research article on covid 19 vaccine

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Article Contents

Development of next-generation covid-19 vaccines: barda supported phase 2b study designs.

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Daniel N Wolfe, Elizabeth Arangies, Gloria L David, Brian Armstrong, Theresa Z Scocca, Janel Fedler, Ramya Natarajan, James Zhou, Lakshmi Jayashankar, Ruben Donis, Mirjana Nesin, H Cody Meissner, Laurence Lemiale, Gerald R Kovacs, Shyam Rele, Robin Mason, Huyen Cao, Development of Next-Generation COVID-19 Vaccines: BARDA Supported Phase 2b Study Designs, Clinical Infectious Diseases , 2024;, ciae286, https://doi.org/10.1093/cid/ciae286

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In response to the COVID-19 pandemic, vaccines were quickly and successfully developed and deployed, saving millions of lives globally. While first generation vaccines are safe and effective in preventing disease caused by SARSCoV-2, next-generation vaccines have the potential to improve efficacy and safety. Vaccines delivered by a mucosal route may elicit greater protective immunity at respiratory surfaces thereby reducing transmission. Inclusion of viral antigens in addition to the spike protein may enhance protection against emerging variants of concern. Next-generation vaccine platforms with a new mechanism of action may necessitate efficacy trials to fulfill regulatory requirements. The Biomedical Advanced Research and Development Authority (BARDA) will be supporting Phase 2b clinical trials of candidate next-generation vaccines. The primary endpoint will be improved efficacy in terms of symptomatic disease relative to a currently approved COVID-19 vaccine. In this paper, we discuss the planned endpoints and potential challenges to this complex program.

• antigens, viral
• drug administration routes
• mucous membrane
• pharmacokinetics
• surrogate endpoints
• covid-19 vaccines
• coronavirus pandemic
• spike protein, human

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Peer-reviewed

Research Article

COVID-19 and vaccine hesitancy: A longitudinal study

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Rady School of Management, University of California San Diego, La Jolla, California, United States of America

Roles Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Roles Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Visualization, Writing – original draft, Writing – review & editing

• Ariel Fridman, 
• Rachel Gershon, 
• Ayelet Gneezy

• Published: April 16, 2021
• https://doi.org/10.1371/journal.pone.0250123
• Peer Review
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How do attitudes toward vaccination change over the course of a public health crisis? We report results from a longitudinal survey of United States residents during six months (March 16 –August 16, 2020) of the COVID-19 pandemic. Contrary to past research suggesting that the increased salience of a disease threat should improve attitudes toward vaccines, we observed a decrease in intentions of getting a COVID-19 vaccine when one becomes available. We further found a decline in general vaccine attitudes and intentions of getting the influenza vaccine. Analyses of heterogeneity indicated that this decline is driven by participants who identify as Republicans, who showed a negative trend in vaccine attitudes and intentions, whereas Democrats remained largely stable. Consistent with research on risk perception and behavior, those with less favorable attitudes toward a COVID-19 vaccination also perceived the virus to be less threatening. We provide suggestive evidence that differential exposure to media channels and social networks could explain the observed asymmetric polarization between self-identified Democrats and Republicans.

Citation: Fridman A, Gershon R, Gneezy A (2021) COVID-19 and vaccine hesitancy: A longitudinal study. PLoS ONE 16(4): e0250123. https://doi.org/10.1371/journal.pone.0250123

Editor: Valerio Capraro, Middlesex University, UNITED KINGDOM

Received: November 12, 2020; Accepted: February 14, 2021; Published: April 16, 2021

Copyright: © 2021 Fridman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data and code are publicly available on the Open Science Framework at https://osf.io/kgvdy/ .

Funding: UC San Diego Global Health Initiative (GHI): awarded to all authors; Project number: 1001288. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. https://medschool.ucsd.edu/som/medicine/divisions/idgph/research/Global-Health/grant-recipients/2019-2020/Pages/Faculty-Postdoc-Travel-and-Research.aspx .

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

Introduction

Vaccinations are among the most important public health tools for reducing the spread and harm caused by dangerous diseases [ 1 ]. The World Health Organization estimates that vaccines prevented at least 10 million deaths between 2010–2015 worldwide [ 2 ]. Despite considerable evidence showing vaccines are safe [ 3 , 4 ], there is increasing skepticism toward vaccination [ 5 , 6 ]. Vaccine hesitancy has led to a decline in vaccine uptake and to an increase in the prevalence of vaccine-preventable diseases (VPDs) [ 7 , 8 ]. Ironically, the objection to vaccines is commonly a consequence of their effectiveness—because individuals have lower exposure to VPDs, they are less concerned about contracting them [ 9 ], which consequently leads to greater vaccine hesitancy [ 10 ]. The COVID-19 pandemic has created a new reality where individuals are faced with a previously unknown disease and its effects, providing a unique opportunity to investigate vaccine attitudes during a period of heightened disease salience. The present research reports findings from a longitudinal study conducted during the COVID-19 health crisis, in which we measured changes in attitudes toward a prospective vaccine, as well as shifts in vaccine attitudes in general.

Factors influencing vaccine attitudes and behaviors

Past research has identified a variety of situational and individual-level factors that influence vaccine attitudes and behavior, the most prominent of which are risk perceptions and demographic characteristics.

Assessments of risk are influenced by both cognitive evaluations (i.e., objective features of the situation such as probabilities of outcomes) and affective reactions [ 11 ], as well as by contextual factors (e.g., the information that is most available or salient at the time [ 12 ]). For example, research shows that media coverage plays a significant role in determining the extent to which we take threats seriously [ 13 ]. When individuals perceive heightened risk of a threat, they become more favorable toward interventions that mitigate that threat, including vaccination (for a meta-analysis on the effect of perceived risk on intentions and behaviors, see [ 14 ]). In the case of COVID-19, this would suggest more positive attitudes toward a vaccine and greater likelihood to get vaccinated. Indeed, research suggests that individuals should exhibit a greater interest in vaccinations during a pandemic because disease threat is more salient [ 15 ].

Past efforts to improve vaccine attitudes have had limited success or even backfired; for example, messages refuting claims about the link between vaccines and autism, as well as messages featuring images of children who were sick with VPDs, had negative effects on vaccine attitudes among those who were already hesitant to vaccinate [ 16 ]. In contrast, messaging that increases disease threat salience has shown promise in reducing vaccine hesitancy [ 5 ], and there is evidence suggesting that increased threat salience for a particular disease may also increase intentions to vaccinate for other diseases [ 17 ]. Building on these findings, we expected to find an increase in pro-vaccine attitudes and in individuals’ interest in a COVID-19 vaccine when the perceived threat of the COVID-19 virus increased.

Vaccine attitudes are also influenced by a variety of demographic and ideological factors (for a review, see [ 18 ]). For example, perceptions of vaccine risk differ among individuals of different ethnic backgrounds [ 19 ], and there is extant work demonstrating a positive correlation between socioeconomic status (SES) and vaccine hesitancy [ 20 , 21 ]. Socio-demographic factors are also linked to vaccine-related behaviors: among college students, those whose parents have attained a higher level of education are more likely to get immunized [ 22 ], and researchers have identified age as a predictor for receiving the influenza vaccine [ 23 ].

Political ideology is another well-documented determinant of vaccine-related attitudes and behaviors. Despite a common belief that liberals tend toward anti-vaccination attitudes in the United States, there is strong evidence that this trend is more present among conservatives [ 24 , 25 ]. According to a recent Gallup Poll, Republicans are twice as likely to believe the widely debunked myth that vaccines cause autism [ 26 ]. Recent work has shown that exposure to anti-vaccination tweets by President Trump—the first known U.S. president to publicly express anti-vaccination attitudes—has led to increased concern about vaccines among his supporters [ 27 ]. Based on these findings, and in conjunction with the sentiments expressed by the White House that diminished the significance of the pandemic [ 28 ], we expected to find diverging trends between Democrats and Republicans.

The current research

We collected vaccine-related attitudes of individuals living in the U.S. over a six-month period. Beginning in March 2020, we elicited attitudes from a cohort of the same individuals every month. We began data collection before any COVID-19 lockdown measures were in place (i.e., prior to the nation’s first shelter-in-place order [ 29 ]). Hence, our data spans the early phase of the pandemic, when there were fewer than 2,000 total confirmed cases in the U.S., through the following six months, at which point cumulative cases reached over 5.3 million [ 30 ].

Despite our prediction—that a public health crisis would increase disease threat, consequently increasing pro-vaccine attitudes and interest in vaccination—our data show an overall decrease in favorable attitudes toward vaccines. A closer look at the data revealed that political orientation explains more variance than any other socio-demographic variable. Specifically, participants who identify as Republican showed a decrease in their intention to get the COVID-19 vaccine and the influenza vaccine as well as a general decrease in pro-vaccine attitudes, whereas Democrats’ responses to these measures did not show a significant change during this period.

Our work is the first, to our knowledge, to longitudinally measure individuals’ attitudes toward vaccines. In doing so, our findings advance the understanding of how vaccine attitudes might change during an unprecedented public health crisis, revealing a strong association between political party affiliation and vaccine attitudes.

Participants

We recruited a panel of U.S. residents on Amazon’s Mechanical Turk platform to respond to multiple survey waves. To incentivize completion of all waves, we informed participants their payment would increase for subsequent surveys. Participants were paid 30 cents for wave 1, 40 cents for wave 2, and 60 cents for waves 3 and 4, $1.00 for wave 5, and $1.20 for wave 6. In addition, participants were informed that those who completed the first three waves would enter a $100 raffle. The median survey completion time was 5.5 minutes. The sample size for the first wave was 1,018, and the number of participants ranged from 608–762 on subsequent waves (see S1 Table for attrition details). This project was certified as exempt from IRB review by the University of California, San Diego Human Research Protections Program (Project #191273XX).

Our panel represents the broad and diverse population of the United States. The first wave sample included participants from all 50 states (except Wyoming) and Washington D.C., with an age range of 18 to 82 years old (mean = 38.48, median = 35). Approximately half (53%) identified as male, 46% as female, and.6% as other. The racial makeup in our sample was: 80% White, 9% Asian, 6% Black or African American, 4% multiple racial or ethnic identities, and 1% other. Relative to the U.S. Census (2019) [ 31 ] estimates, our sample over-represents White and Asian individuals, and under-represents Black or African American individuals and other racial groups.

We elicited political affiliation using a 6-point Likert scale, ranging from Strongly Republican to Strongly Democratic. In wave 1, 62% identified as Democrats and 38% identified as Republican, which is consistent with results from the most recent General Social Survey (GSS) [ 32 ]. There was no significant change in mean political identity from wave 1 to waves 2–6 (see S2 Table ). We classified participants as Democrats or Republicans using wave 1 political party affiliation. See S2 Appendix for additional details about the correlation of political party affiliation with age, gender, and SES.

Questions and measures

Our primary measure of interest was participants’ stated intention to get the COVID-19 vaccine when it becomes available. We were also interested in their perceptions of COVID-19 threat, general vaccination attitudes, and intention to get the flu shot. For all measures, except flu shot intentions, we combined multiple items to create a composite measure (see S2 Table for specific questions and construct compositions). Questions designed to measure general vaccination attitudes were adapted from prior work [ 33 ].

Additional measures of interest were participants’ trust in broad institutions (media, local government, and federal government). These trust measures followed different trends from each other, and therefore were not combined. At the end of the survey, participants responded to demographic questions. We retained all questions used in wave 1 throughout all six waves (our survey included additional items not reported in this paper; see S2 and S3 Tables for a complete list of measured items).

Data and analysis plan

Only participants with non-missing and non-duplicated responses were included in the analyses (see S1 Appendix for additional details). For all outcomes of interest, we tested for linear trends over time using a fixed effects regression specification [ 34 ]. All regression results include individual-level fixed effects, and standard errors are clustered at the individual level, to adjust for within-person correlation. We used this approach to control for the impact of omitted or unobserved time-invariant variables. P-values are not adjusted for multiple testing (see [ 35 ]). All analyses were conducted using R (version 4.0.2), and regressions were run using the package “fixest” (version 0.6.0). All materials, data, and additional analyses including robustness checks can be found here: https://osf.io/kgvdy/ .

We report results for three different vaccination-related measures: attitudes toward a COVID-19 vaccine, general vaccination attitudes, and flu shot intentions. All measures showed a decreasing trend (Ps < .001, except flu shot intentions where p = .05) for the 6-month duration of the study, indicating a reduction in pro-vaccination attitudes and intention to get vaccinated (COVID-19 and influenza vaccines). See S4 Table for full results of all regressions.

Heterogeneity in trend by political party

To better understand whether the decline in vaccine attitudes over time was driven by a particular factor, we used a data-driven approach, regressing all demographic characteristics on vaccine attitudes, in separate regressions. These demographics included education, income, SES, race, gender, an item measuring whether participants considered themselves to be a minority, whether the participant has children, and political party. Education, income, and SES were median split; race and gender were dummy coded; and political party affiliation was dichotomized into Democrat or Republican. Among all demographic characteristics, separating time trends by political affiliation (by adding an interaction term) attained the greatest adjusted within-R 2 in explaining vaccination attitude measures. In other words, political party affiliation explains the greatest within-individual variation in vaccine attitudes over time.

An analysis of responses by political affiliation revealed that the observed decreasing trend in all three vaccine measures was mostly driven by participants who identified as Republican (all Ps < .05), whereas Democrats’ responses showed either no significant trend (for COVID-19 vaccination and flu shot intentions: Ps >.67) or a significantly less negative time trend (general vaccination: p < .001). For these regressions, and moving forward, all results included interactions between wave and political party as well as interactions for wave and age, and wave and SES, to control for potentially different time trends associated with these variables. In each regression we also tested whether the strength of political affiliation moderates the observed results, and we reported the result when it did. We also conducted ANOVAs to compare mean responses for the outcomes of interest between Democrats and Republicans, separately for each wave (see S5 Table ).

COVID-19 vaccination attitudes ( Fig 1 , Panel A).

• PPT PowerPoint slide
• PNG larger image
• TIFF original image

Points represent means, and error bars represent 95% confidence intervals. All scale responses range from 1 to 7.

https://doi.org/10.1371/journal.pone.0250123.g001

A two-item construct ( r = .78) was created, with greater values corresponding to more favorable responses.

In wave 1, Democrats ( M = 5.39, SD = 1.55) had more favorable attitudes toward a COVID-19 vaccine than Republicans ( M = 4.57, SD = 1.76; t = -7.38, p < .001, d = -.48, 95% CI = [-.61, -.35]). Among Democrats, there was no significant time trend ( β = .02, SE = .04, p >.67) whereas Republicans’ responses followed a decreasing time trend ( β = -.09, SE = .05, p = .046). These trends were significantly different from each other ( β = -.11, SE = .02, p < .001).

General vaccination attitudes ( Fig 1 , Panel B).

A ten-item construct ( α = .95) was created, with greater values corresponding to a more positive attitude toward vaccination in general.

In wave 1, Democrats ( M = 5.83, SD = 1.15) expressed more favorable general vaccination attitudes than Republicans ( M = 5.17, SD = 1.31; t = -7.91, p < .001, d = -.52, 95% CI = [-.66, -.39]). Although both Democrats and Republicans had a decreasing time trend (Democrats: β = -.04, SE = .02, p = .029; Republicans: β = -.09, SE = .02, p < .001), the trend for Republicans was significantly more negative ( β = -.04, SE = .01, p < .001).

Flu shot intentions ( Fig 1 , Panel C).

We asked participants whether they plan to get the flu shot next year, with greater values indicating greater intentions.

In wave 1, Democrats ( M = 4.84, SD = 2.34) indicated greater intentions to vaccinate against the flu than Republicans ( M = 4.35, SD = 2.39; t = -3.15, p = .002, d = -.21, 95% CI = [-.34, -.08]). Among Democrats, there was no significant time trend ( β = .01, SE = .04, p = .86), suggesting their vaccination intentions remained largely stable. Republicans’ responses, however, revealed a decreasing time trend ( β = -.12, SE = .04, p = .005), and the two trends were significantly different from each other ( β = -.12, SE = .02, p < .001).

Our analyses revealed an interaction with political affiliation strength among Republicans, whereby participants who identified as more strongly Republican had a more negative time trend ( β = -.05, SE = .02, p = .027). This interaction was not significant for Democrats ( β = -.02, SE = .01, p = .19).

