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

Reviewed and current on 10 August 2021.

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

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

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

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

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

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

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

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

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

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

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Recent advancements in mrna vaccines: from target selection to delivery systems.

1. Introduction

2.1. expansion of the mrna application, 2.1.1. the application of mrna in infectious diseases, 2.1.2. the application of mrna in cancer therapy, 2.1.3. mrna technology in other diseases, 2.2. antigen selection and design, 2.2.1. antigen selection: the key to success in vaccine development, 2.2.2. epitope optimization enhances the adaptive immune responses, 2.3. mrna sequence optimization, 2.3.1. codon optimization contributes to antigen expression, 2.3.2. the shadowed utrs determine the fate of mrna, 2.3.3. the long and structured poly(a) tail in mrna vaccines, 2.4. in vitro transcription, 2.4.1. modified nucleotides protect mrna from immune systems, 2.4.2. cap analogs empower co-transcriptional capping, 2.4.3. multiple measures to minimize the production of dsrna, 2.5. delivery systems for mrna vaccines, 2.5.1. lipid-based mrna delivery systems, 2.5.2. lipids for advanced lnps, 2.5.3. polymer-based mrna delivery systems, 2.5.4. other promising mrna delivery systems, 2.5.5. surface modification expands the applications of lnps, 2.6. adjuvants, 2.7. security issues, 2.7.1. cationic lipid oxidation injuries in the safety of lnps, 2.7.2. anti-peg antibody: potential barriers for mrna application, 3. conclusions, author contributions, conflicts of interest.

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Wu, Z.; Sun, W.; Qi, H. Recent Advancements in mRNA Vaccines: From Target Selection to Delivery Systems. Vaccines 2024 , 12 , 873. https://doi.org/10.3390/vaccines12080873

Wu Z, Sun W, Qi H. Recent Advancements in mRNA Vaccines: From Target Selection to Delivery Systems. Vaccines . 2024; 12(8):873. https://doi.org/10.3390/vaccines12080873

Wu, Zhongyan, Weilu Sun, and Hailong Qi. 2024. "Recent Advancements in mRNA Vaccines: From Target Selection to Delivery Systems" Vaccines 12, no. 8: 873. https://doi.org/10.3390/vaccines12080873

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

Qiao Liu, Chenyuan Qin, Min Liu & 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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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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Adult vaccination coverage in the United States: A database analysis and literature review of improvement strategies

Affiliations.

• 1 Merck & Co., Inc., Rahway, NJ, USA.
• 2 RTI Health Solutions, Didsbury, Manchester, UK.
• 3 RTI Health Solutions, Research Triangle Park, North Carolina, USA.
• PMID: 39079694
• PMCID: PMC11290753
• DOI: 10.1080/21645515.2024.2381283

Despite vaccines being instrumental in reducing vaccine-preventable disease, adult vaccination rates in the United States (US) are below optimal levels. To better understand factors affecting vaccination rates, we analyzed trends in adult vaccination coverage using data from the Behavioral Risk Factor Surveillance System (BRFSS) and conducted a targeted literature review (TLR) on interventions to improve adult vaccination rates in the US. Both the BRFSS analysis and the TLR focused on influenza; pneumococcal disease; tetanus and diphtheria or tetanus, diphtheria, and acellular pertussis; herpes zoster; and human papillomavirus vaccination for US adults aged 18-64 years. The TLR additionally included hepatitis A and hepatitis B vaccination. Vaccination coverage rates (VCRs) and changes in VCRs were calculated using the 2011-2019 BRFSS survey data. For the TLR, the MEDLINE and MEDLINE In-Process databases were searched for articles on vaccination interventions published between January 2015 and June 2021. The BRFSS analysis showed that changes in VCRs were generally modest and positive for most states over the study period. The TLR included 32 articles that met the eligibility criteria; intervention strategies that improved adult vaccination outcomes incorporated an educational component, vaccination reminders or reinforcement at the point of care, or authorized non-clinician members of the healthcare team to vaccinate. Furthermore, interventions combining more than one approach appeared to enhance effectiveness. The strategies identified in this TLR will be valuable for policymakers and stakeholders to inform the development and implementation of evidence-based policies and practices to improve adult vaccination coverage.

Keywords: Adult; health policy; immunization; vaccination programs; vaccinations.

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Conflict of interest statement

LH, DG, CS, JR, MG, and MP are full-time employees of RTI Health Solutions, an independent nonprofit research organization, which was retained by MSD to conduct the research which is the subject of this manuscript. Their compensation is unconnected to the studies on which they work. MG was a full-time employee of RTI Health Solutions at the time this study was conducted. ALE and AB are current employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA.

Change per year in influenza…

Change per year in influenza and pneumococcal vaccination coverage among adults in the…

Change per year in Td/Tdap…

Change per year in Td/Tdap and HZ vaccination coverage among adults in the…

PRISMA flowchart.

Regional distribution of interventions included…

Regional distribution of interventions included in the TLR.

• Centers for Disease Control and Prevention (CDC) . Vaccination coverage among adults. 2020. [accessed 2022 Dec 19]. https://www.cdc.gov/vaccines/imz-managers/coverage/adultvaxview/pubs-res... .
• La EM, Trantham L, Kurosky SK, Odom D, Aris E, Hogea C.. An analysis of factors associated with influenza, pneumoccocal, Tdap, and herpes zoster vaccine uptake in the US adult population and corresponding inter-state variability. Hum Vaccin Immunother. [2018 Feb 1];14(2):430–16. doi: 10.1080/21645515.2017.1403697. - DOI - PMC - PubMed
• Williams WW, Lu PJ, O’Halloran A, Kim DK, Grohskopf LA, Pilishvili T, Skoff TH, Nelson NP, Harpaz R, Markowitz LE, et al. Surveillance of vaccination coverage among adult populations — United States, 2015. MMWR Surveill Summ. [2017 May 5];66(11):1–28. doi:10.15585/mmwr.ss6611a1. - DOI - PMC - PubMed
• Rodrigues CMC, Plotkin SA. Impact of vaccines; health, economic and social perspectives. Front Microbiol. 2020;11:1526. doi: 10.3389/fmicb.2020.01526. - DOI - PMC - PubMed
• Office of Disease Prevention and Health Promotion . Healthy people 2020 objectives for immunizations and infectious diseases. 2019. [accessed 2021 June 24]. https://www.healthypeople.gov/2020/topics-objectives/topic/immunization-... .

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Behind the malaria vaccines: A 40-year quest against one of humanity’s biggest killers

By Andrew Joseph

Aug. 1, 2024

M alaria is one of our most ancient foes — and one of the wiliest.

Caused by parasites that certain mosquitoes spread through their bites, malaria overwhelms us, establishing an infection before we can put up a fight. It can go on to destroy red blood cells, batter organs, and even damage the brain.

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There are untold millions of cases, the vast majority of them in sub-Saharan Africa. Each year, hundreds of thousands of people die from the condition — some 80% of whom are children under 5. For decades, pharmaceutical companies and academic researchers have struggled to devise vaccines that could confer protection, fueling doubts whether such a product was even possible.

And yet, scientists have now succeeded. Twice over.

Related: 4 takeaways from STAT’s story on the development of malaria vaccines

Earlier this year, routine immunization programs began rolling out a vaccine called RTS,S, reaching children in places including Cameroon, Sierra Leone, and Liberia. Last month, another shot, called R21, was introduced in South Sudan and Côte d’Ivoire, with more countries preparing campaigns for their youngest — and most vulnerable — citizens. RTS,S, also called Mosquirix, was developed by GSK and partners, while scientists at the University of Oxford built R21, which, based on the number of available doses alone, promises to be even more impactful.

Health officials have projected that the shots could save the lives of tens of thousands of kids. In some countries, malaria accounts for 25% of all childhood deaths.

The vaccines — the first to target any human parasite — represent a feat of both scientific grit and fundraising ingenuity. Researchers took on a sophisticated biological adversary that eludes our immune systems’ schemes to identify and dispatch it. They also had to find ways to nudge forward products that would never result in blockbuster sales, a reality that sapped much of the biopharma industry’s interest.

Related: Rollout of a new malaria vaccine kicks off in Africa

“We’re very fortunate, and when I say we I mean our generation, to be present for the last mile of this, and to see these vaccines be introduced,” said Eusebio Macete, a Mozambican researcher who two decades ago helped run an early trial of RTS,S. “And to see that one of the major killers in Africa could now have another tool to save lives, that’s amazing.”

The vaccines are by no means perfect, and given their limited effectiveness and durability, they are not the kinds of interventions expected to eliminate malaria in Africa. Rolling them out also poses huge challenges. The vaccines are given in four doses, starting around 5 months of age and ending over a year later with a booster, at intervals that don’t match when other childhood vaccines are administered. That means health workers must wrangle families to clinics or deliver vaccines to them in some of the globe’s most remote reaches.

The vaccines’ shortcomings have led some experts to argue against spending too much of the world’s resources on them instead of expanding existing measures, like insecticide-treated bed nets, mosquito control, and chemoprevention — that is, giving kids preventative drugs during peak transmission periods. As it is, only some 50% of kids sleep under bed nets in certain areas.

“We believe in the vaccine,” said Scott Filler, the head of malaria at the Global Fund, which helped support RTS,S. But, he said, prioritizing other strategies might offer more bang for the world’s buck. “Maybe we want to spend the world’s money first on these tried-and-true things, lay the foundation, and then start to deploy the vaccine in particular areas that have ongoing transmission, where kids continue to die,” he added.

Other experts are more sanguine, even as they agree that the other interventions need to be maintained. They also argue that now is a particularly important time to take action. Progress against malaria has stalled, and after dropping to 576,000 in 2019, deaths caused by the disease have since surpassed 600,000 a year. Mosquitoes are becoming increasingly resistant to insecticides. The parasite that causes malaria is itself becoming increasingly resistant to medications. Climate change and migrating mosquito species are reshaping transmission zones.

Related: Second-generation mosquito nets prevented 13 million malaria cases in large pilot programs

“We’re at a crossroads,” Mary Hamel, the World Health Organization’s lead for malaria vaccines, told STAT. “We’re seeing cases go up in some places, and we have donors that maybe are not wanting to continue giving as much as they used to give. We’re in a period, I think, that’s precarious.”

This history of the malaria vaccines, an odyssey that stretches across decades and continents, is necessarily an abridged one. But it captures the achievement of how two vaccines reached the finish line within months of each other after more than 40 years of work. It’s one that relied on researchers willing to take on a mission that colleagues saw as quixotic, local investigators who pioneered running trials in their communities, and ultimately, the thousands of parents and children who volunteered for the studies — those who had most closely felt the ravages of malaria and enlisted in the global effort to neutralize one of the leading threats to children.

A sk experts for a good starting point to understand the history of the malaria vaccines, and one name comes up most often: Ruth Nussenzweig. Her work not only demonstrated the theoretical foundation of such a vaccine, but also helped uncover the bullseye that the shots target.

Twice an émigré, Ruth Sonntag was born in Vienna in 1928 into a Jewish family with physician parents. They escaped the Nazi occupation in 1938, eventually settling in Brazil. Her father urged her to become a nurse, thinking she would encounter less antisemitism in that role than as a doctor, but she saw medical school as a path to her real interest: research. It was while she was training at the University of São Paulo that she met another student, Victor Nussenzweig. “I was more interested in doing leftist politics than science, but I started dating Ruth and she convinced me that research would benefit people much more than politics,” Victor once told Science .

By then married, the couple headed to New York University for what they thought would be a brief fellowship for Victor but that turned into an academic home. A 1964 coup in Brazil brought in a period of strict military rule, upending their return.

While in Brazil, the Nussenzweigs had studied a parasitic infection called Chagas disease. By the time she got to NYU, Ruth had her eye on another parasite. Her aim was “always the same thing: develop a vaccine for malaria,” she said in an oral history for the university.

Designing a vaccine is not about attacking a bug directly. It’s about priming a person’s immune system to recognize and fight off a pathogen for itself.

But at the time the Nussenzweigs got to work, it wasn’t clear that that was possible with malaria. After all, there wasn’t a strong natural immune response that a vaccine could replicate. People did accrue some protection to malaria, but only after repeated infections, and it didn’t last all that long. It explained why people could be infected multiple times every year, and while older children and adults might build up enough armor to avoid getting seriously ill, young kids remained vulnerable to severe outcomes.

Nussenzweig, however, doubted the conventional wisdom. “The dogma at the time was that malaria doesn’t induce any immune response,” she said. “This was incorrect, and I knew it.”

She also proved it. In 1967, she and her colleagues showed they could protect mice from malaria by immunizing them with parasites that they had weakened with radiation. These parasites couldn’t cause disease, but they did, Nussenzweig found, elicit an immune response that staved off a future infection. That meant that, maybe, a vaccine could do the same.

Instead of using a whole bug to build a vaccine, which would be far more complicated, scientists often rely on an antigen, or a protein from the pathogen that provokes an immune response. The idea is that those generated immune fighters, namely antibodies, can then swarm invaders when they see the antigen in the form of an actual parasite.

But scientists faced a formidable challenge in identifying a suitable antigen from the malaria parasite, which is a much more complex intruder than the bacteria and viruses other vaccines target. Take the coronavirus that causes Covid-19. It has about a dozen genes, making the virus’s spike protein, which it uses to hack into cells, an obvious antigen to design vaccines around.

The malaria parasite has some 5,000 genes. Not only that, it has infected people for so many generations — our history dates back millions of years, to before we were even Homo sapiens — that it has evolved with us, essentially learning how to throw off our immune system’s defenses.

It gets more dizzying from there. Malaria doesn’t even look the same throughout its time in our bodies. When a female Anopheles mosquito bites us (males are vegetarian), she injects a bit of saliva to ensure the blood doesn’t clot as she takes her meal, which she needs to lay eggs. If she’s infected with the parasites, a few dozen of them will slip with the saliva into our skin. At that point, the parasites are squiggly critters called sporozoites.

Within about 30 minutes, the sporozoites are whisked via the bloodstream to the liver, where they multiply into the thousands over several days before busting out and invading red blood cells, triggering the classic symptoms of fever and chills and causing anemia.

Related: Malaria parasite may trigger human odor to lure mosquitoes

With each infection phase, the parasite shapeshifts, with different genes activated and proteins expressed, becoming almost like a new creature. Any successful vaccine then would not only need the right bullseye, but be able to mount an immune response in the right place in the body, at the right stage of the infection.

Again, Nussenzweig came through. Once her earlier work showed that inducing immunity was possible, her team needed to identify which part of the parasite those elicited antibodies were recognizing — what could be a possible antigen. And together with her husband and other colleagues, she later zeroed in on a protein that surrounded the sporozoite. It became known, in the most scientifically sober way, as the circumsporozoite protein, or CSP. (Other research teams contributed key discoveries around this time.)

That finding became the blueprint for the vaccines. The question was, could you design a shot based on CSP as your antigen, building up an army of anti-CSP antibodies? And could those antibodies then block any injected parasites from making it to the liver, preventing an infection from taking hold?

Ruth Nussenzweig died in 2018 at 89, and Victor, now in his mid-90s, is so hard of hearing that an interview was not feasible, said their son Michel Nussenzweig, himself a scientist at Rockefeller University. But it seemed the couple knew their work might one day result in a breakthrough.

“It is therefore conceivable that a vaccine containing only sporozoite antigens would completely protect a portion of the exposed population,” they wrote in one review .

They authored that paper in 1984. Another 40 years of work remained.

W hen Ripley Ballou’s fever struck, he first thought that he was reacting to the home-brewed beer he had tried at a friend’s party. But as he got sicker, he realized what was actually happening: He had given himself malaria. It also meant his experimental vaccine hadn’t worked.

Ballou, who goes by Rip, was a physician at the Walter Reed Army Institute of Research helping lead a team whose task was to turn the antigen the Nussenzweigs had identified into an actual product. The Army, keen for a vaccine that could protect soldiers, selected a company called Smith, Kline & French as its development partner, striking a collaboration with the GSK precursor in 1984. Their particular target became Plasmodium falciparum — the deadliest form of the malaria parasite, and the one that dominates in sub-Saharan Africa.

When the researchers had their first candidate ready to test, Ballou rallied colleagues to join him in rolling up their sleeves for a challenge study, in which volunteers receive an experimental vaccination, then expose themselves to a pathogen to assess if it worked. (In these tests, the military used a malaria strain they knew was treatable.)

Once Ballou and his comrades got the vaccine, it was mosquito munch time. They pressed gauze-covered cups containing infected mosquitoes against their arms, offering up a blood buffet. Days later, Ballou got sick. So did four others. One person, however, did not .

It was by no means a good result, but it was an important one. “That basically showed us it could be done, that it was possible” for a vaccine to block an infection, Ballou said. But for it to be workable, they would need to show much higher rates of protection.

The team spent the next decade refining the vaccine. There are different ways to present an antigen to the immune system, so they tinkered and toiled in hopes of landing on an approach that could stimulate a response so robust as to be protective. They combined the CSP antigen with genes from other pathogens, and turned to proteins used in other vaccines, and made chains of bits of proteins, all in hopes of whipping up a phalanx of antibodies.

And it just wasn’t working.

“We probably did eight or nine challenge trials where nearly everyone had malaria,” Ballou recalled. They even ran out of friends they could rely on at Walter Reed for the studies, so had to recruit in the local community.

Part of the problem may have been that their experimental vaccines weren’t conjuring up the sky-high antibody levels needed to fend off malaria — much higher than the levels needed to protect against many bacteria and viruses, given that the parasites are so good at evading our defenses.

The antibodies also have to be quite the hunters. To stave off an infection, the immune guardians have to clear out all the injected sporozoites before they make it to the liver. While some scientists say that the more sporozoites that reach the liver, the more likely someone is to get sick, others stress that if even one infiltrates a liver cell and starts replicating, it can turn into a full-blown infection. Imagine a teenager cleaning up from the party he threw with his parents out of town — overlooking even one cup could land him in trouble.

“To say it was a discouraging period does not quite capture the feeling,” Ballou, who is now at the infectious diseases nonprofit IAVI, wrote in 2009 about the failed attempts.

But more than 3,000 miles away, a scientist had an idea.

B efore Joe Cohen became a researcher, his jobs included working in a fabric store’s stockroom and analyzing stool samples at a hospital lab.

Cohen was born in Egypt and, when he moved with his mother to France in 1962 after finishing high school, he halted his studies to support his family. He eventually made it to university, where he focused on agricultural engineering. But really, it was the nascent molecular biology field that caught his eye.

He then joined other relatives who had moved to the United States, but he didn’t know how to apply to doctorate programs. He simply showed up at nearby Brooklyn College one day and introduced himself. He was admitted.

When Cohen was wrapping up his training, he struggled to find an academic job that suited him. But he spotted an ad — he can’t remember if it was in Nature or Science — from Smith, Kline & French in Belgium looking for a molecular biologist with experience in yeast genetics. “That essentially described me,” he said.

It wasn’t academia, but he admired the group’s innovative work on a hepatitis B vaccine in development at the time. So he moved his wife, infant daughter, and aging mutt named Clebs to Belgium in 1984, joining the team right as it was wrapping up its hepatitis B work. It was his first non-trainee job in science, at age 40.

A few years later, Cohen’s bosses asked him to take the lead on the malaria project, which the company was transferring from its U.S. labs to Belgium. Other colleagues had already said no to the assignment, Cohen recalled, thinking it was a lost cause.

Cohen didn’t have much experience with parasites, but the scientific challenge appealed to him. So did the impact he might have if the team succeeded. And in taking on the project, he drew inspiration from the hepatitis B vaccine.

GSK scientists had created that shot by engineering yeast cells to express one of the virus’s proteins, which they had identified could act as an antigen. When researchers would crack open the cells, the proteins would spontaneously glom onto each other, forming what’s called a virus-like particle. The vaccine was made of schools of those particles.

What if, Cohen thought, you could just add CSP — the malaria antigen — into the mix?

Cohen grinded away in the lab, into the night, on weekends, on holidays. By linking genes from the hepatitis B virus and the malaria parasite, he was able to express what are known as fusion proteins in the yeast cells — meaning they had antigens from both pathogens — that he still got to ball together into virus-like particles. They looked like blobs encircled by a coating of hepatitis B antigens, and then, jutting out from the surface, like cloves studding an orange, were the malaria antigens.

Related: WHO recommends second malaria vaccine, hoping to address supply issues

The theory was that by presenting the body with a virus-like particle — which resembled a virus in both size and shape — the immune system was going to generate a heartier response than it would when presented with just a bit of the protein itself. After all, the immune system knows what to do when it sees something that looks like a virus.

As it happened, other GSK scientists were building up another branch of vaccine research. They were designing a line of adjuvants, which boost the power of a vaccine by deepening the immune response. Researchers started testing the malaria shot in combination with a number of the adjuvants.

Then, finally, came the challenge study of the vaccine with an adjuvant called AS02.

Ballou was in his kitchen when he got the call: Six of seven volunteers had been protected , as the scientists reported in the New England Journal of Medicine in early 1997.

The vaccine, dubbed RTS,S, had worked. It was time to test it in the field.

O ne of the team’s early calls was to a researcher named Brian Greenwood. Greenwood had already proven the power of insecticide-treated bed nets, but he believed in vaccines, even as other experts dismissed them. Greenwood once even made a bet with another senior scientist — whom he declined to name — about whether the world would ever see a malaria vaccine.

