research paper on vaccines

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Research Article

COVID-19 vaccine: A 2021 analysis of perceptions on vaccine safety and promise in a U.S. sample

Roles Conceptualization, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Department of Global Health, Indiana University School of Medicine, Indianapolis, Indiana, United States of America

Roles Investigation, Methodology, Project administration, Validation, Visualization, Writing – review & editing

Affiliation Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, United States of America

Roles Investigation, Methodology, Validation, Visualization, Writing – review & editing

Affiliation Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, United States of America

Roles Data curation, Formal analysis, Software, Visualization, Writing – review & editing

Affiliation Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, United States of America

Roles Data curation, Funding acquisition, Investigation, Methodology, Resources, Supervision, Validation, Visualization, Writing – review & editing

Affiliation Department of Global Health, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, Indiana, United States of America

• Vitalis C. Osuji, 
• Eric M. Galante, 
• David Mischoulon, 
• James E. Slaven, 
• Gerardo Maupome

• Published: May 19, 2022
• https://doi.org/10.1371/journal.pone.0268784
• Reader Comments

Despite reliable evidence-based research supporting the COVID-19 vaccines, population-wide confidence and trust remain limited. We sought to expand prior knowledge about COVID-19 vaccine perceptions, while determining which population groups are at greatest risk for not getting a vaccine.

Study participants in the U.S. (79% female, median age group 46–60 years) were recruited through an online Qualtrics survey distributed as a Facebook advertisement from 3/19/21–4/30/21. We assumed that every participant is at risk of COVID-19 infection and should be able to get the vaccine with proper access. Bivariate and multivariable models were performed. Collinearity between variables was assessed.

A total of 2,626 responses were generated and 2,259 were included in data analysis. According to our multivariate model analysis, vaccines were perceived as safe by those who had or planned to obtain full vaccination (adjusted odds ratio (aOR) (95% confidence interval) = 40.0 (19.0, 84.2); p< 0.0001) and those who indicated trust in science (aOR = 10.5 (5.1, 21.8); p< 0.0001); vaccines were perceived as not safe by those who self-identified as Republicans vs. self-identified Democrats (aOR = 0.2 (0.1, 0.5); p = 0.0020) and those with high school or lower education (aOR = 0.2 (0.1, 0.4); p = 0.0007). Similarly, according to our multivariate model analysis, the following groups were most likely to reject vaccination based on belief in vaccinations: those with lower income (aOR = 0.8 (0.6, 0.9); p = 0.0106), those who do not know anyone who had been vaccinated (aOR = 0.1 (0.1, 0.4); p< 0.0001), those who are unwilling to get vaccinated even if family and friends had done so (aOR = 0.1 (<0.1, 0.2); p< 0.0001), those who did not trust science (aOR < 0.1 (<0.1, 0.1); p< 0.0001), those who believe that vaccination was unnecessary if others had already been vaccinated (aOR = 2.8 (1.5, 5.1); p = 0.0007), and those who indicate refusal to vaccinate to help others (aOR = 0.1 (0.1, 0.2); p< 0.0001). An alpha of p<0.05 was used for all tests.

Level of education and partisanship, but not race/ethnicity, were the most likely factors associated with vaccine hesitancy or likelihood to vaccinate. Also, low vaccination rates among underrepresented minorities may be due to distrust for healthcare industries. Population sub-groups less likely to be vaccinated and/or receptive to vaccines should be targeted for vaccine education and incentives.

Citation: Osuji VC, Galante EM, Mischoulon D, Slaven JE, Maupome G (2022) COVID-19 vaccine: A 2021 analysis of perceptions on vaccine safety and promise in a U.S. sample. PLoS ONE 17(5): e0268784. https://doi.org/10.1371/journal.pone.0268784

Editor: Weijing He, University of Texas Health Science Center at San Antonio, UNITED STATES

Received: July 26, 2021; Accepted: May 8, 2022; Published: May 19, 2022

Copyright: © 2022 Osuji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting information files.

Funding: The author(s) received no specific funding for this work.

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

Introduction

In early 2020, the SARS-CoV-2 (COVID-19) pandemic unmasked the many flaws that healthcare systems faced worldwide. While some of these issues were difficult to predict, such as the feasibility of pandemic response protocols or federal government regulations to be activated [ 1 ], other healthcare issues were to be expected, especially in the United States. For example, disparities in healthcare treatment and outcomes derived from different socioeconomic factors. Studies published in 2020 showed that the pandemic had much higher infection rates in minority populations such as Black and Hispanic/Latinx compared to their white counterparts; American Indians/ Alaska Natives (AI/ ANs), Black and Hispanic/Latinx communities also experienced significantly higher mortality rates [ 2 , 3 ]. The Centers for Disease Control and Prevention (CDC) released information relating social determinants of health to poorer COVID-19 outcomes, stating that “factors such as discrimination, neighborhood and physical environment, housing, occupation, education, income, and wealth gaps put some racial and ethnic minority groups at increased risk of severe illness from COVID-19, including death” [ 4 ]. Many factors play a role in disparities relevant to the COVID-19 pandemic. These include limited access to health services, education, and transportation, which tend to affect more severely communities of color and people of low socioeconomic status [ 5 ].

Just under one year after the first identification of COVID-19 in China [ 6 , 7 ], the PfizerBioNTech and Moderna COVID-19 vaccines were approved by the US Food and Drug Administration (FDA) under Emergency Use Authorization [ 8 , 9 ]. Ultimately, the Pfizer vaccine was fully approved as of August 23 rd , 2021. These vaccines represented a major milestone in vaccine production history, as no other vaccine had ever been created so rapidly with such positive results [ 10 ]. Although mistrust of vaccines is not uncommon in American culture, hesitation regarding the COVID-19 vaccines may be among the strongest yet [ 11 ]. Despite substantial evidence-based research supporting the vaccines’ safety and efficacy, there are lay public concerns regarding the vaccine rollout. For instance, an analysis [ 12 ] from March 2021 in individuals getting vaccines showed that white Americans were receiving vaccinations at a rate two times that of Black Americans, and the gap for Hispanic/Latinx was even larger. The rationale behind these gaps between racial/ethnic groups remains uncertain and highlights the importance of characterizing the factors and mechanisms underlying potential associations amongst demographic and socioeconomic groups.

With the current vaccines showing 95% efficacy, the estimated percentage of Americans needing vaccination to reach herd immunity ranges from 60 to 72% [ 13 ]. However, according to a November 2020 survey [ 14 ], 40% of Americans said that they will “definitely not” or “probably not” get the COVID-19 vaccine when it becomes available to them. Therefore, more needs to be done to bolster interest and trust in the vaccines. While companies and governmental organizations attempt to convey the necessary strategies to ease vaccine uncertainty and hesitation, a large segment of the lay public remains skeptical. As of May 2021, there were state-level COVID-19 vaccine incentives developed to increase vaccination rates across the United States. Irrespective of these incentives, only 48.6% of the US population was fully vaccinated as of July 2021, while 56% had received at least one dose [ 15 ]. Given these data, reasons surrounding vaccination hesitancy needed to be further explored. We aimed to expand current knowledge about COVID-19 vaccine perceptions through a characterization of sociocultural, socioeconomic, and demographic features in the context of opinions about receiving a COVID-19 vaccine. The objectives of the present survey were to establish:

• What segments of the population believe the COVID-19 vaccines to be safe?
• What are the perceived barriers to obtaining the COVID-19 vaccine—for self and others?
• Is there an association between individual sociocultural characteristics and either acceptance or rejection of the vaccine?
• Is there an association between individual demographic characteristics and either acceptance or rejection of the vaccine?

Materials and methods

This research project was granted IRB approval by Indiana University (protocol #10670).

Data collection was done using an online survey distributed to the general public, and our methodology followed criteria from the CHERRIES checklist [ 16 ]. The survey was created using Qualtrics and piloted with 15 respondents. Based on responses and feedback from our iterative process to pilot the survey, questions were added, rephrased, or deleted. The final survey had 37 questions, with 1–6 questions per page. Question format included 28 multiple choices, with the remainder as yes/no questions. Both English and Spanish versions of the survey were available. A description of the ethical approval, anonymity, and data utilization was provided and acknowledged at the beginning of the survey. Personal information was not required, and participants were offered the option to enter an email address if they wished to participate in an optional raffle draw for five $20 Walmart gift cards. All data were stored in a secure password protected website, to which only study investigators had access. A completeness check prior to submission was not implemented, but a forced response feature on Qualtrics was used for all questions except those involving zip code and email address, to ensure that no significant questions were left unanswered. A link to the final version of the survey was posted to a Facebook page created for the study, and Facebook advertisements were used to promote the study. The survey was made available on March 19 th , 2021 and was closed on April 30 th , 2021. The final data collection survey is available as an attachment ( S1 File ).

This was a survey open to every Facebook user in the United States, based on the assumption that every adult was at risk of COVID-19 infection and should theoretically be able to get the vaccine. We limited responses to people stating they were at least 18-years old and able to read, understand, and agree to the terms of the online survey. Bivariate associations were evaluated using Mantel-Haenszel chi-square tests for questions where one or both variables had ordered categorical responses, and Pearson chi-square tests if both variables had nominal categories. Multivariable models were also performed, using an a priori p-value cut point of 0.20 for inclusion in the model. Collinearity between variables was assessed, leading to the exclusion of several variables from each multivariable model, retaining those based on statistical analysis and the team’s clinical experience. For ease of analysis, race was grouped into 2 categories: white and underrepresented minority. Low income was categorized based on respondents who indicated making less than $40,000 in annual income. The final level of significance for these multivariable models was set at p < 0.05.

All analytic assumptions were verified, and the analyses were performed using SAS/STAT software ® v9.4 [ 17 ].

A total of 2,626 responses were obtained. Based on a total of 3,743 potential participants who clicked our survey link on Facebook, our completion rate was 70.2%. Following data cleaning and exclusion of incomplete responses, a total of 2,259 responses were evaluable.

As outlined in Table 1 , most participants were under 60 years of age (61.5%; median age in the 46–60 years group), female (79.2%) and white (89.6%). Most had never been employed in the healthcare field (63.4%), some were employed full time (44.5%), many had at least some college education (93.1%), about half were affiliated with the Democratic party (54.7%), and many lived within family households (75.7%).

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https://doi.org/10.1371/journal.pone.0268784.t001

To determine what groups perceived the vaccine as safe, bivariate and multivariable models were created. Table 2 shows that subjects who perceived the vaccination as being safe were more likely to have already obtained their second dose or planned on getting it (we allowed for single shot vaccines in our analyses) (97% vs. 12%; p< 0.0001), did not have a prior health condition (98% vs. 86%; p< 0.0001), trusted science (97.1% vs. 21%; p< 0.0001)/vaccines (97% vs. 17%; p< 0.0001)/doctors (97% vs. 21%; p< 0.0001), believed in the effectiveness of hand washing (94% vs. 88%; p = 0.0056)/social distancing (96% vs. 59%; p< 0.0001)/wearing a mask (95% vs. 43%; p< 0.0001), were female (88% vs. 66%; p = 0.0005), were white (90% vs. 82%; p = 0.0063), had higher levels of education (94% vs. 79%; p< 0.0001), and identified as Democrats (58% vs. 7%; p< 0.0001). In the multivariate model, subjects who were still independently associated with the perception of the vaccines being safe were those more likely to have received their second dose (or planned on it) (p< 0.0001), who trusted science (p< 0.0001), had higher levels of education (p = 0.0007), or were Democrats (p = 0.0020).

https://doi.org/10.1371/journal.pone.0268784.t002

To determine what groups were likely to perceive the most barriers to vaccination, bivariate and multivariable models were created ( Table 3 ). By analyzing subjects who were actively seeking vaccination versus those who were not, we found the former were more likely to have had their second dose (or were likely to get it) (92% vs. 20%; p< 0.0001), did not have a prior health condition (94% vs. 85%; p = 0.0283), trusted science (96% vs. 34%; p< 0.0001)/vaccines (95% vs. 31%; p< 0.0001)/doctors (93% vs. 35%; p< 0.0001), believed in the effectiveness of social distancing (91% vs. 68%; p< 0.0001)/wearing a mask (97% vs. 52%; p< 0.0001), were younger (p< 0.0001), were not male (72% vs. 68%; p = 0.0326), were an under-represented minority (40% vs. 23%; p = 0.0043), had a higher median income ($56,000 vs. $49,000; p = 0.0053), or were Democrats (48% vs. 12%; p< 0.0001). In the multivariate model, subjects that were still independently associated with actively seeking a vaccination were those with their second dose already received (or planned on it) (p< 0.0001) and who trusted in science (p = 0.0006).

https://doi.org/10.1371/journal.pone.0268784.t003

Data for the final two objectives were aggregated and analyzed together ( Table 4 ). For those who “do not believe in vaccines”, the variables more likely associated with such outcome included not having a high-risk medical condition (42% vs. 53%; p = 0.0111), not knowing someone who is vaccinated (87% vs. 98%; p< 0.0001), not trusting vaccines (21% vs. 97%; p< 0.0001)/science (26% vs. 97%; p< 0.0001)/doctors (28% vs. 97%; p< 0.0001), not believing in the effectiveness of hand washing (90% vs. 94%; p = 0.0410)/ social distancing (65% vs. 96%; p< 0.0001)/wearing a mask (51% vs. 94%; p< 0.0001), not receiving an annual flu shot (21% vs. 83%; p< 0.0001), thinking there is no need if others have been vaccinated (58% vs. 8%; p< 0.0001), and not wanting to get vaccinated to help others (27% vs. 96%; p< 0.0001). In the multivariate model, subjects that were still independently associated with not believing in vaccines did not know someone who was vaccinated (p< 0.0001), did not trust science (p< 0.0001), believed vaccination is unnecessary if others were vaccinated (p = 0.0007), and would not get vaccinated to help others (p< 0.0001).

https://doi.org/10.1371/journal.pone.0268784.t004

Additionally, the variables associated with subjects who “do not believe in vaccines” included not getting vaccinated even if friends and family had been vaccinated (26% vs. 89%; p< 0.0001), being male (30% vs. 19%; p = 0.0053), being an underrepresented minority (25% vs. 9%; p< 0.0001), not being employed full time (65% vs. 55%; p = 0.0260), having a lower median income ($ 49, 000 vs. $51, 000; p = 0.0020), having lower levels of educational attainment (21% vs. 6%; p< 0.0001), and not being a Democrat (89% vs. 43%; p< 0.0001). In the multivariate model, subjects who were still independently associated with not believing in vaccines were those not getting vaccinated even if friends and family had done so (p< 0.0001), and having a lower median income (p = 0.0106).

Our study is not the first to examine the relationship between various demographics and vaccine hesitancy. Kini and colleagues explored 39 studies regarding demographics of vaccine acceptance and hesitation. Their systematic review suggests that vaccine acceptance increases with age and is higher for males and white individuals [ 18 ]. While our study reports different significant findings (see below), this is likely attributed to the context and sample of the studies, along with possible confounding variables as discussed later. Our results pertain to the time when data were collected: given the long and haphazard evolution of the pandemic and associated perceptions, the relevance of our results must be contextualized to the time and the stage of the pandemic. Our data show some disparities in perception and opinions regarding the COVID-19 vaccines based on the following key variables: age, race, income, educational level, underlying health conditions, and political partisanship. Participants who had received the first of two doses of the COVID-19 vaccine at the time of our study may already have been convinced of the safety of the vaccines. Additionally, during the early stages of vaccine promotion, there was emphasis from the CDC on possible worsening of underlying pulmonary, cardiac, and other health conditions, such as chronic obstructive pulmonary disease, heart failure, and asthma [ 19 ]. This could explain why individuals with underlying health conditions were likely to regard the vaccines as protective and safe.

Our results also showed that those who identifies as white, compared to members of underrepresented minorities, were more likely to consider the vaccine as safe. Based on an assumption of a positive correlation between perceiving the vaccine as safe and actually getting the vaccine, the CDC has shown that as of July 4 th , 2021, of those who had received at least one dose of the vaccine, 59% were white, 9% were black, 16% were Hispanic/Latinx, and 6% were Asian Americans [ 20 ]. However, it is unclear whether such disparity is affected by the communities in which vaccines are most readily available, or if such disparity in fact represents an individual decision due to distrust that might exist between underrepresented minorities and the healthcare industry. As such, it is vital to review past literature as it pertains to recent findings during the pandemic. Regarding vaccine hesitancy of underrepresented minorities, there has been clear evidence of disparities in healthcare treatment for Black and white patients. Davidio et al reviewed multiple papers that describe physician perceptions and treatment of Black vs. white patients with clear significance regarding the negative handling of Black patients [ 21 ]. Armstrong et al point out that experience of discrimination was strongly associated with healthcare system distrust (HCSD) in their study comparing African American and white survey respondents [ 22 ]. Additionally, Balasuriya et al explored factors associated with COVID-19 acceptance and access among Black and Latinx communities, and identified the pervasive mistreatment of Black and Latinx communities, rooted in structural racism, to be a key influence on vaccine acceptance [ 23 ]. Results such as this provide a strong basis to argue why underrepresented minorities may have been less eager to seek out vaccinations. Regarding vaccine hesitancy and political affiliation, other studies corroborate these results. In one study, it was found that US Republican counties consistently had lower general vaccination rates than Democratic counties [ 24 ]. In a polling done by Kaiser Family Foundation in May 2020, it was found that Republicans were less likely to report wearing masks, social distancing or getting vaccinated against COVID-19 [ 25 ].

Level of education has a strong effect on willingness to receive a COVID-19 vaccine: having a college degree has been associated with a 43% increase in likelihood of getting the vaccine [ 26 ]. Assuming the likelihood of obtaining the COVID-19 vaccine is positively correlated with perception that the vaccine is safe, it is worthwhile posing the question whether level of education outweighs other effects of race, gender, political affiliation, and underlying health conditions. Delay in COVID-19 vaccination notwithstanding (earlier in 2021 when our data were collected), the CDC has pointed to a divide in communities based on political party affiliation. To ultimately determine the prime factors in safety perception, we conducted a multivariable analysis and found that the following groups were most likely to perceive vaccines as being safe: 99.3% Democrats (vs. 86.0% Republicans, specifically) and 93.1% with higher educational attainment (vs. 6.8% with high school level specifically). It is important to correlate these results with previous studies that examined similar topics. Regarding results about education impacting vaccine rates, previous studies would support this. Suryadevara and colleagues collaborated with their county health department to educate high-risk, resource-poor families regarding vaccination concerns. Their results showed a drastic increase for general vaccine completion and annual influenza vaccine rates [ 27 ]. Another study showed that when providing low-literacy educational materials to resource-poor families regarding the pneumococcal vaccine, the test group was four times more likely to discuss the vaccination in appointments and five times more likely to receive the vaccine than control group [ 28 ]. Even more recent studies with COVID-19 support our findings. For instance, a recent study indicated that lack of high school education positively correlates with increased vaccine hesitancy and decreased vaccination levels [ 29 ].