Perceived threat of COVID-19 ( Fig 2 ).

https://doi.org/10.1371/journal.pone.0250123.g002

A three-item construct ( α = .82) was created, with greater perceived threat about COVID-19.

In wave 1, Democrats ( M = 4.26, SD = 1.25) expressed greater perceived threat of COVID-19 than Republicans ( M = 3.90, SD = 1.39; t = -4.14, p < .001, d = -.40, 95% CI = [-.27, -.14]). Democrats’ responses showed an increasing time trend ( β = .08, SE = .04, p = .033), indicating they became increasingly concerned about the threat posed by the virus over time. Among Republicans, there was no significant time trend ( β = -.01, SE = .04, p = .83). These trends were significantly different from each other ( β = -.09, SE = .02, p < .001). While our data does not render causal claims, it is possible that the divergence in COVID-19 threat perceptions over time among Republicans and Democrats contributes to the divergence in vaccine attitudes between these groups over time. We revisit this proposition in the General Discussion.

Our analyses revealed an interaction with political affiliation strength among Democrats—participants who identified as more strongly Democrat had a more positive time trend ( β = .03, SE = .01, p = .019), suggesting an increasing threat perception over time. This interaction was not significant for Republicans ( β = .01, SE = .02, p = .61).

Trust in broad institutions.

The measures of trust in media, local government, and federal government were not highly correlated ( α = .66), and were therefore analyzed separately.

Trust in media ( Fig 3 , Panel A) . In wave 1, Democrats ( M = 3.61, SD = 1.66) reported greater trust in the media than Republicans ( M = 2.73, SD = 1.65; t = -8.12, p < .001, d = -.53, 95% CI = [-.66, -.39]). There was no significant time trend for either Democrats ( β = .02, SE = .04, p = .57) or Republicans ( β = -.05, SE = .04, p = .20). However, the trend for Republicans was significantly more negative ( β = -.07, SE = .02, p < .001). The different trends we observe for Democrats and Republicans with respect to trust in the media may explain the divergence in perceived threat and vaccine attitudes between these groups over time (see General discussion ).

https://doi.org/10.1371/journal.pone.0250123.g003

Trust in local government ( Fig 3 , Panel B) . In wave 1, Democrats ( M = 4.07, SD = 1.60) indicated lower trust in local government than Republicans ( M = 4.28, SD = 1.60; t = 2.01, p = .045, d = .13, 95% CI = [.003,.26]). Among Democrats, there was no significant time trend ( β = -.06, SE = .04, p = .18), though among Republicans, there was a decreasing time trend ( β = -.11, SE = .05, p = .015). These trends were significantly different from each other ( β = -.06, SE = .02, p = .004).

Trust in federal government ( Fig 3 , Panel C) . In wave 1, Democrats ( M = 2.96, SD = 1.67) expressed lower trust in the federal government than Republicans ( M = 4.08, SD = 1.60; t = 10.52, p < .001, d = .68, 95% CI = [.55,.82]). Both Democrats and Republicans had decreasing time trends (Democrats: β = -.08, SE = .04, p = .036; Republicans: β = -.10, SE = .04, p = .025). These trends were not significantly different from each other ( β = -.02, SE = .02, p = .37).

To rule out differential attrition, we tested whether the composition of our sample (i.e., age, gender, and political party) changed over time (see S1 Table ). Specifically, we tested whether participants who responded to waves 2–6 were significantly different at baseline (wave 1) from the full sample at baseline. The only significant change detected (Ps < .05) was with respect to participants’ age, though the differences were small—the average age was 38.5 at baseline, and remained between 39.9 and 40.8 at baseline among participants who responded to subsequent waves. We found no other systematic pattern of attrition among our participants.

General discussion

Over the course of six months of the COVID-19 pandemic, beginning with a relatively early phase prior to any U.S. directives to stay home (March 2020) and continuing through a cumulation of over 5 million cases (August 2020), we found a decrease in pro-vaccine attitudes and COVID-19 vaccination intentions, as well as reduced intentions to get the influenza vaccine. These findings are contrary to our prediction that increased salience of COVID-19 would improve attitudes toward vaccines.

Our analyses identify political ideology as the best predictor of the decreasing time trend across our three vaccine-related attitudes and intentions measures. In particular, we found that while Democrats’ responses remained fairly stable over time, Republicans shifted away from their lower initial responses and from Democrats’ responses, leading to increased polarization throughout the six-month period.

Contrary to the polarization observed in our data, social and behavioral scientists have long argued that groups facing threats often come together, demonstrating stronger social cohesion [ 36 ], and more cooperative behaviors [ 37 , 38 ]. Researchers have also found that individuals’ sense of shared identity plays a role in promoting cooperative behavior in response to threat [ 39 – 41 ]. Considering our results in the context of these findings might suggest that our respondents’ sense of shared identity was dominated by their political ideology, as opposed to a broader (e.g. American) identity.

What might be going on?

Although the nature of our data does not render causal claims, it highlights potential explanations. First, we note that participants’ ratings of perceived COVID-19 threat followed a similar diverging pattern by party affiliation to our three vaccine-related measures during the study period. Democrats perceived COVID-19 threat to be greater at the start of the study than Republicans did, and this gap widened significantly as the study progressed. This trend is consistent with previous research showing that vaccine hesitancy is related to perceived risk of a threat; when a VPD threat level is low, individuals are less motivated to take preventative action (i.e., immunize; for a review, see [ 42 ]).

Our data offers one potential explanation for the polarization of threat perception: Republican and Democratic participants in our study reported consuming different sources of information. The most commonly checked news source for Republicans was Fox News (Republicans: 50%, Democrats: 8%; χ 2 = 164.55, p < .001) and for Democrats was CNN (Democrats: 47%, Republicans: 23%, χ 2 = 43.08, p < .001, see S6 Table ). Corroborating this proposition, a Pew Research Center poll conducted in March 2020 found that 56% of respondents whose main news source is Fox News believed that “the news media have greatly exaggerated the risks about the Coronavirus outbreak,” whereas this was only true for 25% of those whose main news source is CNN [ 43 ]. Of note, Facebook and Instagram, were also in the top four most consumed news sources for participants affiliated with either party. Extant work describes these platforms as echo chambers [ 44 , 45 ], which may exacerbate partisan exposure to news and information.

Another trend highlighted by our data shows that similar to vaccine attitudes, Republicans’ trust in the media decreased significantly more during our study than Democrats’, suggesting these patterns might be related. According to Dr. Heidi Larson, an expert on vaccine hesitancy and founder of the Vaccine Confidence Project, misinformation regarding vaccinations is more likely to take root when individuals do not trust the information source [ 46 ]. Future research might further examine the role of trust in the media on vaccine attitudes.

While trust in media or media exposure may be driving COVID-19 threat perceptions and vaccine attitudes, there are many other possible explanatory factors that are not captured by our data or analyses. For example, it is possible that threat perceptions were influenced by how a respondents’ county or state was affected by COVID-19; up until June 2020, COVID-19 cases were more common in Democrat-leaning states [ 47 ], which might have amplified its salience early on and influenced attitudes and behavior. Further, although we included individual-level fixed-effects which control for all time invariant participant characteristics, and controlled for different trends by age and SES, we cannot rule out the possibility that other factors (e.g., educational attainment or population density) may have influenced the observed trends. Finally, as our data collection began after the onset of COVID-19, it is possible that the trend we observe for Republicans represents a return to a pre-pandemic baseline of vaccine-related attitudes.

Contributions

This work advances our understanding of how health-related attitudes evolve over time. Our focus on vaccine-related attitudes and intentions is important because experts agree that having enough people vaccinate against COVID-19 is key to stemming the pandemic [ 48 ]. More broadly, negative attitudes toward vaccination in general, and reduced vaccine uptake, is increasingly a public health concern [ 49 ]. This research provides insight into the trends of such vaccine hesitancy, underlining the importance of risk salience and its roots in ideology and media exposure.

This work also contributes to our understanding of political parties and polarization. Numerous anecdotes and reports have demonstrated a partisan divide in Americans’ response to the COVID-19 pandemic. For example, research found greater negative affective responses to wearing a face covering among politically right (vs. left) leaning individuals [ 50 ]. Here, we show that although these observations are valid, the reality is more nuanced. For example, our analyses reveal that polarization on vaccine measures—both attitudes and intentions—is driven primarily by self-identified Republicans’ gradual movement away from their initial responses whereas Democrats’ responses remained largely stable. This insight has important practical implications: It informs us about the dynamics of individuals’ attitudes, bringing us closer to understanding the underlying factors that influence attitudes and behaviors. Equipped with this knowledge, one could design more effective communications and interventions.

Note on methodology and data availability

The present study contributes to a small but growing literature in the social sciences using longitudinal data [ 51 ]. Using a longitudinal methodology allowed us to track individual-level changes over time. Merely observing a single point in time would allow us to observe across-group differences, but would lack the bigger picture of how polarization between these groups evolved. Another key advantage of panel data is that it allows us to include individual-level fixed effects, which control for the impact of omitted or unobserved time-invariant variables. Finally, panel data allows for more accurate inference of model parameters [ 52 ].

While the focus of this paper is vaccine attitudes, our broad dataset offers a unique opportunity to understand attitudes and behavior over time. Due to the richness of our data, its unique nature, and its timeliness, we believe it is important to make it available to other researchers interested in exploring it and publishing additional findings. The complete dataset is available at https://osf.io/kgvdy/ (see S2 and S3 Tables for all items collected).

Supporting information

S1 appendix. additional information about sample exclusions..

https://doi.org/10.1371/journal.pone.0250123.s001

S2 Appendix. Additional information about political party affiliation.

https://doi.org/10.1371/journal.pone.0250123.s002

S1 Table. Attrition table.

https://doi.org/10.1371/journal.pone.0250123.s003

S2 Table. Summary table of measures and constructs included in the text.

https://doi.org/10.1371/journal.pone.0250123.s004

S3 Table. Summary table of measures excluded from the text.

https://doi.org/10.1371/journal.pone.0250123.s005

S4 Table. Regression results.

https://doi.org/10.1371/journal.pone.0250123.s006

S5 Table. Outcome measures by political party affiliation.

https://doi.org/10.1371/journal.pone.0250123.s007

S6 Table. Summary of news sources.

https://doi.org/10.1371/journal.pone.0250123.s008

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• 34. Wooldridge JM. Econometric analysis of cross section and panel data. MIT press; 2010 Oct 1.
• 46. Anderson J. She Hunts Viral Rumors about Real Viruses. The New York Times. 2020 October 13. https://www.nytimes.com/2020/10/13/health/coronavirus-vaccine-hesitancy-larson.html .
• 47. Bump P. Coronavirus has come to Trump country. The Washington Post. 2020 June 17. https://www.washingtonpost.com/politics/2020/06/17/coronavirus-has-come-trump-country/ .
• 48. Quinn M. Fauci warns U.S. "unlikely" to reach Herd Immunity if too Many Refuse Vaccine. CBS News. 2020 June 29. https://www.cbsnews.com/news/fauci-herd-immunity-coronavirus-vaccine/ .
• 49. World Health Organization. Improving vaccination demand and addressing hesitancy. WHO; 2019. [cited 2020 November 3]. https://www.who.int/immunization/programmes_systems/vaccine_hesitancy/en/ .

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Study shows effectiveness of updated COVID-19 vaccines wanes moderately over time, is lower against current variants

by UNC Gillings School of Global Public Health

Boosters that target the omicron subvariants of SARS-CoV-2 are still providing reasonably durable protection against infection, hospitalization and death from COVID-19, according to new data from a study led by researchers at the UNC Gillings School of Global Public Health.

Published in the New England Journal of Medicine , the study found that COVID-19 boosters targeting the XBB.1.5 subvariants were most effective one month after receiving one. After four weeks, the vaccines were 52.2% effective at preventing infection and 66.8% effective at preventing hospitalization.

The vaccines were also highly effective at preventing death, but exact certainty was hard to quantify given the small number of deaths reported during the study period.

After peaking at four weeks, booster effectiveness waned over time. Effectiveness at preventing infection decreased to 32.6% after 10 weeks and 20.4% after 20 weeks, while effectiveness at preventing hospitalization decreased to 57.1% after 10 weeks.

Danyu Lin, Ph.D., Dennis Gillings Distinguished Professor in the Department of Biostatistics at the Gillings School, is lead author on the study. Using data from the Nebraska Electronic Disease Surveillance System and the Nebraska State Immunization Information System, the research team studied the efficacy of vaccination before and after Oct. 25, 2023, when the JN.1 variant began to emerge.

Vaccine effectiveness was lower in the second group, suggesting that the booster was less protective against the now-dominant JN.1 strain.

"The JN.1 subvariant has been the dominant strain in the United States this year," said Lin. "The relatively low effectiveness of the XBB.1.5 vaccines against the JN.1 subvariant, together with the waning effectiveness over time, underscores the need for new vaccines targeting the JN.1 strain."

Lin says the Food and Drug Administration's general strategy is to deploy new COVID-19 vaccines annually in the fall that target the circulating strains in the spring, and that the findings in this study may contribute to this decision.

"It would be worthwhile to deploy new vaccines this fall that target the JN.1. strain," he said.

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

FDA News Release

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

What You Need to Know

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

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

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

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

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

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

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

Additional Details on Today’s Actions

Specifically, today’s actions include:

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

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

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

Related Information

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

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

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• Published: 27 May 2024

Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England

• Emma Copland   ORCID: orcid.org/0000-0001-9280-5241 1 ,
• Martina Patone 1 ,
• Defne Saatci   ORCID: orcid.org/0000-0002-2414-2906 1 ,
• Lahiru Handunnetthi 2 , 3 ,
• Jennifer Hirst 1 ,
• David P. J. Hunt   ORCID: orcid.org/0000-0003-4230-0207 4 ,
• Nicholas L. Mills   ORCID: orcid.org/0000-0003-0533-7991 5 , 6 ,
• Paul Moss   ORCID: orcid.org/0000-0002-6895-1967 7 ,
• Aziz Sheikh   ORCID: orcid.org/0000-0001-7022-3056 1 , 6 ,
• Carol A. C. Coupland 1 , 8 ,
• Anthony Harnden 1 ,
• Chris Robertson   ORCID: orcid.org/0000-0001-6848-5241 9 &
• Julia Hippisley-Cox   ORCID: orcid.org/0000-0002-2479-7283 1  

Nature Communications volume  15 , Article number:  3822 ( 2024 ) Cite this article

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The risk-benefit profile of COVID-19 vaccination in children remains uncertain. A self-controlled case-series study was conducted using linked data of 5.1 million children in England to compare risks of hospitalisation from vaccine safety outcomes after COVID-19 vaccination and infection. In 5-11-year-olds, we found no increased risks of adverse events 1–42 days following vaccination with BNT162b2, mRNA-1273 or ChAdOX1. In 12-17-year-olds, we estimated 3 (95%CI 0–5) and 5 (95%CI 3–6) additional cases of myocarditis per million following a first and second dose with BNT162b2, respectively. An additional 12 (95%CI 0–23) hospitalisations with epilepsy and 4 (95%CI 0–6) with demyelinating disease (in females only, mainly optic neuritis) were estimated per million following a second dose with BNT162b2. SARS-CoV-2 infection was associated with increased risks of hospitalisation from seven outcomes including multisystem inflammatory syndrome and myocarditis, but these risks were largely absent in those vaccinated prior to infection. We report a favourable safety profile of COVID-19 vaccination in under-18s.

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Introduction.

The United Kingdom (UK) approved COVID-19 vaccination for all children aged 12 and over in September 2021. This was extended to 5–11-year-olds in April 2022 in a one-off programme offering a primary course of COVID-19 vaccination to children who were not in a vulnerable or high-risk group 1 . Despite uptake being very high in adults, with over 80% receiving at least one dose of COVID-19 vaccine as of 11th May 2023, uptake has been lower in children, with 62% of 16–17-year-olds, 46% of 12–15-year-olds and 10% of 5–11-year-olds being vaccinated against COVID-19 2 . In the UK, the vast majority of vaccinated children received the BNT162b2 (Pfizer/BioNTech) COVID-19 vaccine, as the UK Joint Committee on Vaccination and Immunisation (JCVI) advised against using ChAdOX1 (AstraZeneca) in people under 40 or mRNA-1273 (Moderna/SpikeVax) in children under 18 during the time period that most children were vaccinated 3 .