Greenwood, who is British, was running a research site in the Gambia. He had previously worked on a study in Tanzania of a vaccine candidate developed by a Colombian scientist named Manuel Patarroyo, and while that shot ultimately fizzled out, the experience left Greenwood with a lesson. “It taught us how to do a malaria vaccine trial,” he said.

Greenwood and colleagues started recruiting a cohort of men to evaluate RTS,S, with some receiving the experimental shot and some getting a rabies vaccine as the control. At the time, the researchers thought a highly effective vaccine could still be used for adults. Plus, it’s considered unethical to test a vaccine in children before its safety is established in older volunteers.

The results , published in 2001, were a bit of a bust. The shots showed some protection, but it wasn’t very strong and waned quickly. As Ballou wrote in a review , “the vaccine was still clearly not sufficiently efficacious to support its further development as a stand-alone vaccine for travelers or the military.”

But the adult trial furthered the researchers’ belief that the shot had pediatric potential. They reasoned that if the vaccine reduced the risk of malaria to an extent in adults, it was likely to be even more protective in kids, who tend to mount stronger immune responses to vaccines.

The prospect of healthy returns had evaporated, however. A company could never charge much for a product whose only takers would be children in some of the world’s poorest countries. Wealthy tourists and the Defense Department they were not.

Related: GSK CEO on pharma giant’s new direction: ‘We’re in the business of preventing and treating disease’

GSK brass allowed the team to continue with the program, but there was a catch: The company would no longer fund the project without others’ support.

It was a key inflection point, one that underscores how commercial realities shape the programs drugmakers pursue or scuttle. It’s not just the programs companies back, either. With potentially lucrative products, companies start planning future trials and scaling manufacturing at risk even before the prior step in the development gauntlet is complete, all to expedite the process. With neglected disease products, it’s likely that no one is going to put up the money for the next study until it’s clear that it’s going to happen, a factor that dragged out the timeframe of the malaria vaccines.

Public health experts credit GSK for sticking with the malaria program at all, particularly given its daunting nature, and say it’s unclear whether other companies would have done the same. Thomas Breuer, GSK’s chief global health officer, said in an interview with STAT that the company has covered the “lion’s share” of funding for RTS,S throughout its development, at more than $700 million.

While GSK has faced recent criticism for how it’s handled the development of a tuberculosis vaccine , Breuer said that the drugmaker sees a need to partner on these products, not just to share the financial risk, but because the company doesn’t have all the relevant expertise itself. He stressed that GSK continues to invest in global health.

“We have a social responsibility, and this was not just true for the malaria vaccine,” he said, citing the company’s development work in other neglected diseases. But, he added, “Even GSK, who is committed in the long run, cannot fund all the activities.”

Luckily, another funding model was emerging around that time. The Bill & Melinda Gates Foundation, established in 2000, had started backing a nonprofit called PATH and its Malaria Vaccine Initiative. And in 2001, GSK and PATH struck a partnership to push RTS,S forward. In total, said Helen Jamet, a malaria official at the Gates Foundation, the organization put $200 million into RTS,S, primarily through PATH’s work.

With that partnership in place, researchers moved to test the vaccine in kids. For the site, they selected Centro de Investigação em Saúde in Manhiça, Mozambique, which Spanish experts had helped start, but, crucially, was staffed largely by local providers. The team set out to recruit parents in the community to enroll their children in the study, setting aside time to talk with them about the vaccine and address their questions.

It helped that parents were well aware of the risks posed by malaria. Children would get sick two, five, eight times a year. Kids would miss school, and parents would miss work to care for them. At hospitals, where even now a third of consultations in some regions are tied to malaria, bags of blood being readied for transfusions would line the walls. Clinics would be so full that three children would share a bed, all pale and flopped over and breathing shallowly.

Laurinda Carlos Balate was one of the moms who said yes to the study. Some of her friends didn’t understand why, and told her the experimental shot might be dangerous. But she liked the idea of combating malaria, and she trusted the clinic’s staff.

“I’m quite happy, because the vaccine was a success,” she said recently over Zoom.

Her daughter, Loyde Carina Nhabanga, who was just a baby when her mother enrolled her in the study, now has a 7-month-old of her own, whom she said she is planning on getting vaccinated when the shots become available. “It’s going to help us fight against malaria,” she said.

Overall, the Phase 2 trial, run in 2,000 children, showed the vaccine was 30% effective at preventing malaria, and 58% effective at protecting against severe malaria, according to findings published in 2004. It was the first sign that the vaccine could generate a protective response in kids in high-transmission areas.

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Other studies of RTS,S showed similar outcomes, building evidence that was promising enough to move the shot into a pivotal Phase 3 trial. (During this series of trials, the researchers switched the adjuvant from AS02 to one called AS01 that prompted stronger immune responses. AS01 is also used in GSK’s RSV and shingles vaccines.)

It was around this time that researchers in England came up with their own vaccine candidate.

A drian Hill came to malaria vaccines through a circuitous route. Hill, now the director of the University of Oxford’s Jenner Institute, had trained as a geneticist, studying how different genetic variants that had evolved in certain communities made people less vulnerable to malaria. (If the legacy of malaria is written in our history books — it may have killed Alexander the Great, Genghis Khan, and a couple of popes — it is also imprinted in our DNA.)

It was when Hill was studying one of those variants in the Gambia in the 1980s that he got an up-close look at the parasite’s toll. Children were packed into a clinic, arriving so sick they desperately needed blood transfusions. So he pivoted.

“That kind of converted me from thinking, we’ve got to really understand susceptibility to malaria, to thinking, what’s going on with vaccines?” he said in an interview at his Oxford office.

Starting in the 1990s, Hill and his colleagues threw a number of strategies at malaria. They tried DNA-based vaccines and viral vector vaccines — like the one Oxford researchers would later develop with AstraZeneca against Covid-19 — and different combinations of those different kinds of vaccines, without much success.

But they also thought of updating RTS,S. After all, by the early 2010s, some two decades of advances in research methods — including in expressing proteins in yeast — had accrued since the early days of the GSK shot. “Making the vaccine 25 years later helped us,” Hill said.

The issue with RTS,S, at least as far as Hill and his colleagues believed, was that there wasn’t enough malaria antigen on the particle versus hepatitis B antigen. They hypothesized that if they could engineer both a greater amount and higher density of the former, the particle would elicit a more powerful anti-malaria immune response, with more antibodies produced that were even sharper at targeting sporozoites. They essentially wanted to stud more cloves onto the orange.

The task of figuring it out fell to a graduate student named Katharine Collins. The potential trip-up was that if the Oxford researchers increased the amount of malaria antigen in their recipe, the proteins wouldn’t self-assemble into a virus-like particle, which was crucial to generating an actionable immune response. Whether or not proteins arrange into that kind of particle depends on a delicate balance of chemical charges, with the right bonds needed to form for it to be a stable molecule.

It took some trial and error, but by refining the process, Collins made it happen. “I would express the protein in the yeast, bust them open, do a really simple purification, and then go and have a look under an electron microscope,” said Collins, who now works at the charity Open Philanthropy. “And we saw particles. It was like, ‘wow.’”

For their adjuvant, the Oxford team landed on one called Matrix-M from Novavax, which is now used in that company’s Covid jab. The shot became known as R21.

But like RTS,S, R21 ran into funding issues. When it came time to manufacture doses for human trials, Hill turned to Oxford’s own production site, which was cheaper than a contract manufacturer. But with limited resources and know-how, the team struggled to make the vaccine at scale. From the promising lab experiments to having doses for a challenge trial, three years would pass.

W hen data from the Phase 3 trial of RTS,S arrived , the reaction was lukewarm.

The trial, which ran from 2009 to 2014, enrolled nearly 9,000 children from 5 months to 17 months of age in seven countries, places where malaria circulated year-round as well as places with seasonal transmission. While the initial protection appeared strong, the efficacy dropped to between 30% and 50%. Adjectives like “modest” and “moderate” were thrown around.

Some experts excavated a rosier view. Given the scope of the disease, they argued, preventing even a third of malaria cases would have major repercussions for health systems, economies, and families.

“Because of the sheer number of cases of malaria — there are hundreds of millions of cases of malaria every year — what we saw was that in some of the areas where the intensity of malaria transmission was higher, where children got more malaria, we saw over 6,000 cases of malaria prevented for every thousand children vaccinated,” said Ashley Birkett, a longtime PATH official.

But another issue arose — potential safety signals with the vaccine. One was that there were more cases of meningitis, an inflammation around the brain and spinal cord, among children who received RTS,S than those who got the control shots.

It was up to regulators to weigh in. The European Medicines Agency gave the vaccine a positive review in 2015, but it was a WHO recommendation that mattered most. The global agency needs to give its stamp of approval if groups like UNICEF and Gavi, an international organization known as the Vaccine Alliance, which help purchase immunizations and deliver them to low-income countries, are going to add a shot to the portfolio of products they provide.

The WHO’s advisers weren’t overly enthusiastic. Based on the data, the vaccine didn’t seem like a game-changing intervention. With the potential safety issue, they worried not only that introducing the vaccine might lead to meningitis cases, but that moving too quickly could turn people against other immunizations.

The context of the moment also shaped experts’ thinking, those involved at the time recalled in recent interviews. The world had been making steady progress against malaria, with cases cut by 27% from 2000 to 2015. No one foresaw that tide reversing.

“There was not a sense that we desperately needed a vaccine, let alone a vaccine with modest efficacy,” said Pedro Alonso, who directed WHO’s malaria program at the time.

Related: The WHO’s chief scientist on Covid-19 vaccines, patent battles, and speeding up access in Africa

Instead of recommending the vaccine, the WHO in 2016 decided to push forward with a pilot program, which would involve deploying millions of doses to children in three countries. The move was seen as a compromise — the agency was not spurning the vaccine, but it wasn’t endorsing its wide rollout either. The program would also provide the chance for experts to assess the feasibility of using the vaccine outside a trial. Would people get their children to a clinic for four doses? Would they give up other safeguards against malaria?

But if the pilot made sense as a way of shoring up the vaccine’s evidence, it created a new challenge, one that some experts worried could jeopardize the shot. As Birkett said, “Nobody was anticipating the pilot program. Nobody had the money ready to go.”

The Gates Foundation by that point had pulled back from putting more funding into RTS,S, but the WHO scrounged $70 million for the pilot from sources including Unitaid, Gavi, and the Global Fund, with doses donated by GSK. But the time needed to fundraise and plan, including getting the three selected countries — Ghana, Malawi, and Kenya — on board, meant shots didn’t start being administered until 2019, three years after the pilot was decided on.

Once underway, it became clear that the meningitis issue was a statistical fluke from the trial — that there was no real safety issue. And in 2021, the WHO endorsed RTS,S as the world’s first malaria vaccine .

Ultimately, the pilot program demonstrated not only that RTS,S could be reliably rolled out, but that even with its modest efficacy, it could have sweeping impacts. It didn’t lead to drops in other vaccinations. Families kept up with other anti-malaria interventions. And it cut childhood mortality broadly by more than 10%, a sign, perhaps, of how malaria infections leave children vulnerable to other illnesses. Places where the shots were deployed saw malaria hospitalizations cut by a fifth.

“These numbers are huge,” said Kwaku Poku Asante, the director of Ghana’s Kintampo Health Research Centre and an investigator in the pilot program. “If you sit in a district hospital, where every child has malaria, and all of a sudden you’re seeing a reduction by one-fifth, that is huge.”

Some experts maintain the pilot program was necessary — that a wide-scale rollout would not have succeeded had WHO recommended RTS,S in 2016. But in hindsight, others are more conflicted. They find themselves wrestling with the decision, wondering if the vaccine had been put into use then, instead of years later, how many more thousands of children might have been saved?

“This has haunted me for a number of years. The question is, did we do the right thing, or did we not?” said Alonso, now at the University of Barcelona. “I do often think of the costs.”

A fter a successful challenge trial and safety tests, it was time for the Oxford team to try R21 in the field. They scraped together funding from sources including the Wellcome Trust and the European and Developing Countries Clinical Trials Partnership, and in 2019 launched a Phase 2 trial in children from 5 months to 17 months of age in Nanoro, Burkina Faso.

The results surpassed their hopes. The shot showed about 75% efficacy.

“We were expecting in the best case scenario 60% efficacy or something like that,” said Halidou Tinto, who leads the clinical research unit in Nanoro. “And then we were at almost 80%. This was a big surprise, but a very nice surprise.”

For the Phase 3 study, instead of the Oxford team having to pitch companies to fund the research, a partner came to them. One day in 2017, a man named Umesh Shaligram showed up at Hill’s office. Shaligram was a top scientist at the Serum Institute of India, the world’s largest vaccine manufacturer. The institute had heard about Oxford’s promising data, he told Hill, and was curious to learn more.

With the resulting pact between Oxford and Serum, not only did Serum start manufacturing R21, it even funded the Phase 3 trial, a study of 5,000 children in four countries run in 2021 and 2022. The vaccine showed about 70% efficacy.

Last October, the WHO recommended the vaccine .

A few months ago, a package arrived for Brian Greenwood, the old malaria hand who had helped run the early RTS,S trial in the Gambia. It contained six “very nice” bottles of red wine. The other expert with whom Greenwood had made a bet about the feasibility of a malaria vaccine was making good after losing that decades-old wager.

The bottles’ arrival coincided with the rollout of RTS,S in Cameroon in January, the first time a malaria shot was deployed in a routine immunization program. More countries will launch their own vaccination campaigns in the coming months.

Experts debate whether one vaccine is superior to the other. Many favor R21, pointing to its updated design and the higher efficacy scores it reached in trials. Others counter that the differences in the trials — including the timing of the doses relative to peak transmission periods — render comparisons impossible. The WHO has taken to saying that both shots can reduce malaria cases by about 75% when given before peak transmission periods and combined with other interventions.

“The important thing now is to get the vaccines used,” said Greenwood, who worked on studies of both shots and is now at the London School of Hygiene & Tropical Medicine.

R21 does have some inarguable advantages. While manufacturing is still being scaled up , thanks to the partnership with the Serum Institute, 100 million doses could be produced a year, at a cost of $2 to $4 per dose. GSK, meanwhile, is only producing 18 million RTS,S doses from 2023 to 2025, at an approximate cost of $10 per dose, and then committing 15 million doses a year from 2026 to 2028. The company is transferring the vaccine to Bharat Biotech, another large Indian manufacturer, which should result in more doses at a lower cost, but it’s expected that the Bharat facility won’t be supplying RTS,S until 2028.

The vaccines are important in other ways. They established how to run clinical studies, built up trial infrastructures, and gave regulators experience evaluating malaria shots. Even with the financial challenges it faced, R21, with its strong data profile, comparatively breezed through its studies and regulatory reviews, winning approval faster than many experts anticipated. Future vaccines could have an even more streamlined route.

And next-generation vaccines are coming. Some target different life stages of the parasite, so could be combined with a shot like R21. Some could protect adults — including, crucially, during pregnancy, a time when a malaria infection is dangerous to both mother and baby. They could have higher efficacy, greater durability, and even halt transmission — the type of tool that could make eradication a prospect.

In that way, then, RTS,S and R21 have another legacy. They showed that a malaria vaccine was possible.

About the Author

Andrew joseph.

Europe Correspondent

Andrew Joseph covers health, medicine, and the biopharma industry in Europe.

children's health

global health

public health

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This paper is in the following e-collection/theme issue:

Published on 21.10.2021 in Vol 23 , No 10 (2021) : October

Topics and Sentiments of Public Concerns Regarding COVID-19 Vaccines: Social Media Trend Analysis

Authors of this article:

Original Paper

• Michal Monselise 1 , MSc   ; 
• Chia-Hsuan Chang 2 , MSc   ; 
• Gustavo Ferreira 1 , MSc   ; 
• Rita Yang 3 , PharmD   ; 
• Christopher C Yang 1 , PhD  

1 College of Computing and Informatics, Drexel University, Philadelphia, PA, United States

2 Department of Information Management, National Sun Yat-sen University, Kaohsiung, Taiwan

3 Virtua Voorhees Hospital, Voorhees Township, NJ, United States

Corresponding Author:

Christopher C Yang, PhD

College of Computing and Informatics

Drexel University

3675 Market St

Philadelphia, PA, 19104

United States

Phone: 1 215 895 1631

Email: [email protected]

Background: As a number of vaccines for COVID-19 are given emergency use authorization by local health agencies and are being administered in multiple countries, it is crucial to gain public trust in these vaccines to ensure herd immunity through vaccination. One way to gauge public sentiment regarding vaccines for the goal of increasing vaccination rates is by analyzing social media such as Twitter.

Objective: The goal of this research was to understand public sentiment toward COVID-19 vaccines by analyzing discussions about the vaccines on social media for a period of 60 days when the vaccines were started in the United States. Using the combination of topic detection and sentiment analysis, we identified different types of concerns regarding vaccines that were expressed by different groups of the public on social media.

Methods: To better understand public sentiment, we collected tweets for exactly 60 days starting from December 16, 2020 that contained hashtags or keywords related to COVID-19 vaccines. We detected and analyzed different topics of discussion of these tweets as well as their emotional content. Vaccine topics were identified by nonnegative matrix factorization, and emotional content was identified using the Valence Aware Dictionary and sEntiment Reasoner sentiment analysis library as well as by using sentence bidirectional encoder representations from transformer embeddings and comparing the embedding to different emotions using cosine similarity.

Results: After removing all duplicates and retweets, 7,948,886 tweets were collected during the 60-day time period. Topic modeling resulted in 50 topics; of those, we selected 12 topics with the highest volume of tweets for analysis. Administration and access to vaccines were some of the major concerns of the public. Additionally, we classified the tweets in each topic into 1 of the 5 emotions and found fear to be the leading emotion in the tweets, followed by joy.

Conclusions: This research focused not only on negative emotions that may have led to vaccine hesitancy but also on positive emotions toward the vaccine. By identifying both positive and negative emotions, we were able to identify the public's response to the vaccines overall and to news events related to the vaccines. These results are useful for developing plans for disseminating authoritative health information and for better communication to build understanding and trust.

Introduction

In late 2020, the COVID-19 pandemic had approached the year mark when a number of pharmaceutical companies began to release their vaccine clinical trial results. A global sense of relief was felt when the results of the clinical trials looked promising. The first vaccine developed by Pfizer and BioNTech was given for emergency use authorization in December 2020 by the US Food and Drug Administration [ 1 ]. While this timeline seemed too fast for some, most vaccines for COVID-19 relied on many years of previous scientific work. For example, mRNA-based vaccines had been in development for over a decade at that point [ 2 - 4 ]. Despite efforts of the scientific community to assure the public that these vaccines are safe and effective, public sentiment has been mixed. There has been a significant amount of public hesitancy toward vaccination against COVID-19 [ 5 ]. At the same time, many have expressed excitement over the prospect of returning to a prepandemic world. Given this mixed reaction, it is essential to investigate the actual public sentiment regarding COVID-19 vaccines. Particularly, we were interested in learning about public sentiment for a period of 60 days when the vaccines were started in the United States. Social media provides a great data source for listening to the public on what they are thinking and what concerns and questions they have. We used Twitter as a proxy for public sentiment and were able to find the most important discussion topics that pertained to COVID-19 vaccines in the early days of the vaccine rollout. Additionally, we were able to classify public sentiment as it pertained to the vaccines and how this sentiment changed over time overall and in each topic as well. The goal of this research was to examine the discussion topics and public sentiment toward COVID-19 vaccines. By studying the topic and sentiment of the discussion on COVID-19 vaccines on Twitter, we may understand public concerns as they happen and learn more accurately about the source of vaccine hesitancy. By learning what drives vaccine hesitancy, we can better address it and formulate tailored and targeted communication. Conversely, we may also learn about the excitement toward the vaccine and study what is going well and what resonates well with the public on social media. This research will use the results uncovered by the topic and sentiment analysis of the Twitter data and suggest actionable insights for practitioners to address COVID-19 vaccine hesitancy. This research will also address how to utilize positive sentiment toward the vaccine.

Previous Works

Public sentiment on covid-19 vaccine.

A number of studies about vaccine hesitancy on social media have been published during the pandemic. Before any vaccine was approved, research showed hesitancy on social media. Harrison and Wu [ 6 ] examined vaccine hesitancy at the start of the pandemic and discussed methods to reduce vaccine hesitancy in preparation for the vaccine that would eventually come. This paper critiques current approaches for combating vaccine hesitancy with the goal of improving on these approaches when the COVID-19 vaccines are authorized for emergency use. A study by Chou and Budenz [ 7 ] discusses both methods for reducing hesitancy as well as for fostering positive emotions toward the vaccine. They propose acknowledging fear, anger, and other negative emotions and addressing them to convince the public to get vaccinated. A study by Wilson and Wiysonge [ 8 ] showed the existence of organized disinformation campaigns against the vaccines for COVID-19. However, this study focused on exposing negative sentiment against the vaccine and did not measure the positive sentiment toward the vaccine on social media. While the abovementioned studies discuss public sentiment, they do not measure both positive and negative sentiment, and some just make recommendations rather than looking at empirical evidence.

Topic Detection in COVID-19–Related Tweet Sentiment Analysis

Owing to the pandemic and quarantine policy, social media platforms such as Twitter became the main channel for people to share thoughts and to express their opinions about any impacts caused by the COVID-19. The hidden topics underneath such massive textual contents on social media help governments and health care units to understand the demand of the general public so as to make better decision and quick response. Cinelli et al [ 9 ] extracted topics using Partitioning Around Medoids algorithm on word vector representations and proposed a custom epidemic model for characterizing misinformation spreading speed in different social platforms. Since the temporal trends of the hidden topics reflect concerns of the general public through time, Chang et al [ 10 ] proposed 2 temporal models based on nonnegative matrix factorization (NMF), which help to identify the trends of several important themes such as government policy, economic crisis, COVID-19 case updates, COVID-19 urgent events, prevention, vaccines and treatments, and COVID-19 testing.