Our multivariable model outcome also suggests that race and ethnicity are not necessarily the primary determinants of vaccine hesitancy and likelihood of vaccination, because low vaccination rates among underrepresented populations may be explained by the historical distrust within some members of underrepresented minorities toward health care organizations and providers, as well as suspicion about clinical research studies, in view of past atrocities such as the Tuskegee Syphilis experiment [ 30 ], or similar experiments with STD infections in Guatemala [ 31 ]. Our multivariable results support this possibility by indicating those being potential factors in rejecting the COVID-19 vaccine. Specifically, after adjusting for variables, one of the groups found to be independently associated and most likely to reject vaccination according to socioeconomic and demographic factors were individuals with lower income. Considering that low-income populations usually consist of groups that identify as underrepresented minorities [ 32 ], slow rates of vaccination in these groups might reflect individual distrust of health care providers. However, this finding does not rule out the possibility of low distributions in low-income locations (e.g., rural), which could be a barrier by itself for vaccination opportunities. As pointed out by DeMaria-Ghalili and colleagues, “health inequalities are most acute among those living in rural and low resourced areas of the state, and among underrepresented populations (particularly Black/African American and Latino), who lack access to health care, experience digital divide, and face persistent local healthcare workforce shortages.” The report further discusses that people in areas of lower socio-economic status or fewer resources (usually rural areas) have a more difficult time scheduling and going to appointments for vaccinations, noting “pharmacy deserts” to be an issue in having access to appropriate healthcare resources such as vaccines [ 33 ]. Economic precarity and poor technological advancements may be obstacles to both registering for and getting the vaccine, possibly associated with sparse information among low-income populations [ 34 ]. Therefore, to bolster vaccination, efforts should be made to target groups who are most likely to encounter barriers to COVID-19 vaccination, through governmental incentives, including free childcare and rides to vaccination sites, lottery tickets or cash vouchers, complimentary food and drinks at the vaccination sites, and tax credit [ 35 ], rather than privately offered incentives that may vary greatly throughout the country.

Our successful recruitment for this survey was helped by the ever-increasing prevalence of social media in peoples’ lives. This highlights the need for proper, scientific-based information regarding the pandemic to reach the lay public before opinions appear on social media newsfeeds. On the other hand, only 2.1% of our sample thought that social media sites were reliable sources for vaccine information. While this would appear to suggest limited influence of social media with regard to COVID vaccines, we have to interpret this with caution in view of a small, self-selected sample that may not reflect the U.S. population as a whole. While some individuals may have legitimate reasons for declining vaccination, e.g. allergies to some ingredients in the preparation or other medical contraindications, misperceptions about vaccines as presented by some members of the media can lead to vaccine refusal for inappropriate reasons [ 36 ]. Therefore, it is important to disseminate the scientific basis for vaccines whenever possible. Negative press about variant viruses and the possibility of ineffective vaccines lead to further public distrust of the otherwise monumental feat of creating and distributing the COVID-19 vaccines [ 37 ]. Education of the public is essential for the continued success of vaccination efforts in general. As an example, in one study [ 38 ], Human Papilloma Virus (HPV) vaccine education sessions were held for parents, healthcare and school staff who had little knowledge regarding HPV vaccines. After the sessions, results showed that over 90% of respondents felt vaccine education was important and 85–97% were supportive of school-based vaccine clinics. In another study on flu vaccination during pregnancy [ 39 ], pregnant women refused flu vaccines due to likely susceptibility to influenza and concerns for vaccine safety. The study intervention was a brief educational video by the CDC, which addressed vaccination health beliefs in a clear and easy to understand format. The primary outcome was receipt of the flu vaccine on the next prenatal visit, and suggested that appropriate education and reassurance were influential in vaccination. We must do the same for the COVID-19 vaccine, seeing that our findings suggest that educational attainment is one of the two most important factors that determine the likelihood that one will perceive the vaccine as safe and be likely to accept vaccination. Given that an overwhelming majority of our respondents indicated that they considered doctors, nurses, and other healthcare workers as reliable sources of vaccination information, it is imperative to begin incorporating COVID-19 vaccine questions and education during health care visits. Moreover, training healthcare professionals in cultural competency, defined as “the ability of individuals and systems to work or respond effectively across cultures in a way that acknowledges and respects the culture of the person or organization being served” [ 40 ] would help them navigate this conversation with knowledge and transparency to promote mutual trust and possibly increased likelihood of vaccination [ 41 , 42 ]. Unfortunately, cultural competency training is still limited in medical schools and residency programs [ 43 ], and broader implementation is needed. This will be critical for engaging minority/underrepresented groups, though we acknowledge that these groups may have general difficulties accessing any medical care and this in turn may contribute to lower vaccination rates. Some respondents chose “no access” as a reason for not receiving the vaccine. The term “no access” is admittedly broad and could have included decreased vaccination distribution to impoverished neighborhoods, or it could mean that individuals do not know where to go to get their vaccine. We kept our questionnaire concise so as not to overburden respondents, and consequently could not necessarily qualify the specific reasons for perception about no or limited access. Further investigation is needed to characterize the specific obstacles experienced by people seeking the vaccination. As health literacy regarding the still relatively new COVID-19 pandemic remains a challenge [ 44 ], our present survey can hopefully act as a compass to inform providers on the underlying rationale that their patients have for being skeptical about vaccines or medical advice.

In addition, we need steps to encourage the population to get vaccinated irrespective of political affiliation. Per our findings, those who identify as Democrats are more likely to perceive the vaccine as being safe. Partisanship and vaccination status continue to play a role in both U.S. vaccination efforts and the government’s response to the pandemic in general. Other studies have shown similar results [ 45 ], where 65% of Democrats and 51% of vaccinated adults say that the surge in COVID cases makes them angry at people who have not gotten a vaccine, while 59% of Republicans and 56% of unvaccinated adults say that the federal government should be blamed. Our study shows that Republicans less likely to become vaccinated trust information that comes directly from their health care team, more than information that originates from the government. Therefore, ensuring that all personnel on the health care team are culturally competent to facilitate conversations brought on by patients regarding the COVID-19 vaccine will be instrumental in ensuring vaccination acceptance across spectra. Finally, incentives must be focused on core groups that we believe are more likely to reject the vaccine. These include underrepresented minorities, people with lower educational level, those who identify as young, males, and those with high risk underlying medical conditions.

Our study has limitations, especially regarding data collection. Given the current pandemic and difficulty with in-person survey distribution, it was decided that an online distribution would be preferable, based on the assumption that every individual is at risk of contracting the virus and becoming affected by the pandemic. We used Facebook due to its wide reach. However, we recognize that not everyone has access to computers or Facebook, so this survey may favor those of higher socioeconomic status. Likewise, we did not seek parity since the sample was largely one of convenience, based on who responded to the questionnaire. Although forced responses were used for our survey to ensure completion and prevent answers, we could not determine other potential factors that may have caused incomplete responses in cases where respondents were allowed to select up to three options, e.g. for trusted sources of information. Obstacles to completion might have included feeling pressed for time, concerns about privacy in view of the open nature of social media, or rejection based on personally held political views. This could result in a self-selection bias due to differences between respondents and non-respondents, therefore skewing the findings. For example, many participants were white, female, and/or Democrat voters, which is not representative of the U.S. population per se and could bias the results in favor of opting for vaccination, perhaps due to stronger belief in vaccines. Obviously, given the enormous number of Facebook users in the U.S., and the fact that users are allowed to protect their privacy by restricting access to personal data (including by omitting it in their profiles), it would be difficult to assess the “typical” Facebook user in the context of these factors. Along those lines, about 87% of respondents were already vaccinated, which suggests that most considered the benefits greater than the risks. This may therefore result in under-reporting and under-characterizing negative views of the vaccine that we sought to capture in the survey. Another limitation of this study is that it only represents a snapshot in time of opinions of COVID-19 vaccine perceptions, which can be fluid. Because the vaccine data are rapidly changing and information provided to the public may evolve as days progress, our results can only be applicable to this specific point in time. Ideally, the present study should be repeated in the future to ascertain trends over time. From a methodological standpoint, future studies should focus on obtaining a wider and more diverse set of respondents, including individuals that do not have access to computers or Facebook. One feasible alternative could be the distribution of both online and paper surveys to the same group of respondents during the same wave of data collection, thus allowing for estimation of changes across strategies for survey contact.

While our findings are in line with some existing perspectives in the field, as they relate to the role of socioeconomic factors [ 26 , 32 ], educational influence [ 38 , 39 ], and partisanship [ 45 ], we have contributed a more robust and elaborate perception of the U.S population on COVID vaccines, while identifying specific groups at risk for not getting a vaccine. In conclusion, level of education and partisanship, but not race/ethnicity, were the most likely factors associated with vaccine hesitancy or likelihood to vaccinate. This suggests that improved education, not just about vaccines per se, but with regard to formal schooling in general, may be at the heart of promoting greater acceptability of vaccination. Likewise, low vaccination rates among underrepresented minorities may be due to distrust for healthcare industries, but further research is needed to fully characterize the relative contributions of low access vs. distrust. Many white people and many with a Republican party affiliation also expressed reluctance about vaccination, suggesting that mistrust of the healthcare industry, vaccinations in general, and/or the government is not limited to minorities and/or economically challenged populations. Regardless, population sub-groups less likely to be vaccinated and/or receptive to vaccines should be targeted for vaccine education and incentives, and outcomes of these interventions need to be closely studied for determination of efficacy.

Supporting information

S1 file. qualtrics survey questionnaire..

https://doi.org/10.1371/journal.pone.0268784.s001

S1 Data. Inclusion criteria.

https://doi.org/10.1371/journal.pone.0268784.s002

Acknowledgments

The authors would like to thank our collaborators at Qualtrics and Facebook for helping facilitate the successful completion of this study.

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• 15. Mayo Clinic: US COVID-19 Vaccine Tracker. https://www.mayoclinic.org/coronavirus-covid-19/vaccine-tracker Accessed on: 17 th , July 2021.
• 17. All result output were created using SAS. Copyright © 2021 SAS Institute Inc., Cary, NC, USA.
• 19. Centers for Disease Control: Underlying Medical Conditions Associated with Higher Risk for Severe COVID-19 . https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html Accessed on: 18 th , October 2021.
• 20. Centers for Disease Control: Latest Data on COVID-19 vaccination by Race/ Ethnicity . https://www.kff.org/coronavirus-covid-19/issue-brief/latest-data-on-covid-19-vaccinations-race-ethnicity/ Accessed on: 18 th , October 2021.
• 25. Hamel, L., Kearney, A., Kirzinger, A., Lopes, L., Munana, C., Brodie, M. KFF Health Tracking Poll — May 2020 . Kaiser Family Foundation . https://www.kff.org/coronavirus-covid-19/report/kff-health-tracking-poll-may-2020/ Accessed on 19 th , January 2022.
• 26. Thomas, K., Darling, J. Education is now a Bigger Factor than Race in Desire for COVID-19 Vaccine . https://healthpolicy.usc.edu/evidence-base/education-is-now-a-bigger-factor-than-race-in-desire-for-covid-19-vaccine/ Accessed on 17 th , July 2021.
• 30. Ada McVean. McGill. 40 Years of Human Experimentation in America : The Tuskegee Study . https://www.mcgill.ca/oss/article/history/40-years-human-experimentation-america-tuskegee-study Accessed on 19th January, 2022.
• 31. Amy Gutmann. Presidential Commission for the Study of Bioethical Issues. “Ethically Impossible” STD Research in Guatemala from 1946 to 1948. https://bioethicsarchive.georgetown.edu/pcsbi/node/654.html Accessed on 19 th January, 2022.
• 32. Simms, M. The Urban Institute. Racial and Ethnic Disparities among low-income Families . https://www.urban.org/sites/default/files/publication/32976/411936-racial-and-ethnic-disparities-among-low-income-families.pdf Accessed on 18th October, 2021
• 33. DiMaria-Ghalili, R., Foreshaw Rouse, A., Coates, M., Hathaway, Z., Hirsch, J., Wetzel, S., et al. Disrupting Disparities in Pennsylvania: Retooling for Geographic, Racial and Ethnic Growth [White paper]. https://aarp-states.brightspotcdn.com/6f/b6/de161f3a4a63a23e811693d90b68/aarp-drexel-pennsylvania-disrupting-disparities-design-0421-final.pdf Accessed on 19th January, 2022.
• 35. Devon Delfino. Incentives for CoVID-19 Vaccination : Food , Cash , & Other Perks . https://www.goodrx.com/health-topic/vaccines/covid-19-vaccination-incentives Accessed on 20th, January, 2022.
• 37. The Atlantic. 5 Pandemic Mistakes We Keep Repeating . https://www.theatlantic.com/ideas/archive/2021/02/how-public-health-messaging-backfired/618147/ Accessed on 26 th , February 2021.

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COVID‐19 vaccine research and development: ethical issues

1 Department of Microbiology, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta Indonesia

2 Medical and Health Research Ethics Committee, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada / Dr. Sardjito General Hospital, Yogyakarta Indonesia

The achievements of vaccine research and development bring a hope to our societies that we may cope with the COVID‐19 pandemic. There are two aspects that should be maintained in balance: the immediate necessity for speed of vaccine research and the inherent need for protection of research subjects, which is the foremost concern of research ethics. This narrative review highlights ethical issues in COVID‐19 vaccine research and development that every stakeholder needs to be aware of and to consider.

Introduction

COVID‐19 is a deadly disease which continues to affect many countries in the world. The incidence is higher in the Americas (14 117 714 cases and 486 843 deaths) and Europe (4 515 514 cases and 222 624 deaths) than in South East Asia (4 786 594 cases and 84 541 deaths), Africa (1 088 093 cases and 23 101 deaths) and the Western Pacific (520 012 cases and 11 306 deaths) [ 1 ].

Vaccines are the most important public health measure to protect people from COVID‐19 worldwide, since SARS‐CoV‐2 is highly contagious and infects populations widely and globally [ 2 ]. Traditionally, vaccine development takes years, even decades: from about 40 years for polio to 5 years for Ebola,most vaccines took 15 years on average [ 3 , 4 ]. The trial process for vaccines consists of several steps which need to be conducted systematically and in a measurable stride. The length of this process is correlated with the nature of the vaccine itself, which is to protect healthy people from being infected by pathogens. Adverse events and deleterious effects will not be tolerated, vaccines are not the same as drugs that are consumed by the sick. The risk–benefit analysis for prescription drugs and vaccine administration is different.

The invention of a successful and widely available COVID‐19 vaccine will be a great leap forward for humankind, but there are several challenges to overcome: (1) a lack of understanding of the pathogenesis and the predictive role of vaccines in the clinical pathway of persons being infected by SARS‐CoV‐2 [ 5 , 6 , 7 ], (2) a huge disagreement among experts about how to determine the most immunogenic epitopes and antigens of SARS‐CoV‐2 [ 8 , 9 ], (3) the finding that antibody‐dependent enhancement (ADE) may contribute to the exaggeration of SARS‐CoV‐2 disease [ 10 , 11 ], (4) the lack of established animal models for COVID‐19 vaccine challenge testing, which raises the speculation of using controlled human infection (CHI) as a potential approach [ 3 ], and finally, (5) speculation that the duration of protection by immune response in natural infection is not long enough [ 12 ].

The race for COVID‐19 vaccine invention and development against the spread and catastrophic effects of the disease is real. WHO released a draft list of COVID‐19 candidate vaccines on 3 September 2020. At least 34 vaccine candidates are in clinical evaluation to date [ 13 ]. Several new technologies are used as COVID‐19 vaccine development platforms. Conventional techniques for the development of vaccines such as inactivated, inactivated with adjuvant and live attenuated are still being used. However, reversed vaccinology approaches are also being emplyed, such as a recombinant subunit vaccine, and a more advanced approach using vector delivery systems, along with RNA‐ and DNA‐based vaccines (Table  1 ) [ 4 , 9 , 13 ].

Candidate COVID‐19 Vaccines in Clinical Trial Phases*

The attempts to accelerate vaccine development are associated with efforts to streamline the process. Unfortunately, streamlining may have consequences for the traditional ethics of vaccine research and development, especially the long‐held principles of beneficence and non‐maleficence. This short narrative review summarises the ethical issues that may emerge from the current directions in COVID‐19 vaccine research and development during the pandemic.

Vaccine candidates must fulfil several requirements: safety, efficacy and quality. Because of the current escalation of the global COVID‐19 pandemic, some aspects may change. The speed of vaccine development may push public health ministers, heads of states and the pharmaceutical industry to change their strategy for bulk budget investment for vaccine research. They must decide to prepare mass production events based on the limited data of promising vaccine candidates [ 14 ]. The need to protect billions of earth’s inhabitants pushes governments and societies of the world to a ‘great expectation’ for the new vaccine. The overriding expectation, although with diverse interests, may influence the objective judgement typically required of candidate vaccine safety. Protecting human lives should be the priority.

mRNA‐ [ 15 ] and DNA‐based vaccine technologies [ 9 , 16 ] are being implemented in humans, especially as vaccine candidates. Several concerns about mRNA vaccine safety have been identified besides its promising potential advantages. The most important risks include the possibility that mRNA vaccines may generate strong type I interferon responses that could lead to inflammation and autoimmune conditions [ 17 ]. The safety concerns of DNA‐based vaccines involve the possibility that the targeting of DNA into the chromosomal DNA of the acceptor will trigger mutagenic effects in the functional gene located in the insertion loci [ 18 ]. At present, there are no mRNA‐ and DNA‐based vaccines against any disease authorised to be marketed.

The strategy of DNA vaccines is similar to gene therapy in that a delivery system, such as plasmid, delivers targeted DNA into cells, where it is translated into proteins that induce the acceptors’ immune response to generate targeted T‐cell and antibody responses [ 19 ]. We have experience in using DNA for several gene therapies mostly related to inherited diseases or familial predispositions. Mainstream gene therapy scientists have stated that gene therapy is only suitable for terminally ill patients because the risks are very high [ 20 ]. Vaccine administration is completely different from interventions with gene therapy since the vaccine is for healthy human subjects, and the risk–benefit consideration would be completely different too. Both terminally ill and healthy persons have the same risk for the introduction of foreign DNA into their body, but terminally ill persons may benefit through having a chance to recover from their deadly disease, whereas healthy individuals may not have any benefit because they have never encountered the particular pathogen.

When we perform the risk assessment of new technology, it is based on a theoretical framework without direct evidence concerning to what extent the probability of the risk may occur. Theoretically, DNA vaccine may be able to induce autoimmune diseases and can be inserted into any part of the chromosomes [ 21 ]. Scientists know how the mechanism works and are able to predict the risk if it might happen. But nobody knows for certain how great the probability is of producing mutagenic and deleterious effects in one part of a gene sequence when inserted into another. For example, when a test subject named Jessie Gelsinger was injected with adeno‐associated viruses (AAVs), nobody expected the deadly risk that ultimately occurred in this research subject [ 22 ]. Accordingly, the risk–benefit assessment in the use of new technology should be done carefully. It is true that sometimes we have to deal with a risk possibility that is not immediately present but theoretically possible, and vice versa. Mitigation to the deleterious effect could be started prior to the clinical trial. However, there is always the possible existence of risks that have not been identified yet and will only show in the later phases of clinical trials.

In the current pandemic, all societies expect a breakthrough in medical and health technology. In a situation where understanding of the new disease is poor and no satisfactory medical technology is available for prevention and treatment yet, it is natural to think that ‘doing something is better than nothing’. This is going to make safety judgement among stakeholders more prone to deterioration.

Controlled human infection (CHI)

One of the crucial steps of vaccine development is the challenge test, which is used to measure the potential protection of the candidate. The challenge test is usually part of the pre‐clinical study in an animal model. However, in the case of COVID‐19 and some other diseases, an animal model is not available, although there are candidates that need to be verified [ 3 , 23 , 24 , 25 ]. It seems the pathogen does not produce a similar clinical course in common animal models, which excludes safety and efficacy data from animal models alone. There was a proposal of human challenge testing to replace the pre‐clinical challenge test in animal models, with the use of controlled human infection (CHI). It will solve the problem of the animal models’ unreliability and gain time for the developers especially in phase III [ 3 , 26 ].