In November 2022, the JCVI recommended that 16–49-year-olds who are not in a clinical risk group should no longer be offered a third dose of vaccine from February 2023, and that primary course vaccination in 5–49-year-olds should be targeted to groups at high risk of severe COVID-19 4 . They have advised to continue vaccinating clinically vulnerable children aged 6 months and above and to vaccinate otherwise healthy children aged 12 years and above living with immunosuppressed individuals 4 .

Although the benefits of COVID-19 vaccines in older adults clearly outweigh the risks of rare complications 5 , 6 , 7 , 8 , the balance of risks and benefits in young people remains uncertain. Whilst clinical trials have demonstrated the effectiveness of COVID-19 vaccines in reducing the risk of severe COVID-19 in children aged 5–15 years, the absolute risk of severe outcomes, including hospitalisation, intensive care unit (ICU) admission and death, following infection is low 9 , 10 , 11 , 12 . A serious consequence of SARS-CoV-2 infection in children is multisystem inflammatory syndrome (MIS-C) 13 , 14 , which can lead to coronary artery aneurysms, cardiac dysfunction, and multiorgan inflammatory manifestations 15 . Post-COVID syndrome, or long COVID, is another serious outcome of SARS-CoV-2 infection 16 . The possible impact of long COVID in children is still unclear, but it is estimated to affect 10% of those infected by SARS-CoV-2 and could potentially result in lifelong illness 16 , 17 . COVID-19 vaccines in childhood may reduce the risk of MIS-C 13 and long COVID 17 , and secondary benefits might include increasing overall population immunity, thereby minimising disruptions to education and maintaining overall well-being and health within this age group.

Concerns around vaccine safety have been identified as a barrier to COVID-19 vaccine acceptance, particularly in the context of parents and guardians giving consent for their children to be vaccinated 18 , 19 , 20 . An increased risk of myocarditis has been consistently reported after the delivery of mRNA vaccines, predominantly affecting males aged 18 to 35 years and most notably after the second dose 21 , 22 . This elevated risk of mRNA vaccination-associated myocarditis has also been reported in adolescent males, although these cases have generally been mild and the long-term prognosis is favourable 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 . No serious safety concerns have yet been raised in younger children; however, population-based studies assessing the risk of adverse events following vaccination compared with an unvaccinated group are lacking 33 , 34 , 35 .

In light of the JCVI’s advice to continue vaccinating specific groups of children against COVID-19, and the potential for future mass vaccination programmes if new SARS-CoV-2 variants emerge or the number of severe COVID-19 cases increase, it remains important to quantify the overall risks and benefits of COVID-19 vaccination in this age group to inform future vaccine policy. Therefore, our primary aim was to investigate and compare the risks of pre-specified vaccine safety outcomes following vaccination with BNT162b2, mRNA-1273 and ChAdOX1 in children. We also aimed to compare the risks of these safety outcomes following SARS-CoV-2 infection in vaccinated and unvaccinated children, as a guide to inform global public health policy considerations.

We used the English National Immunisation Management Service (NIMS) database of COVID-19 vaccination, linked at the individual-level to national data for mortality, hospital admissions, and SARS-CoV-2 infection. We undertook a self-controlled case series design, originally developed to examine vaccine safety 36 , 37 , to investigate the association between COVID-19 vaccines available in the UK between 8th December 2020 and 7th August 2022 (BNT162b2, mRNA-1273 and ChAdOx1) and hospitalisation with the following pre-specified outcomes: myocarditis 21 , 22 , MIS-C 38 , immune thrombocytopenia (ITP) 39 , epilepsy 40 , acute pancreatitis 41 , acute disseminated encephalomyelitis (ADEM) 42 , Guillain-Barre syndrome 43 , appendicitis 44 , demyelinating disease 6 , myositis 45 , angioedema 46 and anaphylaxis 46 . We also investigated the association of SARS-CoV-2 infection with these outcomes in children who had been vaccinated prior to infection compared to those who were unvaccinated at time of infection. We compared the incidence of hospitalisation from each outcome in the six weeks following vaccination or SARS-CoV-2 infection relative to the baseline period, and estimated the absolute risk as the excess number of events expected per million children exposed. We also conducted a matched cohort analysis using vaccinated and unvaccinated children included the QResearch primary care database to improve the robustness of the study.

Number of children receiving COVID-19 vaccines

A total of 5,197,925 young people aged 5–17 years, comprising 1,842,159 children aged 5–11 years and 3,355,766 adolescents aged 12–17 years were included in the study. 4,347,781 young adults aged 18–24 years, were included as a comparison. The characteristics of the young people included in the study are detailed in Table  1 and Supplementary Table  1 .

In children aged 5–11 years, 32% ( n  = 581,545) received at least one dose of COVID-19 vaccine and 16% ( n  = 303,118) received a second dose within the study period. Over 99.9% of 5–11-year-olds who received at least one COVID-19 vaccine dose received the BNT162b2 vaccine (Table  2 ). 82% ( n  = 1,508,661) of children in this age group had a positive SARS-CoV-2 test recorded between 8th December 2020 and 7th August 2022, 0.4% ( n  = 5665) of whom received their first COVID-19 vaccine dose prior to their first recorded positive SARS-CoV-2 test (Table  2 ).

In adolescents aged 12–17 years, 86% ( n  = 2,882,229) received a first dose of COVID-19 vaccine, 67% ( n  = 2,254,214) received a second dose and 14% ( n  = 454,868) received a third dose (Table   2 ).

The characteristics of the population excluded from the self-controlled case series analysis (i.e. those who did not receive any COVID-19 vaccine and did not have a positive SARS-CoV-2 test recorded during the study period) are presented in Supplementary Table  2 .

Risk of pre-specified safety outcomes following COVID-19 vaccination in children aged 5–11 years

In children aged 5–11 years, we did not observe an increased risk of any of the pre-specified outcomes in the 1–42 days following any dose COVID-19 vaccine with BNT162b2, mRNA-1273 or ChAdOX1 (Table  3 ). However, given that less than 0.1% of vaccinated 5-11-year-olds received a ChAdOX1 or mRNA-1273 vaccine, the probability of type II errors was high as the sample size was too small to detect statistically significant associations for these vaccines.

The clinical characteristics of all children hospitalised with a pre-specified safety event are shown in Supplementary Table  3 . Supplementary Tables  4 – 7 show the incidence rate ratios (IRR) and 95% confidence intervals (CI) for all outcomes 1–42 days and in weekly risk periods following each vaccine dose in 5–11-year-olds in males and females separately, and the effect of ethnicity on the risk of each outcome.

Risks of pre-specified safety outcomes following COVID-19 vaccination in adolescents aged 12–17 years

In the 1–42 days after the first and second doses of BNT162b2, we observed an increased risk of myocarditis in adolescents aged 12–17 years (IRR 1.92, 95%CI 1.08–3.43 and IRR 2.96, 95%CI 1.65–5.32 for first and second dose, respectively) (Table  4 ). We estimated that an additional 3 (95%CI 0–5) cases per million exposed would be anticipated after the first dose and 5 (95%CI 3–6) after the second dose (Fig.  1 ). When we split the risk period into weekly blocks, the increased risk was restricted to 1–14 days following each dose (Supplementary Table  8 ). There was also an increased risk of hospitalisation with epilepsy (IRR 1.17, 95%CI 1.00–1.37; excess events per million: 12, 95%CI 0–23) in the 1–42 days following the second dose of BNT162b2 (Table  4 , Fig.  1 ).

Estimated number of excess events per million (95% CI) based on incidence rate ratios of each outcome in the 1–42 days following vaccination or SARS-CoV-2 positive test compared to baseline period are presented where there were at least five events during the exposure period and when number of excess events is greater than zero. Data available from 8th December 2020 and 7th August 2022. Table  4 contains the data presented in this figure. MIS-C Multisystem inflammatory syndrome; ITP Idiopathic or immune thrombocytopenic purpura, ADEM Acute disseminated encephalomyelitis.

In the sex-stratified analysis, the increased risk of myocarditis after the first dose of BNT162b2 was only observed in females (IRR 4.01, 95%CI 1.33–12.09; excess events per million: 3, 95%CI 1–4), while the increased risk following the second dose was observed in males only (IRR 2.87, 95%CI 1.50–5.51; excess events per million: 9, 95%CI 4–11) (Supplementary Figs.  1 & 2 , Supplementary Tables  4 & 5 ). We additionally observed an increased risk of demyelinating disease, restricted to females (IRR 2.41, 95%CI 1.06-5.48; excess events per million: 4, 95%CI 0–6) following the second dose of BNT162b2. Of the eight female adolescents who experienced demyelinating disease in the 1–42 days following a second dose of BNT162b2, five were coded as optic neuritis.

In a post hoc analysis investigating differences in risk between children of different ethnic backgrounds, we found that the risk of anaphylaxis following a second dose of BNT162b2 in adolescents with non-white ethnicity was higher relative to the risk in adolescents with white ethnicity (relative IRR 2.55, 95%CI 1.00–6.46) (Supplementary Table  6 ). However, when the analysis was restricted to the subgroup of adolescents from non-white ethnic backgrounds, the risk of anaphylaxis in the 1–42 days following a second dose of BNT162b2 was not significantly increased compared to the baseline period (IRR 1.69, 95%CI 0.80–3.54) (Supplementary Table  6 ). We did not identify any differences in vaccine safety between white and non-white ethnicity for any of the other pre-specified outcomes in under-18s.

We found no evidence for significantly increased risks for any of the pre-specified outcomes in the 1–42 days following a first, second or third dose of mRNA-1273 vaccine in 12–17-year-olds (Table  4 ). However, this analysis lacked power to detect statistically significant associations, except for very large effect sizes, as less than 0.1% of adolescents received a first or second dose of mRNA-1273 vaccine.

There was an increased risk of hospitalisation with epilepsy 1–42 days after a first dose of ChAdOX1 (IRR 1.93, 95%CI 1.10–3.39), with an additional 705 (95%CI 129–1033) cases expected per million exposed (Table  4 ). This increased risk was restricted to females in the sex-stratified analysis (IRR 2.26, 95%CI 1.03–4.94) with an additional 813 (95%CI 44–1164) hospitalisations with epilepsy expected per million female adolescents exposed (Supplementary Table  4 ).

We also observed an increased risk of appendicitis in the 1–42 days following the second dose of ChAdOX1 (IRR 4.64, 95%CI 1.77–12.17; excess events per million: 512, 95%CI 283–599) (Table  4 ).

The IRRs and 95% CIs for all outcomes 1–42 days and in weekly risk periods following each vaccine dose in 12–17-year-olds in males and females separately, and the effect of ethnicity on the risk of each outcome, are presented in Supplementary Figs.  1 & 2 , Supplementary Tables  4 – 6 & 8 .

Risks of pre-specified safety outcomes following COVID-19 infection in children aged 5–11 years

In children aged 5-11 years who had received at least one dose of COVID-19 vaccine before the date that their positive SARS-CoV-2 test was recorded, we did not observe increased risks of any of the pre-specified outcomes in the 1–42 days following SARS-CoV-2 infection. In children who had not been vaccinated against COVID-19 prior to infection, there was an increased risk of hospital admission with MIS-C following a SARS-CoV-2 positive test (IRR 11.52, 95%CI 9.25–14.36), with an additional 137 (95%CI 134–140) cases expected per million exposed (Table  3 , Fig.  2 ). In the sex-stratified analysis, the risk of MIS-C was slightly greater in male children (IRR 12.00, 95%CI 8.92–16.12; excess events per million: 162, 95%CI 157-166) compared to female children (IRR 11.13, 95%CI 7.96–15.57; excess events per million: 124, 95%CI 119–127) (Supplementary Figs.  3 & 4 , Supplementary Tables  4 & 5 ). The increased risk was mainly observed in the 22–42 days following the date that the positive SARS-CoV-2 test was recorded (Supplementary Table  7 ).

Estimated number of excess events per million (95% CI) based on incidence rate ratios of each outcome in the 1–42 days following SARS-CoV-2 positive test compared to baseline period are presented where there were at least five events during the exposure period and when number of excess events is greater than zero. Data available from 8th December 2020 and 7th August 2022. Table  3 contains the data presented in this figure. MIS-C Multisystem inflammatory syndrome, ITP Idiopathic or immune thrombocytopenic purpura, ADEM Acute disseminated encephalomyelitis.

We also observed increased risks of hospital admission for myositis, myocarditis, acute pancreatitis and ADEM following SARS-CoV-2 infection before vaccination (Table  3 , Fig.  2 ). In the sex-stratified analyses, we additionally identified increased risks of ITP (in both sexes) and anaphylaxis (in females only) (Supplementary Figs.  3 & 4 , Supplementary Tables  4 & 5 ).

The IRRs and 95% CIs for all outcomes 1–42 days following SARS-CoV-2 infection in 5–11-year-olds in males and females separately, and the effect of ethnicity on the risk of each outcome, are presented in Supplementary Figs.  3 & 4 , Supplementary Tables  4 , 5 , 6 & 7 .

Risks of pre-specified safety outcomes following COVID-19 infection in adolescents aged 12–17 years

In adolescents aged 12–17 years, we observed an increased risk of MIS-C (IRR 12.38, 95%CI 8.88–17.28; excess events per million: 84, 95%CI 81–86) in the 1–42 days following a SARS-CoV-2 infection in those who had not been vaccinated prior to SARS-CoV-2 infection (Table  4 , Fig.  1 ). In the sex-stratified analysis, male adolescents were at higher risk of MIS-C following infection compared to females (IRR 12.33, 95%CI 8.31–18.31 and IRR 13.11, 95%CI 6.90–24.91 in males and females, respectively), with an additional 131 (95%CI 126–135) cases expected per million males exposed compared to 48 (95%CI 44-50) in females (Supplementary Figs.  1 & 2 , Supplementary Tables  4 & 5 ).

We also observed increased risks of hospitalisation with myocarditis, ITP and epilepsy in the 1-42 days following SARS-CoV-2 infection in adolescents who had not been vaccinated against COVID-19 prior to infection as well as an increased risk of hospitalisation with epilepsy in those who had received at least one vaccine dose prior to infection (Table  4 , Fig.  1 ). In the sex-stratified analysis, the increased risks of hospitalisation with myocarditis and epilepsy were restricted to males while the increased risk of ITP following infection was only observed in females (Supplementary Figs.  1 & 2 , Supplementary Tables  4 & 5 ). We additionally identified increased risks of appendicitis (in females only) and anaphylaxis (in males only) following SARS-CoV-2 infection.

The IRRs and 95% CIs for all outcomes 1–42 days following SARS-CoV-2 infection in 12-17-year-olds in males and females separately, and the effect of ethnicity on the risk of each outcome, are presented in Supplementary Figs.  1 & 2 , Supplementary Tables  4 , 5 , 6 & 8 .

The results for all analyses in young adults aged 18-24 years are presented in Supplementary Tables  6 & 9 .

Robustness of the self-controlled case series results

The robustness of the results of the self-controlled case series analyses were assessed by (1) checking that the risk of outcomes during the pre-vaccination period (month prior to vaccination to account for potential bias of people with recent hospitalisation being less likely to get vaccinated) was lower than the baseline period and (2) checking that the risk of the positive control outcome (anaphylaxis) was higher following vaccination or SARS-CoV-2 infection than the baseline period. In the vast majority of analyses the estimates of the pre-vaccination period and the risk of anaphylaxis following vaccination or SARS-CoV-2 agreed with what was expected (Supplementary Tables  8 & 9 ).

Matched cohort study

Our matched cohort analysis included 1,580,869 children aged 5–11 years and 1,535,341 adolescents aged 12–17 years. Characteristics of the cohort are detailed in Supplementary Table  10 .

Incidence rates of vaccine safety outcomes in the 1–42 days following each vaccine dose and following SARS-CoV-2 infection in vaccinated and unvaccinated children are presented in Supplementary Table  11 . Incidence rates for all outcomes were significantly higher following SARS-CoV-2 infection compared to COVID-19 vaccination.

We matched 160,262 children aged 5–11 years and 848,186 adolescents aged 12–17 years who had received at least one dose of COVID-19 vaccine to a child of the same age and sex who had not received any COVID-19 vaccine doses by the date of the vaccinated child’s first vaccine dose (characteristics of matched cohort reported in Supplementary Table  12 ).

As in the self-controlled case series analysis, we identified an increased risk of hospitalisation with epilepsy in the 1–42 days following a second dose of COVID-19 vaccine with BNT162b2 in 12-17-year-olds (unadjusted IRR 1.77, 95%CI 1.05–2.99, adjusted IRR 3.88, 95%CI 1.27–11.86), but did not find significantly increased risks of appendicitis or myocarditis with BNT162b2 vaccination in adolescents (Supplementary Table  13 ).