Sentiment Analysis

Sentiment analysis is a research area that involves the classification of text, images, or audio into a set of one or more sentiments [ 11 ]. In the context of this research, we will be classifying the sentiment of short snippets of text. When classifying text, we can classify at the word, sentence, or document level. There are different classification methods, including rule-based [ 12 - 14 ], support vector machine [ 15 , 16 ], random forest [ 17 ], Naive Bayes [ 18 , 19 ], embedding-based [ 20 , 21 ], as well as sentiment analysis using neural networks [ 22 - 25 ]. Additionally, we may classify sentiment by using unsupervised methods such as methods using rule-based unsupervised sentiment analysis [ 26 ], embeddings such as Word2Vec and Doc2Vec [ 27 ], and lexical resources for sentiment analysis [ 28 ].

Sentiment Analysis in Twitter

Sentiment analysis is an established research field in the area of natural language processing. However, performing sentiment analysis on tweets is a slightly different task. Zimbra et al [ 29 ] reviewed a number of techniques for classifying sentiment in tweets. They found that due to factors such as the brevity of tweets, Twitter-specific language [ 30 ], and a class imbalance [ 31 ], classification algorithms achieved an accuracy of around 70%. However, Adwan et al [ 32 ] also reviewed a large number of techniques and they found a mix of accuracy scores, with some papers passing 80% accuracy while others still perform below 80% even with new algorithms [ 33 ]. Among those who have improved their accuracy, some only focus on specific politics-related data sets [ 34 ], some propose methods that require a large number of steps [ 35 ], while others address the issues with tweets, such as Twitter-specific language [ 36 ].

Our entire pipeline is described in Figure 1 . We first introduce the data collection and preprocessing. We then detail our topic detection algorithm and procedure of sentiment and emotion classification.

Data Collection

We adopted the coronavirus tweets data set [ 37 ] as our data source, which uses over 90 keywords and hashtags [ 38 ] to monitor the real-time coronavirus-related tweets from February 05, 2020 till present. Since the US Food and Drug Administration authorized Pfizer-BioNTech COVID‑19 vaccine and Moderna vaccine for emergency use in mid-December, we only kept tweets that were created during a 60-day period between December 16, 2020 and February 13, 2021 for extracting discussion topics and their sentiment from the general public about COVID-19 vaccines. Owing to the data sharing policy of Twitter, the coronavirus tweets data set only shares the IDs of the collected tweets. Therefore, we employed Twitter’s tweet lookup application programming interface [ 39 ] to retrieve the content and metainformation of each retained tweet. In order to downsize the corpus and retain vaccine-related tweets, we only selected tweets that contained at least 1 keyword in our predefined keyword list: “vaccine,” “vaccines,” “#vaccine,” “#vaccines,” “corona vaccine,” “corona vaccines,” “#coronavaccine,” “#coronavaccines,” “pfizer,” “biontech,” “moderna,” “Pfizer-BioNTech,” “Pfizer/BioNTech,” “Pfizer BioNTech,” “#PfizerBioNTech,” “COVAX,” “COVAX,” “Sinopharm,” “Sinovac,” “AstraZeneca,” “Sputnik V,” and “Gamaleya.” The list of keywords was generated by the authors with the intention of collecting data on COVID-19 vaccines in general as well as the specific vaccines that were available to the public at the start of the data collection period. We also filtered out duplicated content, for example, retweets and non-English contents for providing more consistent data. Thus, we had 7,948,886 tweets for further text analysis.

Topic Detection

Where n i,j is the count of word i ∈ F appearing in tweet j ∈ N , and N (i) is the number of tweets containing word i . With such weighting scheme, the word has more weights, as it is an important word for a tweet. After encoding the corpus, we apply NMF for extracting topics, whose objective of factorization is as follows:

To detect the sentiment conveyed in the tweets, we utilized a two-step approach. In the first step, we computed the polarity score of our tweets, and based on this score, we classified the tweets as either positive, neutral, or negative. In the second step, we classified the emotional content of the tweet into 1 of the 5 emotions: anger, fear, joy, hopefulness, and sadness.

Polarity Classification

The first classification step was performed using the VADER (Valence Aware Dictionary and sEntiment Reasoner) Python library [ 14 ]. The VADER library is a rule-based model for general sentiment analysis. VADER is constructed using existing well-established sentiment lexicons such as Linguistic Inquiry and Word Count and supplemented using lexical features commonly used to express sentiment in social media. After expanding using social media lexical terms, VADER was then human validated and is currently considered a gold standard in social media lexicons [ 44 ]. VADER evaluates the sentiment of each tweet by returning a compound sentiment score between –1 and 1. Based on the classification thresholds determined by the developers of the library, we assigned a negative sentiment to a compound score less than or equal to –0.05, a positive sentiment to all compound scores greater than or equal to 0.05, and a neutral sentiment to a compound score between –0.05 and 0.05 [ 14 ]. Since VADER is more sensitive to expressions of sentiment in the social media context, it performs better than other rule-based classification algorithms in this context [ 45 ]. It has been found that VADER outperforms individual human raters [ 14 ] in the F1 score.

Emotion Classification

In the second step, we separated our data into positive, negative, and neutral and detected 1 of the 2 emotions for positive polarity, that is, joy and hopefulness, and 1 of the 3 emotions for negative polarity, that is, anger, fear, and sadness. Since VADER only includes positive, negative, and neutral sentiment, to detect more fine-grained emotions, we used zero-shot classification, an unsupervised method for discovering the applicable emotion for each tweet. Zero-shot classification is used in machine learning to classify things such as images and text [ 46 , 47 ]. We detected the emotion by finding the BERT (bidirectional encoder representations from transformers) [ 48 ] embeddings of the tweets and of the emotion words (fear, joy, hopefulness, anger, and sadness) and then computing the cosine similarity of the emotion words and each tweet and selecting the emotion with the highest cosine similarity as the emotion associated with the tweet.

BERT [ 48 ] is a word representation model that uses unannotated text to perform various natural language processing tasks such as classification and question answering. By considering the context of a word using the words both before and after the word, we were able to produce embeddings for words that are more context aware. Our research used the pretrained sentence BERT [ 49 ] model to generate the embedding vectors for our emotion classification task.

Combining Topic and Sentiment

Tracking topic over time.

We started by generating 50 topics ( K =50) using the ONMF algorithm with 2000 as the batch size ( s =2000). In order to only retain the representative topics about vaccines, we calculated the ratio of each topic k using the following equation:

With the topic ratio, we could estimate how many tweets belonged to topic k and filtered out 38 insignificant topics whose topic ratios were below the average, that is, 2%. As listed in Table 1 , the remaining 12 topics were then labeled by reviewing the most contributed keywords in each topic.

Figure 2 shows the trends for the 6 most important topics whose topic ratios were greater than 3%. The most important topic discussed the vaccination of frontline workers (topic 1), wherein the ratio stayed above 7% from mid-December to mid-February. Such a high attention of topic 1 indicated that people were concerned about the eligibility of vaccination and relevant plans from governments, especially in the early roll-out phases (ie, phase 1a and phase 1b). A discussion peak was observed on December 20, 2020, and December 21, 2020, as shown in Figure 3 because some congress members got vaccinated before frontline workers, which triggered heated debates. The representative tweets of topic 1 during that period were as follows:

…Speakers: Finding eligible #candidates for #COVID19 vaccine have to be ensured [December 20, 2020]

…What makes Blumenthal and Murphy eligible for the vaccine. Are they frontline workers? [December 20, 2020]

…They are depriving frontline workers of a vaccine. They are literally scum. [December 20, 2020]

The above tweets reported that the priority of accepting COVID-19 vaccines and justice were also critical concerns of the people. The second largest topic was about access to vaccines—signing up online (topic 2). After the early distribution of the vaccines, we observed that people started to be concerned about the access to the vaccines, resulting in a growth starting from the last week of 2020. The following relevant tweets of topic 2 indicated that governments and health care facilities [ 50 ] began implementing online appointments for vaccination.

…Heads up Ottawa County-you can sign up for vaccine notifications online [May 1, 2021]

…@drharshvardhan: Please implement Aadhaar-based online appointment for Covid vaccine as applicable in case of appointment for passport and driving license [May 1, 2021]

…A step-by-step guide for the online vaccine appointment process [wenatcheeworld]

The third largest topic was about the South African variant (topic 3), which peaked in late December and was relevant to the announcement of the South African variant from the South African health officials [ 51 ] and the first variant case detected in the United States [ 52 ], resulting in a rising trend from the late January of 2021. The high ratio of topic 3 indicated that the effectiveness of the released vaccines was of great concern, and people were skeptical and conservative. Finally, comparing the top 3 significant topics, topics 4-6 (ie, Biden Stimulus Plan, mRNA Vaccines, and Complaints about pharma company profits) showed relatively steady discussion trends.

Figure 4 presents the remaining 6 important topics. Topic 8 (Trials in non-mRNA vaccines) and topic 12 (Low distribution of AstraZeneca vaccine) had apparent spikes on January 29, 2021. For the peak of topic 8 (see Figure 5 ), we found that the emerging event “the positive trial results of Johnson & Johnson’s single-shot vaccine” caught the public’s eye and stimulated discussion. The relevant contents were tweeted frequently at that moment, and most of them cited news sources [ 52 - 54 ]. The sample tweets were as follows:

…Single-shot Johnson & Johnson vaccine 66 percent effective against moderate and severe illness [cited from Washington post, January 29, 2021]

…Johnson & Johnson says its single-shot vaccine is 66% effective overall at preventing moderate to severe illness [cited from Fox8live, January 29, 2021]

…Johnson & Johnson’s one-shot #COVID19 vaccine is effective against severe disease [cited from Science News, January 29, 2021]

The spike on Topic 12 (see Figure 6 ) can be related to the dispute between the European Union and AstraZeneca in the third week of January [ 55 ]. The citizens in the European Union expressed their depression about the delay and inefficiency of vaccine ordering, and the representative tweets were as follows:

…EU vaccine delays prompt press frustration [January 28, 2021]

…AstraZeneca is supplying European Union vaccine at cost with zero profit. European Union has a cheek to talk about suing AZ [January 29, 2021]

…The actions of the European Union to cover their abject failure to obtain vaccine [January 29, 2021]

Tracking Sentiment Over Time

When summarizing the sentiment in all 7,948,886 million tweets throughout the entire period, we observed that the top emotion that appeared in our tweets was fear followed by joy. The percentage of tweets containing each of the emotions from the tweets collected during the entire period is described in Table 2 .

Figure 7 presents the trends of the 5 emotions during the 60-day period starting from December 16, 2020. It shows that fear was consistently the most frequently detected emotion. Joy was the second most common emotion followed by neutral sentiment. Hopefulness, sadness, and anger were reflected in a lower proportion of tweets. The Augmented Dickey-Fuller test showed that all emotions, except for sadness, were stationary throughout the entire period, while sadness increased throughout the period.

Sentiment Trends in the 12 Detected Topics

To analyze the sentiment in each of the top 12 topics, we plotted the proportion of each sentiment for each topic and observed how the percentages changed over time. The percentage of tweets in each sentiment is described in Figure 8 .

Negative Sentiment

Negative sentiment was the leading sentiment in our tweets, with fear as the leading emotion.

Our graphs show that for the majority of topics, fear was the most observed emotion. In topics 1, 2, 4, 6, 7, 10, and 11, fear was the most observed emotion throughout the majority of the time period. Topic 1 discussed the vaccination of the frontline workers. Some representative tweets from this topic that contained fear were as follows:

…@POTUS Mr. President, I’m really worried about my state (GA) and the rollout with vaccines. There doesn’t seem to be a plan and we are being pushed to have school and teachers are not vaccinated and barely hospital workers and senior citizens have. [February 13, 2021]

…@CTVNews Hi, I am an Ontario resident and my wife works at X-ray & Ultrasound clinic in Newmarket. I am worried about her and her Associates not getting the vaccine along with hospital workers, she sees patients every day and I think they must be vaccinated ASAP. Thanks, Charlie [January 12, 2021]

The main theme in these tweets was fear that frontline workers would not be vaccinated soon enough and that they would not receive the highest priority in the vaccine rollout.

Topic 2 discussed access to vaccines and signing up online. The most prominent emotion in this topic throughout the period was fear. Below are some example tweets from this topic:

…I got vaccinated. I’m Latino. Making my appt was confusing and my 2nd appt kept getting cancelled even though I work in a hospital. Also lots of fear, distrust and misinformation, people saying the vaccine gives you the 666 sign of the devil, etc. Many people are scared of it. https://t.co/98pguyfuiJ [January 31, 2021]

…I’m very concerned my 82-year-old mother must go online to a website; register for the vaccine in Nevada that is still not available until February 28? How do we solve this for our older generation with no computer knowledge to help them get vaccines quicker? [January 06, 2021]

We could identify with the struggle to obtain an appointment for vaccinations in many states. There were also technical difficulties with multiple websites that caused concern among many Twitter users.

Topic 4 discussed Biden’s stimulus plan. The plan contained funding for COVID-19 vaccine distribution [ 56 ]. In January, the gap between fear and joy widened; however, after Biden took office in January, joy increased and the gap between fear and joy became smaller.

Examples of tweets from topic 4 that conveyed fear are as follows:

…@GovInslee I’m a fan Jay, but I’m worried Washington is going to screw up the vaccine distribution. [January 13, 2021]

…@JoeBiden Please save Texas from @GovAbbott’s ignorance and massive logistical failures with respect to distribution of the vaccine [January 17, 2021]

Many of the tweets in this topic conveyed fear with respect to not executing Biden’s plan rather than fear of the plan itself.

While fear was the most prominent emotion followed by joy, some topics contained spikes of anger-related tweets. Topic 5 contained a few spikes of anger. Here are some examples of angry tweets from topic 5:

…Coronavirus: European Union anger over reduced Pfizer vaccine deliveries. Why to rely on profiteering Pfizer ? There are other vaccine! https://t.co/E27tWB71IJ [January 15, 2021]

…@latimes Is that why it’s killing old people? 20+ dead in Norway alone. Global scientists calling for immediate stoppage of Pfizer drug. Btw it’s not a vaccine by definition. Its mRNA therapy. A vaccine uses a dead virus that’s incubated and cultured. [January 16, 2021]

There was anger due to lack of trust of the vaccine manufacturers as well as anger over rumors of deaths and injuries due to the vaccines.

Sadness was one of the least prominent emotions in our data. It was the highest in topic 10, which discussed concerns about vaccine supply that would enable reaching herd immunity by summer 2021. Here are some representative tweets from this topic containing sadness:

…My dad was so close to getting his vaccine. But he didn’t make it. Meredith pays tribute to her father who died 4 days ago with COVID-19. He was a Cumbrian farmer. She describes him as grumpy but in a charming way. https://t.co/OR5NsNVuZG [January 13, 2021]

…@SHCGreen @NicolaSturgeon @jasonleitch @edinburghpaper @lothianlmc @NHS_Lothian @DrGregorSmith Glad to see some people getting the vaccine. Sadly my aunt didn’t get to have hers. Died early hours from COVID. Will miss her very much.

Many of the tweets in this topic containing sad emotion discussed deaths due to COVID-19 that could have been prevented by a quicker vaccine rollout.

Additionally, we saw the following tweets from topic 1 showing sadness:

…Some of these are so painful. 65-year-old local pharmacist, kept working, hence couldn’t social-distance like, well, a writer. Dead as a consequence. Why frontline workers should be further up in the vaccine queue than even 78-year-olds like me. https://t.co/EYZ6uUr5K8 [January 21, 2021]

…An extended family member was a carer in a home, no vaccine, was in a coma for 2 weeks and passed last week. I didn’t personally know her but her niece is heartbroken. Thought all care home staff had the vaccine according to the Government. [February 03, 2021]

These tweets showed sadness and concern that frontline workers would not be vaccinated soon enough and might contract COVID-19.

Neutral Sentiment

Many neutral tweets contained information from news websites or from official sources. As a result, we observed that many of these tweets contained links or media. Neutral sentiment was not the leading emotion in any of the topics; however, we still detected many neutral tweets in all topics. Below are the tweets from different topics containing neutral sentiment from the top 6 topics:

…Westminster residents ages 65 and older are now eligible to receive the COVID-19 vaccine. Read the full press release below for instructions. #westminsterca #covidvaccine #orangecounty https://t.co/7cgiOLQLl5 (January 13 2021)

After 40 hours of work, the volunteers of Broadbent Arena, in Louisville, KY, are eligible for their own vaccines. Every day, the oldest volunteers with 40 hours under their belts get the leftover doses. https://t.co/tB3NY2ECSE (February 04 2021)

…#Health care workers, anyone 70 years and older, and state/local government employees and contractors who perform #COVID_19 vaccinations and testing in SC can make appointments to get a #vaccine. https://t.co/65iyk1qJWi [January 15, 2021]

…The fastest way to register into this system will be online, WV rolling out new vaccine registration system https://t.co/gTzl9s54vq [January 22, 2021]

Virus Updates: S. Africa Halts AstraZeneca Shot; COVID Reinfections May Be Overlooked https://t.co/VRvgEd0DDV (February 08 2021)

Moderna says it’s working on COVID booster shot for variant in South Africa, says current vaccine provides some protection https://t.co/UQLInvRVoO [January 25, 2021]

…COVID-19 vaccine distribution ramps up for 20 million to be immunized by the start of the new year https://t.co/zWUVzjxTNw [December 21,2020]

…The $900 billion stimulus package includes unemployment support of up to $300 per week. The bill also includes $45 billion in support for transportation, $82 billion for schools, $20 billion for coronavirus vaccine distribution and $25 billion in emergency assistance to renters. [December 20, 2020]

…Sir Ian McKellen says he feels ‘euphoric’ after receiving the Pfizer/BioNTech vaccine; https://t.co/Jr4XvRUDlH [December 17, 2020]

…The @nytimes reported Pfizer announced that they will ship fewer vials of their coronavirus #vaccine to the US, in response to the FDA approving a change to the label saying the vials contain six doses rather than five: https://t.co/w8pmbwWBoB [January 25, 2021]

…Column: Pfizer, Moderna expect billions in profits from COVID vaccines. That’s a scandal https://t.co/LIhZT0uTlB [January 04, 2021]

…The pharmaceutical company expects around $15 billion of revenue from sales of its COVID-19 vaccine this year, while Wall Street had anticipated $12.7 billion. https://t.co/KkjT4vur1d [February 02, 2021]

In all topics, there were a multitude of articles and opinion pieces from different media outlets. The articles typically followed the theme in the topic to which they were classified.

Positive Sentiment

Positive sentiment was the second most common in our data and contained 2 emotions: joy and hopefulness.

In topics 3, 5, 8, and 9, the leading emotion fluctuated throughout the time period. While joy was not the leading topic throughout the entire period, in these few topics, the expression of joy exceeded fear for at least some days during the period.

Topic 5 discussed mRNA vaccines. The vaccines discussed in this topic were only the Pfizer and Moderna vaccines since they were given emergency use authorization for use at the time of data collection.

Examples of tweets from topic 5 that contain joy are as follows:

…Congratulations! Still wear your mask and wash those hands, keep yourself safe! I get my second one tomorrow. Moderna or Pfizer? I got the Pfizer, people I know who have gotten their second dose are having a rough couple days. Molly must be so happy! [February 06, 2021]

…Pfizer and Moderna seem to be the clear vaccine winners [January 29, 2021]

…Wow vaccine is looking awesome. I’m super impressed with Moderna and Pfizer-- and in record time:) [February 13, 2021]

Topic 8 discussed trials of non-mRNA vaccines. While there were many days where fear was the top emotion in this topic, joy was a prominent emotion in the tweets discussing this topic since it was the leading emotion in some days during the time period. Below are examples of tweets containing joy from topic 8:

…Waking up to great news on the COVID vaccines front: Novavax 89% efficacy, Johnson&Johnson single dose, and 100% protected from death 28 days after single shot, AstraZeneca fully approved in EU. #VaccinesSaveLives [January 30, 2021]

…I participated in the Janssen/Johnson & Johnson #ENSEMBLE2 COVID-19 vaccine trial Only time will tell whether I received vaccine or placebo. But so happy to be taking part. Thanks to all the amazing staff at St. Thomas’ Hospital London @GSTTnhs #janssen # COVID-19 https://t.co/brHCDOJC6u [January 13, 2021]

The possibility of having a variety of vaccines that were approved was a cause for joy for many Twitter users.

Hopefulness

Topic 12 contained a spike of hopefulness in late December. This topic discussed the concerns of low distribution of the AstraZeneca vaccine. Below are examples of hopefulness in topic 12:

…Hopefully the Oxford vaccine can help out those countries, not just in EU, who don’t have enough vaccines. https://t.co/BrC3dJ71tN [December 21, 2020]

…@ChristinaSNP What a smashing day. Sun is shining, a British vaccine for COVID is approved. The European Union approved #brexit deal is being flown in at the moment. When signed the @theSNP can surely let us know their plans for our future, not merely criticize others like #NoDealNicola #BetterTogether [December 30, 2020]

We can see that there was some hopefulness regarding the distribution of the AstraZeneca vaccine. However, hopefulness was not the leading emotion during that time period. Additionally, by the end of the time period, fear was by far the most prominent emotion.