To some extent, it is possible to perform these challenge tests with human volunteers. It sounds like an unsafe experimentation, but the choices are extremely limited. The next question is how can we do this experiment with the current ethical review process? The WHO has issued a guideline for CHI [ 27 ]. The guideline is broad and needs local ethics committee approval for its implementation. Considerations of the pros and cons of CHI are widely discussed in COVID‐19 vaccine development. Previously, CHI was used to develop vaccines against malaria [ 28 ], typhoid [ 29 ] and cholera [ 30 ], which are diseases with established treatment [ 31 ]. Subjects who suffered from deleterious effects after experimentation could be rescued by the established treatment. Application of CHI in COVID‐19 is a very different story because there is no standard treatment for this new and highly contagious disease. Nevertheless, there have been thousands of volunteers from 162 countries who declared their willingness to be participants in this CHI [ 32 ]. The need for a vaccine is prevalent in people’s minds and equally necessary from the public health point of view. Without any precedents, it is going to be difficult to judge the risks benefits in this matter [ 33 ].

Controlled human infection could be done in a situation where there is an attenuated virus strain available, for example, using an artificial mutant virus. This approach is to prevent fatal outcomes in trial subjects. But the challenge test results from attenuated virus may not be generalisable – the attenuated strain may not be similar enough to the naturally circulating virus. In addition, producing the attenuated virus may require another step that will take almost as much time to perform as the regular phase III in typical controlled clinical trials. This additional step in an already complicated process will render futile the main purpose to gain more time to develop an effective vaccine [ 34 ].

Location and population

Development sites of COVID‐19 vaccines are involving research subjects from many countries, for example USA, Russia, Argentina, Brazil, Germany, India, Saudi Arabia, Pakistan and others [ 35 ]. The need of multi‐centred research is obvious in the vaccine development. The safety, tolerability, and efficacy of the vaccines should be obtained from different geographic areas, ethnicities, prevalence and varieties of the virus circulating in the areas [ 36 ]. The attempt to fulfil this requirement may result in the involvement of countries with limited resources and whose underdeveloped infrastructure would make the people involved become even more vulnerable as research subjects from the ethical and humane point of view. The possible exploitation of vulnerable people from less developed countries should be reviewed thoroughly. The vaccine trial should give them equitable advantages in trade, such as capacity building, transfer of technology and access to the vaccine during the current pandemic of COVID‐19.

Another concern is the availability of an adequate health facility and system to ensure that trial subjects and their families and/or communities have access to treatment and proper care in case of serious adverse events related to the trial outcomes. This must be assessed before any clinical trials begin. Providing the most comprehensive health services to the trial population will be an added value for population involvement in the trial. The best practice of vaccine clinical trials should have direct benefits for the community, such as improvement and availability of basic health facilities [ 37 ]

Vaccine acceptors are sometimes segmented into target groups, which is related to the host distribution of the target disease, for example by gender, age and specific population in the endemic area. A vaccine clinical trial is usually started in adult subjects and continued to more vulnerable subjects such as infants, young children, the elderly and women. Clinical vaccine trials will recruit vulnerable subjects. Protection measures to safeguard the vulnerable and marginalised populations should be carefully scrutinised during review. Ethical considerations must be adjusted to the individual situation to protect these vulnerable subjects from exploitation and later abandonment [ 38 ].

However, in an emergency pandemic situation, the definition of vulnerability needs to be openly discussed, and emergency calls for exceptions. The exclusion of vulnerable groups may diminish trial validity because of selection bias, so they should not be excluded without reasonable scientific and ethical justification [ 39 ].

Post‐trial access

After clinical vaccine trials, the subjects should have access to the developed vaccine. This is part of their direct advantage for their involvement in the research. While it is mentioned in the international ethical guidelines, not all researchers know and are aware of this important obligation [ 40 ]. The current COVID‐19 vaccine development involves multi‐country and intercontinental research recruiting subjects from different countries and regions. The post‐trial access to COVID‐19 vaccines should be expanded beyond the community where the trial is performed to include the country and region.

Post‐trial access is a matter which must be addressed from the very beginning of research design. Community engagement should be considered prior to the trial and involve all stakeholders: sponsors, industries, developers, investigators, subjects of the trial, communities and the government where the trial is performed.

In summary, the current COVID‐19 vaccine research and development involves people from many countries, which raises ethical issues that must be addressed by all stakeholders. Even in the emergency of a pandemic, the urgency of providing an effective COVID‐19 vaccine for humankind must be balanced with the exigency of research ethics that must be maintained. In any event, the safety and well‐being of research subjects must be protected, especially that of vulnerable subjects.

Sustainable Development Goals (SDGs): SDG 3 (good health and well‐being)

• Scoping Review
• Open access
• Published: 14 November 2021

Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis

• Qiao Liu 1   na1 ,
• Chenyuan Qin 1 , 2   na1 ,
• Min Liu 1 &
• Jue Liu   ORCID: orcid.org/0000-0002-1938-9365 1 , 2  

Infectious Diseases of Poverty volume  10 , Article number:  132 ( 2021 ) Cite this article

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To date, coronavirus disease 2019 (COVID-19) becomes increasingly fierce due to the emergence of variants. Rapid herd immunity through vaccination is needed to block the mutation and prevent the emergence of variants that can completely escape the immune surveillance. We aimed to systematically evaluate the effectiveness and safety of COVID-19 vaccines in the real world and to establish a reliable evidence-based basis for the actual protective effect of the COVID-19 vaccines, especially in the ensuing waves of infections dominated by variants.

We searched PubMed, Embase and Web of Science from inception to July 22, 2021. Observational studies that examined the effectiveness and safety of SARS-CoV-2 vaccines among people vaccinated were included. Random-effects or fixed-effects models were used to estimate the pooled vaccine effectiveness (VE) and incidence rate of adverse events after vaccination, and their 95% confidence intervals ( CI ).

A total of 58 studies (32 studies for vaccine effectiveness and 26 studies for vaccine safety) were included. A single dose of vaccines was 41% (95% CI : 28–54%) effective at preventing SARS-CoV-2 infections, 52% (31–73%) for symptomatic COVID-19, 66% (50–81%) for hospitalization, 45% (42–49%) for Intensive Care Unit (ICU) admissions, and 53% (15–91%) for COVID-19-related death; and two doses were 85% (81–89%) effective at preventing SARS-CoV-2 infections, 97% (97–98%) for symptomatic COVID-19, 93% (89–96%) for hospitalization, 96% (93–98%) for ICU admissions, and 95% (92–98%) effective for COVID-19-related death, respectively. The pooled VE was 85% (80–91%) for the prevention of Alpha variant of SARS-CoV-2 infections, 75% (71–79%) for the Beta variant, 54% (35–74%) for the Gamma variant, and 74% (62–85%) for the Delta variant. The overall pooled incidence rate was 1.5% (1.4–1.6%) for adverse events, 0.4 (0.2–0.5) per 10 000 for severe adverse events, and 0.1 (0.1–0.2) per 10 000 for death after vaccination.

Conclusions

SARS-CoV-2 vaccines have reassuring safety and could effectively reduce the death, severe cases, symptomatic cases, and infections resulting from SARS-CoV-2 across the world. In the context of global pandemic and the continuous emergence of SARS-CoV-2 variants, accelerating vaccination and improving vaccination coverage is still the most important and urgent matter, and it is also the final means to end the pandemic.

Graphical Abstract

Since its outbreak, coronavirus disease 2019 (COVID-19) has spread rapidly, with a sharp rise in the accumulative number of infections worldwide. As of August 8, 2021, COVID-19 has already killed more than 4.2 million people and more than 203 million people were infected [ 1 ]. Given its alarming-spreading speed and the high cost of completely relying on non-pharmaceutical measures, we urgently need safe and effective vaccines to cover susceptible populations and restore people’s lives into the original [ 2 ].

According to global statistics, as of August 2, 2021, there are 326 candidate vaccines, 103 of which are in clinical trials, and 19 vaccines have been put into normal use, including 8 inactivated vaccines and 5 protein subunit vaccines, 2 RNA vaccines, as well as 4 non-replicating viral vector vaccines [ 3 ]. Our World in Data simultaneously reported that 27.3% of the world population has received at least one dose of a COVID-19 vaccine, and 13.8% is fully vaccinated [ 4 ].

To date, COVID-19 become increasingly fierce due to the emergence of variants [ 5 , 6 , 7 ]. Rapid herd immunity through vaccination is needed to block the mutation and prevent the emergence of variants that can completely escape the immune surveillance [ 6 , 8 ]. Several reviews systematically evaluated the effectiveness and/or safety of the three mainstream vaccines on the market (inactivated virus vaccines, RNA vaccines and viral vector vaccines) based on random clinical trials (RCT) yet [ 9 , 10 , 11 , 12 , 13 ].

In general, RNA vaccines are the most effective, followed by viral vector vaccines and inactivated virus vaccines [ 10 , 11 , 12 , 13 ]. The current safety of COVID-19 vaccines is acceptable for mass vaccination, but long-term monitoring of vaccine safety is needed, especially in older people with underlying conditions [ 9 , 10 , 11 , 12 , 13 ]. Inactivated vaccines had the lowest incidence of adverse events and the safety comparisons between mRNA vaccines and viral vectors were controversial [ 9 , 10 ].

RCTs usually conduct under a very demanding research circumstance, and tend to be highly consistent and limited in terms of population characteristics and experimental conditions. Actually, real-world studies differ significantly from RCTs in terms of study conditions and mass vaccination in real world requires taking into account factors, which are far more complex, such as widely heterogeneous populations, vaccine supply, willingness, medical accessibility, etc. Therefore, the real safety and effectiveness of vaccines turn out to be a major concern of international community. The results of a mass vaccination of CoronaVac in Chile demonstrated a protective effectiveness of 65.9% against the onset of COVID-19 after complete vaccination procedures [ 14 ], while the outcomes of phase 3 trials in Brazil and Turkey were 50.7% and 91.3%, reported on Sinovac’s website [ 14 ]. As for the Delta variant, the British claimed 88% protection after two doses of BNT162b2, compared with 67% for AZD1222 [ 15 ]. What is surprising is that the protection of BNT162b2 against infection in Israel is only 39% [ 16 ]. Several studies reported the effectiveness and safety of the COVID-19 vaccine in the real world recently, but the results remain controversial [ 17 , 18 , 19 , 20 ]. A comprehensive meta-analysis based upon the real-world studies is still in an urgent demand, especially for evaluating the effect of vaccines on variation strains. In the present study, we aimed to systematically evaluate the effectiveness and safety of the COVID-19 vaccine in the real world and to establish a reliable evidence-based basis for the actual protective effect of the COVID-19 vaccines, especially in the ensuing waves of infections dominated by variants.

Search strategy and selection criteria

Our methods were described in detail in our published protocol [PROSPERO (Prospective register of systematic reviews) registration, CRD42021267110]. We searched eligible studies published by 22 July 2021, from three databases including PubMed, Embase and Web of Science by the following search terms: (effectiveness OR safety) AND (COVID-19 OR coronavirus OR SARS-CoV-2) AND (vaccine OR vaccination). We used EndNoteX9.0 (Thomson ResearchSoft, Stanford, USA) to manage records, screen and exclude duplicates. This study was strictly performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

We included observational studies that examined the effectiveness and safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among people vaccinated with SARS-CoV-2 vaccines. The following studies were excluded: (1) irrelevant to the subject of the meta-analysis, such as studies that did not use SARS-CoV-2 vaccination as the exposure; (2) insufficient data to calculate the rate for the prevention of COVID-19, the prevention of hospitalization, the prevention of admission to the ICU, the prevention of COVID-19-related death, or adverse events after vaccination; (3) duplicate studies or overlapping participants; (4) RCT studies, reviews, editorials, conference papers, case reports or animal experiments; and (5) studies that did not clarify the identification of COVID-19.

Studies were identified by two investigators (LQ and QCY) independently following the criteria above, while discrepancies reconciled by a third investigator (LJ).

Data extraction and quality assessment

The primary outcome was the effectiveness of SARS-CoV-2 vaccines. The following data were extracted independently by two investigators (LQ and QCY) from the selected studies: (1) basic information of the studies, including first author, publication year and study design; (2) characteristics of the study population, including sample sizes, age groups, setting or locations; (3) kinds of the SARS-CoV-2 vaccines; (4) outcomes for the effectiveness of SARS-CoV-2 vaccines: the number of laboratory-confirmed COVID-19, hospitalization for COVID-19, admission to the ICU for COVID-19, and COVID-19-related death; and (5) outcomes for the safety of SARS-CoV-2 vaccines: the number of adverse events after vaccination.

We evaluated the risk of bias using the Newcastle–Ottawa quality assessment scale for cohort studies and case–control studies [ 21 ]. and assess the methodological quality using the checklist recommended by Agency for Healthcare Research and Quality (AHRQ) [ 22 ]. Cohort studies and case–control studies were classified as having low (≥ 7 stars), moderate (5–6 stars), and high risk of bias (≤ 4 stars) with an overall quality score of 9 stars. For cross-sectional studies, we assigned each item of the AHRQ checklist a score of 1 (answered “yes”) or 0 (answered “no” or “unclear”), and summarized scores across items to generate an overall quality score that ranged from 0 to 11. Low, moderate, and high risk of bias were identified as having a score of 8–11, 4–7 and 0–3, respectively.

Two investigators (LQ and QCY) independently assessed study quality, with disagreements resolved by a third investigator (LJ).

Data synthesis and statistical analysis

We performed a meta-analysis to pool data from included studies and assess the effectiveness and safety of SARS-CoV-2 vaccines by clinical outcomes (rates of the prevention of COVID-19, the prevention of hospitalization, the prevention of admission to the ICU, the prevention of COVID-19-related death, and adverse events after vaccination). Random-effects or fixed-effects models were used to pool the rates and adjusted estimates across studies separately, based on the heterogeneity between estimates ( I 2 ). Fixed-effects models were used if I 2  ≤ 50%, which represented low to moderate heterogeneity and random-effects models were used if I 2  > 50%, representing substantial heterogeneity.

We conducted subgroup analyses to investigate the possible sources of heterogeneity by using vaccine kinds, vaccination status, sample size, and study population as grouping variables. We used the Q test to conduct subgroup comparisons and variables were considered significant between subgroups if the subgroup difference P value was less than 0.05. Publication bias was assessed by funnel plot and Egger’s regression test. We analyzed data using Stata version 16.0 (StataCorp, Texas, USA).

A total of 4844 records were searched from the three databases. 2484 duplicates were excluded. After reading titles and abstracts, we excluded 2264 reviews, RCT studies, duplicates and other studies meeting our exclude criteria. Among the 96 studies under full-text review, 41 studies were excluded (Fig.  1 ). Ultimately, with three grey literatures included, this final meta-analysis comprised 58 eligible studies, including 32 studies [ 14 , 15 , 17 , 18 , 19 , 20 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ] for vaccine effectiveness and 26 studies [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ] for vaccine safety. Characteristics of included studies are showed in Additional file 1 : Table S1, Additional file 2 : Table S2. The risk of bias of all studies we included was moderate or low.

Flowchart of the study selection

Vaccine effectiveness for different clinical outcomes of COVID-19

We separately reported the vaccine effectiveness (VE) by the first and second dose of vaccines, and conducted subgroup analysis by the days after the first or second dose (< 7 days, ≥ 7 days, ≥ 14 days, and ≥ 21 days; studies with no specific days were classified as 1 dose, 2 dose or ≥ 1 dose).

For the first dose of SARS-CoV-2 vaccines, the pooled VE was 41% (95% CI : 28–54%) for the prevention of SARS-CoV-2 infection, 52% (95% CI : 31–73%) for the prevention of symptomatic COVID-19, 66% (95% CI : 50–81%) for the prevention of hospital admissions, 45% (95% CI : 42–49%) for the prevention of ICU admissions, and 53% (95% CI : 15–91%) for the prevention of COVID-19-related death (Table 1 ). The subgroup, ≥ 21 days after the first dose, was found to have the highest VE in each clinical outcome of COVID-19, regardless of ≥ 1 dose group (Table 1 ).

For the second dose of SARS-CoV-2 vaccines, the pooled VE was 85% (95% CI : 81–89%) for the prevention of SARS-CoV-2 infection, 97% (95% CI : 97–98%) for the prevention of symptomatic COVID-19, 93% (95% CI: 89–96%) for the prevention of hospital admissions, 96% (95% CI : 93–98%) for the prevention of ICU admissions, and 95% (95% CI : 92–98%) for the prevention of COVID-19-related death (Table 1 ). VE was 94% (95% CI : 78–98%) in ≥ 21 days after the second dose for the prevention of SARS-CoV-2 infection, higher than other subgroups, regardless of 2 dose group (Table 1 ). For the prevention of symptomatic COVID-19, VE was also relatively higher in 21 days after the second dose (99%, 95% CI : 94–100%). Subgroups showed no statistically significant differences in the prevention of hospital admissions, ICU admissions and COVID-19-related death (subgroup difference P values were 0.991, 0.414, and 0.851, respectively).

Vaccine effectiveness for different variants of SARS-CoV-2 in fully vaccinated people

In the fully vaccinated groups (over 14 days after the second dose), the pooled VE was 85% (95% CI: 80–91%) for the prevention of Alpha variant of SARS-CoV-2 infection, 54% (95% CI : 35–74%) for the Gamma variant, and 74% (95% CI : 62–85%) for the Delta variant. There was only one study [ 23 ] focused on the Beta variant, which showed the VE was 75% (95% CI : 71–79%) for the prevention of the Beta variant of SARS-CoV-2 infection. BNT162b2 vaccine had the highest VE in each variant group; 92% (95% CI : 90–94%) for the Alpha variant, 62% (95% CI : 2–88%) for the Gamma variant, and 84% (95% CI : 75–92%) for the Delta variant (Fig.  2 ).

Forest plots for the vaccine effectiveness of SARS-CoV-2 vaccines in fully vaccinated populations. A Vaccine effectiveness against SARS-CoV-2 variants; B Vaccine effectiveness against SARS-CoV-2 with variants not mentioned. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, COVID-19 coronavirus disease 2019, CI confidence interval

For studies which had not mentioned the variant of SARS-CoV-2, the pooled VE was 86% (95% CI: 76–97%) for the prevention of SARS-CoV-2 infection in fully vaccinated people. mRNA-1273 vaccine had the highest pooled VE (97%, 95% CI: 93–100%, Fig.  2 ).

Safety of SARS-CoV-2 vaccines

As Table 2 showed, the incidence rate of adverse events varied widely among different studies. We conducted subgroup analysis by study population (general population, patients and healthcare workers), vaccine type (BNT162b2, mRNA-1273, CoronaVac, and et al.), and population size (< 1000, 1000–10 000, 10 000–100 000, and > 100 000). The overall pooled incidence rate was 1.5% (95% CI : 1.4–1.6%) for adverse events, 0.4 (95% CI : 0.2–0.5) per 10 000 for severe adverse events, and 0.1 (95% CI : 0.1–0.2) per 10 000 for death after vaccination. Incidence rate of adverse events was higher in healthcare workers (53.2%, 95% CI : 28.4–77.9%), AZD1222 vaccine group (79.6%, 95% CI : 60.8–98.3%), and < 1000 population size group (57.6%, 95% CI : 47.9–67.4%). Incidence rate of sever adverse events was higher in healthcare workers (127.2, 95% CI : 62.7–191.8, per 10 000), Gam-COVID-Vac vaccine group (175.7, 95% CI : 77.2–274.2, per 10 000), and 1000–10 000 population size group (336.6, 95% CI : 41.4–631.8, per 10 000). Incidence rate of death after vaccination was higher in patients (7.6, 95% CI : 0.0–32.2, per 10 000), BNT162b2 vaccine group (29.8, 95% CI : 0.0–71.2, per 10 000), and < 1000 population size group (29.8, 95% CI : 0.0–71.2, per 10 000). Subgroups of general population, vaccine type not mentioned, and > 100 000 population size had the lowest incidence rate of adverse events, severe adverse events, and death after vaccination.