We identified additional increased risks of anaphylaxis and appendicitis in 12-17-year-olds following a first dose of BNT162b2 (unadjusted IRR 3.71, 95%CI 1.23–11.14 and unadjusted IRR 1.37, 95%CI 1.05–1.80, respectively) and an increased risk of hospitalisation with epilepsy following a first dose with BNT162b2 in 5–11-year-olds, although the confidence interval was very wide reflecting the uncertainty of the estimate (unadjusted IRR 16.00, 95%CI 2.12–120.65) (Supplementary Table  13 ).

In general, the estimates from the matched cohort study were in agreement with the results from the self-controlled case series analysis in under-18s.

Unadjusted IRRs and IRRs adjusted for self-reported ethnicity (white, non-white, missing), quintile of deprivation (based on Townsend score) and presence of comorbidity (yes/no) for each outcome are reported in Supplementary Table  13 .

In our study of approximately 5.1 million young people aged 5–17 years, we have examined the risks of vaccine safety outcomes following COVID-19 vaccination and SARS-CoV-2 infection, stratified by age group (5–11 years and 12–17 years) and additionally by sex (males and females). We report several key findings that are relevant to public health policy makers. Firstly, we found no strong evidence for increased risks of any of the 12 safety outcomes investigated following COVID-19 vaccination in children aged 5–11 years. Second, in adolescents aged 12–17 years, we observed an increased risk of hospital admission for myocarditis following a first or second dose of BNT162b2, and an increased risk of hospitalisation with epilepsy and demyelinating disease (in females only) following a second dose of BNT162b2 in our primary analysis. Third, children and adolescents aged 5–17 years who had not received a COVID-19 vaccine dose prior to SARS-CoV-2 infection had an increased risk of hospitalisation from seven of the pre-specified safety outcomes including MIS-C and myocarditis. Finally, the risks of safety outcomes from SARS-CoV-2 infection were largely absent in 5–17-year-olds who received at least one COVID-19 vaccine dose prior to infection.

In our cohort of > 2.8 million vaccinated adolescents aged 12–17 years, we estimated 3 (95%CI 0–5) and 5 (95%CI 3–6) excess cases of myocarditis per million exposed in the 1–42 days following a first and second dose of BNT162b2, respectively. We did not observe an increased risk of myocarditis following vaccination with mRNA-1273 in adolescent males or females as some previous studies have reported 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 . However, the mRNA-1273 vaccine was only given to a relatively small number of adolescents in England, primarily for the third booster dose, therefore the study was underpowered to detect statistically significant associations, except for very large effect sizes. As expected, we observed a substantially increased risk of myocarditis in the 1–42 days following almost all doses of both mRNA vaccines in young adults aged 18–24 years compared to the baseline period, consistent with other studies reporting an increased risk of myocarditis in young adult males following a second mRNA-1273 vaccine dose 24 , 25 , 26 . Importantly, however, there were no deaths following a diagnosis of myocarditis in under-18s, and our findings are likely to reflect self-limiting disease.

We also observed a modest increased risk of hospitalisation with epilepsy in adolescents following a second dose of BNT162b2, with an additional 12 (95%CI 0-23) cases estimated per million exposed in 12–17-year-olds. However, a diagnosis of epilepsy is made over a period of time as it typically involves outpatient referral, a magnetic resonance imaging (MRI) scan and an electroencephalogram 47 . Therefore, this reported increased risk of epilepsy is highly unlikely to reflect new-onset epilepsy triggered by the vaccine. A limitation of the data was that we were only able to exclude prior hospital admissions with epilepsy (or any of the pre-specified outcomes) in the two years preceding the study start date. Therefore, the increase in admissions reported here is more likely to reflect seizures in children with an already underlying diagnosis of epilepsy or other chronic neurological condition but who hadn't been hospitalised in the previous two years, which we were unable to capture in our dataset, rather than new diagnoses.

Seizure exacerbation following COVID-19 vaccination has been reported in previous studies, but primarily in adults with epilepsy rather than children 40 . One survey of 224 children (median age 8 years) with epilepsy reported that 10% of those who had been living with epilepsy for more than two years or who had not been seizure-free in the year prior to vaccination had seizures in the month following the first and second dose of COVID-19 vaccine 48 . However, in children who were seizure-free for at least six months before they were vaccinated, the risk of seizures was decreased following vaccination 48 . Another survey of 278 people with Dravet Syndrome (with a median age 19 years) showed that there was increased seizure frequency following COVID-19 vaccination in 13% of the 120 participants who had received at least one vaccine dose 49 . Our findings suggest that the BNT162b2 vaccine is associated with a small increased risk of hospitalisation with epilepsy, but this risk is most likely restricted to children with pre-existing epilepsy and should be balanced against risks of hospitalisation through natural infection with SARS-CoV-2.

In the sex-stratified analysis, we identified a small increased risk of demyelinating disease in females following a second dose of BNT162b2, with an estimated 4 (95%CI 0-6) excess cases per million. To date there has been weak evidence linking mRNA vaccines with neuroimmunological disorders 50 , 51 , and a similar self-controlled case series in adults only identified links between the ChAdOX1 vaccine and neuroimmunological conditions 6 . The coding description demyelinating disease can refer to a spectrum of monophasic and chronic neuroinflammatory disorders, however, the majority of cases following BNT162b2 were coded as optic neuritis, which is typically monophasic and associated with good visual recovery in most childhood cases 52 . From the neurological perspective, this risk should be balanced against the protection vaccination offers against rare and more severe neuroimmunological sequelae of COVID-19 infection such as ADEM.

This study identified two strong safety signals in adolescents associated with the ChAdOX1 vaccine: appendicitis and epilepsy. A substantially increased risk of appendicitis was observed in adolescents following a second dose of ChAdOX1, with an additional 512 (95%CI 283–599) cases expected per million. This estimate is based on a small sample size as the ChAdOX1 vaccine was not approved for use in under-40s in the UK from April 2021 3 , 53 . Additionally, the increased risk was not identified in the matched cohort study, suggesting the evidence from this study for a causal association between appendicitis and ChAdOX1 vaccination is weak. Appendicitis was highlighted as an outcome of interest for vaccine safety by the US Food and Drug Administration following a clinical trial of BNT162b2, which reported a higher number of appendicitis cases in the vaccine arm compared to the placebo arm 44 . However, subsequent evidence from observational studies and adverse event reporting databases is conflicting, limited to adults and primarily focusing on mRNA vaccines 11 , 54 , 55 .

Following a first dose of ChAdOX1, we observed a substantially increased risk of hospitalisation with epilepsy, particularly in females, with 813 (95%CI 44–1164) excess cases estimated per million female adolescents vaccinated with a first dose of ChAdOX1, but as discussed above, these are not likely to reflect new diagnoses of epilepsy. The small sample size (only 0.3% of adolescents received ChAdOX1 for the first dose) and resulting wide confidence interval for this estimate should be noted. We also found that there was a higher proportion of adolescents with a hospital admission for epilepsy in the two years prior to the study start date who received ChAdOX1 for the first dose (2.7%), compared to BNT162b2 (0.2%) and mRNA-1273 (0.6%). While these individuals were excluded from the analysis, it is indicative that a higher proportion of adolescents who received a ChAdOX1 vaccine were included in a priority group, such as those with a chronic neurological disease including epilepsy 3 , compared to those who received mRNA vaccines and that the majority of hospitalisations with epilepsy following ChAdOX1 were likely in adolescents with a pre-existing condition. We did not identify an increased risk of hospitalisation with epilepsy following vaccination with ChAdOX1 in the matched cohort study. Our findings, together with a recent study that found evidence for increased risk of cardiac death in young women following a first dose of non-mRNA vaccine 56 , suggest that further work would need to be done to ensure the safety of ChAdOX1 in young people if it were to be used in future vaccination programmes.

In our cohort of > 580,000 children aged 5–11 years who were vaccinated against COVID-19, we found no evidence for increased risks of any of the pre-specified adverse events following any dose of BNT162b2, mRNA-1273 or ChAdOX1 vaccine 33 , 34 , 35 . Based on vaccine uptake rates reported by the UK Health Security Agency 2 , this analysis includes most vaccinated children in this age group in England, however, the lack of safety signals identified in this analysis could partially reflect the relatively small sample size due to the low uptake rate of COVID-19 vaccines in 5–11-year-olds. In the matched cohort study including > 160,000 vaccinated 5–11-year-olds, we additionally found an increased risk of hospital admission with epilepsy following a first dose with BNT162b2 compared to unvaccinated children. However, given that epilepsy was not identified as a safety signal in this age group in the self-controlled case series analysis and the lengthy diagnosis pathway for epilepsy as described above, this potential increased risk is most likely restricted to children with pre-existing epilepsy.

Following SARS-CoV-2 infection we observed increased risks of hospital admission from MIS-C, myocarditis, acute pancreatitis, myositis and ADEM in children aged 5–11 years who had not been vaccinated against COVID-19 prior to infection. Most notably, we estimated an additional 137 (95%CI 134–140) hospital admissions from MIS-C in the four to six weeks after the date of a positive test being reported per million children exposed. We also observed increased risks of MIS-C, myocarditis, ITP and hospitalisation with epilepsy in adolescents aged 12–17 years following SARS-CoV-2 infection in those who had not been vaccinated prior to infection. 84 (95%CI 81-86) additional cases of MIS-C per million exposed would be expected following SARS-CoV-2 infection in adolescents of this age group prior to vaccination.

However, in both children and adolescents, these increased risks of serious outcomes from SARS-CoV-2 infection were absent in those who received at least one dose of COVID-19 vaccine prior to infection. The exception was hospitalisation with epilepsy. Our analyses suggested that the risk of admission to hospital with epilepsy was increased following SARS-CoV-2 infection in adolescents aged 12–17 years who were not vaccinated against COVID-19 prior to infection, with an estimated additional 16 (95%CI 2–28) cases per million. A risk was still seen following infection in those who received at least one vaccine dose prior to infection, but at a slightly lower level, with an additional 15 (95%CI 1–24) hospital admissions with epilepsy per million. This study has shown that vaccination is associated with a significantly reduced risk of most SARS-CoV-2 complications in young people, particularly MIS-C, which can be fatal 15 .

This study has several strengths. First, this was a population-based study of prospectively recorded data not subject to recall and selection biases linked to case reports. Second, the large sample size allowed us to investigate rare outcomes, particularly following vaccination with BNT162b2, which could not be assessed through clinical trials. Third, the self-controlled case series study design removes potential confounding from fixed characteristics, and the additional breakdown of our study period into weekly blocks accounted for temporal confounding. We also assessed the robustness of our results through several sensitivity analyses, a matched cohort analysis and a parallel analysis in 18–24-year-olds to ensure that the results from our study were consistent with the current evidence base in adults.

There were also some limitations to this study. First, despite the large sample size, this study may have been under-powered to investigate rare outcomes in 5–11-year-olds due to the relatively small proportion of vaccinated children in this age group. Second, we relied on hospital admission codes and death certification to define the outcomes so our design will not have captured milder events only occurring in the community or only reported in GP records. This could have resulted in a misclassification bias. Third, we only had access to cases of SARS-CoV-2 infection confirmed with a reverse transcription polymerase chain reaction (RT-PCR) test in our database, which were more likely to happen in the early stages of the pandemic or in a hospital setting, and less likely to be used in schools and community settings where the vast majority of routine testing took place. We were also unable to account for unascertained SARS-CoV-2 infections, therefore, some of the adverse events could be misclassified as being associated with vaccination rather than a SARS-CoV-2 infection that was not recorded and the analysis of adverse outcomes following SARS-CoV-2 infection may have been biased by incomplete COVID-19 testing in the English population. Fourth, we were unable to determine the effect of SARS-CoV-2 variant on the risk of adverse events, as detailed data on the viral variant of SARS-CoV-2 underlying recorded infections was also not available in our database. Fifth, although we adjusted for seasonal effects in the self-controlled case series models, we did not explicitly investigate the effect of the wave of the pandemic during which the infection occurred on the risk of adverse events. For example, the incidence of MIS-C has been reported to be lower during the periods when Delta and Omicron variants were dominant, even before 12–15-year-olds started being vaccinated, compared to the period when the Alpha variant was dominant 57 . Given that > 98% of children in this study were vaccinated against COVID-19 during the periods that Delta and Omicron were dominant, we may expect a lower incidence of MIS-C following infection in vaccinated children, who were unlikely to have been infected with the Alpha variant, compared to unvaccinated children, who had a higher likelihood of being infected with the Alpha variant. Lastly, we were unable to assess differences in vaccine safety by level of deprivation, which should be prioritised as a future area of research.

In summary, we found no strong evidence for increased risks of 12 pre-specified vaccine safety outcomes following COVID-19 vaccination in children aged 5–11 years and no new significant safety concerns in 12–17-year-olds following vaccination with mRNA vaccines recommended for use in these age groups in the UK by the JCVI. Additionally, in unvaccinated children we found increased risks of hospitalisation from seven adverse outcomes including MIS-C and myocarditis following SARS-CoV-2 infection that were either not observed, or were reduced, following vaccination. Overall, our findings support a favourable safety profile of COVID-19 vaccination using mRNA vaccines in children and young people aged 5-17 years.

Ethics approval and consent to participate

The QResearch® ethics approval was provided by the East Midlands-Derby Research Ethics Committee [reference 18/EM/0400] and reviewed by the QResearch science committee [Project OX300]. Consent from participants was not required. The study was performed in accordance with the Declaration of Helsinki.

Data sources

We used the NIMS database of COVID-19 vaccination. We linked individual-level vaccination data to national data for mortality (Office for National Statistics), hospital admissions (Hospital Episode Statistics), and SARS-CoV-2 infection assessed by RT-PCR (Second Generation Surveillance System) using the unique NHS number. Additional analyses to assess robustness of the results made use of the QResearch database, which includes anonymised health records from ~1800 family practices across England.

Study design

We undertook a self-controlled case series design, originally developed to examine vaccine safety 36 , 37 , to explore the association between BNT162b2, mRNA-1273 and ChAdOx1 vaccines and pre-specified outcomes. Separate analyses were conducted for each outcome. The analyses were conditional on each case, thus any fixed characteristic during the study period, such as sex and ethnicity, were inherently controlled for by design. Age was considered as a fixed variable because the study period was short.

Study period and population

The cohort included all children aged 5–17 years who had received at least one dose of BNT162b2, mRNA-1273 or ChAdOx1 vaccine or who had a positive SARS-CoV-2 test between 8th December 2020 and 7th August 2022. In each self-controlled case series analysis, we only included children who were admitted to hospital or died from the outcome during the study period and excluded children with a hospitalisation for the same outcome in the two years prior to 8th December 2020 and those who received other COVID-19 vaccine types. We also undertook an analysis in young adults aged 18–24 years as a comparison.

We a priori selected severe outcomes resulting in hospital admission or death which are monitored by national medical regulatory authorities, clinical trials, post-marketing surveillance, emerging scientific literature and neurological, cardiology, paediatric and immunology/vaccine expertise available. Our pre-defined outcomes were previously reported COVID-19 infection- and COVID-19 vaccination-related adverse events with strong evidence in young people: myocarditis 21 , 22 , MIS-C 38 and myositis 45 and those in adults: Guillain-Barre syndrome 43 , demyelinating disease 6 , ITP 39 and appendicitis 44 as well as adverse events reported following any vaccination during childhood and early young adulthood: epilepsy 40 , acute pancreatitis 41 , ADEM 42 and angioedema 46 . The selected outcomes are consistent with previous studies reporting COVID-19 vaccine safety in young people 58 . Anaphylaxis was also included as a positive control outcome because it can occur shortly after vaccination 46 . Outcomes were identified using relevant International Classification of Diseases codes ( https://www.qresearch.org/data/qcode-group-library/ ). For each outcome, we used the first event recorded during the study period and did not incorporate readmissions for the same outcome into the analysis.