Principal Results

Our study aimed to detect the topics and sentiments of public concerns of COVID-19 vaccines by performing a trend analysis on tweets collected for a period of 60 days when the vaccines were started in the United States and to make practical suggestions to address the concerns of different groups in the public as expressed on social media. Approximately 8 million tweets related to COVID-19 vaccines were collected and 12 important topics were selected for analysis. The 3 most important topics with the highest topic ratio were “Vaccination of Frontline Workers,” “Access of Vaccines–Signing Up Online,” and “South African Variant.” The other topics were mostly related to the concerns about the vaccines as well as their supply and distribution. There were also topics related to the stimulus plan, profits of pharmaceutical companies, and conspiracy theories. Through the trend analysis, it was found that the peaks of the topics were impacted by the events reported in the news and spread through social media. The sentiment analysis showed that 46.9% (3,720,960/7,948,886) of the tweets were negative with emotions of mostly fear, followed by sadness and anger, 33.2% (2,645,705/7,948,886) of tweets were positive with emotions of joy and hopefulness, and 19.9% (1,582,221/7,948,886 tweets) of tweets were neutral. Fear and joy were the most detected emotions. Our analysis examined the 6 different sentiments detected in the tweets and their change over time. We observed that the keywords in each topic did not change much over time; therefore, we were able to track our tweets using the same topics throughout the entire period. In some topics, sentiment was stationary throughout the period, while in others, there were significant trends. For example, in topic 3 “South African variant,” we saw an increase in fear and neutral sentiment over the period and a decrease in joy at the same time. Similarly, we saw an increase in fear and a decrease in joy in topic 12 “Low Distribution of the AstraZeneca Vaccine.” Overall, fear was the top emotion followed by joy. Sadness and hopefulness remained low in most topics throughout the entire period.

Identifying Specific Concerns in Each Topic by Using Emotional Content

The most notable conclusion from the data is that the main reaction to the COVID-19 vaccines on social media was fear. However, we could identify every one of the emotions in each topic. In each topic, we could find tweets related to the topic containing each of the emotions. By looking at the representative tweets for each topic and each emotion, we were able to learn what specific concerns people may have that may lead to vaccine hesitancy. For example, from topic 1, we found that there was fear surrounding the vaccination of government officials prior to frontline workers. By addressing this publicly and assuring the public that the frontline workers would receive their vaccines as soon as possible, this would help to build public confidence in the vaccine rollout. We could also identify tweets that contained sadness to identify further concerns about the rollout to frontline workers and see Twitter users expressing sadness regarding frontline workers possibly dying due to lack of vaccines. This could be addressed by being more transparent about vaccination timelines or by advocating for more vaccine supply. By being aware of specific concerns as they happen (eg, the vaccination of frontline workers), we will be better able to address the source of concern and reduce vaccine hesitancy.

Vaccine Administration

The very first dose of the mRNA COVID-19 vaccine by Pfizer and BioNTech was given to a health care worker on December 14, 2020. This may explain why the most significant topic at the start of the study was vaccination of frontline workers (topic 1). As more vaccines were administered, reports of anaphylaxis began to surface, especially with the Moderna vaccine [ 57 ]. In the United States alone, 10 cases of anaphylaxis were reported after 4,041,496 (0.002%) vaccines were given between December 21, 2020, and January 10, 2021. This created fear as indicated in the trend, and fear dominated all other emotions throughout the course of the study period. It will be interesting to find out how many of these tweets are from health care personnel versus that from the general public. According to the Centers for Disease Control recommendation, both health care personnel and residents of long-term care facilities were the first to be offered the COVID vaccine [ 58 ]. Health care personnel include both clinical and nonclinical staffs such as those who work in food, environmental, and administrative services. It can be assumed that clinical staff have adequate knowledge of vaccines and need not to be afraid to take it. Therefore, public health authorities and health care systems can focus on educating the adverse effects of the vaccine to the nonclinical staff and the general public. For example, anaphylactic reactions occur mostly in people who have a similar reaction to other food and drugs, and it usually occurs within minutes after injection. Better understanding of the adverse effects will minimize fear of the vaccine and thus reduce vaccine hesitancy.

Access to Vaccines

Signing up online (topic 2), vaccine distribution in Canada (topic 9), and low distribution of AstraZeneca vaccine (topic 12) can all be categorized as accessibility of vaccines. A good amount of positive emotion all through the study period in topic 2 indicated that there was a sense of hope in the midst of the daily rising COVID cases. There is still a large amount of fear regarding COVID-19. It may be the fear of the inability to obtain an appointment for the vaccine. Unlike the United States, Canada does not have her own domestic manufacturers to produce vaccines. As a result, Canada relies on international vaccine manufacturers. The advance purchase contract was signed but there was no specific date for delivery except for “first quarter of 2021.” There was a shortage of supply of vaccines in Canada because of which the Canadian government prioritized giving the first dose to the population first and the second dose 16 weeks later [ 59 ] as opposed to after 3 or 4 weeks. The European Union was furious when in early January, AstraZeneca announced that there would be 60% fewer doses of vaccines than it had promised to deliver in the first quarter of 2021. The spikes of fear and anger emotions during this period in topic 12 were the direct reflection of this news. Being able to have access to the vaccines is important once COVID-19 vaccines are authorized for emergency use. Therefore, public health authorities must have plans to work with vaccine manufacturers to manufacture and deliver the vaccines in a timely manner. The transparency of the access information from social media and public health officials is helpful to reduce the fear and anger in the public.

Practical Implications

In December 2020, the World Health Organization released a safety surveillance manual for COVID-19 vaccines. This manual addressed a number of topics with regards to vaccine administration, including how to communicate information regarding the vaccine on social media [ 60 ]. Among other points, the report offers proposals to listen proactively and craft tailored messages to different audiences and address specific concerns of different groups. Using this research, we can take the World Health Organization’s recommendations to provide more specific advice to clinicians and policy makers. To address specific concerns, we divided the 12 topics into 3 groups: favoring vaccines, vaccine hesitant, and vaccine opposed.

Favoring Vaccines

The topics that leaned toward those who favor vaccines were topic 1 (vaccination of frontline workers), topic 2 (access to vaccines–signing up online), topic 9 (vaccine distribution in Canada), topic 10 (concerns about supply to reach herd immunity by summer), and topic 12 (low distribution of AstraZeneca vaccine). While these topics also produced negative feelings of fear, anger, and sadness, these negative feelings were regarding concern about not having enough vaccines or not having access to vaccines fast enough. It is crucial to monitor topics that contain tweets from individuals who do want to get vaccinated and keep them informed. Here are some examples of tweets that conveyed fear or concern by individuals who wanted to get vaccinated:

…Anybody know what’s going on with BAT 24-hour appts? Are they fully back up and running again after being shut down for lack of vaccine? My second shot is at 2:45 a.m. next week, and I’m wary of getting up in the middle of the night to go down there to find them closed.

…To be honest, I’d rather risk my life / keep myself in lockdown, for younger key workers to have the vaccine. They are the ones keeping the country going after all.

…Blocking access to a vaccine that could save my life is, oh I don’t know, attempted murder? So is exhaling their COVID breath around me, but the former is active and so much more egregious. Ain’t nobody got time for that mess.

Identifying the topics that vaccine-favoring individuals discussed was crucial to reducing their concern. In accordance with the World Health Organization document, communication on vaccine availability should be active and frequent. An example of using the analysis from this study to inform the public is looking at the visualizations in real time to produce the right messaging on social media. We observed a spike in the volume of topic 1 in the week of December 18. Figure 8 shows that the leading emotion for that week and topic was fear; further, there was a spike in fear during that week for topic 1. Therefore, it was crucial to post messages on social media that week that address the public fear that health care workers would not have adequate access to vaccines. Another key component in keeping the public informed was updating official websites with vaccine information very frequently. During the early days of vaccination, there was a lack of information in many states about the timeline of vaccination for each risk group. Providing more information on the rollout schedule would help ease the concern of individuals in this group. It is crucial to look at the tweets that convey fear and anger in these topics to create the right messaging and address points that concern this group of the public.

Vaccine Hesitant

This group of individuals was the most crucial to reach since they can be persuaded to get vaccinated. Topics that discussed vaccine hesitancy were topic 3 (South African variant), topic 5 (mRNA vaccines), topic 8 (Trials in non-mRNA vaccines), and topic 11 (Genetic concerns about vaccines and kids). Below are examples of tweets of the vaccine hesitant from these topics:

…Just keep in mind that some small percentage of those who received the vaccine did not develop immunity, during the clinical trials. And its effectiveness against variant strains is still not fully known.

…The fact that 3 vaccines all appeared to show lowered effectiveness against the variant from South Africa is not encouraging, and the results Novavax announced Thurs were the 1st to occur outside of a lab, testing how well a vaccine worked in people infected with a new variant.

…There were obviously several people in the United Kingdom who had had a severe allergic reaction to this vaccine and had a history of severe allergic reaction, said Offit Several people!!!!! #vaccine

Like the vaccine favorable group, we should also target this group with facts and do so often. However, with this group, we should focus on messages that can be detected in these topics such as those related to side effects of the vaccine, the efficacy of the different types of the vaccine for the original strain of COVID-19 as well as for variants, and why you can still contract COVID-19 even after being vaccinated. We can craft helpful messaging for this group by looking at the topic and emotion data for these topics. For example, we saw an increase in the volume of topic 3 (South African variant) toward the end of January. The most prominent emotion for that topic during that time was fear. Therefore, we can craft messaging on social media regarding the variant that will help with this fear. As the World Health Organization recommends, we should mainly focus on facts and provide up-to-date information to the public through social media regarding the variant.

Vaccine Opposed

This group was the least likely to be persuaded by messaging on the vaccine but should not be ignored. This is because they produce messaging on social media that may convince others. Therefore, we should attempt to counter their messaging with up-to-date and correct information. Topics that contained a large number of tweets from individuals that were vaccine opposed were topic 6 (Complaints about pharma company profits), but we can find a small number of tweets from this group in all topics, particularly in tweets that were labeled angry or fearful. Examples of tweets from this group were as follows:

…We have been here before with the Nazis and Thalidomide yet the whole world rushes to take an untested vaccine. People are dying after having the vaccine yet no enquiries into what happened just a rapid cremation and silence. We should all be very worried.

…I bind you up Satan in the name of Jesus, no weapon formed against us shall prosper, and I mean this vaccine is Satan here. “Mark of the beast” read your bibles people.

…He didn’t take the vaccine! He’s a Eugenics partner with Bill Gates they don’t take their own vaccines! How about some proof! He’s just trying to coverup the ill side effects and deaths that are already happening!

Those who were opposed to vaccines were hard to persuade, but we must spread truthful messages to counteract the messages that they spread. Many of the tweets by these individuals did not even discuss concerns that could be addressed but were more about vaccine refusal and the freedom to refuse vaccines. It is important to amplify stories of those who suffered severe consequences by refusing to take the vaccine. This is mostly for the sake of the vaccine hesitant rather than the vaccine opposed. An example of messaging can be obtained by looking at the patterns for topic 6. This topic was stable over time and did not experience any spikes. Therefore, we should stay consistent with our messaging over time and counteract any information on this topic with facts on a consistent basis as recommended by the World Health Organization report.

Limitations of This Research

Limitations of twitter.

Twitter is a large social network with 353 million monthly active users [ 61 ]. While this is a significant number of users, there is no guarantee that Twitter users are representative of the global or the US population as a whole. Mislove et al [ 62 ] have investigated the ability of Twitter data to represent the US population and have found that areas that are more densely populated tend to be overrepresented in Twitter. Additionally, Gore et al [ 63 ] and Padilla et al [ 64 ] found geographical bias in their analysis of Twitter data. Both studies found an overrepresentation of urban areas in the demographic data of Twitter users included in their studies. Given this prior research, we must assume that users from urban areas are overrepresented in this data set as well.

Keyword Selection

The keywords that were chosen to generate this data set were selected by the authors. The list of keywords described in the data collection section contains keywords that name the colloquial names for the available vaccines at the time of the study. The list also contains terms such as “vaccine” and “coronavaccine” that were included in order to capture a more general discussion regarding COVID-19 vaccines. The list is not meant to be exhaustive and represents the vaccines publicly available at the start of data collection in December 2020.

Duplicated Tweets

Bots posting on Twitter are a well-documented phenomenon [ 65 - 67 ]. One of the issues our study faced was the duplication of content due to bot activity on the topic of vaccines. Other research has documented bot activity on COVID-19 and COVID-19 vaccine misinformation as well [ 65 , 68 , 69 ]. The main issue this may cause in our analysis is that bot activity may overinflate the importance of certain topics. To combat this, we deduped the Twitter data as part of our analysis and reduced the number of tweets from approximately 20 million to approximately 8 million tweets.

We used topic detection and sentiment analysis as social media trend analysis to better understand the discourse on COVID-19 vaccines tweets. Using this methodology, we could identify the trending topics that reflected the public concerns on COVID-19 vaccines and their responses to the topics indicated by the polarity and emotions on the sentiments. We found that the administration and access to vaccine were some of the major concerns. While most of the information was received from the internet, they were not directly obtained from the health organization. Misinformation may cause negative emotions. In some cases, conspiracy spreading in social media may cause substantial amount of fear. The findings in social media trend analysis are helpful for the health organizations to develop strategies for better communication to the target groups and assist them in coping with their concerns that cause negative emotions or vaccine hesitancy. Disseminating accurate information of COVID-19 vaccines will reduce the negative emotion caused by misinformation or rumors. A report on COVID-19 vaccines by the World Health Organization suggested careful examination of social media to detect specific concerns regarding the vaccines [ 60 ]. By understanding what drives different emotions regarding the vaccines, tailored and targeted communication can be developed to provide authoritative health information, which will be helpful to achieve herd immunity and end the pandemic.

Acknowledgments

This work was supported in part by the National Science Foundation under grant NSF-1741306 and grant IIS-1650531. Any opinions and conclusions or recommendations expressed in this study are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

Conflicts of Interest

None declared.

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Abbreviations

Edited by C Basch; submitted 27.05.21; peer-reviewed by S Wilson, A Ramazan, R Poluru, R Gore; comments to author 30.08.21; revised version received 17.09.21; accepted 17.09.21; published 21.10.21

©Michal Monselise, Chia-Hsuan Chang, Gustavo Ferreira, Rita Yang, Christopher C Yang. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 21.10.2021.

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Comprehensive literature review on COVID-19 vaccines and role of SARS-CoV-2 variants in the pandemic

Charles yap.

School of Medicine, National University of Ireland, Galway, Ireland

Abulhassan Ali

Amogh prabhakar, akul prabhakar, ying yi lim, pramath kakodkar.

School of Medicine, National University of Ireland, Galway, University Road, Galway H91 TK33, Ireland

Since the outbreak of the COVID-19 pandemic, there has been a rapid expansion in vaccine research focusing on exploiting the novel discoveries on the pathophysiology, genomics, and molecular biology of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although the current preventive measures are primarily socially distancing by maintaining a 1 m distance, it is supplemented using facial masks and other personal hygiene measures. However, the induction of vaccines as primary prevention is crucial to eradicating the disease to attempt restoration to normalcy. This literature review aims to describe the physiology of the vaccines and how the spike protein is used as a target to elicit an antibody-dependent immune response in humans. Furthermore, the overview, dosing strategies, efficacy, and side effects will be discussed for the notable vaccines: BioNTech/Pfizer, Moderna, AstraZeneca, Janssen, Gamaleya, and SinoVac. In addition, the development of other prominent COVID-19 vaccines will be highlighted alongside the sustainability of the vaccine-mediated immune response and current contraindications. As the research is rapidly expanding, we have looked at the association between pregnancy and COVID-19 vaccinations, in addition to the current reviews on the mixing of vaccines. Finally, the prominent emerging variants of concern are described, and the efficacy of the notable vaccines toward these variants has been summarized.

Introduction

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 192 million cases and 4.1 million deaths as of July 22, 2021. 1 This pandemic has brought along a massive burden in morbidity and mortality in the healthcare systems. Despite the implementation of stringent public health measures, there have been devasting effects in other sectors contributing to our economy. This has plunged the global economies toward deep recession and has racked up a debt of approximately 19.5 trillion USD. 2

Immune protection in COVID-19 infection can be conceptualized as a spectrum wherein sterile immunity is at the end of positive spectrum. This is followed by transient infection (<3 days) and asymptomatic infection (~1 week). The negative spectrum of immune protection includes patients who are symptomatic, or hospitalized, or admitted to the intensive care unit for multiorgan support. The extreme end of the negative spectrum of immune protection is encompassed by case fatality. The vaccine will intervene prior to the viral insult and stabilize the population at the positive end of the spectrum of the immune protection. It will also prevent the perpetuating cycle of infection and reinfection via variants of SARS-CoV-2 virus in those who have achieved prior convalescence. One study by Dan et al. showed that in patients infected with COVID-19, immunological memory to SARS-CoV-2 remained intact for up to 6 months. 3 Unfortunately, there is no long-term data on the duration of protected immunity against SARS-CoV-2 in patients after convalescence. Therefore, these patients may also require vaccination but the current priority for vaccination can be stretched relative to the unaffected population.

While the ideal goal of the COVID-19 vaccine roll-out is to instill a global herd immunity; it is important to remember that this goal may never be reached. Furthermore, additional goals of vaccination may be to reduce mortality and stress on healthcare systems by reducing the cases of admitted patients. Various countries have already approved COVID-19 vaccines for human use, and more are expected to be licensed in the upcoming year. It is important that these vaccines are safe, efficacious, and can be deployed on a large scale. It is also prudent to eliminate the concerns of both the scientific and general community regarding its effectiveness, side-effects, and dosing strategies.

Historically, the process of vaccine manufacturing and clinical trials required approximately 10 years, but due to the burden of this disease, various observational studies were expedited so that all crucial information regarding the vaccine pharmacokinetics, pharmacodynamics, dosing, efficacy, and adverse events can be collected within a short period of time. Furthermore, there is a need to provide a compilation of accredited and appraised scientific literature on each of these approved vaccines with an aim to instill public health knowledge and vaccine literacy to members of the scientific and general community. A section dedicated to COVID-19 vaccines and pregnancy is also included in the penultimate section of this review.

Finally, the emergence of the SARS-CoV-2 viral variants of concern (VOC) has attained increased replication, transmission, and infectivity warranting exploration of these genomic mutations as their phenotypes. Hence, the final section of this review will aim to clarify the jargon, highlight the vaccine efficacy (VE) against VOCs, and eliminate any misinformation regarding these variants.

Vaccine physiology

The global burden of the pandemic requires an efficacious vaccine that elicits a lasting protective immune response against SARS-CoV-2. This will be an essential armament for the prevention and mitigation of the downstream morbidity and mortality caused by SARS-CoV-2 infection. As of July 20, 2021, there are approximately 108 vaccines in clinical development and 184 vaccines in pre-clinical development with several vaccines being distributed globally. 4

The technologies employed in the vaccine synthesis and development aim to trigger the adaptive immune system and elicit memory cells that will protect the body from subsequent infections. These technologies may be mRNA-based vaccines such as the Moderna and Pfizer/BioNTech, inactivated virus vector vaccines, DNA vaccines, and numerous other technologies. 5

Due to the urgent implementation of vaccine development, the most obvious target will be the robust proteins expressed on the surface of the virus. Therefore, these technologies target molecular expression of the trimeric SARS-CoV-2 spike (S) glycoprotein. These targets could include its mRNA, DNA, full S1 subunit, or fusion subunits. The S protein is a major component of the virus envelope, it is vital for viral fusion, receptor binding, and virus-entry through recognition of host-cellular receptor. The S protein comprises of two main functional units, the S1 subunit, which contains the receptor-binding domain (RBD) and the S2 subunit which is responsible for virus fusion with the host-cell membrane. 6 The choice to proceed with S protein as the target was reinforced when a study by Dan et al. confirmed that in 169 patients infected with SARS-CoV-2, spike-specific immunoglobulin G (IgG) remained stable for over 6 months. 3 In addition, both spike-specific CD4+ T-cells (CD137+ and OX40+) and spike-specific CD8+ T-cells (CD69+ and CD137+) were present at the 6-month post-convalescence period, but their subpopulations exhibited a steady decline with a half-life of 139 days and 225 days, respectively. 3

There are subtle differences in the mechanism by which the different vaccine products interact within host cells to induce immunity. Many successful vaccines of the 20 century utilized the target proteins directly such as the tetanus and pertussis vaccine. A summary of the major types of vaccines and their mechanism of action are shown in Figure 1 .

Summary of major vaccine types and their mechanism of action.

DNA, deoxyribonucleic acid; HPV, Human papillomavirus; mRNA, messenger ribonucleic acid; MMR, Measles, Mumps, and Rubella; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Historically, vaccines usually contained adjuvants which are protein sensitizers that heighten the migratory and sampling response of antigen presenting cells (APCs). Interestingly, the current mRNA vaccines are engineered to code for their own sensitizing protein alongside the S-protein epitopes. Therefore, these new mRNA vaccines usually do not contain any adjuvants. In addition, the mRNA vaccines utilize lipid nanoparticles to deliver the genetic material of a viral S-protein. Contrastingly, vaccines such as the AstraZeneca vaccine may employ a chimpanzee adenovirus vector to carry the DNA genome of the S-protein to the host-cell. 7 Once undergoing the processes of transcription and translation into proteins, these are trafficked and expressed on the host cell surface wherein the adaptive immune system mounts a response via the major histocompatibility complex (MHC) molecules ( Figure 2 ).