Sensitivity analysis and publication bias

In the sensitivity analyses, VE for SARS-CoV-2 infections, symptomatic COVID-19 and COVID-19-related death got relatively lower when omitting over a single dose group of Maria et al.’s work [ 33 ]; when omitting ≥ 14 days after the first dose group and ≥ 14 days after the second dose group of Alejandro et al.’s work [ 14 ], VE for SARS-CoV-2 infections, hospitalization, ICU admission and COVID-19-related death got relatively higher; and VE for all clinical status of COVID-19 became lower when omitting ≥ 14 days after the second dose group of Eric et al.’s work [ 34 ]. Incidence rate of adverse events and severe adverse events got relatively higher when omitting China CDC’s data [ 74 ]. P values of Egger’s regression test for all the meta-analysis were more than 0.05, indicating that there might not be publication bias.

To our knowledge, this is a comprehensive systematic review and meta-analysis assessing the effectiveness and safety of SARS-CoV-2 vaccines based on real-world studies, reporting pooled VE for different variants of SARS-CoV-2 and incidence rate of adverse events. This meta-analysis comprised a total of 58 studies, including 32 studies for vaccine effectiveness and 26 studies for vaccine safety. We found that a single dose of SARS-CoV-2 vaccines was about 40–60% effective at preventing any clinical status of COVID-19 and that two doses were 85% or more effective. Although vaccines were not as effective against variants of SARS-CoV-2 as original virus, the vaccine effectiveness was still over 50% for fully vaccinated people. Normal adverse events were common, while the incidence of severe adverse events or even death was very low, providing reassurance to health care providers and to vaccine recipients and promote confidence in the safety of COVID-19 vaccines. Our findings strengthen and augment evidence from previous review [ 75 ], which confirmed the effectiveness of the BNT162b2 mRNA vaccine, and additionally reported the safety of SARS-CoV-2 vaccines, giving insight on the future of SARS-CoV-2 vaccine schedules.

Although most vaccines for the prevention of COVID-19 are two-dose vaccines, we found that the pooled VE of a single dose of SARS-CoV-2 vaccines was about 50%. Recent study showed that the T cell and antibody responses induced by a single dose of the BNT162b2 vaccine were comparable to those naturally infected with SARE-CoV-2 within weeks or months after infection [ 76 ]. Our findings could help to develop vaccination strategies under certain circumstances such as countries having a shortage of vaccines. In some countries, in order to administer the first dose to a larger population, the second dose was delayed for up to 12 weeks [ 77 ]. Some countries such as Canada had even decided to delay the second dose for 16 weeks [ 78 ]. However, due to a suboptimum immune response in those receiving only a single dose of a vaccine, such an approach had a chance to give rise to the emergence of variants of SARS-CoV-2 [ 79 ]. There remains a need for large clinical trials to assess the efficacy of a single-dose administration of two-dose vaccines and the risk of increasing the emergence of variants.

Two doses of SARS-CoV-2 vaccines were highly effective at preventing hospitalization, severe cases and deaths resulting from COVID-19, while the VE of different groups of days from the second vaccine dose showed no statistically significant differences. Our findings emphasized the importance of getting fully vaccinated, for the fact that most breakthrough infections were mild or asymptomatic. A recent study showed that the occurrence of breakthrough infections with SARS-CoV-2 in fully vaccinated populations was predictable with neutralizing antibody titers during the peri-infection period [ 80 ]. We also found getting fully vaccinated was at least 50% effective at preventing SARS-CoV-2 variants infections, despite reduced effectiveness compared with original virus; and BNT162b2 vaccine was found to have the highest VE in each variant group. Studies showed that the highly mutated variants were indicative of a form of rapid, multistage evolutionary jumps, which could preferentially occur in the milieu of partial immune control [ 81 , 82 ]. Therefore, immunocompromised patients should be prioritized for anti-COVID-19 immunization to mitigate persistent SARS-CoV-2 infections, during which multimutational SARS-CoV-2 variants could arise [ 83 ].

Recently, many countries, including Israel, the United States, China and the United Kingdom, have introduced a booster of COVID-19 vaccine, namely the third dose [ 84 , 85 , 86 , 87 ]. A study of Israel showed that among people vaccinated with BNT162b2 vaccine over 60 years, the risk of COVID-19 infection and severe illness in the non-booster group was 11.3 times (95% CI: 10.4–12.3) and 19.5 times (95% CI: 12.9–29.5) than the booster group, respectively [ 84 ]. Some studies have found that the third dose of Moderna, Pfizer-BioNTech, Oxford-AstraZeneca and Sinovac produced a spike in infection-blocking neutralizing antibodies when given a few months after the second dose [ 85 , 87 , 88 ]. In addition, the common adverse events associated with the third dose did not differ significantly from the symptoms of the first two doses, ranging from mild to moderate [ 85 ]. The overall incidence rate of local and systemic adverse events was 69% (57/97) and 20% (19/97) after receiving the third dose of BNT162b2 vaccine, respectively [ 88 ]. Results of a phase 3 clinical trial involving 306 people aged 18–55 years showed that adverse events after receiving a third dose of BNT162b2 vaccine (5–8 months after completion of two doses) were similar to those reported after receiving a second dose [ 85 ]. Based on V-safe, local reactions were more frequently after dose 3 (5323/6283; 84.7%) than dose 2 (5249/6283; 83.5%) among people who received 3 doses of Moderna. Systemic reactions were reported less frequently after dose 3 (4963/6283; 79.0%) than dose 2 (5105/6283; 81.3%) [ 86 ]. On August 4, WHO called for a halt to booster shots until at least the end of September to achieve an even distribution of the vaccine [ 89 ]. At this stage, the most important thing we should be thinking about is how to reach a global cover of people at risk with the first or second dose, rather than focusing on the third dose.

Based on real world studies, our results preliminarily showed that complete inoculation of COVID-19 vaccines was still effective against infection of variants, although the VE was generally diminished compared with the original virus. Particularly, the pooled VE was 54% (95% CI : 35–74%) for the Gamma variant, and 74% (95% CI : 62–85%) for the Delta variant. Since the wide spread of COVID-19, a number of variants have drawn extensive attention of international community, including Alpha variant (B.1.1.7), first identified in the United Kingdom; Beta variant (B.1.351) in South Africa; Gamma variant (P.1), initially appeared in Brazil; and the most infectious one to date, Delta variant (B.1.617.2) [ 90 ]. Israel recently reported a breakthrough infection of SARS-CoV-2, dominated by variant B.1.1.7 in a small number of fully vaccinated health care workers, raising concerns about the effectiveness of the original vaccine against those variants [ 80 ]. According to an observational cohort study in Qatar, VE of the BNT162b2 vaccine against the Alpha (B.1.1.7) and Beta (B.1.351) variants was 87% (95% CI : 81.8–90.7%) and 75.0% (95% CI : 70.5–7.9%), respectively [ 23 ]. Based on the National Immunization Management System of England, results from a recent real-world study of all the general population showed that the AZD1222 and BNT162b2 vaccines protected against symptomatic SARS-CoV-2 infection of Alpha variant with 74.5% (95% CI : 68.4–79.4%) and 93.7% (95% CI : 91.6–95.3%) [ 15 ]. In contrast, the VE against the Delta variant was 67.0% (95% CI : 61.3–71.8%) for two doses of AZD1222 vaccine and 88% (95% CI : 85.3–90.1%) for BNT162b2 vaccine [ 15 ].

In terms of adverse events after vaccination, the pooled incidence rate was very low, only 1.5% (95% CI : 1.4–1.6%). However, the prevalence of adverse events reported in large population (population size > 100 000) was much lower than that in small to medium population size. On the one hand, the vaccination population in the small to medium scale studies we included were mostly composed by health care workers, patients with specific diseases or the elderly. And these people are more concerned about their health and more sensitive to changes of themselves. But it remains to be proved whether patients or the elderly are more likely to have adverse events than the general. Mainstream vaccines currently on the market have maintained robust safety in specific populations such as cancer patients, organ transplant recipients, patients with rheumatic and musculoskeletal diseases, pregnant women and the elderly [ 54 , 91 , 92 , 93 , 94 ]. A prospective study by Tal Goshen-lag suggests that the safety of BNT162b2 vaccine in cancer patients is consistent with those previous reports [ 91 ]. In addition, the incidence rate of adverse events reported in the heart–lung transplant population is even lower than that in general population [ 95 ]. On the other hand, large scale studies at the national level are mostly based on national electronic health records or adverse event reporting systems, and it is likely that most mild or moderate symptoms are actually not reported.

Compared with the usual local adverse events (such as pain at the injection site, redness at the injection site, etc.) and normal systemic reactions (such as fatigue, myalgia, etc.), serious and life-threatening adverse events were rare due to our results. A meta-analysis based on RCTs only showed three cases of anaphylactic shock among 58 889 COVID-19 vaccine recipients and one in the placebo group [ 11 ]. The exact mechanisms underlying most of the adverse events are still unclear, accordingly we cannot establish a causal relation between severe adverse events and vaccination directly based on observational studies. In general, varying degrees of adverse events occur after different types of COVID-19 vaccination. Nevertheless, the benefits far outweigh the risks.

Our results showed the effectiveness and safety of different types of vaccines varied greatly. Regardless of SARS-CoV-2 variants, vaccine effectiveness varied from 66% (CoronaVac [ 14 ]) to 97% (mRNA-1273 [ 18 , 20 , 45 , 46 ]). The incidence rate of adverse events varied widely among different types of vaccines, which, however, could be explained by the sample size and population group of participants. BNT162b2, AZD1222, mRNA-1273 and CoronaVac were all found to have high vaccine efficacy and acceptable adverse-event profile in recent published studies [ 96 , 97 , 98 , 99 ]. A meta-analysis, focusing on the potential vaccine candidate which have reached to the phase 3 of clinical development, also found that although many of the vaccines caused more adverse events than the controls, most were mild, transient and manageable [ 100 ]. However, severe adverse events did occur, and there remains the need to implement a unified global surveillance system to monitor the adverse events of COVID-19 vaccines around the world [ 101 ]. A recent study employed a knowledge-based or rational strategy to perform a prioritization matrix of approved COVID-19 vaccines, and led to a scale with JANSSEN (Ad26.COV2.S) in the first place, and AZD1222, BNT162b2, and Sputnik V in second place, followed by BBIBP-CorV, CoronaVac and mRNA-1273 in third place [ 101 ]. Moreover, when deciding the priority of vaccines, the socioeconomic characteristics of each country should also be considered.

Our meta-analysis still has several limitations. First, we may include limited basic data on specific populations, as vaccination is slowly being promoted in populations under the age of 18 or over 60. Second, due to the limitation of the original real-world study, we did not conduct subgroup analysis based on more population characteristics, such as age. When analyzing the efficacy and safety of COVID-19 vaccine, we may have neglected the discussion on the heterogeneity from these sources. Third, most of the original studies only collected adverse events within 7 days after vaccination, which may limit the duration of follow-up for safety analysis.

Based on the real-world studies, SARS-CoV-2 vaccines have reassuring safety and could effectively reduce the death, severe cases, symptomatic cases, and infections resulting from SARS-CoV-2 across the world. In the context of global pandemic and the continuous emergence of SARS-CoV-2 variants, accelerating vaccination and improving vaccination coverage is still the most important and urgent matter, and it is also the final means to end the pandemic.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its additional information files.

Abbreviations

Coronavirus disease 2019

Severe Acute Respiratory Syndrome Coronavirus 2

Vaccine effectiveness

Confidence intervals

Intensive care unit

Random clinical trials

Preferred reporting items for systematic reviews and meta-analyses

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (72122001; 71934002) and the National Science and Technology Key Projects on Prevention and Treatment of Major infectious disease of China (2020ZX10001002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. No payment was received by any of the co-authors for the preparation of this article.

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Qiao Liu and Chenyuan Qin are joint first authors

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Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China

Qiao Liu, Chenyuan Qin, Min Liu & Jue Liu

Institute for Global Health and Development, Peking University, Beijing, 100871, China

Chenyuan Qin & Jue Liu

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LQ and QCY contributed equally as first authors. LJ and LM contributed equally as correspondence authors. LJ and LM conceived and designed the study; LQ, QCY and LJ carried out the literature searches, extracted the data, and assessed the study quality; LQ and QCY performed the statistical analysis and wrote the manuscript; LJ, LM, LQ and QCY revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Min Liu or Jue Liu .

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Supplementary Information

Additional file 1: table s1..

Characteristic of studies included for vaccine effectiveness.

Additional file 2: Table S2.

Characteristic of studies included for vaccine safety.

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Liu, Q., Qin, C., Liu, M. et al. Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis. Infect Dis Poverty 10 , 132 (2021). https://doi.org/10.1186/s40249-021-00915-3

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Efficacy and safety of COVID-19 vaccines

Affiliations.

• 1 Cochrane France, Paris, France.
• 2 Centre of Research in Epidemiology and Statistics (CRESS), INSERM, INRAE, Université de Paris, Paris, France.
• 3 Cochrane Review Group on Drugs and Alcohol, Rome, Italy.
• 4 Cochrane Response, Cochrane, London, UK.
• 5 Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland.
• 6 Evidence Synthesis Ireland, Cochrane Ireland and HRB-Trials Methodology Research Network, National University of Ireland, Galway, Ireland.
• 7 UCD Centre for Experimental Pathogen Host Research and UCD School of Medicine, University College Dublin, Dublin, Ireland.
• 8 Department of Clinical Immunology and Infectious Diseases, Henri Mondor Hospital, Vaccine Research Institute, Université Paris Est Créteil, Paris, France.
• 9 Quality Assurance Norms and Standards Department, World Health Organization, Geneva, Switzerland.
• 10 Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa.
• 11 Institute for Evidence in Medicine, Medical Center & Faculty of Medicine, University of Freiburg, Freiburg, Germany.
• 12 Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany.
• 13 Department of Anesthesia, Intensive Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
• 14 Epistemonikos Foundation, Santiago, Chile.
• 15 UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile.
• 16 Centre for Evidence Based Medicine Odense (CEBMO) and Cochrane Denmark, University of Southern Denmark, Odense, Denmark.
• 17 Open Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark.
• PMID: 36473651
• PMCID: PMC9726273
• DOI: 10.1002/14651858.CD015477

Background: Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally. OBJECTIVES: To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2.

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

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

Data collection and analysis: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for all except immunogenicity outcomes. We synthesized data for each vaccine separately and presented summary effect estimates with 95% confidence intervals (CIs). MAIN RESULTS: We included and analyzed 41 RCTs assessing 12 different vaccines, including homologous and heterologous vaccine schedules and the effect of booster doses. Thirty-two RCTs were multicentre and five were multinational. The sample sizes of RCTs were 60 to 44,325 participants. Participants were aged: 18 years or older in 36 RCTs; 12 years or older in one RCT; 12 to 17 years in two RCTs; and three to 17 years in two RCTs. Twenty-nine RCTs provided results for individuals aged over 60 years, and three RCTs included immunocompromized patients. No trials included pregnant women. Sixteen RCTs had two-month follow-up or less, 20 RCTs had two to six months, and five RCTs had greater than six to 12 months or less. Eighteen reports were based on preplanned interim analyses. Overall risk of bias was low for all outcomes in eight RCTs, while 33 had concerns for at least one outcome. We identified 343 registered RCTs with results not yet available. This abstract reports results for the critical outcomes of confirmed symptomatic COVID-19, severe and critical COVID-19, and serious adverse events only for the 10 WHO-approved vaccines. For remaining outcomes and vaccines, see main text. The evidence for mortality was generally sparse and of low or very low certainty for all WHO-approved vaccines, except AD26.COV2.S (Janssen), which probably reduces the risk of all-cause mortality (risk ratio (RR) 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; high-certainty evidence). Confirmed symptomatic COVID-19 High-certainty evidence found that BNT162b2 (BioNtech/Fosun Pharma/Pfizer), mRNA-1273 (ModernaTx), ChAdOx1 (Oxford/AstraZeneca), Ad26.COV2.S, BBIBP-CorV (Sinopharm-Beijing), and BBV152 (Bharat Biotect) reduce the incidence of symptomatic COVID-19 compared to placebo (vaccine efficacy (VE): BNT162b2: 97.84%, 95% CI 44.25% to 99.92%; 2 RCTs, 44,077 participants; mRNA-1273: 93.20%, 95% CI 91.06% to 94.83%; 2 RCTs, 31,632 participants; ChAdOx1: 70.23%, 95% CI 62.10% to 76.62%; 2 RCTs, 43,390 participants; Ad26.COV2.S: 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; BBIBP-CorV: 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; BBV152: 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants). Moderate-certainty evidence found that NVX-CoV2373 (Novavax) probably reduces the incidence of symptomatic COVID-19 compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; 3 RCTs, 42,175 participants). There is low-certainty evidence for CoronaVac (Sinovac) for this outcome (VE 69.81%, 95% CI 12.27% to 89.61%; 2 RCTs, 19,852 participants). Severe or critical COVID-19 High-certainty evidence found that BNT162b2, mRNA-1273, Ad26.COV2.S, and BBV152 result in a large reduction in incidence of severe or critical disease due to COVID-19 compared to placebo (VE: BNT162b2: 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; mRNA-1273: 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; AD26.COV2.S: 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; BBV152: 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants). Moderate-certainty evidence found that NVX-CoV2373 probably reduces the incidence of severe or critical COVID-19 (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants). Two trials reported high efficacy of CoronaVac for severe or critical disease with wide CIs, but these results could not be pooled. Serious adverse events (SAEs) mRNA-1273, ChAdOx1 (Oxford-AstraZeneca)/SII-ChAdOx1 (Serum Institute of India), Ad26.COV2.S, and BBV152 probably result in little or no difference in SAEs compared to placebo (RR: mRNA-1273: 0.92, 95% CI 0.78 to 1.08; 2 RCTs, 34,072 participants; ChAdOx1/SII-ChAdOx1: 0.88, 95% CI 0.72 to 1.07; 7 RCTs, 58,182 participants; Ad26.COV2.S: 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants); BBV152: 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants). In each of these, the likely absolute difference in effects was fewer than 5/1000 participants. Evidence for SAEs is uncertain for BNT162b2, CoronaVac, BBIBP-CorV, and NVX-CoV2373 compared to placebo (RR: BNT162b2: 1.30, 95% CI 0.55 to 3.07; 2 RCTs, 46,107 participants; CoronaVac: 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; BBIBP-CorV: 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; NVX-CoV2373: 0.92, 95% CI 0.74 to 1.14; 4 RCTs, 38,802 participants). For the evaluation of heterologous schedules, booster doses, and efficacy against variants of concern, see main text of review.

Authors' conclusions: Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform (covid-nma.com). Implications for practice Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern. Implications for research Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital.

Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

Publication types

• Systematic Review
• 2019-nCoV Vaccine mRNA-1273*
• COVID-19* / prevention & control
• Middle Aged
• sinovac COVID-19 vaccine
• BIBP COVID-19 vaccine
• BBV152 COVID-19 vaccine
• 2019-nCoV Vaccine mRNA-1273

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• 001/WHO_/World Health Organization/International

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Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: population based cohort study

Linked editorial.

Does timely vaccination help prevent post-viral conditions?

• Related content
• Peer review
• Lisa Lundberg-Morris , doctoral student 1 2 ,
• Susannah Leach , associate professor 1 3 ,
• Yiyi Xu , research fellow 4 ,
• Jari Martikainen , statistician 5 ,
• Ailiana Santosa , research fellow 4 ,
• Magnus Gisslén , professor 6 7 ,
• Huiqi Li , associate professor 4 ,
• Fredrik Nyberg , professor 4 ,
• Maria Bygdell , research fellow 4 8
• 1 Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
• 2 Region Västra Götaland, Department of Clinical Pharmacology, Sahlgrenska University Hospital, Gothenburg, Sweden
• 3 AstraZeneca, Mölndal, Sweden
• 4 School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
• 5 Bioinformatics and Data Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
• 6 Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
• 7 Region Västra Götaland, Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden
• 8 Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
• Correspondence to: M Bygdell maria.bygdell{at}gu.se
• Accepted 16 October 2023

Objective To investigate the effectiveness of primary covid-19 vaccination (first two doses and first booster dose within the recommended schedule) against post-covid-19 condition (PCC).