Our main vaccine exposures were a first, second and third dose of BNT162b2, mRNA-1273 or ChAdOx1. To account for heterologous vaccination, each vaccine type and dose was considered separately. SARS-CoV-2 infection exposure was defined as the first positive SARS-CoV-2 test (assessed by RT-PCR) within the study period and was included as a separate variable, allowing safety outcomes that occurred following vaccination and infection to be allocated to both exposures in the model and mutually adjusted. We did not include reinfections in the analysis. We distinguished between infection occurring before the first vaccine dose, or after. We defined the exposure risk period as 1–42 days after each exposure under the assumption that the adverse events under consideration were unlikely to be related to the exposures if they occurred after 42 days. In the case where two vaccine doses were given within 42 days of each other, the risk period of the earlier dose was truncated on the date prior to the day that the next vaccine dose was received. People with a recent hospital admission may delay vaccination, therefore a pre-risk period of 1–28 days before each exposure was excluded from the baseline period to account for this potential bias 36 . Since people may have SARS-CoV-2 testing on hospital admission, we allocated day zero to a risk period of its own 36 . Whilst these admissions may have been caused by SARS-CoV-2 infection, reverse causality involved in their detection could lead to overestimation of the effect of infection on the outcome. All remaining observation time was included in the baseline period.

Statistical analysis

We analysed the data with the self-controlled case series method using a conditional Poisson regression model with an offset for the length of the exposure risk period. We fixed age as the age at date of first COVID-19 vaccination or date of first positive SARS-CoV-2 test recorded in study period for those who were unvaccinated. To allow for underlying seasonal effects, we split the study observation period into two-week periods and adjusted for these as a factor variable in the statistical models. We censored follow-up at the earliest of time of death, fourth dose or study end. We estimated the additional number of events per million persons exposed following vaccination or infection 59 and assessed significance at the 5% level.

In the primary analysis, we fitted the self-controlled case series model separately in children aged 5–11 years and adolescents aged 12–17 years and stratified by sex (male and female). We additionally fitted the model in 18–24-year-olds for comparison. As sensitivity analyses, we fitted the self-controlled case series model starting the observation period at the day of first, second and third vaccine dose and without censoring for deaths due to the outcome, to ascertain the robustness of our results when the outcome increases the probability of death. We fitted the model excluding those who received a third dose, as they might be the most clinically vulnerable individuals. We also fitted the model including children who were vaccinated but did not have a record of a SARS-CoV-2 infection during the study period, to assess the effect of the vaccine alone, to account for the possibility that an adverse event could have occurred within 42 days of both a vaccine dose and a SARS-CoV-2 infection. Finally, we fitted the model including only SARS-CoV-2 positive patients who had not received any vaccine to assess the effect of SARS-CoV-2 exposure alone. We additionally tested the effect of ethnicity (white or non-white) on the risk of each outcome by including an interaction term between ethnicity and vaccine/infection exposures.

Matched cohort analysis

We also conducted a post hoc matched cohort study using the QResearch database of primary care records, linked to hospital episode statistics, COVID-19 vaccination and SARS-CoV-2 infection data. The study population included all vaccinated children aged 5–17 years with GP records in the QResearch database, and matched unvaccinated children, irrespective of SARS-CoV-2 test status during the study period. We matched vaccinated children to children of the same age and sex who were unvaccinated at the time that the vaccinated child received their first dose (rounded to the nearest 7 days) at a ratio of 1:1. Unvaccinated children were sampled from the whole cohort and included children who were vaccinated later in the study period, and these children were censored on date of their first vaccination. The same matched pairs were included in the analysis of the second and third doses for those who received these doses, and where the matched unvaccinated child remained unvaccinated at the time of the second and third doses being received by the vaccinated child.

We estimated incidence rates and fitted conditional Poisson regression models to estimate IRRs of each outcome in the 1–42 days following a first, second or third dose of BNT162b2, mRNA-1273 or ChAdOX1 COVID-19 vaccine. We estimated unadjusted IRRs and IRRs adjusted for self-reported ethnicity (white, non-white, missing), quintile of deprivation (based on Townsend score) and presence of comorbidity (yes/no) that would result in inclusion in clinical risk group (diagnosis prior to vaccine being available).

We additionally conducted a matched cohort analysis in 18–24-year-olds for comparison.

Stata v17 was used for data analysis.

Reporting summary

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

Data availability

The data that support the findings of this study—NIMS Database of COVID-19, mortality (Office of National Statistics), hospital admissions (Hospital Episode Statistics), SARS-CoV-2 infection data (SGSS) and primary care (QResearch)—are not publicly available because they are based on deidentified national clinical records. Due to national and organizational data privacy regulations, individual-level data such as those used for this study cannot be shared openly. Access to the QResearch data is according to the information on the QResearch website ( www.qresearch.org ).

Code availability

A sample of the code used for a similar study has been deposited in the public git repository of the research group, available at https://github.com/qresearchcode/COVID-19-vaccine-safety . This sample code can be used to run a self-controlled case series analysis in STATA.

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Acknowledgements

This research is funded by the NIHR School for Primary Care Research, Grant Reference Number 622. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. We acknowledge the contribution of EMIS practices who contribute to QResearch and EMIS Health and the Universities of Nottingham and Oxford for expertise in establishing, developing or supporting the QResearch database. This project involves data derived from anonymised patient-level information collected by the NHS. The SARS-CoV-2 test data were originally collated, maintained and quality assured by Public Health England (PHE) and transferred to NHS England during the study. Access to the data was therefore facilitated by NHS England. The Hospital Episode Statistics, Secondary Users Service (SUS-PLUS) datasets and civil registration data are used by permission from NHS England who retain the copyright in that data. NHS England and Public Health England bears no responsibility for the analysis or interpretation of the data. JHC is supported by an NIHR senior investigator award. NLM is supported by a British Heart Foundation Chair Award (CH/F/21/90010), Programme Grant (RG/20/10/34966) and Research Excellence Award (RE/18/5/34216). DPJH is supported by the Wellcome Trust (215621/Z/19/Z), Medical Research Foundation and UKDRI (principal funder UKRI Medical Research Council).

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M.P., E.C., J.H.C., C.A.C.C. led the study conceptualization, development of the research question and analysis plan and interpretation of the results. M.P. and J.H.C. obtained funding, obtained data approvals, undertook the data specification and curation. M.P. and E.C. designed the analysis, contributed to interpretation of the analysis, undertook data analysis and wrote the first draft of the paper. D.S., L.H., J.H., N.L.M., P.M., A.S., A.H., C.R. and D.P.J.H. contributed to the discussion on protocol development and provided critical feedback on drafts of the manuscript. All authors approved the protocol, contributed to the critical revision of the manuscript and approved the final version of the manuscript.

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J.H.C. reports grants from National Institute for Health Research (NIHR) Biomedical Research Centre, Oxford, John Fell Oxford University Press Research Fund, Cancer Research UK and Oxford Wellcome Institutional Strategic Support Fund and other research councils, during the conduct of the study outside the scope of this work. J.H.C. is founder and was shareholder until 9 Aug 2023 of ClinRisk Ltd, which produces open and closed source software to implement clinical risk algorithms (outside this work) into clinical computer systems. J.H.C. is an unpaid director of QResearch, a not-for-profit organisation which is a partnership between the University of Oxford and EMIS Health who supply the QResearch database used for this work and is a consultant for Endeavour Predict Ltd outside this work. A.S. serves on a number of UK and Scottish Government COVID-19 advisory groups and was a member of AstraZeneca’s Thrombotic Thrombocytopenic Taskforce; all roles are unremunerated. A.H. is Deputy Chair of the Joint Committee on Vaccination and Immunisation. D.H. serves on the UK Government Commission on Human Medicines P.M. has received speaker and advisory board fees from Moderna and Astra Zeneca. All other authors declare no competing interests related to this paper.

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Copland, E., Patone, M., Saatci, D. et al. Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England. Nat Commun 15 , 3822 (2024). https://doi.org/10.1038/s41467-024-47745-z

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Shown are the 28-day risk period rates of the 28 included adverse events of special interest to COVID-19 vaccines following XBB.1.5-containing mRNA vaccine immunization as a fifth dose compared with reference period rates in Danish people aged 65 years and older from October 1, 2023, to January 8, 2024. The 28-day risk period outcome rates following fifth dose vaccination with an XBB.1.5-containing mRNA vaccine was compared with reference period rates from day 43 after the fourth or fifth dose and onward. Individuals could contribute with person-time during both the 28-day risk period and the 2 reference periods while the number of events and person-time from the 2 reference periods were aggregated. Each outcome was studied separately, which is why there may be slight differences in the denominators due to different exclusions. The arrows indicate that the 95% CI exceeds the upper or lower limits on the x-axis. IRR indicates incidence rate ratio; NE, not estimable; and TIA, transient ischemic attack.

eTable. Eligibility Criteria and Outcome and Covariates Definitions

eFigure. Schematic Figure of the Study Design

eReferences

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Andersson NW , Thiesson EM , Hviid A. Adverse Events After XBB.1.5-Containing COVID-19 mRNA Vaccines. JAMA. 2024;331(12):1057–1059. doi:10.1001/jama.2024.1036

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Adverse Events After XBB.1.5-Containing COVID-19 mRNA Vaccines

• 1 Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

The monovalent Omicron XBB.1.5–containing COVID-19 mRNA vaccines were authorized in the US and Europe for use in autumn and winter 2023-2024. 1 , 2 In Denmark, the XBB.1.5-containing vaccines were recommended as a fifth COVID-19 vaccine dose to individuals aged 65 years and older beginning October 1, 2023. However, data to support safety evaluations are lacking.

We investigated the association between the XBB.1.5-containing vaccine administered as a fifth COVID-19 vaccine dose and the risk of 28 adverse events.

A study cohort of all individuals in Denmark aged 65 and older who had received 4 COVID-19 vaccine doses was established by cross-linking nationwide health care and demography registers on an individual level. The study period was September 15, 2022 (ie, the national rollout date of the fourth dose), to January 8, 2024, and vaccination status was classified in a time-varying manner (the eTable in Supplement 1 provides further details). The 28 adverse events were adapted from prioritized lists of adverse events of special interest to COVID-19 vaccines (eTable in Supplement 1 ). 3 - 5 Each outcome was studied separately and identified as any first hospital contact where an outcome diagnosis was recorded. The diagnosis date served as the event date.

Individuals were followed up from day 43 after the fourth dose (days 29-42 considered a buffer period) until first outcome event while censoring upon emigration, death, receipt of a sixth vaccine dose (as such a dose was not rolled out to the general Danish population during the study period), or end of the study period (eFigure in Supplement 1 ). Outcome rates within the risk period of 28 days following XBB.1.5-containing vaccine administration as a fifth dose was compared with reference period rates from day 43 after a fourth or fifth dose and onward as previously described; the number of events and person-time from the 2 reference periods were aggregated. 5 Individuals could contribute person-time both during the 28-day risk period and the 2 reference periods; individuals not receiving the XBB.1.5-containing vaccine only contributed to reference period person-time. Using Poisson regression, the risk and reference period outcome rates were compared by incidence rate ratios, adjusted for sex, age, region of residence, considered at high risk of severe COVID-19, health care worker, calendar time, and number of comorbidities. Statistical tests were 2-sided and conducted in R (version 4.1.1; R Project for Statistical Computing). A 95% CI that did not cross 1 was defined as statistically significant. Analysis was performed as surveillance activities as part of the advisory tasks of the governmental institution Statens Serum Institut (SSI), which monitors the spread of disease in accordance with §222 of the Danish Health Act, for the Danish Ministry of Health. According to Danish law, national surveillance activities conducted by SSI do not require approval from an ethics committee.

Among the 1 076 531 included individuals (mean [SD] age, 74.7 [7.4] years; 53.8% female), 902 803 received an XBB.1.5-containing vaccine as a fifth dose during follow-up ( Table ).

Receipt of an XBB.1.5-containing vaccine was not associated with a statistically significant increased rate of hospital contacts for any of the 28 different adverse events within 28 days after vaccination compared with the reference period rates ( Figure ). For example, the incidence rate ratio was 0.96 (95% CI, 0.87-1.07) for an ischemic cardiac event, 0.87 (95% CI, 0.79-0.96) for a cerebral infarction, and 0.60 (95% CI, 0.14-2.66) for myocarditis. Some outcomes were very rare during follow-up (eg, cerebral venous thrombosis), resulting in lower statistical precision; however, for 18 of the 28 adverse events examined, the upper bound of the CI was inconsistent with moderate to large increases in relative risk of 1.4 or greater.

In a nationwide cohort of more than 1 million adults aged 65 years and older, no increased risk of 28 adverse events was observed following vaccination with a monovalent XBB.1.5-containing vaccine.

Limitations of this study include potential residual confounding; differences in ascertainment of adverse events between compared periods cannot be excluded, but, in contrast to what was observed, would bias toward increased risks if present. This was mitigated by comparing the 28-day risk period rates following a fifth dose vaccination with an XBB.1.5-containing vaccine with reference period rates from 43 days or more after the fourth and fifth vaccine dose as opposed to never vaccinated period rates. Additionally, analyses were not adjusted for multiple testing, and some results showed lower risk for XBB.1.5-containing vaccines; yet, a time-varying healthy vaccinee effect cannot be excluded. Also, no medical record review of cases was done, but any outcome misclassification would most likely be nondifferential.

Accepted for Publication: January 23, 2024.

Published Online: February 26, 2024. doi:10.1001/jama.2024.1036

Corresponding Author: Niklas Worm Andersson, MD, Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen S 2300, Denmark ( [email protected] ).

Author Contributions: Dr Andersson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Andersson.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Andersson, Thiesson.

Supervision: Hviid.

Conflict of Interest Disclosures: Dr Hviid reported receiving grants from Lundbeck Foundation, Novo Nordisk Foundation, and Danish Medical Research Council and being a scientific advisory board member for VAC4EU. No other disclosures were reported.

Data Sharing Statement: See Supplement 2 .

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Social Media

Misleading COVID-19 headlines from mainstream sources did more harm on Facebook than fake news

MIT Sloan Office of Communications

May 30, 2024

New MIT Sloan research shows that unflagged but misleading content on Facebook was less persuasive, but much more widely seen, and thus generated more COVID-19 vaccine skepticism than flagged misinformation.

CAMBRIDGE, Mass., May 30, 2024 – Since the rollout of the COVID-19 vaccine in 2021, fake news on social media has been widely blamed for low vaccine uptake in the United States — but research by MIT Sloan School of Management PhD candidate Jennifer Allen and Professor David Rand finds that the blame lies elsewhere. 

In a new paper published in Science and co-authored by Duncan J. Watts of the University of Pennsylvania, the researchers introduce a new methodology for measuring social media content’s causal impact at scale. They show that misleading content from mainstream news sources — rather than outright misinformation or “fake news” — was the primary driver of vaccine hesitancy on Facebook. 

A new approach to estimating impact

“Misinformation has been correlated with many societal challenges, but there’s not a lot of research showing that exposure to misinformation actually causes harm,” explained Allen. 

During the COVID-19 pandemic, for example, the spread of misinformation related to the virus and vaccine received significant public attention. However, existing research has, for the most part, only established correlations between vaccine refusal and factors such as sharing misinformation online — and largely overlooked the role of “vaccine-skeptical” content, which was potentially misleading but not flagged as misinformation by Facebook fact-checkers. 

To address that gap, the researchers first asked a key question: What would be necessary for misinformation or any other type of content to have far-reaching impacts? 

“To change behavior at scale, content has to not only be persuasive enough to convince people not to get the vaccine, but also widely seen,” Allen said. “Potential harm results from the combination of persuasion and exposure.”

To quantify content’s persuasive ability, the researchers conducted randomized experiments in which they showed thousands of survey participants the headlines from 130 vaccine-related stories — including both mainstream content and known misinformation — and tested how those headlines impacted their intentions to get vaccinated against COVID-19. Researchers also asked a separate group of respondents to rate the headlines across various attributes, including plausibility and political leaning. One factor reliably predicted impacts on vaccination intentions: the extent to which a headline suggested that the vaccine was harmful to a person’s health. 

Using the “ wisdom of crowds ” and natural language processing AI tools, Allen and her co-authors extrapolated those survey results to predict the persuasive power of all 13,206 vaccine-related URLs that were widely viewed on Facebook in the first three months of the vaccine rollout. By combining these predictions with data from Facebook showing the number of users who viewed each URL, the researchers could predict each headline’s overall impact — the number of people it might have persuaded not to get the vaccine. The results were surprising. 

The underestimated power of exposure

Contrary to popular perceptions, the researchers estimated that vaccine-skeptical content reduced vaccination intentions 46 times more than misinformation flagged by fact-checkers. 

The reason? Even though flagged misinformation was more harmful when seen, it had relatively low reach. In total, the vaccine-related headlines in the Facebook data set received 2.7 billion views — but content flagged as misinformation received just 0.3% of those views, and content from domains rated as low-credibility received 5.1%. 