Mechanism of induction of immunity through vaccination.

APC, antigen presenting cells; DNA, deoxyribonucleic acid; MHC, major histocompatibility complex; mRNA, messenger ribonucleic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

There are two types of MHC molecules, the first one that will be discussed is the MHC-II, which is found exclusively on APC: these comprise of B-cells, macrophages, and dendritic cells in the lymph nodes. Once the S-protein antigen is presented at the cell surface of the MHC-II molecules, the naïve helper T-cell’s (Th Cells) T-cell receptor (TCR) complex will interact with this antigen leading to activation of CD4+ Th cells. This activation is perpetuated by a secondary activation signal with B7 on the APC recognizing the CD28 on the Th cell which triggers the proliferation of Th cells that can recognize the S-protein antigen. Activated CD4+ Th cells then secrete numerous cytokines, namely interleukin (IL)-2 which activates CD8+ cytotoxic T-cells (Tc cell) and trigger clonal expansion of B-cells in memory B-cells and plasma cells. The cytokines IL-4 and IL-5 facilitate B-cell isotype switching and maturation to plasma cells; promoting secretion of IgG antibodies against S-protein. 8 Formation of antibodies allows the immune system to direct an immune response against cells expressing the S-protein of the virus. The second process involves MHC-I, which activates CD8+ Naïve Tc cells through TCR complex interaction with processed endogenously synthesized S-protein expressed on MHC-I. MHC-I is expressed in all nucleated cells, APCs, and platelets and require a second activation signal provided by IL-2 from activated CD4+ Th cells. This activates CD8+ Tc cells which can mount a cytotoxic response against SARS-CoV-2-infected cells through two mechanisms of apoptosis. The first mechanism is the secretion of perforin which create pores to allow granzyme to enter the targeted cell, thus activating apoptosis. The second mechanism is via the expression of FasL, which binds Fas on target cells and induces apoptosis. 8 A crucial part of this process is the stimulation of memory T-cells and memory B-cells. Importantly, while the SARS-CoV-2 vaccine’s lasting effect is still being researched in the context of the pandemic, theoretically these should provide lasting immunity and allow the immune system to mount a faster and more effective response should a vaccinated individual encounter the virus in the future.

Current prominent COVID-19 vaccines

Biontech/pfizer.

The BNT162b2 COVID-19 vaccine developed by BioNTech and Pfizer is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a prefusion membrane-anchored SARS-CoV-2 full-length spike protein. 9 It was the first vaccine approved by the US Food and Drug Association (FDA) and now it has been approved in many other countries. 10 The BNT162b2 COVID-19 vaccine may be stored at standard refrigerator temperatures prior to use, but it requires very cold temperatures for long-term storage and shipping (−70°C) to maintain the stability of the lipid nanoparticle. In a phase-1 trial, it was compared to another vaccine candidate BNT162b1, and it was found to have a milder systemic side-effect profile with a similar antibody response. 11 Therefore, it was pushed forward to a blinded phase-2/3 clinical study. 9 In total, 43,548 participants were randomized to receive either two doses of the BNT162b2 vaccine (n = 21,720) or a placebo (n = 21,728) 21 days apart. The participant ages ranged from 16 to 91 years, 35.1% of participants were classified as having obesity and comorbidities within participants included HIV, malignancy, diabetes, and vascular diseases. 9 Based on the results of the study, 7 days after the second BNT162b2 dose, the VE was 95% (95% confidence interval (CI), 90.3–97.6) with only eight observed cases of COVID-19 in the vaccine recipients and 162 cases in the placebo recipients. 9 The efficacy remained consistent across subgroups characterized by age, sex, race, ethnicity, body mass index (BMI), and comorbidities (generally 90–100%). 9 Although there were 10 cases of severe COVID-19 with onset after the first dose, only one occurred in a vaccine recipient and nine in placebo recipients. Like the phase-1 trial results, the safety profile remained favorable with the most common local reaction being mild-to-moderate pain at the injection site while the most common systemic symptoms were fatigue and headache (reported in ⩾50%). 9 In both the vaccine and placebo group, the incidence of severe adverse events did not differ significantly (0.6% and 0.5%, respectively) and no deaths occurred related to the vaccine. As indicated by the manufacturer’s information, contraindications for use include hypersensitivity to the active substance or any of the excipients. 12 These studies show that the mRNA-vaccine BNT162b2 is safe and effective in protecting against COVID-19. However, further investigations are needed to confirm long-term safety and to establish safety and efficacy for populations not included in this study.

The mRNA-1273 vaccine, developed by Moderna, relies on mRNA technology to encode prefusion stabilized SARS-CoV-2 spike protein. It is the second COVID-19 vaccine to receive emergency use approval by the US FDA, and it is given as two 100-µg doses intramuscularly into the deltoid muscle, 28 days apart. 13 Storage of the vaccine is done at temperatures between −25°C to −15°C for long-term storage, 2°C to 8°C for 30 days, or 8°C to 25°C for up to 12 hours. Results from the COVE phase-3 trial showed that the mRNA-1273 vaccine was effective at preventing COVID-19 illness in persons 18 years of age or older. A total of 30,420 participants aged 18 years or older were randomized 1:1 to receive either two doses of the vaccine or a placebo, 28 days apart. 14 The mean age of the participants was 51.4 years, and enrollment was adjusted for equal representation of racial and ethnic minorities. In the trial, symptomatic COVID-19 illness occurred in 11 participants within the vaccine group versus 185 participants within the placebo group, showing a 94.1% (95% CI, 89.3–96.8%) efficacy of the vaccine. Efficacy was similar across age, sex, race, and ethnicity as well as in patients with and without risk factors for severe disease (e.g. chronic lung disease, cardiac disease, and severe obesity). Importantly, a secondary endpoint for determining the efficacy of the vaccine in preventing severe COVID-19 was also used. All 30 participants with severe COVID-19 were in the placebo group, indicating a 100% efficacy of no hospital admissions. 14 Regarding the side effects of the vaccine, adverse events at the injection site and systemic adverse events occurred more commonly with the mRNA-1273 group compared to the placebo. The most common local reaction was mild to moderate pain at the injection site (75%). The most common systemic symptoms were fatigue, myalgia, arthralgia, and headache (50%). 14 The overall incidence of serious adverse events did not differ significantly between groups and no deaths occurred in relation to the vaccine. While this vaccine is already being administered, further investigations are still necessary to establish safety and efficacy profiles for populations not included in this study as well as to assess its long-term effects. Current contraindications of the mRNA-1273 vaccine include any persons with known allergy to polyethylene glycol (PEG), another mRNA vaccine component or polysorbate. 15

AstraZeneca

The Oxford and AstraZeneca ChAdOx1 COVID-19 vaccine uses a chimpanzee adenovirus vector to deliver the genetic sequence of a full-length spike protein of SARS-CoV-2 into host cells. 16 The storage for the ChAdOx1 vaccine is favorable, as it may be refrigerated at 2°C–8°C for 6 months. Pooled analysis of four ongoing clinical studies was used to assess efficacy, safety, and immunogenicity of the ChAdOx1 vaccine: COV001 (phase 1/2), COV002 (phase 2/3), COV003 (phase 3), and COV005 (phase 1/2). 17 Across the four studies participants over 18 were randomized to receive either the vaccine or a control (meningococcal group A, C, W, or saline). ChAdOx1 vaccine recipients received two standard doses (SDs) of the vaccine (SD/SD cohort) except for a subset in the COV002 trial who received a half lower dose (LD) followed by an SD (LD/SD cohort). 17 In the four studies, there was a total 23,848 participants, all of whom were used for gathering safety data; only 11,636 participants from the COV002 and COV003 trials were included in the primary efficacy analysis. 17 Of the 11,636 participants in the efficacy analysis, 2741 were in the LD/SD cohort, 88% were between 18 and 55 years old, and comorbidities present included cardiovascular disease, respiratory disease, and diabetes. 17 The results show that in the intended dosing regimen (SD/SD cohort), the VE was 62.1% (95% CI, 41.0–75.7) ⩾14 days after the second injection for symptomatic COVID-19 (27 cases vs 71 cases respectively). 17 In the group that received an LD (LD/SD cohort), the VE was 90.0% (95% CI, 67.4–97.0; 3 cases vs 30 cases, respectively) while across the two dosing regimens the overall efficacy was 70.4% (95.8% CI, 54.8–80.6;30 cases vs 101 cases, respectively). 17 The higher efficacy observed in the LD/SD cohort can be attributed to this group having a longer dosing interval between the two doses in comparison to the SD/SD cohort. Regarding safety, most of the adverse events were mild-moderate with the most frequently reported being injection site pain/tenderness, fatigue, headache, malaise, and myalgia. 18 About 175 serious adverse events were noted, only three of which were possibly linked to intervention: transverse myelitis 14 days after second dose, haemolytic anemia in a control recipient and fever >40°C in a participant still masked to group allocation. One contraindication for use of the vaccine is hypersensitivity to any of its components. In very rare cases, AstraZeneca has been associated internationally with venous thromboembolic events with thrombocytopenia with current estimates being 10–15 cases per million vaccinated patients. 19 This adverse event has been termed thrombosis with thrombocytopenia syndrome (TTS). In summary, these studies demonstrate that the AstraZeneca ChAdOx1 vaccine has a good efficacy and side-effect profile. Limitations include that less than 4% of participants were >70, no one over 55 got the mixed-dose regimen (LD/SD cohort), and those with comorbidities were a minority. Additional investigations are required to analyze long-term effects and assess efficacy and safety in populations not included or underrepresented.

Janssen COVID-19 vaccine

The Janssen (Johnson & Johnson) COVID-19 vaccine, developed by Janssen Pharmaceutical in Netherlands. It is a single-dose intramuscular (IM) vaccine that contains a recombinant, replication incompetent human adenovirus (Ad26) vector encoding the spike protein of SARS-CoV-2 in the stabilized conformation. 20 It can be stored between 2°C and 8°C for up to 6 hours or at room temperature for a duration of 2 hours. The ENSEMBLE Phase-3 trial (n = 43,783) is a randomized, double-blind, placebo-controlled study which included participants ⩾18 years. Efficacy assessment was performed at day 14 and 28. The primary outcome only included moderate and severe (hospitalization and death) infection. Overall, the VE in the moderate to severe cohort was 66.9% (95% CI: 59.0–73.4) at 14 days and 66.1% (95% CI: 55.0–74.8) at 28 days. 20 In the severe cohort, the VE was 76.7% (95% CI: 54.6–89.1) and 85.4% (95% CI: 54.2–96.9) at day 14 and 28 days, respectively. 20 At the time of the study, 96.4% of the strains in the United States, 96.4% were identified as the Wuhan-H1 variant D614G. The VE in the United States for the moderate to severe cohort was 74.4% (95% CI: 65.0–81.6) and 72.0% (95% CI: 58.2–81.7) at 14 days and 28 days, respectively. 20 In the US severe cohort, the VE was 78.0% (95% CI: 33.1–94.6) and 85.9% (95% CI: −9.4 to 99.7) at day 14 and 28 days, respectively. 20 Alternatively, 94.5% of the strains in South Africa were identified as beta variant. The VE in South Africa for the moderate to severe cohort was 52.0% (95% CI: 30.3–67.4) and 64.0% (95% CI: 41.2–78.7) at 14 days and 28 days, respectively. 20 In the South African severe cohort, the VE was 73.1% (95% CI: 40.0–89.4) and 81.7% (95% CI: 46.2–95.4) at day 14 and 28 days, respectively. 20 In Brazil, 69.4% of the strains were identified as P.2 lineage variant and 30.6% were identified as Wuhan-H1 variant D614G. The VE in Brazil for the moderate to severe cohort was 66.2% (95% CI: 51.0–77.1) and 68.1% (95% CI: 48.8–80.7) at 14 days and 28 days, respectively. 20 In the Brazilian severe cohort, the VE was 81.9% (95% CI: 17.0–98.1) and 87.6% (95% CI: 7.8–99.7) at day 14 and 28 days, respectively. 20 The most common localized solitary adverse reaction was the injection site pain (48.6%). Conversely, the most common systemic adverse reactions included headache, fatigue, myalgia, and nausea. 20 In the post authorization phase, adverse reaction included anaphylaxis, thrombosis with thrombocytopenia, Guillain Barré syndrome, and capillary leak syndrome. 20 Overall, the data demonstrate that the Janssen vaccine has a good efficacy and side-effect profile.

Sputnik V or Gam-COVID-Vac, developed by the Gamaleya Institute, is a recombinant human adenovirus-based vaccine that uses two different vectors (rAd26 and rAd5) to carry the gene encoding for the spike protein of SARS-CoV-2. Only one vector (rAd26) is given at dose 1 and the other (rAd5) at dose 2. This strategy prevents immunity against the vector. It can be stored as either a liquid at −18°C, or it can be freeze-dried and stored at 2°C to 8°C. 21 Regarding the safety and efficacy of the vaccine, both were evaluated in a randomized, double-blind phase-3 trial performed in Moscow, Russia. In the trial, a total of 21,977 participants aged 18 years or older were randomized in a 3:1 ratio to the vaccine or placebo groups. Two doses of the vaccine or placebo were given 21 days apart to the respective groups. 21 The mean age of the participants was 45.3 years, and the majority of participants were Caucasian (98.5%). 21 From 21 days after the first dose of the vaccine, efficacy against symptomatic COVID-19 illness was 91.6% (95% CI, 85.6–95.2%) with 16 confirmed cases of COVID-19 in the vaccine group and 62 confirmed in the placebo group. 21 There were also 20 cases of moderate to severe COVID-19 infection confirmed in the placebo group at least 21 days after the first dose and 0 in the vaccine group, indicating a VE of 100% against moderate to severe infection. 21 The most common adverse effects in both groups were flu-like illness, injection site reactions, headaches, and asthenia, with the majority being grade 1 (94.0%). 21 Serious adverse events were also reported in both the vaccine group and placebo group, but they were deemed not to be associated with the vaccination. Further investigations are still needed to determine the duration of protection of the vaccine and to determine the safety and efficacy of the vaccine in populations not included in the study (e.g. children, adolescents, and pregnant and lactating women).

CoronaVac is an inactivated vaccine developed by SinoVac Biotech containing inactivated SARS-CoV-2. 22 The vaccine can be stored at 2°C to 8°C for up to 3 years making it an attractive option for development. Two phase-1/2 clinical trials assessed the safety, tolerability, and immunogenicity of the CoronaVac vaccine. 22 , 23 The first study (18–59 years old included only) placed 744 participants in either a vaccine or placebo group where they were further divided based on vaccination schedule and dosage (3 and 6 μg). In the second study (⩾60 years old included only), 422 participants were randomized to receive two doses of CoronaVac or placebo 28 days apart and then further divided based on dosage amount only (3 and 6 μg for phase 1; 1.5, 3, and 6 μg for phase 2). Safety results from both trials show a favorable side-effect profile with most symptoms being transient and of mild severity. The most common adverse effect was injection site pain; others included fatigue and fever. In the 18–59 years old study, one serious adverse event of acute hypersensitivity was possibly related to vaccination. 22 No serious adverse events were associated with the vaccine or placebo in the ⩾60-year-old study. Between the dosage amounts in both studies, the tolerability was consistent and the immunogenicity was also similar for the 3 and 6 μg doses (less in 1.5 μg). 23 Multiple phase-3 trials have also taken place to determine the effectiveness of CoronaVac in countries, such as Brazil, Indonesia, and Turkey. In the Brazil trial, 252 cases of COVID-19 were recorded from roughly 9200 health care workers, with 167 in the placebo group and 85 in the vaccine group. 24 The reported efficacy of the vaccine in preventing mild and severe COVID-19 infection was 50.4%. In comparison, the Turkey trial reported that the vaccine was 83.5% effective at preventing symptomatic infection based on 29 COVID-19 cases among 1,322 volunteers while results from the Indonesia trial found that the vaccine was 65.3% effective at preventing symptomatic infection based on 25 COVID-19 cases among 1,600 people. 24 Some reasons for the lower efficacy of CoronaVac in the Brazil trial may include increased likelihood of exposure to the virus since participants were healthcare workers, and insufficient time for participants to reach peak immunity since the doses were administered only 2 weeks apart. 24 The phase-3 SinoVac study in Chile showed the VE 14 days post second dose to prevent symptomatic COVID-19 (67%, 95% CI: 65–69%), hospital admission (85%, 95% CI: 83–87%), intensive care unit (ICU) admission (89%, 95%CI: 84–92%) and death (80%, 95%CI: 73–86%). 25 The Phase-3 SinoVac trial in Brazil showed an overall VE against symptomatic COVID-19 (50.7%, 95% CI: 35.9–62%), moderate cases requiring hospitalization (83.7%, 95% CI: 58–93.7%), and severe cases requiring hospitalization (100%, 95%CI: 56.4–100%). 26 As with any vaccine, a contraindication for CoronaVac is anaphylaxis to it or to one of its constituents.

Other prominent COVID-19 vaccines

Due to the disease burden of SARS-CoV-2, the development and manufacturing of COVID-19 vaccines has been occurring at a remarkable pace which has not been seen before. There are many emerging vaccines with different mechanisms of actions that will be briefly explored. Bharat Biotech, an Indian company, has designed the inactivated COVID-19 vaccine Covaxin (BBV152). Once inside the body, the inactivated viruses can initiate an immune response through the interaction of surface proteins with APCs. Phase-1/2 trials showed no serious side effects and phase-3 trials are currently underway. 27 The state-owned Chinese company Sinopharm has also made an inactivated COVID-19 vaccine called BBIBP-CorV. The Sinopharm phase-3 trial showed that the VE in symptomatic cases for the WIV04 strain-based vaccine (72.8, 95% CI: 58.1–82.4%) and HB02 strain-based vaccine (78.1 95% CI: 64.8–86.3%). 28 , 29 It is approved in Bahrain, U.A.E, and China. NVX-CoV2373 is another promising vaccine produced by Novavax. It is a protein subunit vaccine made by assembling SARS-CoV-2 spike proteins into nanoparticles. A phase-3 trial in the United Kingdom displayed an efficacy rate of 89.3%; however, a phase-2 trial in South Africa had an efficacy just under 50%. 28 This discrepancy is thought to arise because of a new variant in South Africa. Other emerging vaccines include CoVLP produced by Medicago which uses the plant N. benthamiana to create virus-like particles that mimic SARS-CoV-2, CVnCoV produced by CureVac which is an mRNA vaccine, Convidecia produced by CanSino Biologics which is adenovirus based (Ad5), Ad26.COV2.S produced by Johnson & Johnson which is also adenovirus based (Ad26), and ZF2001 created by Anhui Zhifei Longcom which is a protein subunit vaccine. Even though highly effective, COVID-19 vaccines are already in use, it is still important to have a range of vaccines such as those listed above to bring the pandemic under control. Having a diverse profile ensures that vaccines will work for individuals from all ethnic backgrounds and with various underlying health conditions. 30 Getting the virus under control will also require doses for a large proportion of the world. To meet this requirement as soon as possible, having multiple vaccines will help in maximizing the volume of doses that can be produced. In addition, there are many technical issues such as cold storage and transportation, cost, and dosing of certain vaccines that arise when trying to vaccinate remote populations. For example, both the Pfizer-BioNTech and Moderna vaccines are expensive and transported at temperatures of −70°C and −20°C making it difficult to access many locations all at once. Since most vaccines require two doses spaced a few weeks apart, it can be challenging for individuals without regular access to healthcare as well. 30 Such considerations highlight the importance of having a range of single-dose vaccines and vaccines without the need for cold storage. A summary of efficacy, prominent side effects and storage recommendations for all the notable COVID-19 vaccines are shown in Table 1 .

Summary of vaccine efficacy, dosing strategy, and side-effects of different COVID-19 vaccines.

CI, confidence interval; COVID-19, coronavirus disease 2019; IM, intramuscular.

Post-vaccination contagion

With the endurance of the COVID-19 vaccine still being heavily researched, a chief concern is the sustainability of the vaccine-mediated immune response. This is important in the consideration of whether vaccinated individuals could still contract, transmit, or be carriers of SARS-CoV-2 virus. Vaccinated individuals currently may not understand the rationale behind why social restriction rules still apply to them. Most COVID-19 mRNA vaccines require at least 3 weeks to mount an immunological response and create the required antibodies and proliferate accessory cells of the adaptive immune system of the appropriate recognition repertoire. 50 This may be particularly relevant in the context of travel, as the World Health Organization (WHO) states that a proof of vaccination should not exempt international travelers from complying with social restrictions and risk-reduction measures. 51

Contraindications for COVID-19 vaccines

All vaccines are contraindicated in cases of documented hypersensitivity to the active substance or any of the excipients. There are a set of general guidelines relative to patients which must be adhered to until further information is provided; predominantly regarding groups such as pregnant or lactating women and immunodeficient patients. The Centers for Disease Control and Prevention (CDC) considers absolute contraindications to patients who have had severe anaphylactic reactions to a previous dose of an mRNA COVID-19 vaccine or PEG, a component of the vaccine. Moreover, immediate allergic reactions of any severity to polysorbate are also a significant contraindication. Importantly, there are many precautions which are not classified as contraindications but must be considered, such as patients who have had allergic reactions to any vaccine or injectable therapy. In the cases of patients with a precaution to the vaccine, they should be counseled on the benefits and risks, but are not contraindicated from vaccination. 15 In the instance of patients with autoimmune diseases, there is currently insubstantial data regarding the efficacy of the vaccine; however, current guidelines suggest that individuals with autoimmune conditions may take the vaccine if they do not have any absolute contraindications. In the case of patients with HIV, limited data from COVID-19 mRNA vaccination trials suggest that they can receive the vaccine barring any contraindications.