Design Population based cohort study.

Setting Swedish Covid-19 Investigation for Future Insights—a Population Epidemiology Approach using Register Linkage (SCIFI-PEARL) project, a register based cohort study in Sweden.

Participants All adults (≥18 years) with covid-19 first registered between 27 December 2020 and 9 February 2022 (n=589 722) in the two largest regions of Sweden. Individuals were followed from a first infection until death, emigration, vaccination, reinfection, a PCC diagnosis (ICD-10 diagnosis code U09.9), or end of follow-up (30 November 2022), whichever came first. Individuals who had received at least one dose of a covid-19 vaccine before infection were considered vaccinated.

Main outcome measure The primary outcome was a clinical diagnosis of PCC. Vaccine effectiveness against PCC was estimated using Cox regressions adjusted for age, sex, comorbidities (diabetes and cardiovascular, respiratory, and psychiatric disease), number of healthcare contacts during 2019, socioeconomic factors, and dominant virus variant at time of infection.

Results Of 299 692 vaccinated individuals with covid-19, 1201 (0.4%) had a diagnosis of PCC during follow-up, compared with 4118 (1.4%) of 290 030 unvaccinated individuals. Covid-19 vaccination with any number of doses before infection was associated with a reduced risk of PCC (adjusted hazard ratio 0.42, 95% confidence interval 0.38 to 0.46), with a vaccine effectiveness of 58%. Of the vaccinated individuals, 21 111 received one dose only, 205 650 received two doses, and 72 931 received three or more doses. Vaccine effectiveness against PCC for one dose, two doses, and three or more doses was 21%, 59%, and 73%, respectively.

Conclusions The results of this study suggest a strong association between covid-19 vaccination before infection and reduced risk of receiving a diagnosis of PCC. The findings highlight the importance of primary vaccination against covid-19 to reduce the population burden of PCC.

Introduction

A global pandemic due to covid-19 was declared in March 2020, and by June 2023 just over 767 million covid-19 cases, including 6.9 million deaths, had been reported to the World Health Organization. 1 Effective vaccines against covid-19 were rapidly developed, and the first vaccine dose in Sweden was administered in December 2020, less than one year after the start of the pandemic. 2 The efficacy and effectiveness of covid-19 vaccines against SARS-CoV-2 infection and severe manifestations of acute covid-19 have been shown. 3 4 5 6 Shortly after the start of the pandemic, reports emerged describing persistent symptoms among some people who had recovered from covid-19, regardless of whether they had been admitted to hospital with the disease, often referred to as long covid or post-covid-19 condition (PCC). We previously found that 2% of adults with covid-19 in Sweden received a diagnosis of PCC, although studies relying on self-reported persistent symptoms usually report a higher incidence rate. A recent umbrella review showed that the prevalence of prolonged symptoms of covid-19 varied between 2% and 53% among different study populations. 7 Generally described symptoms of PCC include fatigue, dyspnoea, cognitive impairment, headache, muscle pain, and cardiac abnormalities such as chest pain and palpitations. 8 Furthermore, by using machine learning algorithms a recent study identified four clinical phenotype clusters within the PCC group; chronic fatigue-like syndrome, respiratory syndrome, chronic pain syndrome, and neurosensorial syndrome. 9 According to a Delphi consensus held by WHO, PCC can occur “in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually three months from the onset of covid-19 with symptoms that last for at least two months and cannot be explained by an alternative diagnosis.” 10 Few studies have evaluated the effectiveness of covid-19 vaccines to prevent PCC in large population based settings. A recent systematic review concluded that receiving a covid-19 vaccine before SARS-CoV-2 infection had a protective effect against PCC in 10 of the 12 included studies, with effect estimates (odds ratios and hazard ratios) ranging from 0.48 to 0.87 for any vaccine dose before infection. 11 The authors did not, however, conduct a meta-analysis because of the high heterogeneity in the methodology and data between studies. They concluded that owing to inadequate adjustment for confounders and risk of bias in the included studies, the certainty of evidence was low.

Sweden has a long history of collecting health and demographic data from its population in national registers. By using an individual’s personal identification number as the unique identifier in multiple registers, it is possible to link information between different data sources with high linkage quality. 12 In Sweden, the ICD-10 (international classification of diseases, 10th revision) diagnosis code for PCC (U09.9) had already been implemented in October 2020. Since then the National Board of Health and Welfare has encouraged the use of the diagnosis code for conditions related to previous covid-19 and describes it as: “An additional code that can be used to describe a condition’s association with covid-19.” During the pandemic, the National Board of Health and Welfare continuously released reports describing the prevalence of PCC using the diagnosis code from specialist healthcare and aggregated level data from primary healthcare. 13 14 15 We have recently shown that most patients (>85%) with a PCC diagnosis in Sweden received their diagnosis in primary healthcare. 16 Hence the use of individual level primary healthcare data is vital when studying PCC in Sweden. Through the SCIFI-PEARL (Swedish Covid-19 Investigation for Future Insights—a Population Epidemiology Approach using Register Linkage) project database, we had access to national register data on vaccination status, diseases, sociodemographic information, and primary healthcare data from the two largest regions of Sweden (covering about 40% of the Swedish population). We investigated the effectiveness of primary covid-19 vaccination (the first two vaccine doses and the first booster dose within the recommended schedule) against PCC among individuals vaccinated before infection using real world data.

Study design and data sources

This population based cohort study is part of the project SCIFI-PEARL, a nationwide linked multiregister, observational study of the covid-19 pandemic in Sweden. 17 Because primary healthcare data are important when studying PCC in Sweden, 16 we used register data for all adult (≥18 years) residents in Region Stockholm and Region Västra Götaland (Sweden’s two largest regions, covering about 40% of the Swedish population 18 ), from which we had access to information from primary healthcare. By using unique personal identification numbers, we retrieved data on administered covid-19 vaccines for each individual from the National Vaccination Register; positive SARS-CoV-2 polymerase chain reaction (PCR) results from the National Register of Notifiable Diseases; ICD-10 diagnosis codes for covid-19, PCC, and comorbidities; and number of healthcare contacts during 2019 for inpatient and outpatient specialist care from the National Patient Register and for primary care from two regional databases of all public and most private primary healthcare (VAL and VEGA, in Region Stockholm and Region Västra Götaland, respectively); as well as death, emigration, demographic, and socioeconomic data from the Longitudinal Integrated Database for Health Insurance and Labour Market Studies of Statistics Sweden. We used the Swedish Intensive Care Register together with the inpatient part of the National Patient Register to identify patients with covid-19 who were admitted to hospital, including those treated in the intensive care unit (ICU).

Study population and follow-up

We included individuals with covid-19 first registered during the study inclusion period, defined as between 27 December 2020 (when vaccination started in Sweden 2 ) and 9 February 2022 (the end of full population PCR testing in Sweden 19 ). This period was selected to include the time during which simultaneous vaccination and PCR testing occurred in Sweden. Covid-19 was defined as a positive SARS-CoV-2 PCR test result registered in the National Register of Notifiable Diseases, or an ICD-10 diagnosis code (U07.1 or U07.2 as a main or secondary diagnosis) registered in the National Patient Register, VAL, VEGA, or the Swedish Intensive Care Register. The covid-19 index date represents the first registration of covid-19 in any of these registers. Included individuals were then followed from 28 days after the covid-19 index date until PCC diagnosis, vaccination, reinfection, death, emigration, or end of follow-up (30 November 2022), whichever came first. The inclusion criteria were to be alive and living in Region Stockholm or Västra Götaland, Sweden, at the start of follow-up, and not to have been vaccinated after the covid-19 index date to start of follow-up. Thus we excluded those individuals who had been vaccinated, emigrated, or died within 28 days after infection. We regarded an additional registered SARS-CoV-2 infection ≥90 days after the covid-19 index date as reinfection.

Vaccination and outcome

In Sweden, the covid-19 vaccination programme started on 27 December 2020 and was implemented in four consecutive stages; stages 1-3 (older age groups (≥60 years), healthcare or elderly care workers, and various risk groups) and stage 4 (younger age groups who had not been part of the previous stages), with stage 4 initiated in most parts of Sweden by May 2021. 20 In the present study, at least one administered dose of any of the available covid-19 vaccines in Sweden before the covid-19 index date was defined as having received a vaccine. We studied the primary vaccination series—that is, the first two doses and the first booster dose within the recommended schedule. During the study period, the available vaccines in Sweden included BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), AZD1222 (Oxford-AstraZeneca), Ad26.COV2.S (Janssen/Johnson & Johnson), and NVX-CoV2373 (Novavax). 21 To minimise the risk of including double registrations of one vaccine dose, we required a minimum number of days between two registered doses. Based on vaccination guidelines and the type of vaccine previously received, a requirement of at least 19 days was set for BNT162b2 and at least 25 days for AZD1222 and mRNA-1273. 22 We classified vaccines by dose (≥1 dose, as well as subdivided into one dose, two doses, and three or more doses). The primary outcome was a clinical diagnosis of PCC, defined as ICD-10 code U09.9 in the National Patient Register, VEGA, or VAL as the main or secondary diagnosis ≥28 days after the covid-19 index date. A minimum of 28 days between the covid-19 index date and PCC diagnosis was required, as a PCC diagnosis within the 28 days was interpreted as a likley misclassification relating to acute infection rather than PCC.

We obtained information on age, sex, education level, employment status, country of birth, emigration, and date of death from the Longitudinal Integrated Database for Health Insurance and Labour Market Studies database. Age was defined at study start (27 December 2020) and categorised into five groups (18-34, 35-44, 45-54, 55-64, and ≥65 years). Level of education was divided into four categories: primary school (<10 years), secondary school (10-12 years), tertiary school (>12 years), and unknown. Employment status was categorised as employed, unemployed, or unknown. Countries of birth were merged into continental regions, including Asia and Oceania; Africa; Europe, except for Sweden; North and South America; and unknown. The included comorbidities have been shown to relate to vaccination status and PCC diagnosis 16 23 24 and comprised broad categories of diabetes (ICD-10: E10-E11), cardiovascular disease (ICD-10: I00-I99), respiratory disease (ICD-10: J40-J99), and psychiatric disease (ICD-10: F00-F99) as main and secondary diagnoses from inpatient and outpatient specialist care in the National Patient Register and from primary healthcare in VEGA and VAL, 1 January 2015 to 31 December 2019. We categorised the severity of acute covid-19 as hospital admission (treated or not treated in an ICU) or no hospital admission, using main and secondary diagnoses of covid-19 within 28 days after the covid-19 index date in the Swedish Intensive Care Register and the inpatient part of the National Patient Register. The number of healthcare contacts during 2019 was categorised as 0, 1-3, 4-10, >10, or unknown. We defined a healthcare contact as any registered contact (including by telephone) with primary healthcare, specialist outpatient care, and specialist inpatient care. If more than one contact was registered on the same day, it was counted as one contact only. For inpatient care, we used the date of admission, with every inpatient period counted as one contact. Study individuals were also classified according to the covid-19 variant of concern that predominated during their covid-19 index date. In Sweden, pre-alpha variants predominated roughly from February 2020 to January 2021, followed by alpha (February 2021 to June 2021), delta (July 2021 to December 2021), and omicron (January 2022 to end of study inclusion). 25 Owing to the low numbers of people with covid-19 in the period when the pre-alpha variants were predominant, for the purpose of analysis we combined the periods when the pre-alpha variants and alpha were predominant.

Statistical analyses

Descriptive statistics are presented as number and percentage, or as median and interquartile range (IQR). We tested for significance between the groups using the χ 2 test and the Mann-Whitney U test. In addition, to be able to further assess the distribution of baseline variables of different types and magnitude or prevalence between the unvaccinated and vaccinated groups, we used the standardised mean difference, with larger values indicating larger differences (greater imbalance) between the groups, and values ≤0.1 indicating good balance.

We performed Cox proportional hazards regressions to estimate the effectiveness of covid-19 vaccination before infection and risk of developing PCC. The assumption of proportional hazards was fulfilled as assessed by visual evaluation of a Schoenfeld residual plot of the vaccination status. We included three models: a crude model with no adjustments; a partially adjusted model with adjustments for age, sex, and predominant variant at the time of infection; and a fully adjusted model with the same adjustments as for the partially adjusted model in addition to comorbidities (diabetes and cardiovascular, respiratory, and psychiatric disease), number of healthcare contacts during 2019, education level, employment status, and region of birth. The results are presented as hazard ratios or adjusted hazard ratios (corresponding to the fully adjusted model) along with corresponding 95% confidence intervals. Vaccine effectiveness was calculated as 100×(1−hazard ratio). In the main analysis, at least one vaccine dose (any dose) before the covid-19 index date was defined as having been vaccinated. Separate analyses were also performed with vaccination stratified into one dose, two doses, or three or more doses before the covid-19 index date. The Kaplan-Meier method was used to estimate cumulative incidence curves of PCC in the unvaccinated and vaccinated groups. In exploratory analyses, we further investigated a possible pathway for the potential protective effect of the covid-19 vaccines against PCC by adding severity of the acute infection into the regression model as a mediating factor. We also stratified by severity of the acute infection. All analyses were performed using R Statistical Software (version 4.2.2; R Core Team 2023).

Subgroup and sensitivity analyses

Analyses to evaluate effect modification were performed by including an interaction term between the vaccination variable (any vaccine before covid-19) and each adjustment variable (one interaction term at a time). We regarded an interaction as statistically significant if the P value of the interaction term was <0.05. Further stratification was planned for the three most relevant variables if they showed significant interaction terms: sex, age group, and predominant variant at the time of the covid-19 index date. Stratification was also done for comorbidities and for the median time between vaccination and the covid-19 index date (vaccination ≥126 days before covid-19 index date, and <126 days). Separate subgroup analyses for the different vaccines were also perfomed, categorised by the combination of vaccines used for the first two doses before infection. These analyses were restricted to the period 3 February 2021 to 16 August 2021 (when the first dose of the three most common vaccines in Sweden was administered: BNT162b2, mRNA-1273, and AZD1222) (see supplementary figure S1).

Three sensitivity analyses were also performed. Firstly, we restricted the vaccinated population to those who had received their last vaccine dose more than 14 days before the covid-19 index date. Secondly, we required at least 90 (instead of 28) days between the covid-19 index date and a diagnosis of PCC. Finally, we restricted the vaccinated population to those who had received two or three doses before the covid-19 index date.

Patient and public involvement

No patients or members of the public were directly involved in this research. A patient reviewer did, however, provide insightful comments during the review process.

Descriptive statistics

During the study inclusion period, 649 071 individuals in Sweden’s two largest regions were registered as having covid-19 for the first time. Overall, 59 349 individuals were excluded: 56 760 were vaccinated, 2515 died, and 74 emigrated within 28 days of the covid-19 index date. In total, 589 722 individuals fulfilled the inclusion criteria to participate in the study ( fig 1 ).

Flowchart of study population with covid-19 during study inclusion period 27 December 2020 to 9 February 2022. PCC=post-covid-19 condition

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Of the 589 722 individuals in the study population, 299 692 (50.8%) had received at least one dose of a covid-19 vaccine before the covid-19 index date, and 290 030 (49.2%) had not been vaccinated at the time of infection ( table 1 ). Of the vaccinated individuals, 21 111 received one dose only, 205 650 received two doses, 72 843 received three doses, and 88 received more than three doses before the covid-19 index date ( table 1 ). BNT162b2 was most commonly used for the first two doses (see supplementary table S1). The median time from last vaccination to the covid-19 index date was 126 days (IQR 47-160 days). More women than men had been vaccinated before covid-19 (56.7% v 44.3%, P<0.001), and the median age among those vaccinated was significantly higher than among those not vaccinated (42 years (IQR 32-53) v 39 years (29-50), P<0.001) ( table 1 ). Although most of the study population was not admitted to hospital with covid-19, unvaccinated individuals were more likely to be admitted than vaccinated individuals (4.0% v 1.5%, P<0.001) ( table 1 ). In the unvaccinated group, 174 689 individuals (60.2%) had a covid-19 index date during the period when the alpha variant was predominant, whereas individuals in the vaccinated group were mostly infected during the omicron era (n=224 330, 74.9%) ( table 1 ).

Descriptive statistics of study population, stratified according to vaccination status before covid-19 infection. Values are number (percentage) unless stated otherwise

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Median follow-up from 28 days after the covid-19 index date was 129 (IQR 51-287) days in the total study population (vaccinated: 197 (IQR 42-288) days, not vaccinated: 112 (IQR 57-282) days). Median follow-up until a PCC diagnosis was similar between the vaccinated and unvaccinated groups (18 (IQR 7-47) days v 17 (IQR 6-39) days). Individuals who received three or more vaccine doses before infection had the longest follow-up (median 250 (IQR 126-283) days), whereas those who had only received one dose before infection had the shortest follow-up (median 42 (IQR 11-281) days). For both vaccinated and unvaccinated individuals, the most common reason for censoring during follow-up was vaccination, followed by end of follow-up (see supplementary table S2). Captured reinfections were rare during the study period (n=12 888, 2.2%) and significantly more common in the unvaccinated group than vaccinated group (3.3% v 1.1%, P<0.001) (see supplementary table S2). Among vaccinated individuals, 1201 (0.4%) had a diagnosis of PCC during follow-up, compared with 4118 (1.4%) among unvaccinated individuals ( fig 2 and supplementary table S2).

Cumulative incidence of PCC, using Kaplan-Meier failure function, for individuals vaccinated or not vaccinated against covid-19. Study population included all adult (≥18 years) residents in the two largest regions of Sweden with covid-19 first registered during the study inclusion period, 27 December 2020 to 9 February 2022. PCC=post-covid-19 condition

Vaccine effectiveness

Receiving at least one dose of a covid-19 vaccine before the covid-19 index date was associated with a reduced risk of PCC (adjusted hazard ratio 0.42 (95% confidence interval 0.38 to 0.46), with a vaccine effectiveness of 58% ( table 2 ). Vaccine effectiveness increased with increasing number of vaccine doses before covid-19. Adjusted hazard ratios for one dose, two doses, and three doses were 0.79 (0.68 to 0.91), 0.41 (0.37 to 0.45), and 0.27 (0.23 to 0.32), with a respective vaccine effectiveness of 21%, 59%, and 73% ( table 2 ).

Vaccine effectiveness and hazard ratios, with 95% confidence intervals, between covid-19 vaccination before infection and a diagnosis of post-covid-19 condition, overall and in separate analyses stratified by number of vaccine doses

To evaluate potential vaccine effectiveness against PCC through the reduced risk of hospital admission for acute infection, we added severity of the acute infection (hospital admission requiring ICU admission, hospital admission not requiring ICU admission, no hospital admission) to the regression model. The adjusted hazard ratio for any dose before infection was 0.54 (0.50 to 0.60) and for one dose, two doses, and three or more doses was 0.81 (0.70 to 0.93), 0.53 (0.48 to 0.59), and 0.42 (0.35 to 0.49), respectively (see supplementary table S3). We then stratified the analysis of any dose by severity of the acute infection, resulting in similar adjusted hazard ratios between the hospital admission without ICU admission group and the no hospital admission group (0.57 (0.48 to 0.68) v 0.56 (0.50 to 0.62), respectively) (see supplementary table S4).