“Even though the outright false content reduced vaccination intentions the most when viewed, comparatively few people saw it,” explained Rand. “Essentially, that means there’s this class of gray-area content that is less harmful per exposure but is seen far more often —and thus more impactful overall — that has been largely overlooked by both academics and social media companies.”

Notably, several of the most impactful URLs within the data set were articles from mainstream sources that cast doubt on the vaccine’s safety. For instance, the most-viewed was an article — from a well-regarded mainstream news source — suggesting that a medical doctor died two weeks after receiving the COVID-19 vaccine. This single headline received 54.9 million views — more than six times the combined views of all flagged misinformation. 

While the body of this article did acknowledge the uncertainty of the doctor’s cause of death, its “clickbait” headline was highly suggestive and implied that the vaccine was likely responsible. That’s significant since the vast majority of viewers on social media likely never click out to read past the headline. 

How journalists and social media platforms can help

According to Rand, one implication of this work is that media outlets need to take more care with their headlines, even if that means they aren’t as attention-grabbing. 

“When you are writing a headline, you should not just be asking yourself if it’s false or not,” he said. “You should be asking yourself if the headline is likely to cause inaccurate perceptions.” 

For platforms, added Allen, the research also points to the need for more nuanced moderation — across all subjects, not just public health. 

“Content moderation focuses on identifying the most egregiously false information — but that may not be an effective way of identifying the most overall harmful content,” she says. “Platforms  should also prioritize reviewing content from the people or organizations with the largest numbers of followers while balancing freedom of expression. We need to invest in more research and creative solutions in this space – for example, crowdsourced moderation tools like X’s Community Notes .”

“Content moderation decisions can be really difficult because of the inherent tension between wanting to mitigate harm and allowing people to express themselves,” Rand said. “Our paper introduces a framework to help balance that trade-off by allowing tech companies to actually quantify potential harm.”

And the trade-offs could be large. An exploratory analysis by the authors found that if Facebook users hadn’t been exposed to this vaccine-skeptical content, as many as 3 million more Americans could have been vaccinated. 

“We can’t just ignore this gray area-content,” Allen concluded. “Lives could have been saved.”

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COVID-19 Vaccine: A comprehensive status report

The current COVID-19 pandemic has urged the scientific community internationally to find answers in terms of therapeutics and vaccines to control SARS-CoV-2. Published investigations mostly on SARS-CoV and to some extent on MERS has taught lessons on vaccination strategies to this novel coronavirus. This is attributed to the fact that SARS-CoV-2 uses the same receptor as SARS-CoV on the host cell i.e. human Angiotensin Converting Enzyme 2 (hACE2) and is approximately 79% similar genetically to SARS-CoV. Though the efforts on COVID-19 vaccines started very early, initially in China, as soon as the outbreak of novel coronavirus erupted and then world-over as the disease was declared a pandemic by WHO. But we will not be having an effective COVID-19 vaccine before September, 2020 as per very optimistic estimates. This is because a successful COVID-19 vaccine will require a cautious validation of efficacy and adverse reactivity as the target vaccinee population include high-risk individuals over the age of 60, particularly those with chronic co-morbid conditions, frontline healthcare workers and those involved in essentials industries. Various platforms for vaccine development are available namely: virus vectored vaccines, protein subunit vaccines, genetic vaccines, and monoclonal antibodies for passive immunization which are under evaluations for SARS-CoV-2, with each having discrete benefits and hindrances. The COVID-19 pandemic which probably is the most devastating one in the last 100 years after Spanish flu mandates the speedy evaluation of the multiple approaches for competence to elicit protective immunity and safety to curtail unwanted immune-potentiation which plays an important role in the pathogenesis of this virus. This review is aimed at providing an overview of the efforts dedicated to an effective vaccine for this novel coronavirus which has crippled the world in terms of economy, human health and life.

1. Introduction

The novel beta-coronavirus SARS-CoV-2 is believed to have emerged last year in 2019 in Wuhan from Bats. Crossing the species barrier it entered human beings with furtherance of infection through human to human transmission. The beta-coronaviruses have jumped between the species and have caused three zoonotic outbreaks namely, SARS CoV (2002-03), MERS-CoV (2012), and SARS-CoV-2 (2019- till date) in the last 2 decades. The existence of a myriad of coronaviruses in bats, including many SARS-related CoV (Severe Acute Respiratory Syndrome related Coronaviruses) and the sporadic crossing over of the species barriers of the coronaviruses to humans, suggest that the future occurrences of zoonotic transmission events may sustain ( Ou et al., 2020 ).

Since its emergence in Nov 2019, it has spread to 188 countries and 25 territories around the globe, despite elaborate efforts by WHO and Governments to contain the infection, primarily owing to the highly infectious nature of this virus ( Anon, 2020a ; Anon, 2020b ). As of 2 July 2020, 10,533,779 cases have been reported globally with 512,842 deaths ( (WHO) World Health Organisation, 2020 ). There has been a monumental increase in the number of infected patients, with a 7-day moving average of 210,209 cases per day, as of 2 July 2020 ( Anon, 2020a ). SARS-CoV-2, a highly contagious virus, tends to spread by the inhalation of the respiratory aerosols, direct human contact, and via fomites. Social distancing, personal hygiene, frequent hand washing or sanitizing using the alcohol (61-70%) based hand-sanitizers, and disinfection of the surfaces are some steps which can protect the individuals from getting infected ( (CDC), Centers for Disease Control and Prevention, 2020 ). R 0 is an epidemiological scale; used to measure the contagiousness of an infectious agent. Its magnitude depends upon various biological, environmental, and socio-behavioral factors. It can be defined as “the average number of secondary cases one would produce in a completely susceptible population in the absence of any deliberate intervention in disease transmission ( Delamater et al., 2019 ).” SARS-CoV-2 has an R 0 value range of 2-3 ( Park, 2020 ) which is significantly higher in comparison to Spanish flu for which the R 0 was recorded at 0.9-2.1 ( Pyrek, 2018 ). According to WHO, people living with non-communicable diseases (co-morbid conditions) are prone to severe illness due to COVID-19 infection. The incubation period of the virus ranges from 2-14 days with a median of 5.1 days ( Lauer et al., 2020 ). The symptoms include fever, dry cough, fatigue, shortness of breath, chills, muscles pain, headache, gastric disturbances and weight loss ( CDC, 2020 ). Some patients may have lymphopenia and bilateral ground-glass opacity changes in the chest CT scans. The histological examinations of the lungs’ biopsy samples have shown a bilaterally diffused alveolar damage with cellular fibromyxoid exudates. A few interstitial mononuclear inflammatory infiltrates were observed both in the liver and the heart specimens ( Xu et al., 2020 ). However, a large population of the infected patients have no or mild symptoms and remain asymptomatic ( Shang et al., 2020 ).

Structurally coronaviruses are pleomorphic, enveloped viruses with a characteristic fringe of projections composed of S protein on their surface. These viruses are equipped with a positive sense ssRNA genome, which is complexed with the nucleocapsid (N) protein forming helical nucleocapsids. The genome is both capped and polyadenylated ( Carter and Saunders, 2007 ). The genetic analysis of SARS-CoV-2 and SARS-CoV has revealed 79% similarity with a total of 380 amino acid substitutions condensed mainly within the NSP genes. Out of these substitutions, there are 27 amino acid replacements in the immune-dominant S protein while 102 and 61 amino acid substitutions are found in the NSP3 and NSP2. Whereas, NSP7, NSP13, E protein, and some accessory proteins are devoid of any amino acid substitutions ( Wu et al., 2020 ). SARS-CoV and SARS-CoV-2 bind a common host receptor, hACE2, to gain entry into the cell but SARS-CoV-2 binds the receptor with a higher affinity than the SARS-CoV. MERS-CoV uses an entirely different receptor that is, Dipeptidyl Peptidase 4 (DPP4) ( Wan et al., 2020 ) and the virus is distantly related to SARS-CoV-2 with around 50% similarity as per the sequence analysis of the two viruses ( Prof Roujian et al., 2020 ).

The genome of SARS-CoV-2 is transcribed in at least 10 Open Reading Frames (ORFs). ORF1ab translates into a polyprotein which is processed into 16 non-structural proteins (NSPs) ( Yoshimoto, 2020 ). The NSPs perform various functions like genome replication, inducing the cleavage of host mRNA, membrane rearrangement, generation of the autophagosome, cleavage of the NSP polyprotein, capping, tailing, methylation, unwinding of the RNA duplex, etc. which are essential for the viral life cycle ( da Silva et al., 2020 ). Besides, the SARS-CoV-2 virus contains four structural proteins namely, spike (S), nucleocapsid (N), envelope (E), and membrane (M) proteins which are encoded by the 3’-end of the viral genome ( Wrapp et al., 2020 ). Amongst the 4 structural proteins the S glycoprotein, being a large multi-functional trans-membrane protein, plays the vital role of viral attachment, fusion, and entry into the host cell ( Wrapp et al., 2020 ). The S protein consists of S1 and S2 subunits, which are further split into different functional domains. The S1 subunit has two functional domains viz. N-terminal Domain (NTD) and Receptor Binding Domain (RBD) and the latter contains conserved receptor binding motif (RBM) ( Jiang et al., 2020 ). The alignment studies have revealed that the region of RBD sequence lies between the residues 331 and 524 of the S protein ( Tai et al., 2020 ). Whereas, the S2 subunit has three operational domains namely, fusion peptide (FP), heptad repeat (HR) 1, and 2. The S1 protein trimer aligns itself at the top of the trimeric S2 stalk to form the immune-dominant S protein ( Jiang et al., 2020 ). Interestingly, a furin cleavage site is observed within the spike protein of SARS-CoV-2 while it is absent in the SARS-CoV which may be a possible explanation of the variation in the pathogenicity of the virus ( Walls et al., 2020 ). A host trans-membrane protease serine 2, (TMPRSS2) is responsible for the initial priming of the spike protein. The virus can utilize both TMPRSS2 and endosomal cysteine proteases cathepsin B and L (CatB/L) to initiate entry into the cell. The TMPRSS2 is responsible for the cleavage of the S protein to expose the FP region of the S2 subunit which is responsible for the initiation of the endosome mediated entry into the host cell. This indicates that TMPRSS2 is a host factor that is essential for viral entry; therefore, the drugs approved for the inhibition of this protease (like camostatmesylate) could be used for therapeutic purposes ( Hoffmann and Kleine-Weber, 2020 ). SARS-CoV-2 uses the human angiotensin-converting enzyme 2 (hACE2) receptor to seize the target cell through the spike glycoprotein (S-Protein), . It has been suggested that the coronaviruses exercise the use of conformational masking and glycan shielding of the spike protein to circumvent the host immune cells. The Cryo-EM structures have revealed the presence of two distinct: closed and open conformations of the S-Protein ectodomain trimer, as a consequence of the opening of the structure at the trimer apex. This conformational diversification is necessary for the receptor binding as the trimer opening exposes the RBM which is present at the interface between the protomers in the closed trimers ( Walls, 2020 ).

The E protein that forms E channels (called the viroporins), and is involved in a myriad of functions in the viral replication cycle involving assembly, release, pathogenesis, etc. ( Gralinski and Menachery, 2020 ). These reprobate ion channels exist in the form of homo-pentamers with each subunit containing 50-120 amino acids. E channels contain at least one trans-membrane domain (TMD) which facilitates the linkage in host cell membranes. SARS CoVs generally contain three categories of ion channels namely: E, 8a, and 3a. The E and 8a ion channels contain the PDZ (Post Synaptic Density Protein; Disc Large Tumor Suppressor; Zonula Occludens-1 Protein) Domain Binding Motif (PBM) which is responsible for the over-expression of the inflammatory cytokines which may result in the cytokine storm ( Pharmaceutical Targeting the Envelope Protein of SARS-CoV-2: the Screening for Inhibitors in Approved Drugs, 2020 ). From the sequence alignment study of the E protein, it was observed that a negatively charged glutamate residue (E69) in SARS-CoV corresponds to a positively charged arginine residue (R69) in SARS-CoV-2 ( Yoshimoto, 2020 ). However, this mutation is remote from the inhibitor binding site; therefore, E protein can be used as a pharmaceutical target ( Pharmaceutical Targeting the Envelope Protein of SARS-CoV-2: the Screening for Inhibitors in Approved Drugs, 2020 ).

M protein, the central organizer of CoV assembly, is most abundantly expressed in the virus particle. It functions crucially in the morphogenesis and assembly of the SARS-CoV-2 by interacting with the essential structural proteins ( Conserved Protein Domain Family: SARS-like-CoV_M, 2020 ). The binding of the M and N protein stabilizes the N protein and RNA complex, and the internal core of the virus. In case of SARS-CoV, the M protein has also been shown to induce the process of apoptosis in the host cell ( Yoshimoto, 2020 ).

In addition to stabilizing the ssRNA genome of the virus particle, the N protein is an antagonist of the antiviral RNAi. It is responsible for the inhibition of the cell cycle of the host cell as it can inhibit the entry of the cell into the S-phase ( Yoshimoto, 2020 ).

Immunotherapy is considered as an effective method for the prophylaxis and treatment of various infectious diseases and cancers, which involves the artificial triggering of the immune system to elicit the immune response ( Masihi, 2001 ). A vaccine that elicits the production of S protein neutralizing antibodies in the vaccinated subjects is the primary aim of all the programs for COVID-19 vaccines. Studies have revealed that there is a limited to no cross-neutralization between the sera of SARS-CoV and SARS-CoV-2, indicating that recovery from one infection may not shield against the other ( Ou et al., 2020 ). Furthermore, a database of approximately 5500 full-length genomes of SARS-CoV-2 isolated from various countries is now available at NCBI which facilitates delineating the polymorphisms in S protein and other important proteins of the virus concerning vaccine development. The rationale for writing this review is to gather all the information about the COVID-19 vaccine development programs and give the readers and researchers insight into types of vaccines being worked upon and the current status of the clinical trials of these vaccines for ready reference.

2. Vaccination strategies

Many efforts have been directed towards the development of the vaccines against COVID-19, to avert the pandemic and most of the developing vaccine candidates have been using the S-protein of SARS-CoV-2 ( Dhama et al., 2020 ). As of July 2, 2020, the worldwide SARS-CoV-2 vaccine landscape includes 158 vaccine candidates, out of which 135 are in the preclinical or the exploratory stage of their development. Currently, mRNA-1273 (Moderna), Ad5-nCoV (CanSino Biologicals), INO-4800 (Inovio, Inc.), LV-SMENP-DC, Pathogen-specific aAPC (ShinzenGeno-Immune Medical Institute), and ChAdOx1 (University of Oxford) have entered the phase I/II clinical trials ( WHO, 2020 ). The vaccines which are in the conduit are based upon inactivated or live attenuated viruses, protein sub-unit, virus-like particles (VLP), viral vector (replicating and non- replicating), DNA, RNA, nanoparticles, etc. with each exhibiting unique advantages and hindarances ( Table 1 ) ( Ning et al., 2020 ). COVID-19 vaccine landscape with percentage share of different types of vaccine is represented in Fig. 1 . To enhance the immunogenicity, various adjuvant technologies like AS03 (GSK), MF-59 (Novartis), CpG 1018 (Dynavax), etc. are now accessible to the researchers for the vaccine development ( Le et al., 2020 ). The immuno-informatics approach is also used for the epitope identification for the SARS-CoV-2 vaccine candidates. It can be used to identify the significant cytotoxic T cell and B-cell epitopes in the viral proteins ( Gupta et al., 2006 ; Baruah and Bose, 2020 ).

Outline of the vaccine production platforms for SARS-CoV-2 and their advantages and limitations

Pie Chart showing the different categories of SARS-CoV-2 vaccines under research ( Anon, 2020c ).