COVID-19 vaccines and pregnancy

Prior to discussing the relationship between the current vaccines for COVID-19 and pregnancy, it is crucial to gain an insight of the relationship between pregnancy and COVID-19 itself. Adhikari et al. showed that there was no difference in the frequency of Caesarean section, pre-eclampsia, preterm births, and abnormal fetal cardiotocography in pregnant women with and without SARS-CoV-2 infection. In addition, examination of the placenta revealed were no abnormalities, which were initially suspected due to the cross-matching between the SARS-CoV-2 spike protein and the placental synctyin-1 protein. 52 Similarly, there was no association found between COVID-19 and first-trimester spontaneous abortions. 53 A systematic review and meta-analysis revealed that COVID-19 leads to higher preterm deliveries (odds ratio (OR): 3.01, 95% CI: 1.16–7.85) and an increase in the ICU admission rates (OR: 71.63, 95% CI: 9.81–523.06) in pregnant women. 54

Pregnancy remained an exclusion criterion for all the COVID-19 vaccine trial; therefore, the efficacy of the COVID-19 vaccines in pregnant women is unavailable. However, given the effectiveness of the influenza vaccines elucidated in a meta-analysis conducted by Quach et al ., it can be hypothesized that the effects of pregnancy on the vaccine would be minimal, but more data would be needed for confirmation. 55 Pfizer’s animal studies revealed antibodies in the maternal rats, fetus, and offspring, in addition to no effects on fertility pregnancy or fetal development. 56 A similar study was conducted with the Moderna vaccine which led the US FDA to conclude that the vaccine did not have any adverse effects on female reproduction, fetal development, or postnatal development. 34 Furthermore, the Oxford-AstraZeneca vaccine animal studies are still pending. However, as a precaution, the National Immunization Advisory Committee (NIAC) has recommended for the two-dose schedule to not commence before 14 weeks of gestation and to be completed by week 33 of gestation. This precaution reduces any potential associations with miscarriage or pre-term birth. 57

Despite the exclusion of pregnancy in the preliminary stages of the trials, 23 Pfizer, 13 Moderna, and 21 AstraZeneca subjects became pregnant after enrolment into the trial. Among this cohort, there was one miscarriage part of the Pfizer control group, no miscarriages part of the Pfizer vaccine group, one miscarriage part of the Moderna control group, no miscarriages part of the Moderna vaccine group, three miscarriages part of the AstraZeneca control group, and two miscarriages part of the AstraZeneca vaccine group. While these preliminary numbers support the current guidelines regarding the vaccines being safe in pregnancy, it is crucial to be aware of the ongoing studies as new data emerges.

The CDC v-safe COVID-19 Pregnancy Study explored the effect of mRNA vaccine (Pfizer-BioNTech or Moderna) on the pregnancy. The pregnancy loss within those with a completed pregnancy included a spontaneous abortion (<20 weeks) rate of 12.6% (104 out of 827) and stillbirth (⩾20 weeks) incidence of 0.1% (1 out of 725). 58 The neonatal outcomes within the live birth infant cohort showed preterm birth (<37 weeks) incidence at 9.4% (60 out of 636), small for gestational age incidence of 3.2% (23 out of 724), and congenital anomalies were seen in 2.2% (16 out of 724). 58 No neonatal deaths were observed in this study.

Vaccine dosing strategies

Limited vaccine resources have caused some governments to extend the date of the second dose beyond the recommended manufacturer date. On December 30, NHS England had made the decision to prioritize the administration of the first doses, and to extend the second doses of the vaccine to the end of 12 weeks, rather than the recommended 3–4 weeks as shown in the clinical phase-3 trial. Pfizer-BioNTech at the time had no data to support this decision, and thus stated that the safety and efficacy of the vaccine had not been evaluated on different dosing schedules, and importantly, the second dose should not be administered later than 42 days. 59

Newly accrued evidence might warrant changes in the landscape of this vaccination program. Estimation of the effectiveness of the Pfizer-BioNTech after a single dose from the primary data from Israeli population (n = 500,000) showed that from day 0 to day 8 post–vaccination, the likelihood of contracting COVID-19 infection doubled. 60 This result may appear counterintuitive, but it takes 3 weeks for the vaccine to instill efficacy during which this real-world population could have not maintained the stringent public health measures which lead to the increased incidence in COVID-19 in this time-period. Then from day 8 to day 21 the incidence of COVID-19 declined and at day 21 the vaccine effectiveness was documented at 91%. 60 This efficacy was seen to stabilize at 90% for the duration of the study (9 weeks), and the authors of this study extrapolate this stability up to 6 months. 60 This concludes that the single dose of Pfizer-BioNTech is highly protective from day 21 onwards and supports the NHS England’s vaccination policy for extending gaps between the doses. The data from the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) trial in the Scottish population revealed that a single dose of Pfizer (n = 650,000) and Oxford-AstraZeneca (n = 490,000) vaccines resulted in a decline in hospitalization at 4 weeks by 84% and 94%, respectively. 61

However, the trials for the Oxford-AstraZeneca vaccine included varied spacing schedules between doses. The findings from these trials displayed that a greater space between the first and second dose provided a superior immune response. This is supported by a combined trial between a UK and Brazil study, which demonstrated a higher VE 14 days after a second dose in patients who had greater than 6 weeks between their first and second dose than patients who had less than 6 weeks by 53.4%. 17 , 62

It was also proposed that to meet the supply shortage that vaccine dose can be halved. Half-dose of Moderna vaccine (50ug) was in a phase-IIa trial. Immune response in the half-dose group compared to those that received a full dose were the same. Therefore, this dosing strategy is supported from an immunogenicity perspective. It is reasonable to infer that the immunogenicity would translate to immune protection, but unfortunately no clinical trial has validated the immune protection for this dosing strategy.

SARS-CoV-2 genome mutations

Mutations are changes in the SARS-CoV-2 viral genome that occur naturally over time. These mutations from the parent SARS-CoV-2 virus create variants. A certain amount of genetic variation is expected as SARS-CoV-2 replicates as such it is important to monitor circulating viral variants to collate key mutations. Fortunately, coronaviruses have a slower rate of mutation of 1 to 2 nucleotides per month. 63 These definitions become complicated when environmental factors apply selective pressures on these variants that enable them to express distinct phenotypes that may facilitate viral fitness. This ability of a variant to express distinct phenotypes is termed as a strain. A compilation of beneficial lineage defining mutations can create a strain that has a higher transmission rate or induce severe disease. This raises the question: will the current vaccines or convalescent immunity from a non-variant SARS-CoV-2 infection provide adequate immunological protection against these new variants?

Coronaviruses mutate spontaneously via antigenic drift. This process typically utilizes the virus-specific transcription regulatory network (TRN) sequence to initiate the change, resulting in a new mRNA sequence virus being formed. Homologous and genetic recombination allows for the virus to gain more ecological features and has been speculated to be the reason why SARS-CoV-2 was zoonotic in origin. 64 A variant of the original SARS-CoV-2 virus with a D614G substitution in the spike protein encoding gene emerged in early February 2020, and by June 2020, D614G became the dominant form of the virus circulating globally. 65 Studies have shown that the D614G mutation resulted in increased infectivity and transmissibility. 66 Since then, there have been many viral lineages to note, most notable VOC include the B.1.1.7/20I/501.Y.V1 variant that was first detected in the United Kingdom in October 2020, the B.1.351/20 H/501Y.V2 variant that was detected in South Africa in December 2020, and the Lineage P.1. (B.1.1.28.1) variant that was detected in Tokyo in January 2021 but is believed to have originated from Brazil.

Currently, there exists two open-source real-time software tools to analyze and assign nomenclature of genetic variations in the SARS-CoV-2 virus: Nextstrain and PANGOLIN. 64 , 67 Both refer to the GISAID (Global Initiative on Sharing All Influenza Data) genomic database but have slight differences with regards to their nomenclature to describe various lineages of the virus. The COVID-19 Genomics UK Consortium has also developed CoV-GLUE, an open-source browser application that allows for easy referral of all sequenced SARS-CoV-2 genetic replacements, insertions, and deletions. 68 Therefore, sequencing every local infection will yield a repository to track the development of new mutations and variants.

Notable mutation drivers in the SARS-CoV-2 genome

Before diving deeper into these variants, it is important to understand the physical alteration in the S-protein at a molecular level and the perceived functional advantages that the SARS-CoV-2 gains. Table 2 highlights some of the notable S-protein mutations as they evolve amid the pandemic.

Summary of the physical and functional alterations of S-protein due to notable amino acid substitutions.

RBD, receptor-binding domain; VOC, variants of concern.

Notable emerging VOC

Newly emerged variants of SARS-CoV-2 have now become VOC which can be attributed to their new ability of increased transmission and infectivity. Therefore, it is important to collate the data on the mutations they acquired, the extend of spread, and the efficacy of different vaccines to create a repository for further analysis ( Table 3 ).

Summary of data on features, acquired cluster of S-protein mutations, and vaccine efficacy studies for the major COVID-19 variants of concern.

CI, confidence interval; COVID-19, coronavirus disease 2019; VOC, variants of concern.

There are more variants emerging as the pandemic progresses, but it is important to note that there is still a myriad of available vaccines in our armamentarium that are adequately efficacious in the performed neutralization assays as well as the real-world data. Furthermore, while vaccines induce the antibody-dependent immunity, they can also stimulate other components of the adaptative immune system such as the Memory B-cells, CD8+ Tc cells, and CD4+ Th cells to mount their own response against the viral variants. This can compensate for the reduction in neutralization rate by the vaccine induced antibodies. Interestingly, the adaptative immune system can proliferate libraries of memory B-cells with mutated antibody repertoires that can predict viral variants. Therefore, it is prudent to commence vaccinations in accordance with the local public health bodies. This combined with the continued implementation of public health measures until target level of herd immunity is acquired can lead toward mitigating the prevalence and incidence of COVID-19 variants.

This review highlighted the current available vaccines and candidates being rolled out amid the ongoing prevention measures and summarized the documented findings with regards to their efficacies, side-effects, and storage requirements. An overview of the physiology of immunogenic responses against the disease provided by the more prominent vaccines were discussed, alongside questions regarding the implementation of vaccines; heterologous prime-boosting, vaccine contraindications, dosing strategies, side effects, and the presence of SARS-CoV-2 mutations and variants.

There are still many unanswered questions that need to be addressed with regards to antibodies produced in individuals including their impact on the clinical course and severity of the disease, how long will they remain in the body to protect from the disease, and if what we have is enough to deal with newly emerging variants. Studies on these topics are rapidly being conducted and published on a global scale, and scientific communities are working on the clock to produce as much information to bring us a better understanding on how to deal with this disease.

For this global pandemic to end, it is imperative that people are vaccinated as quickly as possible until herd immunity can be achieved. One aspect of achieving this, in the face of vaccine hesitancy, is to address the lack of community understanding on how vaccines work, the risks, and the factors that keep this area of research volatile and distribution policies ever-changing. In addition, it is important to remain cautious about the information being released and to trust the accredited sources and experts, rather than the aberrant rumors being spread through social media. Nonetheless, the COVID-19 vaccines have shown to be highly promising and we recommend for everyone that is eligible to take the vaccine at the correct dosing interval when they are given the chance as this would potentiate a positive trend toward pandemic resolution.

Authors’ contributions: CY, AA, Amogh P, Akul P, AP performed acquisition and curation of the data; CY, AA, Amogh P, Akul P, AP, YYL and PK analyzed the data, performed interpretation of the data, and wrote of the original draft; YYL and PK performed the critical revision; All authors have read and approved the final manuscript.

Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Contributor Information

Charles Yap, School of Medicine, National University of Ireland, Galway, Ireland.

Abulhassan Ali, School of Medicine, National University of Ireland, Galway, Ireland.

Amogh Prabhakar, School of Medicine, National University of Ireland, Galway, Ireland.

Akul Prabhakar, School of Medicine, National University of Ireland, Galway, Ireland.

Aman Pal, School of Medicine, National University of Ireland, Galway, Ireland.

Ying Yi Lim, School of Medicine, National University of Ireland, Galway, Ireland.

Pramath Kakodkar, School of Medicine, National University of Ireland, Galway, University Road, Galway H91 TK33, Ireland.

More From Forbes

Shingrix, the shingles vaccine, could reduce your risk of dementia.

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The new recombinant shingles vaccine, ‘Shingrix,’ is associated with a reduced risk of dementia compared to an earlier shingles vaccine, according to a major new study.

Shingrix (herpes zoster vaccine (recombinant, adjuvanted)). (Credit: Whispyhistory / CC BY-SA 4.0)

Evidence from a team of scientists at the University of Oxford indicates that the newer shingles vaccine is more protective against dementia compared to the previous shingles vaccine. Both shingles vaccines were associated with a lowered risk of dementia when compared to either the influenza vaccine or the tetanus / diphtheria / pertussis (Tdap) vaccine.

The scientists studied health outcomes of more than 200,000 people who received one of the two different shingles vaccines and found that the recombinant shingles vaccine, Shingrix, reduces dementia by at least 17% more than the older, but now discontinued, live shingles vaccine, Zostavax. Further, they found that Shingrix reduced dementia risk by 23-27% than did vaccines against other illnesses. This equates to 5-9 months or more dementia-free days of life.

This protective effect was seen in both sexes, but was greater in women.

Interestingly, after the live vaccine against shingles, Zostavax, was introduced in 2006, several studies suggested it might reduce the risk of dementia. Later, Zostavax was discontinued in many countries, including the USA and UK, in favor of the much more effective vaccine, Shingrix. Unlike Zostavax, Shingrix is not a live virus vaccine. It’s a recombinant vaccine made from a piece of the virus. It’s given in two doses, with the second given 2 to 6 months after the first.

It was during this switchover between the two vaccine types that participants were identified for this comparative study. This provided the rare opportunity to compare the risk of dementia in the six years following Shingrix compared to the otherwise similar group of people who received Zostavax. There were more than 100,000 people in each group. The study also compared Shingrix to vaccines against other infections (flu and tetanus, diphtheria, and pertussis).

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“The size and nature of this study makes these findings convincing, and should motivate further research,” said the study’s lead author, Maxime Taquet, a NIHR Clinical Lecturer with educational backgrounds in both clinical psychiatry and engineering.

“They support the hypothesis that vaccination against shingles might prevent dementia. If validated in clinical trials, these findings could have significant implications for older adults, health services, and public health.”

How might Shingrix protect against dementia?

“One possibility is that infection with the Herpes zoster virus might increase the risk of dementia, and therefore by inhibiting the virus, the vaccine could reduce this risk,” replied co-author, John Todd, a Professor of Precision Medicine at the University of Oxford and Director of the Wellcome Centre for Human Genetics and of the JDRF/Wellcome Diabetes and Inflammation Laboratory (DIL).

“Alternatively, the vaccine also contains chemicals which might have separate beneficial effects on brain health,” Dr Todd added. These chemicals, known as adjuvants, are designed to ensure that your immune system reacts strongly to the vaccine so a lasting immune response develops.

“The Shingrix vaccine has got different and perhaps more potent chemical adjuvants in it than the previous vaccine.”

Various analyses showed that these findings are robust but further research is still needed before any suggestion can be made that the shingles vaccine itself should be used to help prevent or delay dementia onset.

“The findings are intriguing and encouraging,” said the study’s senior author, Paul Harrison, Theme Leader in the NIHR Oxford Health Biomedical Research Centre, and a Group Leader in the Oxford Wellcome Centre for Integrative Neuroimaging.

Diagnosis Shingles, pills and stethoscope.

Shingles is caused by the varicella-zoster virus (VZV), which causes chickenpox, a common childhood illness. After recovery, VZV quietly hides in the nervous system for decades, but can re-emerge to cause shingles when the immune system is compromised or due to age or stress.

Shingles is a painful and potentially serious illness that can arise in people over the age of 50. Although most people recover from a shingles attack within one year, approximately one in five people will end up with post-herpetic neuralgia, which can last weeks, months, or years. These sequelae include vision damage or blindness (which are permanent), lasting pain that can be quite severe, scarring, and more.

For these reasons, the CDC recommends that adults age 50 and older should get the Shingrix vaccine to prevent shingles and the potentially severe complications from the illness. People who have already had shingles can get the Shingrix vaccine as can those who received Zostavax in the past. It’s also worthwhile to get the vaccine if you don’t know if you’ve had chickenpox as a child.

This study’s findings raise an interesting question — especially in this age of ‘anti-vaxx’ lunacy — might the public increase their uptake of the Shingrix vaccine to reduce their risk of dementia along with protecting against a dreaded shingles attack?

“Anything that might reduce the risk of dementia is to be welcomed,” Dr Harrison said, “given the large and increasing number of people affected by it.”

Maxime Taquet, Quentin Dercon, John A. Todd & Paul J. Harrison (2024). The recombinant shingles vaccine is associated with lower risk of dementia , Nature Medicine | doi: 10.1038/s41591-024-03201-5

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Watch CBS News

Latest shingles vaccine may also delay dementia, study finds

By Sara Moniuszko

Edited By Lucia Suarez Sang

Updated on: July 26, 2024 / 10:24 AM EDT / CBS News

There may be new hope in the fight against dementia , according to recent research that found the latest shingles vaccine appears to delay the onset of the memory-impairing condition.

In the study, published in Nature Medicine  on Thursday, researchers found people who got the vaccine lived, on average, an additional 164 days without a dementia diagnosis compared to those who received the previous shingles vaccines.

On "CBS Mornings" Friday , Dr. Céline Gounder, CBS News medical contributor and editor-at-large for public health at KFF Health News, said the results were exciting. 

"The fact that we have a vaccine that's already approved, already out there, covered by insurance, super easy to get. The fact that that is showing this kind of level of protection is really promising for a lot," she said.

In an expert reaction shared alongside the study, Dr. Sheona Scales, the director of research at Alzheimer's Research UK, said, "Dementia isn't an inevitable part of aging; it's caused by diseases like Alzheimer's. So finding new ways to reduce people's risk of developing these diseases is vital."

But, it isn't clear how the vaccine might be reducing risk, Scales' comment continued, adding "It will be critical to study this apparent effect further."

The authors also note further research is needed to understand what exactly creates this association.

Who should get the shingles vaccine?

The CDC already recommends that everyone get the two-dose shingles vaccine starting at age 50.

"I think the real question before us now is, should we be starting to vaccinate even earlier? Will you need more doses if you start vaccinating vaccinating earlier? We don't have answers to that yet," Gounder said. 

• Your guide to other vaccines, preventative health screenings you should get, from your 20s to your 60s

Other steps to prevent dementia

Preventing dementia later in life involves a lot of the same things experts advise for overall health.

"You want to control your blood pressure, avoid developing diabetes through good diet and exercise, but if you have diabetes, be sure to manage it well, quit smoking," Gounder said. 

A newer risk factor to be aware of, she said, is  air pollution caused by wildfire smoke .

"Try to minimize your exposure, get some indoor air filtration units. You might want to be wearing a mask outdoors during those periods," Gounder advised. 

Sara Moniuszko is a health and lifestyle reporter at CBSNews.com. Previously, she wrote for USA Today, where she was selected to help launch the newspaper's wellness vertical. She now covers breaking and trending news for CBS News' HealthWatch.

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• Review Article
• Published: 12 April 2021

Vaccine development for emerging infectious diseases

• Jean-Louis Excler   ORCID: orcid.org/0000-0002-6462-5101 1 ,
• Melanie Saville 2 ,
• Seth Berkley 3 &
• Jerome H. Kim   ORCID: orcid.org/0000-0003-0461-6438 1  

Nature Medicine volume  27 ,  pages 591–600 ( 2021 ) Cite this article

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• Viral infection

Examination of the vaccine strategies and technical platforms used for the COVID-19 pandemic in the context of those used for previous emerging and reemerging infectious diseases and pandemics may offer some mutually beneficial lessons. The unprecedented scale and rapidity of dissemination of recent emerging infectious diseases pose new challenges for vaccine developers, regulators, health authorities and political constituencies. Vaccine manufacturing and distribution are complex and challenging. While speed is essential, clinical development to emergency use authorization and licensure, pharmacovigilance of vaccine safety and surveillance of virus variants are also critical. Access to vaccines and vaccination needs to be prioritized in low- and middle-income countries. The combination of these factors will weigh heavily on the ultimate success of efforts to bring the current and any future emerging infectious disease pandemics to a close.

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Progress of the COVID-19 vaccine effort: viruses, vaccines and variants versus efficacy, effectiveness and escape

Newly emerging and reemerging infectious viral diseases have threatened humanity throughout history. Several interlaced and synergistic factors including demographic trends and high-density urbanization, modernization favoring high mobility of people by all modes of transportation, large gatherings, altered human behaviors, environmental changes with modification of ecosystems and inadequate global public health mechanisms have accelerated both the emergence and spread of animal viruses as existential human threats. In 1918, at the time of the ‘Spanish flu’, the world population was estimated at 1.8 billion. It is projected to reach 9.9 billion by 2050, an increase of more than 25% from the current 2020 population of 7.8 billion ( https://www.worldometers.info ). The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the coronavirus disease 2019 (COVID-19) pandemic 1 , 2 , 3 engulfed the entire world in less than 6 months, with high mortality in the elderly and those with associated comorbidities. The pandemic has severely disrupted the world economy. Short of lockdowns, the only means of control have been limited to series of mitigation measures such as self-distancing, wearing masks, travel restrictions and avoiding gatherings, all imperfect and constraining. Now with more than 100 million people infected and more than 2 million deaths, it seems that the addition of vaccine(s) to existing countermeasures holds the best hope for pandemic control. Taken together, these reasons compel researchers and policymakers to be vigilant, reexamine the approach to surveillance and management of emerging infectious disease threats, and revisit global mechanisms for the control of pandemic disease 4 , 5 .