In the subgroup analysis stratifying on the median time between last vaccination and infection (126 days), vaccine effectiveness against PCC for any dose before covid-19 was slightly lower for longer duration since last dose and slightly higher for shorter duration compared with the main analysis (≥126 days: 49%, <126 days: 63%) (see supplementary table S5). Individuals with a last vaccination more than 126 days from infection mainly received two doses (0.1% had received ≥3 doses, data not shown). The interaction terms for age, sex, predominant variant at the time of the covid-19 index date, employment status, number of healthcare contacts, diabetes, and cardiovascular disease were significant when separately added to the full model. Men showed a higher vaccine effectiveness than women (≥1 dose: 64% and 54%, respectively). The highest vaccine effectiveness by age group was shown in those aged 55-64 years (≥1 dose: 69%) and the lowest in those aged 18-34 years (≥1 dose: 28%). We also stratified infection on the preodominant variant and found that vaccine effectiveness was highest in individuals with covid-19 during the delta period (68%) (see supplementary table S4). No major differences were found in the analyses stratified by combinations of vaccines for the first two doses before covid-19, with adjusted hazard ratios ranging from 0.43 (0.32 to 0.58) to 0.49 (0.44 to 0.54); except for the combination of AZD1222 and BNT162b2 (see supplementary table S6).

In the first sensitivity analysis, we restricted the vaccinated group to those individuals who were vaccinated at least 14 days before the covid-19 index date (n=265 299, 88.5% of the total vaccinated group), which only marginally changed the results compared with the main analyses (see supplementary table S7). In the second sensitivity analysis, we restricted to a minimum of 90 days between the covid-19 index date and PCC diagnosis, which yielded similar results to the analysis with a requirement of 28 days (see supplementary table S8). Lastly, when we restricted the vaccinated group to those who only received two or three doses before infection, vaccine effectiveness was 64% (see supplementary table S9).

In this large register based cohort study including 589 722 residents from the two largest regions of Sweden, we found a strong association between vaccination before first registered covid-19 and a reduced risk of receiving a diagnosis of PCC. In the study population, unvaccinated individuals had an almost fourfold higher proportion of PCC diagnoses compared with those who were vaccinated before infection (1.4% v 0.4%). We found a vaccine effectiveness against PCC of 58% for any dose within the primary vaccination series (ie, the first two doses and the first booster dose administered within the recommended schedule) given before a first registered infection. Vaccine effectiveness increased with each dose in the series: 21% for one dose, 59% for two doses, and 73% for three or more doses.

Findings in context

The few earlier studies on vaccine effectiveness against the long term effects of covid-19 have mostly shown protective effects, with a wide range of effect estimates, 26 27 but some failed to show an overall protective effect. 28 29 The methodology and data included in the earlier studies were heterogeneous and had limitations. Study populations have rarely been population based and often have included a small number of participants. 30 31 Analyses of different effects for different numbers of vaccine doses before covid-19 have not always been performed. 27 32 Because vaccination during follow-up has often not been a criterion for censoring, both vaccinated and unvaccinated individuals have been included in the unvaccinated group. In the present study, we used population based survival data of 589 722 individuals, censoring at both vaccination and reinfection, and report vaccine effectiveness separately for any dose, one dose, two doses, and three or more doses. Earlier studies have generally lacked a clear definition of PCC, and symptoms have often been self-reported, 29 30 31 33 whereas we used register based clinical diagnoses of PCC as the outcome. Furthermore, in earlier studies follow-up duration has often been short, 29 whereas in our study the median follow-up was 129 days from 28 days after a first registered infection. A recent systematic review concluded that being vaccinated against covid-19 before infection had a protective effect on PCC in 10 of the 12 included studies, with effect estimates ranging from 0.48 to 0.87 for any vaccine dose given before infection. 11 Owing to high heterogeneity between studies and the low certainty of evidence, no meta-analysis was performed. In other systematic reviews, meta-analyses have, however, included several of these studies, but the results should be interpreted with caution. 34 35 One of these meta-analyses concluded that receiving two doses of vaccine before covid-19 was associated with a lower risk of PCC compared with no vaccination, with an odds ratio of 0.64, 34 and that the odds ratio was 0.71 with at least one dose before infection. 35

Using register data from the whole adult population in the two largest regions of Sweden, we showed that vaccination against covid-19 before infection was associated with a decreased risk of receiving a diagnosis of PCC. When stratifying by the median time between last vaccination and infection (126 days) to assess the potential different effects of recent versus earlier vaccination, we found that receiving the last vaccine dose more than 126 days before covid-19 was still associated with a relatively high vaccine effectiveness against PCC, and only slightly lower than in the main analysis. In addition, to ensure sufficient time between vaccination and the acute infection, in a sensitivity analysis we restricted the vaccinated population to those who received their last vaccine dose more than 14 days before covid-19, and the estimated vaccine effect did not markedly change from the main analysis. Furthermore, in the main analyses we only considered the first PCC diagnosis at least 28 days from infection, but in sensitivity analyses we required at least 90 days from infection, with similar results.

Studies have shown that women may develop greater immune responses to vaccination than men, 36 although this does not necessarily translate to better protection against the disease. In our study, men showed a higher vaccine effectiveness against PCC than women. It has not yet been fully established whether PCC is more likely to occur with particular variants. Available data suggest, however, that individuals infected with the omicron variant are at lower risk of developing long term effects of covid-19 than individuals infected with the other variants. 37 38 39 Nonetheless, it is difficult to determine if this lower risk is associated with the specific variant or is the result of immunity from previous infections or vaccinations, or as a result of shorter follow-up durations. A small study evaluating the protective effect of covid-19 vaccines against PCC, which included individuals with infections during the omicron period as well as the earlier periods, did not show significantly different results between the variants. 30 In the present study, the study population included individuals with infections at the time when the alpha and delta variants predominated, and also during part of the pre-alpha and omicron periods. Although vaccination coverage was not evenly distributed during these periods, stratifying on the period of dominant variant at the time of infection showed only a slightly lower vaccine effectiveness against PCC in the omicron period than in the pre-alpha and alpha periods. As we did not have access to virus sequencing data in our analysis, we used the time of infection as a proxy for variant. Consequently, the variant causing acute infection in some of the study individuals might have been misclassified.

The pathogenesis of PCC has not yet been clarified, but several mechanisms have been proposed relating to the different symptom manifestations and it has become increasingly evident that patients with PCC are a heterogenous group. Potential mechanisms include organ damage, abnormal immune activation during acute infection, reactivation of other viruses, altered systemic immunity, autoimmunity, and sustained immune activation due to viral persistence. 40 Determining the pathogenesis might suggest potential pathways for the protective effect of the vaccines—for example, a reduced viral load during the acute infection after vaccination could reduce the virus’s persistence with lasting immune activation. Different symptom clusters of PCC may have different pathogeneses and therefore different mechanisms for the vaccine effect. We have shown that almost 37% of patients with covid-19 treated in the ICU subsequently have a PCC diagnosis. 16 Covid-19 vaccines have been shown to protect against hospital admission with covid-19, 41 which could be one pathway for the vaccines to exert a protective effect against PCC. In our analysis, vaccine effectiveness against PCC seemed to be only partly explained by a decreased risk of hospital admission. In addition, analyses stratified on severity of acute disease as indicated by the need for hospital admission showed that vaccine effectiveness was similar in both the group admitted to hospital without ICU admission and the group with no hospital admission. Furthermore, a study showed that those who were vaccinated after covid-19 had a lower risk of developing PCC compared with those who were unvaccinated 12 weeks after covid-19. 26 This, together with the findings in the present study, support the hypothesis of pathways beyond the protective effect against hospital admission that may contribute to the protective effect of covid-19 vaccines against PCC. It is also important to note that symptoms of PCC are frequently observed not only in patients with confirmed covid-19 but also in those without a positive SARS-CoV-2 PCR test result. 42

Strengths and limitations of this study

The present study has several strengths. Firstly, we used register based data collected from high quality registers, resulting in essentially no loss to follow-up and a low risk of self-reporting bias. In Sweden, it is mandatory and regulated by law to register every administered covid-19 vaccine dose in the national vaccination register. Therefore the exposure data (vaccination) are particulary comprehensive and accurately measured. Secondly, we had access to individual level data from primary healthcare as well as inpatient and outpatient specialist healthcare. This is of importance when studying the diagnosis of PCC, since we have previously shown that most (>85%) patients with PCC in Sweden received their diagnosis in primary healthcare. 16 In addition, to fully account for health seeking behaviour and the potential that the PCC group is a biased group of healthcare seekers, the number of healthcare contacts in 2019 was included as a confounder in the full model. Futhermore, the study was population based, covering the two largest regions of Sweden (Region Stockholm and Västra Götaland, 40% of the total Swedish population). Lastly, most previously published studies investigating the protective effect of vaccination before covid-19 against PCC have not been able to account for vaccinations given after infection. By not considering these vaccinations, the total protective effect against PCC will potentially be diminished as a result of the groups becoming more similar to each other. By using survival data in combination with data on vaccinations from the national vaccination register, we were able to censor individuals at vaccinations given after the acute infection.

The limitations of the present study include that both PCC and the ICD-10 diagnosis code, U09.9, are relatively new and the code has not yet been validated in a Swedish setting. It is possible that PCC might be overdiagnosed as well as underdiagnosed, which could affect both the sensitivity and the specificity of PCC as an outcome measure. If this affects both unvaccinated and vaccinated individuals fairly equally, this would lead to a non-differential misclassification of the outcome, which on average would result in some bias towards the null. However, we cannot fully rule out the possibility that vaccinated individuals are less likely than unvaccinated individuals to receive a PCC diagnosis owing to expectations from both patients and healthcare providers about the protective effect of vaccination—although it may be less likely that this bias would increase with increasing number of vaccine doses and show the strong dose-response association in our results. A recent paper from Sweden investigating healthcare use after covid-19 among patients with the PCC diagnosis code, in comparison with controls matched on age, sex, and number of healthcare contacts before infection, showed that the PCC group had significantly more healthcare contacts after covid-19. 24 Therefore, we believe that the specificity of the PCC diagnosis code might be good, while its sensitivity remains less clear. In addition, it is possible that vaccine effectiveness differs in patients who experience a specific symptom compared with those who experience another symptom within the PCC spectrum. However, if the protective effect of the vaccines would be valid for a few specific symptoms within the PCC spectrum only, the relatively strong effect on the PCC diagnosis we see in the present study would be less likely to occur. A few studies have also investigated the impact of vaccination on existing PCC, showing both no effect as well as alleviation and aggravation of PCC symptoms. 43 44 45 The register based data used in the present study had limited data on symptoms and therefore it would be difficult to assess changes in symptoms of an already existing PCC. Furthermore, although PCC is diagnosed on a specific date, the condition and symptoms usually have been present before the date of diagnosis. Lastly, our results are based on first SARS-CoV-2 infections, whereas reinfections might represent most of the infections today. The potential impact of reinfections on the covid-19 vaccine effectiveness of PCC remains to be elucidated.

Conclusions

This study found a strong association between receiving covid-19 vaccine doses within the primary vaccination series (ie, the first two doses and the first booster dose within the recommended schedule) before infection and a reduced risk of receiving a diagnosis of PCC. Vaccine effectiveness increased with each dose in the series given before covid-19. The results from this study highlight the importance of complete primary vaccination coverage against covid-19, not only to reduce the risk of severe acute covid-19 infection but also the burden of PCC in the population.

What is already known on this topic

The efficacy and effectiveness of covid-19 vaccines against SARS-CoV-2 infection and severe manifestations of acute covid-19 have been shown

The effectiveness of covid-19 vaccines on post-covid-19 condition (PCC) has been less evaluated using population based real world data

What this study adds

The findings suggest a strong association between receiving the first three doses of vaccine before covid-19 and a reduced risk of receiving a diagnosis of PCC

Vaccine effectiveness increased with each successive dose

These results highlight the importance of primary vaccination against covid-19 to reduce the burden of PCC in the population

Ethics statements

Ethical approval.

This study was approved by the Swedish Ethical Review Authority (Dnr: 2020-01800 with several amendments), which waived the need for informed consent as this is a register based study.

Contributors: LL, SL, FN, and MB conceived and designed the study. All authors made substantial contributions to the acquisition (YX, AS, HL, MG, FN), analysis (LL, JM, HL, MB), or interpretation (LL, SL, YX, JM, AS, MG, HL, FN, MB) of the data. LL and MB drafted the manuscript, and all authors revised it critically for important intellectual content and gave their final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MB is the guarantor and accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: MB is funded through research grants from the Swedish Society for Medical Research (PD20-0012), the Swedish Research Council for Health, Working Life, and Welfare (FORTE, 2022-00444), and the Swedish Research Council (2022-06395). SL has received a salary from AstraZeneca since January 2023. MG is funded by grants from the Swedish state, under an agreement between the Swedish government and the county councils (ALF agreement ALFGBG-965885); by SciLifeLab from the Knut and Alice Wallenberg Foundation (2020.0182 and 2020.0241); by the Swedish Research Council (2021-05045 and 2021-06545); and by King Gustaf V:s and Queen Victoria’s Foundation. FN has funding from the SciLifeLab from the Knut and Alice Wallenberg Foundation (KAW 2021-0010/VC2021.0018 and KAW 2020.0299/VC 2022.0008) and the Swedish Research Council (2021-05045 and 2021-05450). The SCIFI-PEARL (Swedish Covid-19 Investigation for Future Insights—a Population Epidemiology Approach using Register Linkage) project, which provides the data for this analysis, has basic funding based on grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (Avtal om Läkarutbildning och Forskning/Medical Training and Research Agreement) (ALFGBG-938453, ALFGBG-971130, ALFGBG-978954), and previously from a joint grant from FORTE (Swedish Research Council for Health, Working Life, and Welfare) and FORMAS (Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning), a government research council for sustainable development (2020-02828). The funding organisations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The manuscript’s guarantor confirms the independence of researchers from funders and that all authors, external and internal, had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Swedish Society for Medical Research, the Swedish Research Council for Health, Working life, and Welfare (FORTE), and the Swedish Research Council for the submitted work; MB is funded through research grants from the Swedish Society for Medical Research, the Swedish Research Council for Health, Working Life, and Welfare (FORTE), and the Swedish Research Council; SL was funded by a Swedish government research grant through the ALF-agreement; SL has been employed by AstraZeneca since January 2023; MG receives funding through a Swedish government research grant through the ALF-agreement, Swedish Research Council, King Gustaf V:s and Queen Victoria’s Foundation, and from the Swedish Research Council for Sustainable Development (FORMAS); MG has received research grants from Gilead Sciences and honorariums as speaker, member of the data safety and monitoring board and scientific advisor for Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen-Cilag, MSD, Novocure, Novo Nordic, Pfizer, and Sanofi; FN was funded for the submitted work by a Swedish government research grant through the ALF-agreement and by a previous joint grant from the Swedish Research Council for Health, Working Life, and Welfare (FORTE) and the Swedish Research Council for Sustainable Development (FORMAS); FN is funded through research grants from the Swedish Research Council, Swedish Heart Lung Foundation, SciLifeLab/Knut and Alice Wallenberg Foundation, and Swedish Social Insurance Agency; FN was employed by AstraZeneca until 2019 and owns some AstraZeneca shares; no other relationships or activities that could appear to have influenced the submitted work.

Data sharing The data used in this study are deidentified individual level data from Swedish healthcare registers and can be obtained from the respective Swedish public data holders on the basis of ethical approval for the research in question, subject to relevant legislation, processes, and data protection.

The lead author (MB) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Dissemination to participants and related patient and public communities: The research findings from this manuscript will be disseminated through, for example, presentation of our findings at scientific conferences and press releases to national and international media, as well plain language summaries available on the University of Gothenburg’s homepage.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/ .

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Changes in T cell populations and cytokine production in SARS-CoV-2 infected individuals; their role in prognosis

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At the time of writing this call for papers for the special issue: “Changes in T cell populations and cytokine production in SARS-CoV-2 infected individuals; their role in prognosis” (June 10, 2022), over 534 million people have been infected with SARS-CoV-2 virus, of whom over 6.3 million have ...

Keywords : COVID-19, Effector T cells, Regulatory T cells, TFH cells, Th17 cells, cytokines, inflammation, antibodies, variants of concern, long COVID, vaccines, Antigen presenting cells, B-cells, Gene expression, Post-translational modification, Therapy

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170 Vaccination Research Paper Topics For Stellar Students

Research papers are a monumental highlight in your academic journey. They are a critical milestone in your studies that must be tackled with the utmost care and stellar diligence. Vaccination topics are susceptible as you have to show complete mastery of all details.

If you are pursuing a medicine course, then vaccination research topics might be an excellent area of interest. A good research paper starts with a great topic, and we are here to help you nail that. We understand the significance of research papers, and that is why we have handpicked 170 out-of-the-box vaccination research paper topics, titles, and ideas to make your work seamless.

Debate Topics About Vaccination

• What is reverse vaccinology?
• Look at the ways of harnessing the participation of dendritic cells in tolerance and immunity
• What are some of the approaches to advance cancer vaccines to clinical utility?
• Highlight innovative therapeutic and vaccine approaches against respiratory pathogens
• Examine immunity to malaria and vaccine strategies
• Assess molecular vaccines against pathogens in the post-genomic era
• Comprehending the limitations of today’s influenza vaccine strategies and further development of more efficient therapeutic and preventative interventions
• Study HIV-associated persistent inflammation and immune activation
• Analyze recent advances in respiratory virus infection
• What is the novel approach for anti-tumor vaccines
• Unravel the challenges and progress in the development of a B cell-based hepatitis C virus vaccine
• What is the functional relevance of Tatraspanins in the immune system?
• Look at advanced immunization technologies for next-generation vaccines
• Evaluate epitope discovery and synthetic vaccine design
• In what ways can tuberculosis be treated by targeting host immunity
• What are the immunomodulatory effects of drugs in the treatment of immune-related diseases
• Highlight natural antibodies in health and disease
• Discuss different influenza virus vaccines and immunotherapy
• What are some of the shadows of cancer immunotherapy
• Understanding the therapeutical potential of extracellular vesicles
• A review of the ethical theories and problems associated with vaccination in America
• Do vaccines love the Darwinian fitness of immune cells

Vaccination Behavior Research Topics

• Unraveling demand and supply effects on the up-take of influenza vaccinations
• Point out new approaches to the seasonal flu vaccine
• Exploring the impact of vaccination
• Investigating patient experience with, and the use of, an electronic monitoring system to assess vaccination responses
• A meta-analysis of interventions that enhance the use of adult immunization and cancer screening services
• Do vaccines seem to work against bacterial and viral infections, and are they effective?
• Gathering the evidence for the introduction of typhoid vaccine: worldwide vaccine testing
• Explore molecular mimicry to broaden the immune response to carbohydrate antigens for vaccine development
• Tumor-associated glycan and immune surveillance
• Rational design and application of idiotope vaccines
• Assessing the effects of vaccines on immune-deficient people
• What are the impacts of rapid growth and deployment of high-volume vaccines for pandemic response

Anti-vaccination Research Paper Topics

• Should the state impose vaccinations, or should the choice be left up to the child’s parents?
• What is the connection between vaccination and autism?
• Is natural immunity better than immunity through immunization?
• Examining cultural perspectives on vaccination
• Are they worth it? adverse effects of vaccination on children
• To vaccinate or not against HPV? A content analysis of vocabularies of motives
• Vaccines: religious and cultural arguments from an Islamic perspective
• Anti-science populism or biomedicine’s unresolved knots? Comparing views on the movements against mandatory pediatric vaccines
• An anthropological commentary on vaccine hesitancy, decision-making, and interventionism among religious minorities
• Understanding attitudes to vaccination