2.1. Protein Sub-unit vaccine

A subunit vaccine is the one which is based on the synthetic peptides or recombinant antigenic proteins, which are necessary for invigorating long-lasting protective and/or therapeutic immune response ( Ning et al., 2020 ). The subunit vaccine, however, exhibits low immunogenicity and requires auxiliary support of an adjuvant to potentiate the vaccine-induced immune responses. An adjuvant may enhance the biological half-life of the antigenic material, or it may ameliorate the immunomodulatory cytokine response. The addition of an adjuvant, therefore, helps in overcoming the shortcomings of the protein subunit vaccines ( Cao et al., 2018 ). The S protein of the SARS-CoV-2 is the most suitable antigen to induce the neutralizing antibodies against the pathogen. The S Protein consists of two subunits. The S1 subunit has the NTD, RBD, and RBM domains while the S2 subunit comprises of FP, HR 1, &2 ( Ou et al., 2020 ). The virus enters into the cell via endocytosis by utilizing the S-Protein mediated binding to the hACE2 receptor. Therefore, the S-Protein and its antigenic fragments are the prime targets for the institution of the subunit vaccine ( Ning et al., 2020 ). The S glycoprotein is a dynamic protein, possessing two conformational states i.e. pre-fusion and post-fusion state. Therefore, the antigen must maintain its surface chemistry and profile of the original pre-fusion spike protein to preserve the epitopes for igniting good quality antibody responses ( Graham, 2020 ). Moreover, means to target the masked RBM as an antigen will enhance the neutralizing antibody response and improve the overall efficacy of the vaccine.

2.1.1. NVX-CoV2373 (Novavax, Inc.| Emergent BioSolutions)

NVX-CoV2373 is a nano-particle based immunogenic vaccine which is based upon the recombinant expression of the stable pre-fusion, coronavirus S-Protein ( Coleman et al., 2020 ). The protein was stably expressed in the Baculovirus system ( Tu et al., 2020 ). The company plans to use the Matrix-M adjuvant to enhance the immune response against SARS-CoV-2 spike protein by the induction of high levels of neutralizing antibodies. In the animal models, a single immunization resulted in the high level of anti-spike protein antibodies which blocked the hACE2 receptor binding domain and could elicit SARS-CoV-2 wild type virus-neutralizing antibodies ( Novavax covid 19 vaccine trial, 2020 ).

2.1.2. Molecular Clamp Stabilized spike protein vaccine candidate

It is being developed by the University of Queensland in collaboration with GSK and Dynavax. The University will have access to vaccine adjuvant platform technology (AS03 Adjuvant system), which is believed to strengthen the vaccine response and minimize the amount of vaccine required per dose ( Lee, 2020 ). The University is developing a stabilized pre-fusion, recombinant viral protein sub-unit vaccine which is based upon the Molecular Clamp technology. This technology has been proved to induce the production of the neutralizing antibodies ( Tu et al., 2020 )

2.1.3. PittCoVacc (University of Pittsburgh)

It is a Micro-Needle Array (MNA) based recombinant SARS-CoV-2 vaccine which involves the administration of rSARS-CoV-2 S1 and rSARS-CoV-2-S1fRS09 (recombinant immunogens). A substantial increase in the antigen specific antibodies with a statistical significance was observed in the pre-clinical trials at the end of two weeks in the mice models. Furthermore, the immunogenicity of the vaccine was maintained even after the sterilization using gamma radiation. The statistically significant titers of antibodies at the early stages and also before boosting, support the feasibility of the MNA-SARS-CoV-2 vaccine ( Kim et al., 2020 ).

2.1.4. Triple Antigen Vaccine (Premas Biotech, India)

It is a multi-antigenic VLP vaccine prototype wherein the recombinant spike, membrane, and envelope protein of SARS-CoV-2 have been co-expressed in an engineered Saccharomyces cerevisiae expression platform (D-Crypt™). The proteins then undergo self-assembly as the VLP. The TEM and allied analytical data simultaneously furnished the biophysical characterization of the VLP. This prototype has the potential to enter the pre-clinical trials as a vaccine candidate after further research and development. Furthermore, it is thought to be safe and easy to manufacture on a mass scale, in a cost-effective manner ( Arora and Rastogi, 2020 ).

2.2. Viral Vectored vaccines

A vaccine based on viral vectors is a promising prophylactic solution against a pathogen. These vaccines are highly specific in delivering the genes to the target cells, highly efficient in the gene transduction, and efficiently induce the immune response, ( Ura et al., 2014 ). They offer a long term and high level of antigenic protein expression and therefore, have a great potential for prophylactic use as these vaccines trigger and prime the cytotoxic T cells (CTL) which ultimately leads to the elimination of the virus infected cells ( Le et al., 2020 ).

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

It is a recombinant, replication defective adenovirus type-5 vector (Ad5) expressing the recombinant spike protein of SARS-CoV-2. It was prepared by cloning an optimized full-length gene of the S Protein along with the plasminogen activator signal peptide gene in the Ad5 vector devoid of E1 and E3 genes. The vaccine was constructed using the Admax system from the Microbix Biosystem ( Zhu et al., 2020 ). The phase I clinical trials have established a positive antibody response or seroconversion. A four-fold increase in the RBD and S protein-specific neutralizing antibodies was noted within 14 days of immunization and peaked at day 28, post-vaccination. Furthermore, the CD4 + T cells and CD8 + T cells response peaked at day 14 post-vaccination. However, the pre-existing anti-Ad5 immunity partly limited both the antibody and the T cell responses ( Zhu et al., 2020 ). The study will further evaluate antibody response in the recipients who are between the age of 18 and 60, and received one of three study doses, with follow-up taking place at 3- and 6-months post-vaccination ( Anon, 2020d ).

2.2.2. Coroflu (University of Wisconsin-Madison | FluGen | Bharat Biotech)

M2SR, a self-limiting version of the influenza virus, which is modified by insertion of the SARS-CoV-2 gene sequence of the spike protein. Furthermore, the vaccine expresses the hemagglutinin protein of the influenza virus, thereby inducing immune response against both the viruses. The M2SR is self-limiting and does not undergo replication as it lacks the M2 gene. It is able to enter into the cell, thereby inducing the immunity against the virus. It shall be administered intra-nasally, mimicking the natural route of viral infection. This route activates several modes of the immune system and has higher immunogenicity as compared to the intramuscular injections ( Anon, 2020e ).

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

The LV-SMENP-DC vaccine is prepared by engineering the dendritic cells (DC) with the lentiviral vector expressing the conserved domains of the SARS-CoV-2 structural proteins and the protease using the SMENP minigenes. The subcutaneous inoculation of the vaccine presents the antigens on antigen presenting cells (APCs), that ultimately activate the Cytotoxic T cells and generate the immune response ( Le et al., 2020 ).

2.2.4. ChAdOx1 (University of Oxford)

ChAdOx1 recombinant adenovirus vaccine was developed using codon optimized S glycoprotein and synthesized with the tissue plasminogen activator (tPA) leader sequence at 5’ end. The sequence of SARS-CoV-2 coding for amino acids (2 to 1273) and the tPA leader and was propagated in the shuttle plasmid. This shuttle plasmid is responsible for encoding the major immediate early genes of the human cytomegalovirus (IE CMV) along with tetracycline operator (TetO) sites and polyadenylation signal from bovine growth hormone (BGH) between the Gateway® recombination cloning site. The Adenovirus vector genome is constructed in the Bacterial Artificial Chromosome by inserting the SARS-CoV-2 S gene into the E1 locus of ChAdOx1 adenovirus genome. The virus was then allowed to reproduce in the T-Rex 293 HEK (Human Embryonic Kidney 293) cell lines and purified by the CsCl gradient ultracentrifugation. The absence of any sub-genomic RNA (sgRNA) in the intra-muscularly vaccinated animals from the pre-clinical trials is indicative of the escalated immunity against the virus ( Doremalen et al., 2020 ). The previous studies have suggested that a single shot should marshal the immune response ( Ou et al., 2020 ). The vaccine has entered phase II clinical trials, where it shall be evaluated in a large sample of the population ( Anon, 2020f ).

2.3. mRNA Vaccine

mRNA is an emerging, non-infectious, and a non-integrating platform with almost no potential risk of insertional mutagenesis. Currently, the non-replicating RNA and the virus derived self-replicating RNAs are being studied. The immunogenicity of the mRNA can be minimized, and alterations can be made to increase the stability of these vaccines. Furthermore, the anti-vector immunity is also avoided as the mRNA is the minimally immunogenic genetic vector, allowing repeated administration of the vaccine ( Cuiling et al., 2020 ). This platform has empowered the rapid vaccine development program due to its flexibility and ability to mimic the antigen structure and expression as seen in the course of a natural infection ( Mulligan and Lyke, 2020 ).

2.3.1. mRNA-1273 (Moderna TX, Inc)

It is a vaccine composed of synthetic mRNA encapsulated in Lipid nanoparticle (LNP) which codes for the full-length, pre-fusion stabilized spike protein (S) of SARS-CoV-2. It has the potential to elicit a highly S-protein specific antiviral response. Furthermore, it is considered to be relatively safe as it is neither made up of the inactivated pathogen nor the sub-units of the live pathogen ( Tu et al., 2020 ). The vaccine has got a fast-track approval from FDA, to conduct the Phase II trials ( Anon, 2020g ).The company has released the interim phase I antibody data of eight participants who received various dose levels. The participants of the 25 μg dose group gave results comparable to the convalescent sera. Whereas, in participants who received the 100 μg dose, the levels of nAb essentially surpassed the levels found in convalescent sera. The vaccine was found to be predominantly safe and well tolerated in the 25 μg and 100 μg dose cohorts, while three participants experienced grade 3 systemic symptoms after the administration of the second dose of 250 μg dose levels ( Anon, 2020h ).

2.3.2. BNT162b1 (BioNTech| FosunPharma| Pfizer)

BNT162b1 is a codon-optimized mRNA vaccine that encodes for the trimerized SARS-CoV-2 RBD, a critical target of the virus nAb. The vaccine portrays an increased immunogenicity due to the addition of T4 fibritin-derived foldon trimerization domain to the RBD antigen. The mRNA is encapsulated in 80 nm ionizable cationic lipid nanoparticles, which ensures its efficient delivery. The Phase 1/2 clinical trials have revealed elevated RBD-specific IgG antibodies levels with a geometric mean concentration to be as high as 8 to 46.3 times titer of convalescent serum. Whereas, the geometric mean titers of the SARS-CoV-2 neutralizing antibodies were found to be 1.8 to 2.8 times the convalescent serum panel. Moderate and transient local reactions and systemic events were observed with no adverse effect. However, the data analysis did not evaluate the safety and immune responses beyond 2 weeks following the administration of the second dose ( Mulligan and Lyke, 2020 ).

2.4. DNA Vaccines

The most revolutionary approach to vaccination is the introduction of the DNA vaccine which encodes for the antigen and an adjuvant which induces the adaptive immune response. The transfected cells express the transgene which provides a steady supply of the transgene specific proteins which is quite similar to the live virus. Furthermore, the antigenic material is endocytosed by the immature Dendritic Cells which ultimately present the antigen to the CD4+ and CD8+ T cells in association with MHC 2 and MHC 1 antigens on the cell surface hence stimulating effective humoral as well as cell-mediated immune responses ( Hobernik and Bros, 2018 ).

2.4.1. INO-4800 (Inovio Pharmaceuticals)

It is a prophylactic DNA vaccine against SARS-CoV-2 ( Anon, 2020i ). It uses codon optimized S protein sequence of SARS-CoV-2 to which an IgE leader sequence is affixed. The SARS-CoV-2 IgE-spike sequence was synthesized and digested using BamHI and XhoI . The digested DNA was incorporated into the expression plasmid pGX0001 under the governance of IE CMV, and BGH polyadenylation signal. The presence of functional antibodies and T cell response in the preclinical trials suggest that the vaccine can produce an effective immune response within 7 days post-vaccination ( Smith et al., 2020 ). The vaccine has entered the Phase I clinical trials (Phase I: {"type":"clinical-trial","attrs":{"text":"NCT04336410","term_id":"NCT04336410"}} NCT04336410 ) and it is estimated to complete this phase of clinical trials by July, wherein the participants received 1.0 mg of INO-4800 by electroporation using CELLECTRA® 2000 device per dosing visit. The trial will evaluate the immunological profile, safety, and tolerability of the vaccine candidate upon intradermal injection and the electroporation in healthy human adults ( Anon, 2020i ).

2.5. Live Attenuated Vaccines

2.5.1. delns1-sars-cov2-rbd (university of hong kong).

This LAV is influenza-based vaccine strain with a deletion in the NS1 gene. It is re-organized to express the RBD domain of SARS-CoV-2 spike protein on its surface and, is cultivated in the chick embryo and/or Madin Darby Canine Kidney Cells (MDCK) cells. It is potentially more immunogenic than the wild type influenza virus and can be administered as a nasal spray ( Anon, 2020j ).

2.6. Others

The revelation of the structure and genome of the SARS-CoV-2 has led to the rapid development of various vaccine candidates with potential immunogenicity but also adverse reactogenicities. The task of vaccine development is long and cumbersome which requires evaluation in some long-lasting clinical trials. Various Biotech ventures are using different technologies for the development of their vaccine candidates; British and American Tobacco Company (BAT) recently unfolded the COVID-19 vaccine using their new, and fast-growing tobacco plant technology ( Anon, 2020k ), while Tianjin University has developed an oral vaccine which has successfully employed Saccharomyces cerevisiae to carry the S protein. The GRAS (Generally Regarded As Safe) status of the yeast provides high scalability, robustness, and cost-effective production of cosmic dosages required to fight off this pandemic ( Zhai et al., 2020 ). Furthermore, in silico studies, using various databases like VaxiJen, have revealed that the epitope sequences WTAGAAAYY and YDPLQPEL can be employed for the formulation of epitope-based peptide vaccines ( Garg et al., 2020 ).

2.6.1. Self Assembling Vaccine (HaloVax)

The vaccine uses a heat shock protein (hsp) to activate the immune system. It is composed of a fusion protein sandwiched between an hsp and Avidin. Biotinylated immunogenic peptides are also incorporated to customize the vaccine ( Voltron Therapeutics, Inc., 2020 ) Table 2 , Table 3 .

Rapidly progressing Anti COVID-19 vaccines. This table contains the information of rapidly developing vaccine candidates only, the list of all vaccine candidates in the pipeline can be accessed from: https://airtable.com/shrSAi6t5WFwqo3GM/tblEzPQS5fnc0FHYR/viweyymxOAtNvo7yH?blocks=bip

Legend: CCHF: Crimean-Congo Hemorrhagic Fever; CHIKV: Chikungunya Virus; DengV: Dengue Virus; FMD: Foot and Mouth Disease; EBOV: Ebola Virus; HAV: Hepatitis A Virus; HBV: Hepatitis B Virus; HIV: Human Immunodeficiency Virus; HPV: Human Papilloma Virus; Inf: Influenza; LASV: Lassa Fever Virus; MenB: Meningitis B; NIPV: Nipah Virus; NORV: Norovirus; RABV: Rabies Virus; RVF: Rift Valley Fever; SARS: Severe Acute Respiratory Syndrome; SIV: Simian Immunodeficiency Virus; TB: Tuberculosis; VEE: Venezuelan Equine; Encephalitis Virus; VZV: Varicella Vaccine (Chickenpox); YFV: Yellow Fever Virus; ZIKV: Zika Virus.

Latest developments in the status of the promising SARS-CoV-2 vaccines

3. Passive Immunization/adoptive immunity

It is the use of preformed antibodies in therapeutics of various diseases. It can be achieved by use of sera from convalescent patients, polyclonal serum raised in other animals such as horse, neutralizing monoclonal antibodies produced by hybridoma technology or humanized antibodies.

3.1. Convalescent Plasma therapy

To date, no distinct treatment has been proven to be efficacious against the COVID-19. Convalescent plasma (CP) therapy has been approved as an empirical treatment during the outbreaks ( (WHO), World Health Organisation, 2014 ). It is considered as the archetypal immunotherapy which has been used for the treatment and prevention of various viral diseases in the past such as SARS, MERS, H1N1 pandemic, measles, mumps, etc. ( Kai et al., 2020 ). A possible explanation for the efficacy of this classic adoptive immunotherapy is that the neutralizing immune-globulins from CP may conquer viremia, block new infection, and accelerate clearance of the infected cells.

