso, Mali and Niger – scaled-up activities relating to licensure, vaccine management, campaign planning and monitoring and management of adverse events following immunisation.

The innovative and affordable vaccine was introduced in late 2010 and more than 300 million people living in the meningitis belt countries have since been vaccinated resulting in a dramatic decline, all but ridding these countries of this major cause of deadly epidemics.

Looking forward

The Ebola and meningitis vaccines are two of the most exciting developments in global public health in recent history. So too is the evolution of the routine immunization programmes that have so successfully halted the measles and polio outbreaks that once ravaged communities, killing and maiming young children. Pneumococcal and rotavirus vaccines have been successful against some of the most common causes of pneumonia and diarrhoeal deaths. Innovative financing expedited the introduction of the pneumococcal vaccine, enabling it to be launched in 2011, in a world-first, in rich and poor countries simultaneously.

Immunisation saves millions of lives every year. We now have vaccines to prevent and control 25 infections, helping people of all ages live longer, healthier lives. The wealth of experience accrued by WHO and its partners over decades is now being deployed to accelerate the development and distribution of vaccines against COVID-19, so that when we have a safe and effective vaccine, no one will be left behind. Vaccines remain the safest, most cost-effective protection against disease and will provide a powerful tool to address the COVID-19 pandemic.

A new meningitis vaccine for Africa

Vaccines and the power to protect

Two vaccines to protect pregnant women and their babies in Peru’s Amazon region

Vaccine Ingredients: Fetal Cells

Note to readers.

The information on this page addresses vaccines available in the U.S. If a vaccine is available in the U.S. and not discussed on this page, it does not employ the use of fetal cells in production. For example, no influenza vaccine available in the U.S. requires the use of fetal cells for production.

Vaccines for  varicella (chickenpox) , rubella (the “R” in the MMR vaccine), hepatitis A , rabies  (one version, called Imovax) and COVID-19 (Johnson & Johnson (J&J)/Janssen, which is no longer used in the U.S.) are all made by growing the viruses in fetal cells.

Why are fetal cells used to make some vaccines?

Viruses reproduce in cells, so to grow viruses for a vaccine, one of the necessary “tools” is a type of cell in which the virus will grow. Viruses will not grow in just any cell type, so one of the first things a scientist needs to do is to figure out what cells the virus will infect in the lab. Because viruses infect people, human cells are a good place to start checking.

The most important benefit offered by using fetal cells was that they were isolated from the sterile environment of the womb. This meant the cells would not be infected with other viruses, and the vaccine produced in these cells would not inadvertently introduce any other viruses.

To find out more about the decision to use fetal cells to grow vaccine viruses, check out the video, Stanley Plotkin: Pioneering the use of fetal cells to make rubella vaccine .

What types of fetal cells are used?

All vaccines made using fetal cells, except the COVID-19 vaccine, are made using fibroblast cells. The COVID-19 vaccine (J&J/Janssen) is made using fetal retinal cells.

Fibroblast cell history

Fibroblast cells are the cells needed to hold skin and other connective tissue together. The fetal fibroblast cells used to grow vaccine viruses were first obtained from elective termination of two pregnancies in the early 1960s. These same fetal cells obtained from the early 1960s have continued to grow in the laboratory and are used to make vaccines today. No further sources of fetal cells are needed to make these vaccines.

The reasons that fetal cells were originally used included:

• Viruses need cells to grow and tend to grow better in cells from humans than animals (because they infect humans).
• Almost all cells die after they have divided a certain number of times; scientifically, this number is known as the Hayflick limit. For most cell lines, including fetal cells, it is around 50 divisions; however, because fetal cells have not divided as many times as other cell types, they can be used longer. In addition, because of the ability to maintain cells at very low temperatures, such as in liquid nitrogen, scientists are able to continue using the same fetal cell lines that were isolated in the 1960s.

As scientists studied these viruses in the lab, they found that the best cells to use were the fetal cells mentioned above. When it was time to make a vaccine, they continued growing the viruses in the cells that worked best during these earlier studies.

Retinal cell history

The retinal cells used to make the COVID-19 adenovirus vaccine (J&J/Janssen) were isolated from a terminated fetus in 1985 and adapted for use in growing adenovirus-based vaccines in the late 1990s.

Adenovirus-based vaccines that cannot replicate when administered to people need to be produced in cells that have the necessary gene to allow for large quantities of the virus to be made. The retinal cell line, called PER.C6, was adapted to enable production of these altered viruses.

Find out more in this Vaccine Update article.

Other questions you may have about the use of fetal cells and vaccines

Can vaccines made using fetal cells alter a person’s dna.

Even though fetal cells are used to grow vaccine viruses, vaccines do not contain these cells or pieces of DNA that are recognizable as human DNA. People can be reassured by the following:

• When viruses grow in cells, the cells are killed because in most cases the new viruses burst the cells to be released.
• Once the vaccine virus is grown, it is purified, so that cellular debris and growth reagents are removed.
• During this process of purification, any remaining cellular DNA is also broken down. To learn more about DNA and vaccine, visit the “Vaccine ingredients – DNA” page .

Do vaccines contain parts of fetuses or fetal cells?

In order to grow viruses in the lab, cells need to be made into single cell suspensions, meaning they can no longer be grouped together in the form of tissues or organs. As such, vaccines do not contain “parts of fetuses.”

Vaccines also do not contain fetal cells. Once the vaccine viruses are grown in the cells, the next step in the manufacturing process is to purify the vaccine viruses away from the cells and substances used to help cells grow. If you have ever picked blueberries, you can think of this part of the process as similar. While you are picking, you might get some of the blueberry plant — stems, leaves and even branches — in your berry bucket, but to use the berries, you remove all of those things, so your pie contains only the blueberries (and any other ingredients you choose to add).