Emerging and reemerging infectious diseases

The appearance of new infectious diseases has been recognized for millennia, well before the discovery of causative infectious agents. Despite advances in development of countermeasures (diagnostics, therapeutics and vaccines), world travel and increased global interdependence have added layers of complexity to containing these infectious diseases. Emerging infectious diseases (EIDs) are threats to human health and global stability 6 , 7 . A review of emerging pandemic diseases throughout history offers a perspective on the emergence and characteristics of coronavirus epidemics, with emphasis on the SARS-CoV-2 pandemic 8 , 9 . As human societies grow in size and complexity, an endless variety of opportunities is created for infectious agents to emerge into the unfilled ecologic niches we continue to create. To illustrate this constant vulnerability of populations to emerging and reemerging pathogens and their respective risks to rapidly evolve into devastating outbreaks and pandemics, a partial list of emerging viral infectious diseases that occurred between 1900 and 2020 is shown in Table 1 .

Although nonemerging infectious diseases (not listed in Table 1 ), two other major mosquito-borne viral infections are yellow fever and dengue. Yellow fever, known for centuries and an Aedes mosquito-borne disease, is endemic in more than 40 countries across Africa and South America. Since 2016, several yellow fever outbreaks have occurred in Angola, Democratic Republic of Congo, Nigeria and Brazil to cite a few 10 , raising major concerns about the adequacy of yellow fever vaccine supply. Four live attenuated vaccines derived from the live attenuated yellow fever strain (17D) 11 and prequalified by the WHO (World Health Organization) are available 12 .

Dengue is an increasing global public health threat with the four dengue virus types (DENV1–4) now cocirculating in most dengue endemic areas. Population growth, an expansion of areas hospitable for Aedes mosquito species and the ease of travel have all contributed to a steady rise in dengue infections and disease. Dengue is common in more than 100 countries around the world. Each year, up to 400 million people acquire dengue. Approximately 100 million people get sick from infection, and 22,000 die from severe dengue. Most seriously affected by outbreaks are the Americas, South/Southeast Asia and the Western Pacific; Asia represents ~70% of the global burden of disease ( https://www.cdc.gov/dengue ). Several vaccines have been developed 13 . A single dengue vaccine, Sanofi Pasteur’s Dengvaxia based on the yellow fever 17D backbone, has been licensed in 20 countries, but uptake has been poor. A safety signal in dengue-seronegative vaccine recipients stimulated an international review of the vaccine performance profile, new WHO recommendations for use and controversy in the Philippines involving the government, regulatory agencies, Sanofi Pasteur, clinicians responsible for testing and administering the vaccine, and the parents of vaccinated children 14 .

Two bacterial diseases, old scourges of humanity, are endemic and responsible for recurrent outbreaks and are increasingly antimicrobial resistant. Cholera, caused by pathogenic strains of Vibrio cholerae , is currently in its seventh global pandemic since 1817; notably, the seventh pandemic started in 1961 15 . Global mortality due to cholera infection remains high, mainly due to delay in rehydrating patients. The global burden of cholera is estimated to be between 1.4 and 4.3 million cases with about 21,000–143,000 deaths per year, mostly in Asia and Africa. Tragic outbreaks have occurred in Yemen and Haiti. Adding to rehydration therapy, antibiotics have been used in the treatment of cholera to shorten the duration of diarrhea and to limit bacterial spread. Over the years, antimicrobial resistance developed in Asia and Africa to many useful antibiotics including chloramphenicol, furazolidone, trimethoprim-sulfamethoxazole, nalidixic acid, tetracycline and fluoroquinolones. Several vaccines have been developed and WHO prequalified; these vaccines constitute a Gavi-supported global stockpile for rapid deployment during outbreaks 16 .

Typhoid fever is a severe disease caused by the Gram-negative bacterium Salmonella enterica subsp. enterica serovar Typhi ( S . Typhi). Antimicrobial-resistant S . Typhi strains have become increasingly common. The first large-scale emergence and spread of a novel extensively drug-resistant (XDR) S . Typhi clone was first reported in Sindh, Pakistan 17 , 18 , and has subsequently been reported in India, Bangladesh, Nepal, the Philippines, Iraq and Guatemala 19 , 20 . The world is in a critical period as XDR S . Typhi has appeared in densely populated areas. The successful development of improved typhoid vaccines (conjugation of the Vi polysaccharide with a carrier protein) with increased immunogenicity and efficacy including in children less than 2 years of age will facilitate the control of typhoid, in particular in XDR areas by decreasing the incidence of typhoid fever cases needing antibiotic treatment 21 , 22 .

A model of vaccine development for emerging infectious diseases

The understanding of emerging infectious diseases has evolved over the past two decades. A look back at the SARS-CoV outbreak in 2002 shows that—despite a small number of deaths and infections—its high mortality and transmissibility caused significant global disruption (see Table 1 ). The epidemic ended as work on vaccines was initiated. Since then, the disease has not reappeared—wet markets were closed and transmission to humans from civets ceased. Consequently, work on vaccines against SARS-CoV ended and its funding was cut. Only a whole inactivated vaccine 23 and a DNA vaccine 24 were tested in phase 1 clinical trials.

Following a traditional research and development pipeline, it takes between 5 and 10 years to develop a vaccine for an infectious agent. This approach is not well suited for the needs imposed by the emergence of a new pathogen during an epidemic. Figure 1 shows a comparison of the epidemic curves and vaccine development timelines between the 2014 West African Ebola outbreak and COVID-19. The 2014 Ebola epidemic lasted more than 24 months with 11,325 deaths and was sufficiently prolonged to enable the development and testing of vaccines for Ebola, with efficacy being shown for one vaccine (of several) toward the end of the epidemic 25 , 26 . What makes the COVID-19 pandemic remarkable is that the whole research and development pipeline, from the first SARS-CoV-2 viral sequenced to interim analyses of vaccine efficacy trials, was accomplished in just under 300 days 27 . Amid increasing concerns about unmitigated transmission during the 2013–2016 Western African Ebola outbreak in mid-2014, WHO urged acceleration of the development and evaluation of candidate vaccines 25 . To ensure that manufacturers would take the Ebola vaccine to full development and deployment, Gavi, the Vaccine Alliance, publicly announced support of up to US$300 million for vaccine purchase and followed that announcement with an advance purchase agreement. Ironically, there had been Ebola vaccines previously developed and tested for biodefense purposes in nonhuman primates, but this previous work was neither ‘ready’ for clinical trials during the epidemic nor considered commercially attractive enough to finish development 28 .

a , The number of months from the onset of the epidemic is shown against the number of reported cases per day. Note that the COVID-19 (left) and Ebola (right) axes are scaled differently. b , Vaccine development timelines for COVID-19 versus Ebola in the context of particular events during the respective outbreaks. PHEIC, public health emergency of international concern.

From these perceived shortcomings in vaccine development during public health emergencies arose the Coalition for Epidemic Preparedness Innovations (CEPI), a not-for-profit organization dedicated to timely vaccine development capabilities in anticipation of epidemics 29 , 30 . CEPI initially focused on diseases chosen from a list of WHO priority pathogens for EIDs—Middle East respiratory syndrome (MERS), Lassa fever, Nipah, Rift Valley fever (RVF) and chikungunya. The goal of CEPI was to advance candidate vaccines through phase 2 and to prepare stockpiles of vaccine against eventual use/testing under epidemic circumstances. CEPI had also prepared for ‘disease X’ by investing in innovative rapid response platforms that could move from sequence to clinical trials in weeks rather than months or years, such as mRNA and DNA technology, platforms that were useful when COVID-19 was declared a global health emergency in January 2020, and a pandemic in March 2020 31 , 32 .

CEPI has been able to fund several vaccine development efforts, among them product development by Moderna, Inovio, Oxford–AstraZeneca and Novavax. Providing upfront funding helped these groups to advance vaccine candidates to clinical trials and develop scaled manufacturing processes in parallel, minimizing financial risk to vaccine developers. The launch of the larger US-funded Operation Warp Speed 33 further provided companies with funding—reducing risks associated with rapid vaccine development and securing initial commitments in vaccine doses.

Vaccine platforms and vaccines for emerging infectious diseases

Vaccines are the cornerstone of the management of infectious disease outbreaks and are the surest means to defuse pandemic and epidemic risk. The faster a vaccine is deployed, the faster an outbreak can be controlled. As discussed in the previous section, the standard vaccine development cycle is not suited to the needs of explosive pandemics. New vaccine platform technologies however may shorten that cycle and make it possible for multiple vaccines to be more rapidly developed, tested and produced 34 . Table 2 provides examples of the most important technical vaccine platforms for vaccines developed or under development for emerging viral infectious diseases. Two COVID-19 vaccines were developed using mRNA technology (Pfizer–BioNTech 35 and Moderna 36 ), both showing safety and high efficacy, and now with US Food and Drug Administration (FDA) emergency use authorization (EUA) 37 , 38 and European Medicines Agency (EMA) conditional marketing authorization 39 , 40 . While innovative and encouraging for other EIDs, it is too early to assert that mRNA vaccines represent a universal vaccine approach that could be broadly applied to other EIDs (such as bacterial or enteric pathogens). While COVID-19 mRNA vaccines are a useful proof of concept, gathering lessons from their large-scale deployment and effectiveness studies still requires more work and time.

While several DNA vaccines are licensed for veterinary applications, and DNA vaccines have shown safety and immunogenicity in human clinical trials, no DNA vaccine has reached licensure for use in humans 41 . Recombinant proteins vary greatly in design for the same pathogen (for example, subunit, virus-like particles) and are often formulated with adjuvants but have longer development times. Virus-like particle-based vaccines used for hepatitis B and human papillomavirus are safe, highly immunogenic, efficacious and easy to manufacture in large quantity. The technology is also easily transferable. Whole inactivated pathogens (for example, SARS-CoV-2, polio, cholera) or live attenuated vaccines (for example, SARS-CoV-2, polio, chikungunya) are unique to each pathogen. Depending on the pathogen, these vaccines also may require biosafety level 3 manufacturing (at least for COVID-19 and polio), which may limit the possibility of technology transfer for increasing the global manufacturing capacity.

Other vaccines are based on recombinant vector platforms, subdivided into nonreplicating vectors (for example, adenovirus 5 (Ad5), Ad26, chimpanzee adenovirus-derived ChAdOx, highly attenuated vectors like modified vaccinia Ankara (MVA)) and live attenuated vectors such as the measles-based vector or the vesicular stomatitis virus (VSV) vector. Either each vector is designed with specific inserts for the pathogen targeted, or the same vector can be designed with different inserts for the same disease. The development of the Merck Ebola vaccine is an example. ERVEBO is a live attenuated, recombinant VSV-based, chimeric-vector vaccine, where the VSV envelope G protein was deleted and replaced by the envelope glycoprotein of Zaire ebolavirus . ERVEBO is safe and highly efficacious, now approved by the US FDA and the EMA, and WHO prequalified, making VSV an attractive ‘platform’ for COVID-19 and perhaps for other EID vaccines 26 although the −70 °C ultracold chain storage requirement still presents a challenge.

Other equally important considerations are speed of development, ease of manufacture and scale-up, ease of logistics (presentation, storage conditions and administration), technology transfer to other manufacturers to ensure worldwide supply, and cost of goods. Viral vectors such as Ad5, Ad26 and MVA have been used in HIV as well as in Ebola vaccines 42 . Finally, regulatory authorities do not approve platforms but vaccines. Each vaccine is different. However, with each use of a specific technology, regulatory agencies may, over time, become more comfortable with underlying technology and the overall safety and efficacy of the vaccine platform, allowing expedited review and approvals in the context of a pandemic 43 . With COVID-19, it meant that the regulatory authorities could permit expedited review of ‘platform’ technologies, such as RNA and DNA, that had been used (for other conditions) and had safety profiles in hundreds of people.

A heterologous prime–boost (HPB) vaccine approach has been extensively explored for HIV 44 and Ebola vaccines 42 . It is being investigated for COVID-19 vaccines with the Oxford–AstraZeneca AZD1222 and Gamaleya Sputnik V COVID-19 vaccines 45 or with the Pfizer–BioNTech vaccine ( https://www.comcovstudy.org.uk ). Other HPB combinations might be considered involving mRNA, DNA, viral vector-based and protein-based vaccines. This may offer the potential benefit of improving the immune response and avoiding mutlidose reactogenicity or anti-vector immune responses. Additionally, people previously vaccinated with the standard regimen (for example, single or two dose) could be offered a booster immunization with a different vaccine. This might mitigate current shortages in vaccines, particularly in low- and middle-income countries (LMICs). Such a matrix of HPB possibilities deserves further consideration by manufacturers, funders and regulators supported by clinical trial studies and assessment of implementation challenges.

Important improvements could speed up availability. Standardized labeling of vaccines so that they can be interchanged across countries and regions, date of production rather than expiration so that shelf life can be tracked, three-dimensional bar coding to allow critical information to be updated, standard indemnification and liability language that would allow agreement with all manufacturers, a no-fault compensation mechanism for serious adverse events related to vaccine administration, and regulatory harmonization are all critical and being worked on as part of the COVID-19 vaccine response and must be optimized for future outbreaks.

The pathway to EUA, licensure and beyond

Big pharmaceutical or biotechnology companies supported by organizations such as CEPI or efforts such as Operation Warp Speed have conducted efficacy trials in countries or regions with the highest SARS-CoV-2 incidence rates. The same groups have also committed funding for large-scale manufacturing at risk. With more than 60 vaccine candidates in clinical trials and another 170 in preclinical development (WHO COVID-19 vaccine landscape) 46 , it is uncertain whether vaccine candidates not in the first wave of testing/approvals will be able to progress to EUA and licensure based solely on results of randomized clinical efficacy trials with clinical endpoints. Regulators and ethics committees may decide that noninferiority clinical trials against comparator vaccines with proven clinical efficacy will be needed for further approvals. Would the demonstration of equivalence between immune responses generated by a new vaccine and those of a clinically proven efficacious vaccine (bridging studies) 47 be accepted by regulatory authorities and replace the need for noninferiority clinical endpoint studies? For that to occur there must be agreement on what are immune correlates of protection (ICP) to COVID-19, and these have yet to be identified. Moreover, it is not yet clear that ICP will translate equally between different vaccine platforms; for example, are immune responses generated by chimpanzee adenovirus the same as those generated by proteins or whole inactivated virus? As incidence rates of a disease decrease over time due to sustained mitigation measures and implementation of vaccination, larger sample sizes in multicountry trials, additional participant accrual time and complex logistics will likely be required for future approvals, compromising the speed of clinical development and increasing cost. Early deployment of scarce doses of still-investigational vaccines (under emergency use listing (EUL) or similar regulatory mechanisms) could bring additional public health benefits if accompanied by firm commitment to maintaining blinded follow-up of participants in ongoing or future placebo-controlled trials until a licensed vaccine is fully deployed in the population 48 .

Randomized controlled trials might underestimate the protective effect of vaccines at the population level. This would occur if the COVID-19 vaccine, in addition to conferring direct protection to individuals, reduces transmission of COVID-19 between individuals, providing protection to unvaccinated individuals and enhanced protection of vaccinated individuals in contact with vaccinated individuals. Vaccine-induced herd protection, which might be crucial to the public health value of a vaccine, will be missed when trials are individually randomized and analyses fail to take account of the geographical distribution of individuals in the population 49 . For these reasons, other clinical trial designs have been proposed once COVID-19 vaccines have achieved licensure via current phase 3 trials to assess how useful the vaccines will be in practice and addressing vaccine effectiveness, including the level of protection of both vaccinated and nonvaccinated individuals in targeted populations 50 .

In the particular context of the COVID-19 pandemic, whether regulatory authorities would require clinical endpoints in future efficacy trials or would consider ICP remains unclear. Clinical endpoints provide increased accuracy with regard to definitive clinical outcomes where outcome-related analyses using ICP are inferential. ICP will contribute to our understanding of viral pathogenesis and immunity, be useful for future approval of vaccines, and help in our understanding of waning of protective immunity following vaccination or infection. The paradox is that the higher the efficacy, the more difficult it will be to identify these correlates because there may not be enough infected vaccine recipients to compare with uninfected vaccine recipients. The analysis of ICP may be possible only in clinical trials showing a lower vaccine efficacy 50 . They would also not provide a rigorous evaluation of long-term safety and the potential for vaccine-associated enhanced respiratory disease 51 .

Pharmacovigilance and surveillance

In May 2020, the 42nd Global Advisory Committee on Vaccine Safety addressed pharmacovigilance preparedness for the launch of the future COVID-19 vaccines 52 . One of their recommendations was that infrastructure and capacity for surveillance of the safety of COVID-19 vaccines should be in place in all countries and engaged before a vaccine is introduced. The WHO’s COVID-19 vaccine safety surveillance manual develops the monitoring and reporting of adverse events following immunization and adverse events of special interest, data management systems and safety communication, and the need for postauthorization safety surveillance studies 53 . One critical element of this surveillance is the duration of the observation period. The implementation of this surveillance will require local, national, regional and global collaboration. While countries should include preparedness plans for COVID-19 vaccine safety in their overall plans for vaccine introduction, building on WHO guidance, it is imperative that the COVID-19 Vaccines Global Access (COVAX) initiative (coordinated by CEPI, Gavi, the Vaccine Alliance, and WHO) works with partners on capacity building and the practical aspects of implementation with technical and training support tailored to the settings.

In view of the public health urgency and the extensive vaccination campaigns foreseen worldwide, the EMA and the national competent authorities in EU member states have prepared themselves for the expected high data volume by putting pharmacovigilance plans specific for COVID-19 vaccines in place. Good pharmacovigilance practices include detailed requirements and guidance on the principles of a risk management plan (RMP) and requirements for vaccines. In addition, core RMP requirements for COVID-19 vaccines have been developed to facilitate and harmonize the preparation of RMPs by companies and their evaluation by assessors. The RMP preparation addresses the planning of the postauthorization safety follow-up of COVID-19 vaccines by marketing authorization holders, while acknowledging uncertainties in the pandemic setting and recommending ways to prepare for pharmacovigilance activities 54 . Similarly, the US Advisory Committee on Immunization Practices (ACIP) initially convened the COVID-19 Vaccine Safety Technical Working Group in June 2020 to advise the ACIP COVID-19 Vaccine Workgroup and the full ACIP on the safety monitoring of COVID-19 vaccines under development and pharmacovigilance postapproval 55 .

Key lessons could be learnt from past situations where new vaccines were introduced in response to pandemic and epidemic emergencies. For the 2009 H1N1 influenza pandemic, few countries had a pandemic preparedness plan that comprehensively addressed vaccine deployment and monitoring of adverse events. The African Vaccine Regulatory Forum, a regional network of regulators and ethics committees, working closely with regulators from other parts of the world, participated in the review of clinical trial protocols and results, the joint monitoring of trials and the joint authorization and deployment of vaccines 56 . Such models can be used to guide pharmacovigilance for the deployment of COVID-19 vaccines, particularly in LMICs with limited resources. The introduction of the first licensed dengue vaccine, while not in the context of an international public health emergency, illustrated a number of lessons for the pharmacovigilance of newly introduced vaccines, particularly the vaccine-associated enhanced disease that was observed 13 , 14 . Due to the significant sequence homology between SARS-CoV-2 and SARS-CoV, antibody-dependent enhancement (ADE) and vaccine-associated enhanced respiratory disease (VAERD) were raised as potential safety issues 57 , 58 . VAERD and ADE have not been described in current reports of SARS-CoV-2 vaccine phase 3 trials. Similarly, VAERD has not been reported in animal challenge studies with SARS-CoV-2 vaccines that conferred protection 50 . With ADE the effect of waning antibody titers after vaccination (or after infection) and potential safety signals are unknown, which emphasizes the importance of follow-up monitoring 57 .

Pregnant women seem to be disproportionately affected during pandemics and emerging pathogen outbreaks 59 , 60 . The Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) Working Group has published a roadmap to guide the inclusion of the interests of pregnant women in the development and deployment of vaccines against emerging pathogens 61 , 62 .

Equally important is the surveillance on SARS-CoV-2 circulating strains as well as of other coronaviruses (MERS, seasonal) 63 . SARS-CoV-2 is evolving, with new lineages being reported all over the world. Amongst previous lineages, D614G was shown to have faster growth in vitro and enhanced transmission in small animals, and has subsequently become globally dominant 64 , 65 , 66 . Other variants of concern have been described in the UK (B.1.1.7) 67 and in Brazil (B.1.1.28.1/P1) 68 with higher capacity for transmission and, potentially, lethality. N501Y (B.1.351) isolated in South Africa has an increased affinity for the human ACE2 receptor, which together with the repeated and independent evolution of 501Y-containing lineages 69 strongly argues for enhanced transmissibility. The B.1.351 variant has nine spike alterations; it rapidly emerged in South Africa during the second half of 2020 and has shown resistance to neutralizing antibodies elicited by infection and vaccination with previously circulating lineages. The AstraZeneca COVID-19 vaccine rollout in South Africa was recently halted after the analysis showed minimal efficacy against mild and moderate cases due to B.1.351, which accounts for 90% of the cases in this country 70 . The Novavax vaccine efficacy is 86% against the variant identified in the UK and 60% against the variant identified in South Africa 71 . The efficacy of a single dose of Johnson & Johnson’s Ad26 was 57% against moderate to severe COVID-19 infection in South Africa 72 .