Various studies conducted to evaluate therapeutic potential of CP have convincingly shown that administration of the neutralizing antibodies in the critically ill patients led to the amelioration of the clinical status in all patients without any deaths ( Kai et al., 2020 ; Shen et al., 2020a ; Ahn et al., 2020a ; Anon, 2020C ). The dosage prescribed for the CP therapy has not been standardized yet and needs Randomised Clinical Trials not only to eliminate the effect of other medicines but also to evaluate the efficacy and safety of CP therapy. ( Zhang et al., 2020 ). The patients who were considered critically ill with some of them having co-morbid conditions like hypertension, cardiovascular diseases, cerebrovascular diseases, chronic renal failure, etc. were included in the study. They were all admitted to the ICUs and were receiving either mechanical ventilation, high-flow nasal cannula oxygenation, or the low-flow nasal cannula oxygenation. All the patients in these studies were receiving antiviral or antibacterial or antifungal drugs for the treatment of co-infections ( Kai et al., 2020 ). Compared to the control group, the CP treatment group showed no notable differences in the baseline characteristics but exhibited a sizable difference in the clinical outcomes (i.e. normalization of the body temperature, absorption of pulmonary lesions, resolution of ARDS, weaning off the mechanical ventilators, etc.), and the death rates. The patients were tested negative for the viral loads after 7-37 days of CP infusion ( Shen et al., 2020b ). A reduction in the net quantity of inflammatory biomarkers CRP, procalcitonin, and Interleukin 6 (IL-6) in the trial group was observed along with a significant increase in the antibody titers (RBD specific IgM and IgG) post-convalescent plasma therapy ( Ahn et al., 2020b ). However, these uncontrolled and non-randomized trials for the CP therapy impede the researchers to come to a conclusive statement about the prospective potency of this treatment, and these observations require further evaluation which is ongoing in the clinical trials ( Yan, 2020 ).

3.2. Monoclonal Antibody

The monoclonal antibodies (mAb) or therapeutic antibodies, created in the laboratory are the clones of a unique parent which can bind to a single epitope, that is, they have a monovalent affinity ( Gelboin et al., 1999 ). The use of mAb in the prevention and treatment of infectious diseases can overcome various drawbacks which are cognate with the convalescent plasma therapy in terms of specificity, safety, low risk of blood-borne infection, purity, and other factors. A wide array of monoclonal antibodies have already been developed which are implemented in the anti-tumor, anti-platelet, or antiviral therapy ( Breedveld, 2000 ).

A SARS-CoV specific human mAb CR3022 has been found to bind with the RBD of the S protein of SARS-CoV-2, stipulating it as a prospective therapeutic agent, which can either be used alone or in combination therapy for the management of COVID-19 ( Tian et al., 2020 ). To achieve higher efficiency of disease prevention and treatment, a combinatorial effect of monoclonal antibodies recognizing different epitopes of the viral surface can be considered for the neutralization of the virus as it may prove to be more effective and prevent the viral escape ( Tian et al., 2020 ).

There are over 61 patents which claim to have prepared the SARS-specific, MERS-specific, and the diagnostic antibodies. Another group of 38 patents claims to have developed the antibodies that target the host proteins like IL-6/IL-6R, TLR3, CD16, ITAM (immune-receptor tyrosine-based activation motif), DC-SIGN (dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin), ICAM-3 (intercellular adhesion molecule 3), or IP-10/CXCL10 (interferon γ-inducible protein 10). These antibodies can be used to counteract against the cytokine storm that has been reported to harmonize with the SARS-CoV-2 infection ( Liu et al., 2020 ). Tocilizumab, an anti-IL 6 receptor antibody is likely to control the hyper-inflammatory pulmonary symptoms which are coupled with the cytokine storm involving the chemokine dysregulation and various interleukins. Tocilizumab has been reported to block the cytokine axis IL6 hence inhibiting the inflammatory cascade. However, further clinical trials are essential to establish the effectiveness of the mAb ( Michot et al., 2020 ). Israel Institute for Biological Research (IIBR) claims to have successfully developed the mAb against SARS-CoV-2. The institute is in the process of patenting it which may soon be commercialized ( Upadhyay, 2020 ). A group led by Professor Vijay Chaudhary at the University of Delhi, Centre for Innovation in Infectious Disease Research, Education and Training (UDSC-CIIDRET), is isolating the genes encoding the antibodies responsible for the neutralization of the SARS-CoV-2. These genes will be employed to foster the recombinant Ab by exploiting the pre-existing in-house antibody library and a library fabricated from the cells of convalescent COVID-19 patients ( PIB, Delhi, 2020 ).

4. Limitations

The duration of clinical trials poses a sizable amount of hindrance to swift vaccine development. According to the norms laid down by the US Food and Drug Administration (FDA), and WHO, a vaccine candidate has to pass through at least three phases of placebo-controlled clinical trials for the validation of its safety and efficacy, which can take years to complete. Considering the severity of the pandemic, which has forced a complete shut-down of the global economy, speedy vaccine development is necessary. Some authors suggest that the controlled human challenge studies may be conducted to suitably divert the Phase 3 testing, and allow the rapid licensure of the immunogenic vaccines. However, in the expanded field study participants will be monitored constantly to look for any long-term implications posed by the vaccine. Furthermore, the safety trials for the special groups including, children and pregnant women, and immuno-compromised patients can be conducted before the extension of the vaccination to these groups ( Eyal et al., 2020 ).

The testing and development of safe and effective vaccines rely upon laboratory animal models. These animal models must show a similar course of the disease as in human beings. However, the standard inbred strains of mice are not susceptible to the COVID-19 infection, due to the difference between the humans and mice ACE2 receptors ( Anon, 2020D ). This calls for the development of transgenic mice, expressing the hACE2 receptor. Two animal models (hACE2 transgenic mice model and another, primate Macaques model) were previously developed for the SARS-CoV but the current situation requires steady breeding and distribution of these animal models to meet demands of the researchers around the globe ( Mice and Bao, 2020 ). The SARS-CoV-2 virus isolates can efficiently replicate in the lungs of the Syrian hamsters. The lungs of infected hamsters exhibit the pathological lesions analogous to the COVID-19 patients with pneumonia. Moreover, the nAb response exhibited by the infected hamster demonstrated immunity against the succeeding re-challenge studies. Furthermore, the transfusion of convalescent sera into the naïve hamsters mounted the antibody response and hence hindered the viral replication in the lungs. The assemblage of these experiments have illustrated the Syrian hamster may be a perfect model for comprehending SARS-CoV-2 pathogenesis, and evaluating antiviral drugs, and the immunotherapies ( Imai and Iwatsuki-Horimoto, 2020 ). Nevertheless, the assessment of the vaccine dependent immune enhancement cannot be extrapolated from the animal models and requires a legitimate survey from stage III human trials or the human challenge studies.

The Antibody dependent enhancement (ADE) is exploited by various viruses like Dengue, HIV, animal coronaviruses, etc. as an alternative method of infecting a variety of host cells. The virus-antibody complex can bind to the Fc receptors, activate the complement system, or induce a conformational change in the glycoprotein of the viral envelope ( Yip et al., 2016 ). This mechanism is observed when the vaccine-induced antibodies are either non-neutralizing or they are present in inadequate concentrations. This process triggers the viral entry into the cell due to the intensified binding efficiency of the virus-antibody complexes to FcR bearing cells. The clinical and preclinical trials of SARS-CoV vaccine candidates have demonstrated the aggravation of the disease due to ADE. Vaccine Associated Enhanced Respiratory Disease (VAERD) can also be induced by virus-antibody immune complex and T H 2-biased responses ( Graham, 2020 ).

The viral genome is vulnerable to mutations and can undergo the antigenic shift and the antigenic drift, as it continues to spread from one population to the next. The mutations may vary according to the environmental conditions of a geographical area, and the population density. By screening the 7500 samples of the infected patients, the scientists were able to figure out 198 mutations that may have materialized independently which may indicate the evolution of the virus inside the human host. These mutations may lead to different subtypes which may allow the virus to escape the immune system even after the administration of the vaccine ( Dorp et al., 2020 ).

5. Conclusion

SARS-CoV-2 has been the matter of the moment from the date it was declared as a pandemic, it has led to the termination of economic activities universally. Scientists across the continents are joining hands for the innovative tie-ups with both the pharmaceutical giants and the medical start-ups to repurpose drugs, develop vaccines, and devices to impede the progress of this overwhelming pandemic. A large number of COVID-19 vaccine candidates based upon various platforms have already been identified. Despite the undergoing efforts, a definitive answer does not exist. The process of vaccine development is quite laborious with various stages, including the pre-clinical stage, and clinical development which is a three-phase process. However, if sufficient data is already available, it has been recommended to skip a few stages, to accelerate the attainment of a vaccine faster with a quick regulatory review, approval, manufacturing, and quality control. This novel Coronavirus has therefore forced the scientific community to use unconventional approaches to accelerate the process of vaccine development. According to WHO: “vaccine must provide a highly favorable benefit-risk contour; with high efficacy, only mild or transient adverse effects and no serious ailments.” The vaccine must be suitable for all ages, pregnant, and lactating women and should provide a rapid onset of protection with a single dose and confer safety for at least up to one year of administration.

The use of novel technologies for vaccine development requires extensive testing for the safety and efficacy of a vaccine. The scientific community needs to construct various processes and capacities for the largescale manufacturing and administration of the coronavirus vaccines. The Coalition for Epidemic Preparedness Innovation (CEPI), an international non-governmental organization, which is funded by the Wellcome Trust, the European Commission, the Bill and Melinda Gates Foundation, and eight countries, is subsidizing the development of a large number of pandemic vaccine candidates around the globe. Moderna and the Vaccine Research Centre are co-developing an mRNA based vaccine candidate, wherein the mRNA is encapsulated in the lipid nanoparticles while Codagenix in collaboration with the Serum Institute of India is currently focused on developing the live attenuated viral vaccine. The pharmaceutical giants like Novavax, Sichuan Clover Biopharmaceuticals, iBio, and the University of Queensland are in the preclinical stage of the recombinant S glycoprotein vaccines. Additional strategies like the viral vector-based vaccines, targeting the S glycoprotein are being developed by the University of Oxford and CanSino Biologics, and other companies, Inovio and the Applied DNA Sciences are currently developing the DNA based vaccine candidates against the SARS-CoV-2 S Protein. Some of these vaccine candidates are at least months, away from being ready for human use, while others may take longer if at all approved for final use.

In India alone, six biotech ventures i.e. Serum Institute of India, ZydusCadila, Biological E, Indian Immunologicals, Bharat Biotech, and Mynvax are working in collaboration with various international vaccine developers. They are working on DNA vaccines, live attenuated recombinant measles vaccines, inactivated viral vaccines, subunit vaccines, and the vaccines developed by codon-optimization ( Coronavirus, 2020 ). Furthermore, the academic institutes like National Institute of Immunology (NII), Indian Institute of Science (IISc), International Center for Genetic Engineering and Biotechnology (ICGEB) New Delhi, Translational Health Science and Technology Institute (THSTI), etc. are attempting to develop the vaccines, and therapies, and the SARS-CoV-2 animal models to restrain the pandemic shortly ( Nandi, 2020 ).

The need of the hour is to develop a safe and effective COVID-19 vaccine which can induce an appropriate immune response to terminate this pandemic. It is the universal priority to spot the international funding mechanisms to support the development, manufacturing, and stockpiling of the coronavirus vaccines. This pandemic should serve as the guidepost to the international research community to not only acknowledge the outbreak but also indurate the following coronavirus crossing into mammals. A pan-coronavirus vaccine is urgently needed as the delay of vaccine rollout even by one week will accompany millions of deaths. Furthermore, it appears to be a scientifically feasible task if sufficient resources are made available in due time.

Funding Information

This work received no specific grant from any funding agency.

Declaration of Competing Interest

The author(s) declare that there are no conflicts of interest.

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Scientists are testing mRNA vaccines to protect cows and people against bird flu

FILE - Cows stand in the milking parlor of a dairy farm in New Vienna, Iowa, on Monday, July 24, 2023. The bird flu outbreak in U.S. dairy cows is prompting development of new, next-generation mRNA vaccines — akin to COVID-19 shots — that are being tested in both animals and people. In June 2024, the U.S. Agriculture Department is to begin testing a vaccine developed by University of Pennsylvania researchers by giving it to calves. (AP Photo/Charlie Neibergall, File)

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The bird flu outbreak in U.S. dairy cows is prompting development of new, next-generation mRNA vaccines — akin to COVID-19 shots — that are being tested in both animals and people.

Next month, the U.S. Agriculture Department is to begin testing a vaccine developed by University of Pennsylvania researchers by giving it to calves. The idea: If vaccinating cows protects dairy workers, that could mean fewer chances for the virus to jump into people and mutate in ways that could spur human-to-human spread.

Meanwhile. the U.S. Department of Health and Human Services has been talking to manufacturers about possible mRNA flu vaccines for people that, if needed, could supplement millions of bird flu vaccine doses already in government hands.

“If there’s a pandemic, there’s going to be a huge demand for vaccine,” said Richard Webby, a flu researcher at St. Jude Children’s Research Hospital in Memphis. “The more different (vaccine manufacturing) platforms that can respond to that, the better.”

The bird flu virus has been spreading among more animal species in scores of countries since 2020. It was detected in U.S. dairy herds in March, although investigators think it may have been in cows since December. This week, the USDA announced it had been found in alpacas for the first time.

At least three people — all workers at farms with infected cows — have been diagnosed with bird flu, although the illnesses were considered mild.

But earlier versions of the same H5N1 flu virus have been highly lethal to humans in other parts of the world. Officials are taking steps to be prepared if the virus mutates in a way to make it more deadly or enables it to spread more easily from person to person.

Traditionally, most flu vaccines are made via an egg-based manufacturing process that’s been used for more than 70 years. It involves injecting a candidate virus into fertilized chicken eggs, which are incubated for several days to allow the viruses to grow. Fluid is harvested from the eggs and is used as the basis for vaccines, with killed or weakened virus priming the body’s immune system.

Rather than eggs — also vulnerable to bird flu-caused supply constraints — some flu vaccine is made in giant vats of cells.

Officials say they already have two candidate vaccines for people that appear to be well-matched to the bird flu virus in U.S. dairy herds. The Centers for Disease Control and Prevention used the circulating bird flu virus as the seed strain for them.

The government has hundreds of thousands of vaccine doses in pre-filled syringes and vials that likely could go out in a matter of weeks, if needed, federal health officials say.

They also say they have bulk antigen that could generate nearly 10 million more doses that could be filled, finished and distributed in a matter of a few months. CSL Seqirus, which manufactures cell-based flu vaccine, this week announced that the government hired it to fill and finish about 4.8 million of those doses. The work could be done by late summer, U.S. health officials said this week.

But the production lines for flu vaccines are already working on this fall’s seasonal shots — work that would have to be interrupted to produce millions more doses of bird flu vaccine. So the government has been pursuing another, quicker approach: the mRNA technology used to produce the primary vaccines deployed against COVID-19.

These messenger RNA vaccines are made using a small section of genetic material from the virus. The genetic blueprint is designed to teach the body how to make a protein used to build immunity.

The pharmaceutical company Moderna already has a bird flu mRNA vaccine in very early-stage human testing. In a statement, Moderna confirmed that “we are in discussions with the U.S. government on advancing our pandemic flu candidate.”

Similar work has been going on at Pfizer. Company researchers in December gave human volunteers an mRNA vaccine against a bird flu strain that’s similar to — but not exactly the same as — the one in cows. Since then, researchers have performed a lab experiment exposing blood samples from those volunteers to the strain seen in dairy farms, and saw a “notable increases in antibody responses,” Pfizer said in a statement.

As for the vaccine for cows, Penn immunologist Scott Hensley worked with mRNA pioneer and Nobel laureate Drew Weissman to produce the experimental doses. Hensley said that vaccine is similar to the Moderna one for people.

In first-step testing, mice and ferrets produced high levels of bird flu virus-fighting antibodies after vaccination.

In another experiment, researchers vaccinated one group of ferrets and deliberately infected them, and then compared what happened to ferrets that hadn’t been vaccinated. All the vaccinated animals survived and the unvaccinated did not, Hensley said.

“The vaccine was really successful,” said Webby, whose lab did that work last year in collaboration with Hensley.

The cow study will be akin to the first-step testing initially done in smaller animals. The plan is for initially about 10 calves to be vaccinated, half with one dose and half with another. Then their blood will be drawn and examined to look for how much bird flu-fighting antibodies were produced.

The USDA study first will have to determine the right dose for such a large animal, Hensley said, before testing if it protects them like it did smaller animals.

What “scares me the most is the amount of interaction between cattle and humans,” Hensley said.

“We’re not talking about an animal that lives on a mountain top,” he said. “If this was a bobcat outbreak I’d feel bad for the bobcats, but that’s not a big human risk.”

If a vaccine reduces the amount of virus in the cow, “then ultimately we reduce the chance that a mutant virus that spreads in humans is going to emerge,” he said.

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.