This purification part of the process is important for two reasons. The first, and perhaps most obvious, is the manufacturing reason. From a manufacturer’s perspective, an efficient process that results in the purest possible product makes the final product easier to characterize. However, as consumers, the second, and more important, reason matters more. A pure product will not introduce unnecessary components that could trigger immune responses or affect us in other ways.

How can cells from the 1960s still be used today?

Cells grown in a laboratory setting are provided with an environment conducive to growth. As the cells reproduce and fill the container in which they are grown, researchers care for them by putting them in new containers and giving them additional nutrients to enable continued growth. As a result, the cells are able to replicate exponentially. Periodically, a portion of the cells will be frozen in liquid nitrogen for long-term storage. The extremely cold temperatures of liquid nitrogen freezers, around -200° C, cause biological activity to cease without killing the cells. Decades later, the cells, if thawed and provided with the appropriate nutrients and environment, will begin to grow again. As the cells grow, the newly produced cells can also be frozen, and the process extended again.

To read more about how this process is done in the laboratory, check out the article about Dr. Plotkin’s work on the Hilleman Film website .

Do more abortions need to be done?

No. Because the cells isolated in the 1960s have been cared for as described above, vaccine manufacturers do not need to seek new cell sources.

My religion is against abortions, so I don’t want to get these vaccines. Are alternatives available?

An alternative version of rabies vaccine is available; however, that is not the case for the rubella, chickenpox and hepatitis A vaccines.

Religious leaders from the major religions, including Catholicism, have evaluated the use of these cells in making vaccines and determined that it is not sinful to accept vaccines made in this manner.

To read more about religious positions related to vaccines, including the use of fetal cells, visit the Immunization Action Coalition’s “Religious Concerns” webpage .

Resources for additional information

• Stanley Plotkin: Pioneering the use of fetal cells to make rubella vaccine
• Are Fetal Cells Used to Make Vaccines?
• Vaccine Ingredients — DNA
• Religious Concerns: Resources & Information on the Immunize.org website
• The Vaccine Race , by Meredith Wadman — Read a summary of the book and find how to get it in this article from the Vaccine Update newsletter.
• Vaccines and Your Child: Separating Fact from Fiction — See an excerpt, including information related to fetal cells, in this booklet.

DNA, Fetal Cells & Vaccines Q&A

English | Spanish

Offit PA and Moser CA. Vaccines and Your Child: Separating Fact from Fiction . 2011. Columbia University Press.

Reviewed by Paul A. Offit, MD, on January 16, 2024

Evaluating the Association between Routine Pneumococcal Vaccination and Covid-19 Severity Among Older Adults in the United States: A Case Control Study

13 Pages Posted: 29 Aug 2024

Ottavia Prunas

University of Basel - Swiss Tropical and Public Health Institute

Georgetown University

Kayoko Shioda

Boston University

Shweta Bansal

Daniel weinberger.

Yale University - Department of Epidemiology of Microbial Diseases

The relationship between infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and disease caused by Streptococcus pneumoniae remains uncertain. This case-control study investigated the association between pneumococcal vaccination and the progression to severe outcomes among COVID-19 patients aged 65 and older in the United States. We identified COVID-19 patients aged 65 and older with severe outcomes (cases) and those with non-severe or less severe outcomes (controls) from Medicare data from April 2020 to December 2021. Logistic regression models were employed to evaluate the association between prior receipt of pneumococcal vaccination (13-valent conjugate vaccine [PCV13] and/or 23-valent pneumococcal polysaccharide vaccine [PPSV23]) and severe COVID-19 outcomes. A total of 28,124 COVID-19 patients exhibited severe respiratory symptoms or were admitted to the intensive care unit (ICU). The odds of progression from non-severe symptoms to severe respiratory symptoms were modestly lower among COVID-19 patients with PCV13 receipt (odds ratio (OR): 0.91 (95% confidence interval [CI], 0.88, 0.93), compared to those without PCV13. The odds of requiring ICU admission were lower among COVID-19 patients with severe respiratory outcomes who received PCV13, compared to those who did not (OR: 0.92; 95% CI, 0.88, 0.97). The magnitude of the associations was similar when evaluating the associations between the receipt of influenza or zoster vaccinations and the severity of COVID-19 outcomes. Finally, there was no association between receiving PPSV23 more than five years ago and COVID-19 severity. Overall, our findings indicated modest to no association between pneumococcal vaccination and severe COVID-19 outcomes among older adults with COVID-19.

Note: Funding Information: This work was funded by an investigator-initiated grant (MISP 60274) from Merck Research Laboratories to Georgetown University, with a subcontract to Yale University. Declaration of Interests: DMW has received consulting fees from Pfizer, Merck, and GSK for work unrelated to this manuscript and has served as Principal Investigator on grants from Pfizer and Merck to Yale University. SB has served as Principal Investigator on grants from Merck, the Coalition for Epidemic Preparedness Innovations (CEPI), and the FluLab Foundation to Georgetown University. Ethical Approval Statement: This work was approved by the Institutional Review Board of Georgetown University as Study # STUDY00002324.

Keywords: case-control study, COVID-19 severity, SARS-CoV-2, Streptococcus pneumoniae, pneumococcal conjugate vaccine, older adults.

Suggested Citation: Suggested Citation

Ottavia Prunas (Contact Author)

University of basel - swiss tropical and public health institute ( email ).

Basel Switzerland

Georgetown University ( email )

Washington, DC 20057 United States

Boston University ( email )

Yale university - department of epidemiology of microbial diseases ( email ).

United States

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