Research Topics For Covid-19 Vaccination

• Medical mistrust in the context of Covid-19: implications for intended care-seeking and quarantine policy support in the United States
• What is the acceptability of the potential COVID-19 vaccine among smokers and non-smokers?
• COVID-19 vaccine hesitancy in healthcare personnel: are there any differences among classifications
• Discuss various options that one can use to convince people to get the covid-19 vaccine
• Examining COVID-19 vaccine efficacy after the first dose: Pfizer, Moderna, AstraZeneca
• Discuss the impacts of herd immunity during the covid-19 pandemic
• What are some of the effects of covid-19 vaccination on transmission of disease?
• Discuss whether antibodies generated through vaccination recognize all-new variants of covid-19
• Investigate how the intensity of lockdowns accelerate or influence mutation of the COVID virus
• Examine how the new covid-19 strain identified in England will affect the available vaccines.
• Outline which immunoglobulin types can be used as the markers for covid-19 vaccination
• Which is the best way to deal with swaps after completing vaccinations in nursing homes
• How do we curb vaccine hesitancy among healthcare providers?
• Which one is the more dangerous, covid-19 or covid-19 vaccine? What must be the individual decision?
• Analyzing Ebola and the evolving ethics of quarantine
• Break down some of the side effects of covid-19 vaccination
• How long will immunity last after receiving the covid-19 vaccination?
• Will, a covid-19 vaccine work for everyone? Are there people who cannot get vaccinated?
• Is bivalent OPV immunization capable of mitigating the impact of covid-19?
• What are the expected long-term side effects of the vaccination for covid-19?
• Evaluate differences between the first and second doses of the covid-19 mRNA vaccine?
• Examine the ingredients in the covid-19 mRNA vaccine
• Can a person’s DNA change through mRNA vaccines?
• Factors that stops the body from continuing to produce COVID-19 spike protein after getting a COVID-19 mRNA
• Discuss whether a person vaccinated against covid-19 will be able to spread the virus to susceptible people
• Investigating vaccination adverse outcomes and costs of vaccine injury claims(VICs): In the past, present, and during COVID-19.
• Who gets cured: Covid-19 and the development of critical sociology and anthropology of cure
• Development of perception and attitude scales related to COVID-19 pandemic
• Does the mutation of the coronavirus affect the capacity of the vaccines to prevent disease?
• A case-control study: finding a link between pre-existing antibodies got after the childhood vaccinations or past infections and COVID-19?
• Queue questions: ethics of COVID-19 vaccine prioritization
• Disparities between Black and White in H1N1 vaccination among adults in the U.S. in 2009: A cautionary tale for the COVID-19 pandemic
• Autonomy and refusal in pandemics: What to do with those who refuse COVID-19 vaccines
• Knowledge, attitude, and acceptance of a COVID-19 vaccine: a global cross-sectional study
• Prospects of COVID-19 vaccine implementation in the U.S.: Challenges and potential solutions
• What are the effects of COVID-19 vaccines on pregnant women?
• Compare and contrast the efficacy of different covid-19 vaccines.
• Ways to improve covid-19 vaccine acceptance
• Determination of causation between COVID-19 vaccines and potential adverse effects

Vaccination Of Children Topics

• What is the essence of increasing HPV vaccination among children?
• Analyze the primary diseases that vaccines prevent in children
• What will happen if a child’s vaccination schedule is delayed
• Look at the vaccination schedule for children in the U.S.
• Can children receive more than one vaccine at a time?
• Examine revaccination outcomes of children with proximate vaccine seizures
• What are the impacts of measles-containing vaccination in children with the severe underlying neurologic disease?
• Evaluate the challenges involved in measuring immunization activity coverage among measles zero-dose children
• What is the connection between the polio vaccine and the risk of cancer among children?
• Do multiple vaccines affect babies’ health and immune system in an adverse war, or can their bodies handle them?
• What are the various vaccination options available for children, and are they harmful to children’s overall health?
• The case for further research and development: assessing the potential cost-effectiveness of microneedle patches in childhood measles vaccination programs
• Evaluate the accuracy of parental recall of child immunization in an inner-city population
• Evaluating maternal acculturation and childhood immunization levels among children in African-American families in Florida
• Policy analysis: the impact of the vaccine for children’s program on child immunization delivery
• The effect of managed care: investigating access of infant immunizations for poor inner-city families
• Who takes up free flu shots? Investigating the effects of an expansion in coverage
• What are the societal and parental values for the risks and benefits of childhood combination vaccines?
• Looking into trends in vaccination intentions and risk perceptions: a longitudinal study of the first year of the H1N1 pandemic

Healthcare Topics About Vaccination

• Conscious consideration of herd immunity in influenza vaccination decisions
• A case study of ethnic or racial differences in Medicare experiences and immunization
• What preservatives are used in vaccines
• Discuss the relationship between vaccines and autism
• What is the role of epidemiology in infection control?
• How t design and select the most relevant immunogenic peptide sequences
• Discuss why the Zika virus has not had a significant impact in Africa as compared to America
• What are the advantages of using the phage display technology of antibodies versus hybridism technology?
• Analyzing the impact and cost-effectiveness of vaccination programs in a country using mathematical models
• Malaria vaccines: progress and problems
• Malaria: cloning genes for antigens of plasmodium falciparum
• Fighting profits on the pandemic: The fight for vaccines in today’s economic and geopolitical context
• Molecular and biotechnological approaches to fish vaccines
• Immunogenicity of a whole-cell pertussis vaccine with low lipopolysaccharide content in infants
• Immunogrid: an integrative environment for large-scale simulation of the immune system for vaccine discovery, design, and optimization

Thesis Topics In Vaccination

• Investigating challenges and opportunities in vaccine delivery, discovery, and development
• Discuss classic methods of vaccine development
• What are some of the current problems in vaccinology?
• Assess some of the latest tools for vaccine development
• Using cost-effectiveness analysis to support research and development portfolio prioritization for product innovations in measles vaccination
• Communicating vaccine safety during the introduction and development of vaccines
• Highlighting viral vectors for use in the development of biodefense vaccines
• What is the role of US. military research programs in the invention of USA-approved vaccines for naturally occurring infectious diseases
• Curbing outbreaks: utilizing international governmental risk pools to fund research and development of infectious disease medicines and vaccines
• Vaccine stabilization: research commercialization and likely impacts
• Exam the unequal interactions of the role of patient-centered care in the inequitable diffusion of medical innovation, the human papillomavirus(HPV) vaccine
• A case study of the status of development of vaccines and vaccine research for malaria
• Enteric infections vs vaccines: a public health and clinical research agenda for developing countries
• A review of research and vaccine development for industry animals in third world countries
• How the research-based industry approaches vaccine development and establishes priorities
• A look at the status of vaccine research and development of a vaccine for HIV-1
• Modeling a cost-effective vaccination strategy for the prevention of herpes zoster infection
• Using an adequate T.B. vaccination regiment to identify immune responses associated with protection in the murine model
• A systematic analysis of the link between vaccines and atopic dermatitis
• Do vaccines provide better immunity than natural infections?
• Is there a need to be vaccinated against a disease that is not available in your country or community
• How to strengthen adult immunization via coordinated action
• Using the general equilibrium method to assess the value of a malaria vaccine: An application to African countries
• Who should take up free flu shots?
• Evaluate the impact of vaccination among health care personnel
• Retail clinics and their impact on vaccination in the U.S.
• Discuss the societal values for the benefits and risks of childhood combination vaccines
• How safe and effective is the synovial vaccine for people above 60 years
• Evaluating vaccination effectiveness of group-specific fractional-dose strategies

Law Research Topics On Vaccination

• Explain why there are age restrictions for Rotavirus vaccination?
• Vaccination or hygiene : Which factor contributes to the decline of infectious diseases?
• Outline the main factors that cause vaccine failure
• Discuss why HIV is so hard to vaccinate in uninfected people?
• In what ways do maternal vaccinations affect the fetal nervous system development
• How to deliver malaria vaccine effectively and efficiently
• Highlight the vaccines that are specifically licensed in the U.S. for pregnant women
• How does an immune genetic algorithm work?
• Evaluate the relationship between the success of artificial insemination and vaccination
• Outline the reasons why vaccines underperform in low-income countries
• Discuss U.S. immigration and vaccination policy
• Assessing the effectiveness of compelled vaccination

Vaccination Ethical Topics

• What are the requirements for a strain to be used as a vaccine?
• What is the best way to administer vaccines in children?
• Assessing the benefits of maternal vaccination on breastfed infants
• Evaluating the pros and cons of intraperitoneal vaccination
• Examine ways to measure the pattern of vaccination acceptance
• Investigate Covid-19 transmission, vaccination rate, and the fate of resistant strains
• Look into dark web marketplaces and covid-19 vaccines.
• A close look at covid-19 vaccines and kidney diseases
• Contextualizing the impact of covid-19 vaccine misinformation on vaccination intent in the U.S.
• Examining behaviors and attitudes of medical students towards covid-19 vaccines

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Abara WE , Gee J , Marquez P, et al. Reports of Guillain-Barré Syndrome After COVID-19 Vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi:10.1001/jamanetworkopen.2022.53845

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Reports of Guillain-Barré Syndrome After COVID-19 Vaccination in the United States

• 1 COVID-19 Response Team, Centers for Disease Control and Prevention, Atlanta, Georgia
• 2 Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland
• Correction Errors in Abstract, Results, and Discussion JAMA Network Open

Question   Are Ad26.COV2.S (Janssen), BNT162b2 (Pfizer-BioNTech), or mRNA-1273 (Moderna) COVID-19 vaccines associated with Guillain-Barré syndrome (GBS) within 21 or 42 days after vaccination?

Findings   This cohort study of 487 651 785 COVID-19 vaccine doses found that in observed-to-expected analyses, the observed number of GBS reports was higher than expected based on background rates within 21 and 42 days after vaccination for Ad26.COV2.S but not BNT162b2 or mRNA-1273. GBS reporting rates within 21 and 42 days of Ad26.COV2.S vaccination were 9 to 12 times higher than after BNT162b2 or mRNA-1273 vaccination.

Meaning   These findings suggest that Ad26.COV2.S vaccination was associated with GBS and that GBS after BNT162b2 and mRNA-1273 may represent background incidence.

Importance   Because of historical associations between vaccines and Guillain-Barré syndrome (GBS), the condition was a prespecified adverse event of special interest for COVID-19 vaccine monitoring.

Objective   To evaluate GBS reports to the Vaccine Adverse Event Reporting System (VAERS) and compare reporting patterns within 21 and 42 days after vaccination with Ad26.COV2.S (Janssen), BNT162b2 (Pfizer-BioNTech), and mRNA-1273 (Moderna) COVID-19 vaccines.

Design, Setting, and Participants   This retrospective cohort study was conducted using US VAERS reports submitted during December 2020 to January 2022. GBS case reports verified as meeting the Brighton Collaboration case definition for GBS in US adults after COVID-19 vaccination were included.

Exposures   Receipt of the Ad26.COV2.S, BNT162b2, or mRNA-1273 COVID-19 vaccine.

Main Outcomes and Measures   Descriptive analyses of GBS case were conducted. GBS reporting rates within 21 and 42 days after Ad26.COV2.S, BNT162b2, or mRNA-1273 vaccination based on doses administered were calculated. Reporting rate ratios (RRRs) after receipt of Ad26.COV2.S vs BNT162b2 or mRNA-1273 within 21- and 42-day postvaccination intervals were calculated. Observed-to-expected (OE) ratios were estimated using published GBS background rates.

Results   Among 487 651 785 COVID-19 vaccine doses, 17 944 515 doses (3.7%) were Ad26.COV2.S, 266 859 784 doses (54.7%) were BNT162b2, and 202 847 486 doses (41.6%) were mRNA-1273. Of 295 verified reports of individuals with GBS identified after COVID-19 vaccination (12 Asian [4.1%], 18 Black [6.1%], and 193 White [65.4%]; 17 Hispanic [5.8%]; 169 males [57.3%]; median [IQR] age, 59.0 [46.0-68.0] years), 275 reports (93.2%) documented hospitalization. There were 209 and 253 reports of GBS that occurred within 21 days and 42 days of vaccination, respectively. Within 21 days of vaccination, GBS reporting rates per 1 000 000 doses were 3.29 for Ad26.COV.2, 0.29 for BNT162b2, and 0.35 for mRNA-1273 administered; within 42 days of vaccination, they were 4.07 for Ad26.COV.2, 0.34 for BNT162b2, and 0.44 for mRNA-1273. GBS was more frequently reported within 21 days after Ad26.COV2.S than after BNT162b2 (RRR = 11.40; 95% CI, 8.11-15.99) or mRNA-1273 (RRR = 9.26; 95% CI, 6.57-13.07) vaccination; similar findings were observed within 42 days after vaccination (BNT162b2: RRR = 12.06; 95% CI, 8.86-16.43; mRNA-1273: RRR = 9.27; 95% CI, 6.80-12.63). OE ratios were 3.79 (95% CI, 2.88-4.88) for 21-day and 2.34 (95% CI, 1.83-2.94) for 42-day intervals after Ad26.COV2.S vaccination and less than 1 (not significantly increased) after BNT162b2 and mRNA-1273 vaccination within both postvaccination periods.

Conclusions and Relevance   This study found disproportionate reporting and imbalances after Ad26.COV2.S vaccination, suggesting that Ad26.COV2.S vaccination was associated with increased risk for GBS. No associations between mRNA COVID-19 vaccines and increased risk of GBS were observed.

Guillain-Barré syndrome (GBS) is a rare, immune-mediated neurologic disorder of the peripheral nervous system that is characterized by ascending weakness and paralysis. 1 Between 3000 and 6000 cases of GBS (1-2 cases/100 000 persons) are diagnosed annually in the United States. 2 , 3 Although the etiology of GBS is unclear, molecular mimicry is thought to play a role in its pathogenesis. 4 Autoimmune antibodies likely target epitopes on peripheral nerves, leading to neuronal demyelination and axonal damage. 4 Production of these autoimmune antibodies may be triggered by an antecedent infection. Approximately two-thirds of patients with GBS report an antecedent gastrointestinal or respiratory infection within 3 weeks before symptom onset. 5 Rarely, vaccination has been associated with GBS. The first epidemiological association was found in 1976, when an increased GBS risk was observed among persons who received the swine flu vaccine. 6 Subsequently, an increased GBS risk was found after recombinant zoster vaccination. 7 Associations between seasonal influenza vaccination and GBS have been inconsistently noted; some studies have shown a small increase in GBS risk among vaccinated persons while others have not. 8 , 9

Postauthorization and postlicensure monitoring of adverse events are essential components of the US COVID-19 vaccination program. 10 Initial surveillance findings suggested that the Ad26.COV2.S (Janssen) vaccine, a replication-incompetent human adenovirus vector COVID-19 vaccine, was associated with increased risk of GBS, including an imbalance in spontaneous reports and GBS diagnoses for Ad26.COV2.S compared with mRNA COVID-19 vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]). 11 , 12 We described and compared reports to the Vaccine Adverse Events Reporting System (VAERS) of verified GBS after the 3 available US COVID-19 vaccines among people ages 18 years and older and investigated whether surveillance data supported an association between Ad26.COV2.S, BNT162b2, or mRNA-1273 vaccines and GBS within 21 and 42 days after vaccination.

The Centers for Disease Control and Prevention (CDC) determined that this cohort study was part of public health surveillance (45 CFR §46.102[l][2] 13 ) and did not require evaluation by an institutional review board or informed consent. This cohort study and its results followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

VAERS is a national passive vaccine safety surveillance system that is coadministered by the CDC and Food and Drug Administration. The system accepts reports of adverse events after vaccination from vaccine recipients or their parents or guardians, clinicians, health care institutions, vaccine manufacturers, and members of the public regardless of whether the reported events could plausibly be associated with vaccination. 14 VAERS reports include demographic information and medical history of the vaccinated person, type of vaccine or vaccines received, date of vaccination, possible adverse events experienced by the vaccinated person and date of onset, history of adverse events after vaccination, and current illnesses and medications. 14 Each report is reviewed by a trained coder who assigns Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PTs) 15 based on clinical information in the report and any additional information from medical records obtained through follow-up.

Among US (domestic) VAERS reports submitted from December 14, 2020, through January 28, 2022, for people ages 18 years and older who received a COVID-19 vaccine (Ad26.COV2.S, BNT162b2, or mRNA-1273), we searched for the following MedDRA PTs: acute motor axonal neuropathy, acute motor-sensory axonal neuropathy, autoimmune neuropathy, demyelinating polyneuropathy, demyelination, subacute inflammatory demyelinating polyneuropathy, immune mediated neuropathy, Guillain Barré syndrome, or Miller-Fisher syndrome. Reports with any of these MedDRA PTs were deemed possible GBS cases regardless of time to symptom onset after vaccination. Available medical records, including death certificates, were reviewed. If VAERS reports did not include medical records, we contacted clinicians or health care institutions and requested these records. Medical records were considered unavailable for review if we did not receive a response from a clinician or health care institution by April 15, 2022.

CDC staff collected clinical data from available records concerning GBS signs and symptoms (hyporeflexia or areflexia, paresthesia, ophthalmoplegia or ophthalmoparesis, ataxia, limb weakness, and corticospinal tract signs), GBS testing (cerebrospinal fluid analysis, nerve conduction studies, or electromyography), GBS treatment (intravenous immunoglobulin, plasmapheresis, or both), and whether a GBS diagnosis was made by a physician, particularly a neurologist. CDC clinical reviewers then determined whether GBS reports met the Brighton Collaboration case definition for GBS. 1 Brighton Collaboration criteria are used to assign diagnostic certainty to GBS cases. 1 A Brighton level 1 case corresponds to the highest level of GBS diagnostic certainty, while level 4 corresponds to suspected GBS cases. 1 GBS cases classified as Brighton level 1, 2, or 3 were considered verified GBS for this analysis. We obtained data about self-reported patient demographic characteristics, clinical and medical history, COVID-19 vaccine type and vaccination date, history of flulike or gastrointestinal symptoms within 42 days of the most recent COVID-19 vaccination, and time to GBS symptom onset after vaccination. Race and ethnicity were self-reported. Individuals were classified as Hispanic if categorized as having Hispanic ethnicity regardless of whether race was known. Individuals who identified as non-Hispanic and more than 1 race were classified as having multiple races. Individuals were classified as having unknown race and ethnicity if both race and ethnicity were missing. Categories for ethnicity were Hispanic and non-Hispanic; categories for race were American Indian or Alaska Native, Asian, Black, Native Hawaiian or Pacific Islander, White, unknown, and multiple races. Race and ethnicity were evaluated to assess racial distribution of GBS cases after COVID-19 vaccination. Duplicate VAERS reports were consolidated into a single report. We obtained data about number of COVID-19 doses administered during the surveillance period among people ages 18 years and older from the COVID Data Tracker. 16 Two secondary reviewers (T.R.M. and J.R.S.) examined a 20% random sample of verified GBS reports (60 of 295 [20.3%]) to provide a quality check on the initial adjudication of verified GBS cases made by primary reviewers.

Descriptive statistics were used to describe verified GBS cases by type of COVID-19 vaccine received (Ad26.COV2.S, BNT162b2, or mRNA-1273). We calculated reporting rates (cases/1 000 000 vaccine doses administered) and reporting incidence rates (cases/100 000 person-y) of verified GBS cases with symptom onset within 21 and 42 days after vaccination by COVID-19 vaccine type. Person-time at risk was calculated using cumulative vaccine administration data. For person-time at risk (in person-y) during 21-day and 42-day postvaccination intervals, the calculations were N × 21/365.25 and N × 42/365.25, respectively, where N was number of vaccine doses administered. We selected a 21-day postvaccination risk interval because a second dose of mRNA COVID-19 vaccine could be received after this interval. The 42-day risk interval is commonly used in vaccine safety surveillance studies for GBS because higher GBS rates were observed within 5 to 6 weeks (35-42 days) of swine flu vaccination during the 1976 national swine flu immunization program. 6 To estimate whether GBS reporting rates after Ad26.COV2.S vaccination were significantly different from rates after BNT162b2 or mRNA-1273 vaccination within the 21-day and 42-day postvaccination intervals, we calculated unadjusted reporting rate ratios (RRRs) (ie, GBS reporting rate after Ad26.COV2.S divided by reporting rate after BNT162b2 or mRNA-1273, respectively) using Poisson regression models.