For the many people who have already been infected with SARS-CoV-2 globally and are presumed to have accumulated some level of immunity, new variants such as B.1.351 pose a significant reinfection risk, although vaccine-induced cell-mediated immune responses might mitigate this risk. Scientists do not know how variant lineages will evolve under vaccine-induced immune pressure during the vaccination rollout or whether choices that alter the schedule or dose may impact virus evolution. Whether vaccines efficacious against current circulating strains including the variants identified in the UK and Brazil will keep their efficacy against emerging variants is unknown and deserves enhanced global COVID-19 surveillance in both humans and animals, similar to those developed for influenza. Global influenza surveillance has been conducted through WHO’s Global Influenza Surveillance and Response System since 1952. The Global Influenza Surveillance and Response System is a global mechanism of surveillance, preparedness and response for seasonal, pandemic and zoonotic influenza, a global platform for monitoring influenza epidemiology and disease, and a global alert system for novel influenza viruses and other respiratory pathogens 73 . The Global Initiative on Sharing Avian Influenza Database ( https://www.gisaid.org ) promotes the rapid sharing of data from all influenza viruses and the coronavirus causing COVID-19. These include genetic sequence and related clinical and epidemiological data associated with human viruses, and geographical as well as species-specific data associated with avian and other animal viruses. This molecular epidemiology surveillance should be expanded to all EIDs, particularly the deadliest and most transmissible, as recently described for Ebola 25 . As with influenza, preparations for SARS-CoV-2 vaccine variants should be proactive, with a view that platforms such as mRNA could generate new vaccine strains very rapidly. A clear regulatory pathway for strain change needs discussion with the regulators.

Approval process for licensure and EUA and the risk of speed

Vaccines are classically approved by the country’s national regulatory authority such as the US FDA or by a centralized procedure through the EMA. Once approved for licensure by a stringent or functional national regulatory authority in the country of manufacture, the manufacturing company can submit a dossier for WHO prequalification. However, for SARS-CoV-2 vaccines intended for COVAX, WHO prequalification is not required for initial use if they have received WHO EUL. COVAX is one of three pillars of the Access to COVID-19 Tools Accelerator, which was launched in April 2020 by the WHO, the EC (European Commission) and France. Vaccines receiving WHO EUL can be purchased by UNICEF (United Nations International Children’s Emergency Fund), the largest purchaser of vaccines for Gavi, the Vaccine Alliance. Countries participating in COVAX can access the vaccines through the COVAX Facility either as 1 of the 98 self-financing countries or, for the 92 LMICs, funded through the Gavi COVAX advance market commitment (AMC; https://www.gavi.org ).

In the current pandemic situation, the US FDA is using the EUA process to allow initial use of the vaccines from Pfizer, Moderna and Johnson & Johnson 74 . EMA is taking the approach of conditional approval 75 . The WHO emergency use assessment and listing (EUAL) procedure was developed in the wake of the Ebola virus disease outbreak in Africa to expedite the availability of vaccines. The EUAL was intended as guidance for national regulatory authorities in circumstances when the “community may be more willing to tolerate less certainty about the efficacy and safety of products, given the morbidity and/or mortality of the disease and the shortfall of treatment and/or prevention options” 76 . In early 2020, the WHO issued a revised EUL procedure to assess whether submitted data demonstrate a reasonable likelihood that a vaccine’s quality, safety and performance are acceptable and that the benefits outweigh the foreseeable risks and uncertainties in the context of a public health emergency of international concern 77 . It is intended that vaccines approved through EUAL would eventually go to full review and receive prequalification. WHO member states have the prerogative through their national regulatory authority to use the EUL procedure to authorize the use of unlicensed vaccines.

Some countries have used their national regulatory authorities to secure approval of nationally produced vaccines. The Russian government approved the Ad26 and Ad5 combination-based COVID-19 vaccine, Sputnik V, produced by the Gamaleya Research Institute, for use by individuals aged 60 years and above 78 , 79 . China’s National Medical Products Agency has given conditional approval to the whole inactivated virus BBIBP-CorV COVID-19 vaccine developed by the Beijing Institute of Biological Products, a Sinopharm subsidiary 80 . The authorization allows the general public’s use of the inoculation and comes after the company announced that its vaccine proved 79.3% effective in phase 3 trials 81 . Although the interim results are not yet published, they must have been reviewed and approved by the Chinese Center for Disease Control and Prevention and National Medical Products Agency. The United Arab Emirates was first to approve the Sinopharm vaccine for EUA in early December 2020 based on interim analysis results 82 . The Sinovac CoronaVac vaccine was recently granted conditional approval on the basis of interim efficacy results 83 . The CanSinoBIO COVID-19 vaccine achieved 65.7% efficacy in preventing symptomatic cases in clinical trials (unpublished). The vaccine also showed a 90.98% success rate in stopping severe disease in one of its interim analysis. The vaccine was granted EUA in Mexico and Pakistan 84 .

Manufacturing—how to make more, faster

Production and distribution of hundreds of millions of doses of COVID-19 vaccine within a year of identification of the pandemic pathogen is unprecedented, and while the principles are straightforward, the manufacturing equation is complex and prone to delay. The technical platform utilized to make a vaccine (mRNA, whole inactivated virus, vector, protein with or without adjuvant), the dosage (low, mid, high), the schedule of vaccination (single or two dose) and the manufacturer capability, capacity and reputation are all important considerations for regulators and the WHO. The initial phase of manufacturing scale-up will be a key regulator of vaccine access initially. This could potentially be impacted by vaccine nationalism and the announced bilateral agreements between manufacturers and high-income countries. Companies such as Sinopharm, the Serum Institute of India or Bharat have a huge capacity for production but must supply the gigantic markets of China and India. Delays in the production of several western 85 and Chinese COVID-19 vaccines 86 have already been reported.

The Developing Countries Vaccine Manufacturers Network (DCVMN) was established in 2000 with the mission to increase the availability and affordability of quality vaccines to protect against known and emerging infectious diseases 87 . About 70% of the global EPI vaccine supplies and about 75% procured by UN (United Nations) agencies are produced by DCVMN members 88 . Several technology transfers to DCVMN members have occurred over the past decades to significantly contribute to global health. Following an initial collaboration on the oral cholera vaccine between Sweden and VABIOTECH in Vietnam, the International Vaccine Institute improved the vaccine and then transferred the technology back to VABIOTECH and to several DCVMN members, including Shantha Biotechnics (Shanchol), India; EuBiologics (Euvichol), Republic of Korea; and Incepta (Cholvax), Bangladesh. Shanchol, Euvichol and Euvichol Plus are WHO prequalified and the major contributors to the Gavi-supported global stockpile 16 while Cholvax is marketed in Bangladesh.

For COVID-19 vaccines, several companies have licensed or contracted vaccine production to other manufacturers—AstraZeneca and Novavax with the Serum Institute (India) and SK Bioscience (Korea); Moderna with Lonza (Switzerland), Johnson & Johnson with Biological E (India); and Chinese Sinovac with Butantan (Brazil) and BioFarma (Indonesia). Hopefully the license and contract manufacturing arrangements will allow the production of sufficient doses of vaccines to provide equitable access to at-risk populations globally 89 .

Under the pressures of the pandemic, and with the need for accelerated development of COVID-19 vaccines, optimization of more practical aspects of vaccine implementation, supply and dosing was secondary to the need for rapid proof of concept. COVID-19 mRNA vaccines and the VSV-EBO Ebola vaccine from Merck have a similar requirement for ultracold chain storage. While that might be overcome by relatively simple technology, the scalability of these technologies for universal vaccination is unknown. Additional development is needed to establish the stability of vaccines at higher temperatures (Pfizer mRNA). There is evidence to suggest the presence of some protection against COVID-19 after the first dose; this is critical information not only for COVID-19 but also to frame thinking around other EID vaccines.

Leave no one behind, or the unequal access to vaccines and treatments

The 2030 Agenda for Sustainable Development has the vision to leave no one behind, particularly low-income countries. COVID-19 has seen exceptionalism at either extreme. On the one hand, COVAX aims to provide at least 2 billion doses of WHO-approved vaccine to participating countries by the end of 2021—roughly 20% of each country’s vaccination needs. A total of 92 LMICs will receive vaccine largely through an AMC arranged by Gavi 90 . It now appears that the USA will join COVAX, which recently announced that it had secured agreements for sufficient doses to meet the 2021 target 50 .

Critically, vaccinating people in LMICs will require additional vaccine purchases, at a cost estimated in billions of dollars. In purely economic terms, it appears that such an investment could have substantial benefit for the global economy 91 . On the other hand, COVAX is on track to achieve its goals and poised to start delivering vaccines, and yet no AMC countries had yet been vaccinated when tens of millions of people were already being vaccinated in high-income countries. Among high-income countries, billions of doses have been preordered, several times more than justified by their populations. Can COVAX achieve its target of providing 2 billion doses by 2021, or will manufacturing bottlenecks lead to delay that will allow the coronavirus to continue to circulate in poorer countries and prolong the pandemic? If unable to access COVID-19 vaccines in a timely manner, the 2030 Agenda for Sustainable Development, especially Sustainable Development Goal 3 focusing on health, will be difficult to achieve, and low-income countries will be under extraordinary pressure as the COVID-19 pandemic forces them further into poverty and deeper inequality.

UN Secretary-General António Guterres has again stressed that COVID-19 vaccines must be a global public good, available to everyone, everywhere. “Vaccinationalism is self-defeating and would delay a global recovery” 92 . Modeling studies suggest that if high-income countries take the first 2 billion doses of available COVID-19 vaccines without regard to equity, global COVID-19 deaths will double 93 . Ensuring that all countries have rapid, fair and equitable access to COVID-19 vaccines is the promise of COVAX.

Final remarks

The lessons of the COVID-19 pandemic need to be compiled and applied to the development of future vaccines against emerging infectious diseases and novel pandemic pathogens. The permanent threat of emerging pathogens calls for vigilance, surveillance and preparedness for vaccine development and deployment, all crosscutting activities to be conducted flawlessly between epidemiologists, scientists, developers, human and veterinary health authorities, regulators and funders. Global health stakeholders have learned something about developing vaccines efficiently: they still have much to learn about making and using them with due regard to equity and access.

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Jean-Louis Excler & Jerome H. Kim

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J.-L.E., M.S., S.B. and J.H.K. equally contributed to the synopsis of the manuscript. J.-L.E. and J.H.K. wrote the text and tables of the manuscript. J.H.K. provided the figure. M.S. and S.B. edited the manuscript.

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J.-L.E. is a consultant for vaccine safety for the Brighton Collaboration, Johnson & Johnson and the US Military HIV Research Program. J.H.K. is a consultant to SK Bioscience. M.S. has a financial interest in Sanofi (shares). S.B. does not have any financial or nonfinancial conflicts of interest.

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Excler, JL., Saville, M., Berkley, S. et al. Vaccine development for emerging infectious diseases. Nat Med 27 , 591–600 (2021). https://doi.org/10.1038/s41591-021-01301-0

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eTable.  ICD-10 codes used to define severe cardiovascular events of interest

eReferences

• Surveillance for Adverse Events After COVID-19 mRNA Vaccination JAMA Original Investigation October 12, 2021 This study reports an interim analysis of safety surveillance data of 23 serious outcomes following vaccination with 1 of the mRNA COVID-19 vaccines based on comprehensive health records from a large US population. Nicola P. Klein, MD, PhD; Ned Lewis, MPH; Kristin Goddard, MPH; Bruce Fireman, MA; Ousseny Zerbo, PhD; Kayla E. Hanson, MPH; James G. Donahue, DVM, PhD; Elyse O. Kharbanda, MD, MPH; Allison Naleway, PhD; Jennifer Clark Nelson, PhD; Stan Xu, PhD; W. Katherine Yih, PhD, MPH; Jason M. Glanz, PhD; Joshua T. B. Williams, MD; Simon J. Hambidge, MD, PhD; Bruno J. Lewin, MD; Tom T. Shimabukuro, MD, MPH, MBA; Frank DeStefano, MD, MPH; Eric S. Weintraub, MPH
• Acute Myocardial Infarction and Ischemic Stroke After COVID-19 by Vaccination Status JAMA Research Letter September 6, 2022 This retrospective cohort study examines the incidence of acute myocardial infarction and ischemic stroke after COVID-19 infection among vaccinated vs unvaccinated adults in Korea. Young-Eun Kim, PhD; Kyungmin Huh, MD; Young-Joon Park, MD, MPH; Kyong Ran Peck, MD, PhD; Jaehun Jung, MD, PhD
• BA1 Bivalent COVID-19 Vaccine Use and Stroke in England JAMA Research Letter July 11, 2023 This study investigates the association between bivalent COVID-19 vaccines and ischemic stroke, as well as the effect of simultaneous influenza vaccination on the association. Nick Andrews, PhD; Julia Stowe, PhD; Elizabeth Miller, MBBS; Mary Ramsay, MBBS
• Patients With Acute Myocarditis Following mRNA COVID-19 Vaccination JAMA Cardiology Brief Report October 1, 2021 This study describes 4 patients who presented with acute myocarditis after mRNA COVID-19 vaccination. Han W. Kim, MD; Elizabeth R. Jenista, PhD; David C. Wendell, PhD; Clerio F. Azevedo, MD; Michael J. Campbell, MD; Stephen N. Darty, BS; Michele A. Parker, MS; Raymond J. Kim, MD

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While more than half the world's population has received at least one dose of a COVID-19 vaccine, it should be remembered that all-cause mortality has not been an outcome in COVID-19 vaccine trials.

Hence a reminder here that

1. Not reporting all-cause mortality is a limitation, especially when sudden death may be a complication of undiagnosed myocardial infarction, stroke, or pulmonary embolism

2. Any non-randomized controlled research has a major limitation of bias due to unmeasured and unknown confounders.

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Jabagi MJ , Botton J , Bertrand M, et al. Myocardial Infarction, Stroke, and Pulmonary Embolism After BNT162b2 mRNA COVID-19 Vaccine in People Aged 75 Years or Older. JAMA. 2022;327(1):80–82. doi:10.1001/jama.2021.21699

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Myocardial Infarction, Stroke, and Pulmonary Embolism After BNT162b2 mRNA COVID-19 Vaccine in People Aged 75 Years or Older

• 1 EPI-PHARE, French National Agency for Medicines and Health Products Safety, French National Health Insurance, Saint-Denis, France
• 2 School of Mathematics and Statistics, the Open University, Milton Keynes, United Kingdom
• Original Investigation Surveillance for Adverse Events After COVID-19 mRNA Vaccination Nicola P. Klein, MD, PhD; Ned Lewis, MPH; Kristin Goddard, MPH; Bruce Fireman, MA; Ousseny Zerbo, PhD; Kayla E. Hanson, MPH; James G. Donahue, DVM, PhD; Elyse O. Kharbanda, MD, MPH; Allison Naleway, PhD; Jennifer Clark Nelson, PhD; Stan Xu, PhD; W. Katherine Yih, PhD, MPH; Jason M. Glanz, PhD; Joshua T. B. Williams, MD; Simon J. Hambidge, MD, PhD; Bruno J. Lewin, MD; Tom T. Shimabukuro, MD, MPH, MBA; Frank DeStefano, MD, MPH; Eric S. Weintraub, MPH JAMA
• Research Letter Acute Myocardial Infarction and Ischemic Stroke After COVID-19 by Vaccination Status Young-Eun Kim, PhD; Kyungmin Huh, MD; Young-Joon Park, MD, MPH; Kyong Ran Peck, MD, PhD; Jaehun Jung, MD, PhD JAMA
• Research Letter BA1 Bivalent COVID-19 Vaccine Use and Stroke in England Nick Andrews, PhD; Julia Stowe, PhD; Elizabeth Miller, MBBS; Mary Ramsay, MBBS JAMA
• Brief Report Patients With Acute Myocarditis Following mRNA COVID-19 Vaccination Han W. Kim, MD; Elizabeth R. Jenista, PhD; David C. Wendell, PhD; Clerio F. Azevedo, MD; Michael J. Campbell, MD; Stephen N. Darty, BS; Michele A. Parker, MS; Raymond J. Kim, MD JAMA Cardiology

The BNT162b2 mRNA vaccine (Pfizer-BioNTech) was the first SARS-CoV-2 vaccine authorized and the most widely used in older persons in France. Although no increases in cardiovascular events were reported in phase 3 trials, 1 questions emerged once the vaccine was used on a large scale because older people were underrepresented in the trials. We evaluated the short-term risk of severe cardiovascular events among French people aged 75 years or older after the administration of the BNT162b2 mRNA vaccine.

This population-based study used the French National Health Data System linked to the national COVID-19 vaccination database. Eligible participants were all persons unvaccinated or vaccinated with the BNT162b2 vaccine, aged 75 years or older, admitted to the hospital between December 15, 2020, and April 30, 2021, for acute myocardial infarction, hemorrhagic stroke, ischemic stroke, or pulmonary embolism (diagnoses identified using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes) ( Table 1 and eTable in the Supplement ).

We undertook within-person comparisons using a self-controlled case-series method adapted to cardiovascular event–dependent exposures and high event-related mortality that can cancel or defer subsequent vaccination or increase short-term mortality 2 (eMethods in the Supplement ). Only exposures preceding the event were considered. Exposure risk intervals were days 1 through 14 following each of the 2 vaccine doses. The exposure risk interval was further subdivided into days 1 through 7 and days 8 through 14. Except for the vaccination day, the remaining periods were regarded as nonrisk periods. Unvaccinated persons were included to account for temporal effects. Unbiased estimating equations were used to calculate the relative incidence (RI) adjusted for temporality (in 7-day increments) to consider any changes in background rates of both events and vaccination. All analyses were performed using the SCCS package in R, version 3.6.1. A 95% CI around the RI that did not include 1 defined statistical significance.

The research group has permanent regulatory access to the data from the French National Health Data System (French decree No. 2016-1871 of December 26, 2016, on the processing of personal data called National Health Data System and French law). No informed consent was required because data are anonymized.

As of April 30, 2021, nearly 3.9 million persons aged 75 years or older had received at least 1 dose of the BNT162b2 vaccine and 3.2 million had received 2 doses. Over the observation period, 11 113 persons aged 75 years or older were hospitalized for an acute myocardial infarction, 17 014 for an ischemic stroke, 4804 for a hemorrhagic stroke, and 7221 for pulmonary embolism, of whom 58.6%, 54.0%, 42.7%, and 55.3%, respectively, received at least 1 dose of the vaccine ( Table 1 ). In the 14 days following either dose, no significant increased risk was found for any outcome: the RI for myocardial infarction for the first dose was 0.97 (95% CI, 0.88-1.06) and for the second dose, 1.04 (95% CI, 0.93-1.16); for ischemic stroke for the first dose, 0.90 (95% CI, 0.84-0.98) and for the second dose, 0.92 (95% CI, 0.84-1.02); for hemorrhagic stroke for the first dose, 0.90 (95% CI, 0.78-1.04) and for the second dose, 0.97 (95% CI, 0.81-1.15); and for pulmonary embolism for the first dose, 0.85 (95% CI, 0.75-0.96) and for the second dose, 1.10 (95% CI, 0.95-1.26) ( Table 2 ). No significant increase for any of the cardiovascular events was observed in the 2 subdivided exposure intervals (days 1-7 and days 8-14) ( Table 2 ).

In this nationwide study involving persons aged 75 years or older in France, no increase in the incidence of acute myocardial infarction, stroke, and pulmonary embolism was detected 14 days following each BNT162b2 mRNA vaccine dose.

Israeli and US studies reported that persons receiving the BNT162b2 vaccine were not at increased risk of myocardial infarction, pulmonary embolism, or cerebrovascular events in the 42 days 3 and 21 days 4 following vaccination. Based on a self-controlled case-series design that compensates for the lack of randomization by eliminating the effect of time-invariant confounding factors, this study provides further evidence regarding the risk of serious cardiovascular adverse events in older people. Limitations of the study include the possibility of residual time-dependent confounding.

Further investigations are needed to measure these risks in younger populations and for other types of vaccines against SARS-CoV-2.

Corresponding Author: Marie Joelle Jabagi, PharmD, PhD, EPI-PHARE, 143-147 Boulevard Anatole France, F-93285 Saint-Denis CEDEX, France ( [email protected] ).

Accepted for Publication: November 15, 2021.

Published Online: November 22, 2021. doi:10.1001/jama.2021.21699

Author Contributions: Dr Jabagi and Ms Bertrand 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: All authors.

Acquisition, analysis, or interpretation of data: Jabagi, Botton, Bertrand, Weill, Zureik, Dray-Spira.

Drafting of the manuscript: Jabagi, Bertrand, Zureik.

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

Statistical analysis: Jabagi, Botton, Bertrand, Farrington.

Supervision: Botton, Weill, Zureik, Dray-Spira.

Conflict of Interest Disclosures: None reported.

Additional Contributions: Stephane Le Vu, PharmD, PhD, and Kim Bouillon, MD, PhD, EPI-PHARE, reviewed the manuscript without compensation. Bérangère Baricault, MSc, and Jerome Drouin, MSc, EPI-PHARE, provided unpaid technical support related to data management.

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