We performed observed-to-expected (OE) analyses using all verified GBS cases and after stratifying by sex (male and female) and age group (18-49 years, 50-64 years, and ≥65 years), for each COVID-19 vaccine. We compared the observed number of verified GBS cases among vaccinated persons to an expected number of GBS cases in the general population during 21-day and 42-day risk intervals using pre-COVID-19 published GBS background rates. 17 We derived GBS background rates based on the work of Sejvar et al, 3 who estimated GBS background rates as a function of age group using a formula: exp[−12.0771 + 0.01813 (age in years)] × 100 000, where exp is the exponential function and age is the midpoint of the selected age group. 3 For example, in the ages 18 to 29 years group, the midpoint is 24 years; thus, the GBS background rate is estimated as 0.88/100 000 person-years. We then used age-specific background rates to estimate an expected number of GBS reports for 21- and 42-day postvaccination risk intervals. 17 We derived age-specific GBS background rates for males using the formula exp[−12.4038 + 0.01914(age in years) + 0.5777] × 100 000 and for females using the formula exp[−12.4038 + 0.01914(age in years)] × 100 000. 3 Each respective background rate was used to estimate an expected number of GBS cases by age group and by sex for the 2 postvaccination risk intervals. 17

OE ratios after Ad26.COV2.S, BNT162b2, or mRNA-1273 vaccination for 21-day and 42-day intervals were estimated by dividing the number of observed cases among doses administered by the expected number of cases based on historical background rates; 95% CIs were modeled using the Poisson distribution. 18  P values were 2-sided, and P values < .05 were considered statistically significant. Analyses were done using SAS statistical software version 9.4 (SAS Institute).

During the surveillance period from December 14, 2020, through January 28, 2022, a total of 487 651 785 COVID-19 vaccine doses were administered in the US (17 944 515 Ad26.COV2.S doses [3.7%], 266 859 784 BNT162b2 doses [54.7%], and 202 847 486 mRNA-1273 doses [41.6%]). Using the MedDRA search strategy, we identified 912 possible GBS reports in VAERS; 806 of these reports (88.4%) had medical records available for review. After review and adjudication of these 806 VAERS reports and associated medical records, we verified 295 reports of individuals with GBS (12 Asian [4.1%], 18 Black [6.1%], and 193 White [65.4%]; 17 Hispanic [5.8%]; 169 males [57.3%]; median [IQR] age, 59 [46-68] years) per the Brighton Collaboration GBS case definition. These included 72 level 1 cases, 183 level 2 cases, 3 level 2 Miller-Fisher syndrome cases, 36 level 3 cases, and 1 level 3 Miller-Fisher syndrome case. Among verified cases, 82 cases listed Ad26.COV2.S vaccination (27.8%), 104 listed BNT162b2 vaccination (35.3%), 107 listed mRNA-1273 vaccination (36.3%), and 2 listed receipt of an unknown COVID-19 vaccine (0.6%) ( Table 1 ). 3 , 17 Among verified reports, 275 documented hospitalization (93.2%).

Within 21 days after vaccination, 209 reports of GBS documented symptoms (70.8%); 253 GBS reports documented symptoms within 42 days after vaccination (85.8%). Of 209 GBS cases that occurred within 21 days of vaccination, 59 cases (28.2%) occurred after Ad26.COV2.S, 77 cases (36.8%) occurred after BNT162b2, and 72 cases (34.4%) occurred after mRNA-1273 vaccination. The type of COVID-19 vaccine received was unknown in 1 case. The median (IQR) time from vaccination to symptom onset among GBS cases occurring within 21 days after vaccination was 8.0 (3.0-13.0) days (11.0 [6.0-14.0] days after Ad26.COV2.S, 7.0 [2.0-12.0] days after BNT162b2, and 7.5 [2.5-12.5] days after mRNA-1273 vaccination). Of 253 GBS cases that occurred within 42 days of vaccination, 73 cases (28.9%) occurred after Ad26.COV2.S, 90 cases (35.6%) occurred after BNT162b2, and 89 cases (35.2%) occurred after mRNA-1273 vaccination. The type of COVID-19 vaccine received was unknown in 1 case. The median (IQR) time from vaccination to symptom onset among GBS cases occurring within 42 days after vaccination was 10.0 (5.0-17.0) days (13.0 [7.0-19.0] days after Ad26.COV2.S, 7.0 [3.0-14.0] days after BNT162b2, and 10.0 [4.0-18.0] days after mRNA-1273 vaccination). The Figure shows a distribution of verified GBS cases by time from vaccination to symptom onset.

There were 10 deaths reported (2 deaths after Ad26.COV2.S, 4 after BNT162b2, and 4 after mRNA-1273 vaccination) among all verified GBS cases. Demographic characteristics and clinical summaries of each individual who died are shown in the eTable in Supplement 1 . Most individuals who died were non-Hispanic White (8 individuals [80.0%]) and male (7 males [70.0%]), received mechanical ventilation (7 individuals) and intravenous immunoglobulin treatment (10 individuals [100%]), and were categorized as Brighton level 2 (6 individuals [60.0%]); the median (range) age was 70 (57-88) years. The median (IQR) time from vaccination to symptom onset was 17.5 (5.0-70.0) days. GBS was determined to be the cause of death in 7 reports (70.0%) after review of death certificates (5 reports) and clinical notes (5 reports) by 2 clinician reviewers (J.R.S. and D.K.S.).

GBS reporting rates within 21 days after vaccination were 3.29 cases per 1 000 000 Ad26.COV2.S vaccine doses, 0.29 cases per 1 000 000 BNT162b2 vaccine doses, and 0.35 cases per 1 000 000 mRNA-1273 vaccine doses among all adults ( Table 2 ). Stratifying by age group (18-49 years, 50-64 years, and ≥65 years), GBS reporting rates remained consistently highest after Ad26.COV2.S vaccination among all age groups within the 21-day postvaccination interval. GBS reporting rates within the 42-day postvaccination interval were also highest after Ad26.COV2.S vaccination among all adults (Ad26.COV2.S: 4.07 cases/1 000 000 doses; BNT162b2: 0.34 cases/1 000 000 doses; mRNA-1273: 0.44 cases/1 000 000 doses) and among all age groups.

We estimated RRRs to investigate whether GBS reporting varied by vaccine product received ( Table 2 ). Within a 21-day postvaccination interval, GBS reporting rates among adults were greater after Ad26.COV2.S than BNT162b2 (RRR = 11.40; 95% CI, 8.11-15.99) or mRNA-1273 (RRR = 9.26; 95% CI, 6.57-13.07) vaccination. These same differences were also noted uniformly after stratifying by age group. Within a 42-day postvaccination interval, GBS reporting rates were greater after Ad26.COV2.S than BNT162b2 (RRR = 12.06; 95% CI, 8.86-16.43) and mRNA-1273 (RRR = 9.27; 95% CI, 6.80-12.63) vaccination among all adults and age groups when stratified by age group.

Significant differences were found in OE analysis of GBS cases within 21 days (OE ratio = 3.79; 95% CI, 2.88-4.88) and 42 days (OE ratio = 2.34; 95% CI, 1.83-2.94) after Ad26.COV2.S vaccination among all adults and individually by age group ( Table 3 ). 3 , 17 Similar patterns were found in sex-specific analyses. The OE ratios within 21 days of Ad26.COV2.S vaccination (males: 3.15; 95% CI, 2.23-4.37; females: 4.23; 95% CI, 2.65-6.39]) and within 42 days of Ad26.COV2.S vaccination (males: 1.84; 95% CI, 1.33-2.48; females: 2.89; 95% CI, 1.94-4.11]) were significantly increased. OE ratios for the 21-day postvaccination interval for BNT162b2 (0.33; 95% CI, 0.26-0.42) and mRNA-1273 (0.41; 95% CI, 0.32-0.51) and 42-day postvaccination interval for BNT162b2 (0.19; 95% CI, 0.16-0.24) and mRNA-1273 (0.25; 95% CI, 0.20-0.31) did not demonstrate significant increases between observed and expected numbers of GBS cases among all adults or after stratifying by age and sex ( Table 4 ). 3 , 17

In this retrospective cohort study, we identified 295 verified GBS cases among VAERS reports submitted from December 2020 through January 2022. GBS reporting after Ad26.COV2.S vaccination was approximately 9 to 12 times more common than after BNT162b2 or mRNA-1273 vaccination within 21- and 42-day postvaccination intervals. Similarly, observed GBS cases after Ad26.COV2.S vaccination were 2 to 3 times greater than expected based on background rates within 21- and 42-day postvaccination intervals. There was no significant increase between observed and expected numbers of GBS cases after either mRNA COVID-19 vaccine.

Our findings are similar to those from 2 previous studies. An analysis of VAERS reports made during February to July 2021 showed a potential association between Ad26.COV2.S vaccination and presumptive (ie, unverified) GBS cases. 11 Our analysis included reports of verified GBS cases submitted from December 2020 through January 2022 that met levels 1 through 3 of the Brighton Collaboration GBS case definition. We compared the associations of Ad26.COV2.S, BNT162b2, and mRNA-1273 vaccination with GBS. An analysis of surveillance data collected during December 2020 to November 2021 by the Vaccine Safety Datalink (VSD) showed an imbalance between verified GBS diagnoses after Ad26.COV2.S vaccination compared with mRNA COVID-19 vaccination. 12 Our US-level analysis with VAERS data included verified cases from health care settings not necessarily included in VSD. Our data covered a longer surveillance period than the previous VAERS analysis of presumptive GBS cases. Our results include almost 300 reports of verified GBS cases in VAERS over a 14-month period and therefore may provide a more precise estimate of the relative risk of GBS after Ad26.COV2.S vaccination.

Of 10 deaths reported among individuals aged 57 through 88 years, GBS was the documented cause of death after medical record and death certificate review for 7 individuals. Increasing age is associated with a poorer GBS prognosis and an increased mortality risk. 19 Of these deaths, 8 occurred after mRNA COVID-19 vaccination; however, there was no epidemiologic evidence to suggest an association between either mRNA vaccine and GBS. There were 2 deaths reported after Ad26.COV2.S vaccination. In 1 death, the individual was noted to have onset of GBS symptoms at 70 days after vaccination, which is outside an epidemiologically accepted risk interval to assume an association between vaccination and GBS. The other individual was noted to have symptom onset 5 days after Ad26.COV2.S vaccination; GBS was documented as the cause of death. Based on the available evidence, it is biologically plausible that Ad26.COV2.S vaccination may have been associated with the death, although definitively establishing such an association is difficult with the available information and conclusions about causality cannot be made in this observational study. Under COVID-19 vaccine Emergency Use Authorization regulations, clinicians and health care institutions are required to report deaths and life-threatening events and other specified serious adverse events that occur after COVID-19 vaccination to VAERS regardless of the potential association of vaccination with these outcomes. 20 These reporting requirements are different from those for other licensed and routinely recommended vaccines; therefore, it is difficult to make direct comparisons between numbers of deaths reported to VAERS after COVID-19 vaccination and deaths after vaccines routinely administered to older adults. 21

The specific contributing cause of and risk factors associated with individual GBS cases are often unclear, and its pathogenesis remains incompletely understood. However, molecular mimicry may play a role in the etiology of GBS. 4 Ad26.COV2.S is a recombinant vaccine that uses a nonreplicating adenovirus vector encoding the SARS-CoV-2 spike protein to trigger an immunologic antibody response. 22 It is theoretically possible that antibodies induced by Ad26.COV2.S vaccine may cross-react with glycoproteins on the myelin sheath of the axons of peripheral nerves, resulting in GBS. 23 An increased risk of GBS after ChAdOx1 nCov-19 COVID-19 vaccination (AstraZeneca) has also been reported. 24 , 25 This vaccine uses a replication-incompetent chimpanzee adenovirus vector and has been widely administered in Europe. 24 , 25 In 1 study, the number of GBS cases within 14 days of ChAdOx1 nCov-19 vaccination was 1.4- to 10-fold greater than expected. 24 Increased risk of GBS after these vaccines may suggest an adenovirus vector vaccine class association, at least with respect to COVID-19 vaccines. This possibility merits further evaluation and research concerning plausible mechanisms.

There are limitations to this analysis. First, VAERS data are subject to underreporting because VAERS is a passive surveillance system and reports received may be incomplete. While additional records were requested for review, they may not have been received at all or in a timely manner. Second, some cases that may have met the Brighton Collaboration case definition were likely missed among 106 possible cases that lacked medical records for review. Third, GBS background rates during the COVID-19 pandemic may be different than prepandemic rates; such differences could affect the interpretation of any risk of vaccine-associated GBS. 17 , 26 Fourth, while we checked data quality and integrity, a secondary review was conducted for only 20% of verified GBS cases to confirm that they met the Brighton Collaboration case definition. Fifth, we were not able to conduct dose-specific analyses.

Strengths of this VAERS analysis include the use of a specific, consistently applied definition of GBS among reports received from the entire US vaccinated population. Another strength of our analysis was our ability to conduct analyses of verified GBS cases by age group and sex, unlike other studies.

In this retrospective cohort study, we found evidence for increased risks of GBS within 21- and 42-day intervals after Ad26.COV2.S vaccination. The absolute risk of GBS after Ad26.COV2.S vaccination was likely on the order of several cases per million doses of vaccine administered. Conversely, we did not find increased risks for GBS after receipt of either mRNA COVID-19 vaccine, suggesting that GBS cases observed after mRNA COVID-19 vaccination may represent background GBS incidence. The Advisory Committee on Immunization Practices preferentially recommends that individuals aged 18 years and older receive an mRNA COVID-19 vaccine rather than the Ad26.COV2.S vaccine when both types of COVID-19 vaccine are available. Notably, this recommendation is based primarily on the increased risk of the rare serious condition thrombosis with thrombocytopenia syndrome after Ad26.COV2.S vaccination, but it is also based on a recognized association with GBS. 27

Accepted for Publication: December 1, 2022.

Published: February 1, 2023. doi:10.1001/jamanetworkopen.2022.53845

Correction: This article was corrected on May 12, 2023, to fix errors in the Results (observed-to-expected ratio [OE] for 42-day postvaccination interval for BNT162b2 and number of Brighton level 1 cases) and the missing terms “increase” or “increased” in descriptions of OE ratios and risk of Guillain-Barré syndrome for BNT162b2 and mRNA-1273 vaccines in the Abstract, Results, and Discussion.

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

Corresponding Author: Winston E. Abara, MD, COVID-19 Response Team, Centers for Disease Control and Prevention, 1600 Clifton Rd, US 12-3, Atlanta, GA 30333 ( [email protected] ).

Author Contributions: Dr Abara and Ms Marquez had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Abara, Gee, Nair, Shimabukuro.

Acquisition, analysis, or interpretation of data: Abara, Marquez, J. Woo, Myers, DeSantis, Baumblatt, E.J. Woo, Thompson, Su, Shimabukuro.

Drafting of the manuscript: Abara, Gee, Marquez, J. Woo, Myers, DeSantis, E.J. Woo, Shimabukuro.

Critical revision of the manuscript for important intellectual content: Gee, Baumblatt, Thompson, Nair, Su, Shimabukuro.

Statistical analysis: Abara, Marquez, J. Woo, DeSantis, Shimabukuro.

Administrative, technical, or material support: Abara, Gee, Myers, Thompson, Su.

Supervision: Abara, Gee, Nair, Shimabukuro.

Conflict of Interest Disclosures: None reported.

Data Sharing Statement: See Supplement 2 .

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of Centers for Disease Control and Prevention (CDC) or Food and Drug Administration (FDA). Mention of a product or company name is for identification purposes only and does not constitute endorsement by the CDC or FDA.

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Vaccine - Free Essay Examples And Topic Ideas

Vaccines are biological preparations that provide immunity against particular diseases by stimulating the body’s immune response. Essays on vaccines could explore their development, efficacy, and the public health implications of vaccination programs. Discussions might also delve into the historical milestones in vaccine development, the controversies surrounding vaccinations, and the challenges in global vaccine distribution. Moreover, analyzing the ethical considerations, the economic impact, and the future advancements in vaccine technology can provide a comprehensive understanding of the vital role vaccines play in global health and wellbeing. A vast selection of complimentary essay illustrations pertaining to Vaccine you can find in Papersowl database. You can use our samples for inspiration to write your own essay, research paper, or just to explore a new topic for yourself.

Vaccine Development

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Vaccines should be Mandatory

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Should Vaccinations be Required for Students to Attend Public School?

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A Discussion of the Importance of Flu and Pneumonia Vaccine for the Elderly

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Animal Testing: is it Ethical?

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Review of Zika Virus Vaccine Market Place

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Children Vaccination

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The Progress of Childhood Diseases

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Childhood Immunization

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Pros and Cons of Animal Testing

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Problems with Animal Testing: Inhumane Practices and Neglected Interests

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New and Safe Treatments for Humanity

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Using Animals for Medical Testing is both Ethical and Essential?

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Animal Research for Human Benefit is Unnecessary

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Arguments for and against Vaccination against Diseases such as Polio

Getting vaccinated is a very controversial topic right now; some people are against it, and some people are for it. This is a very important topic because it can either harm a child or save them from a disease that is going around or is super contagious. According to omicsonline.org, A vaccine is a biological preparation that provides active acquired immunity to a particular disease. When disease germs enter your body, they start to reproduce. Your immune system recognizes these […]

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Research paper on vaccines.

March 15, 2013 UsefulResearchPapers Research Papers 0

The term “vaccines” refers to special preparations, which are made up of killed or weakened pathogens or their waste products. These biological preparations get their name from smallpox vaccination, which was made from cowpox virus. The technique of antigen inoculation to the patient is called vaccination or immunization.

English physician Edward Jenner was the first to discover the healing power of vaccines in 1796. I was he, who artificially inoculated vaccinia virus to the child. In the issue, the child had developed immunity to smallpox. French scientist Louis Pasteur, founder of Medical Microbiology, laid the foundations of the scientific theory of therapeutic vaccination.

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Vaccines have stood in the way of many extremely difficult and dangerous infectious diseases that had previously been considered untreatable. Among these diseases are noted children’s polio and tuberculosis, which are treated successfully enough using vaccination. Vaccination can prevent measles, whooping cough, tetanus, gas gangrene, diphtheria, and many other infection diseases.

It is impossible to overestimate the contribution that the vaccination has made to the fight against infectious diseases. This simple method of treatment and prevention of diseases undoubtedly saved millions of lives around the world. In their research papers on vaccines, medical students have to elaborate on the background and history of the origin of vaccination, tell about the pioneers in this field, who first took the liberty to use a virus of a deadly infectious disease in order to save the lives of their patients. The formation of the scientific theory of the treatment infectious diseases using weakened or killed bacteria must be traced by the investigators all the way from the beginning. It is necessary to show what results have been achieved by vaccination and find out in what areas of modern medicine the use of vaccination brings new and unexpected results. There is also need to talk about vaccines and autism and explain what edible and DNA vaccines are.

To write a good research paper, an author must comply with the standards of research papers writing and requirements of scientific style. These measures provide an unambiguous perception and evaluation of data by readers. According to these standards, the main part of your work should present results of your research along with the arguments on how they relate to the main idea of ??the paper. In addition to that, you need to compare the results with the initial goal of the work, the value of your results for future research. With all said, we can anticipate that some of the students will have some troubles in writing their paper. For these students there are many free example research papers on the Web that will surely help them understand the standards of proper research paper writing.

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