research paper covid 19 vaccine

• 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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El Sahly HM, Baden LR, Essink B, Doblecki-Lewis S, Martin JM, Anderson EJ, Campbell TB, Clark J, Jackson LA, Fichtenbaum CJ, et al. Efficacy of the mRNA-1273 SARS-CoV-2 vaccine at completion of blinded phase. N Engl J Med. 2021. https://doi.org/10.1056/NEJMoa2113017 .

Tanriover MD, Doğanay HL, Akova M, Güner HR, Azap A, Akhan S, Köse Ş, Erdinç F, Akalın EH, Tabak ÖF, et al. Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey. Lancet. 2021;398(10296):213–22. https://doi.org/10.1016/s0140-6736(21)01429-x .

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Burgos-Salcedo J. A rational strategy to support approved COVID-19 vaccines prioritization. Hum Vaccin Immunother. 2021;17(10):3474–7. https://doi.org/10.1080/21645515.2021.1922060 .

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Acknowledgements

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

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Qiao Liu and Chenyuan Qin are joint first authors

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

Qiao Liu, Chenyuan Qin, Min Liu & Jue Liu

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

Chenyuan Qin & Jue Liu

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

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Correspondence to Min Liu or Jue Liu .

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Supplementary Information

Additional file 1: table s1..

Characteristic of studies included for vaccine effectiveness.

Additional file 2: Table S2.

Characteristic of studies included for vaccine safety.

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

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COVID-19: New Research Shows How the Virus Enters Our Cells and May Lead to Better Vaccines

A study has captured new views of the intricate molecular dance between our cells and the COVID-19-causing virus, SARS-CoV-2—findings that could inform the development of more effective vaccines as additional variants emerge.

Published August 15 in the journal Science , the study reveals how SARS-CoV-2 uses its spike protein, pointy molecules that stud the virus’s outer surface, to grab on to and drag itself to touch the surface of human cells and eventually deliver its viral genomes into cells. The study was carried out by researchers at Yale School of Medicine (YSM), Northeastern University, and Rice University.

This is the first time we’ve seen the structure of the intermediate stages of the spike during fusion. We found that this region is even more dynamic than what we thought before. Wenwei Li, PhD

The virus’s attachment to cells via its spike protein is the first key step for the virus to fuse with and infect the cells. Current COVID-19 vaccines work by blocking the virus from attaching to cells; the new study shows details of how certain human antibodies can block the next step, virus-to-cell fusion. This is important, because as effective as the vaccines have been for millions of people, they could come up short against future SARS-CoV-2 variants due to the virus’s rapid mutation.

“Understanding how these antibodies work to block the fusion machine can help us understand how to better design immunogens [for better vaccines],” said Michael Grunst, the first author on the study and a doctoral student working in the lab of Walther Mothes, PhD , Paul B. Beeson Professor of Medicine at YSM.

A two-part viral spike

The viral spike protein is made of two parts: one that binds the human protein ACE2, which sits on the surface of many kinds of human cells and is the virus’s portal for infection, and another part that changes its shape to move the virus closer to the human cell once it is attached. Bringing the virus and cell very close together is necessary for infection, as the membranes of the virus and the cell need to fuse for the virus to enter the cell.

COVID-19 vaccines now on the market were designed to include the ACE2-binding portion of the spike protein, which is prone to pick up mutations as the virus evolves. Even with yearly updates to the vaccine, COVID vaccine designers won’t be able to keep up with mutations that have occurred in this part of the protein. But a different potential target of opportunity — the shape-changing part of the protein — is very unlikely to mutate, because its structure is so critical for narrowing the gap between virus and cell.

A video shows a SARS-CoV-2 spike protein refolding in the presence of an antibody

The stable structure in that area suggests that future vaccines that target it might be universally effective against more dangerous SARS-CoV2 variants, and could even work against other coronaviruses, such as the viruses that cause Middle East Respiratory Syndrome (MERS) or the original Severe Acute Respiratory Syndrome (SARS), said Mothes. Antibodies against this region are effective against a wide variety of SARS-CoV-2 variants, including so-called variants of concern, which are newly evolved variants that may be more infectious or more transmissible than the original virus.

To simulate binding between the proteins that is close to real-life conditions, the Yale scientists used virus-like particles coated with either the spike protein or ACE2. They imaged the interaction between the two proteins using a microscopy technique known as cryogenic electron tomography, or cryo-ET, which captures detailed 3D structures of molecules. Their collaborators at Northeastern and Rice then used the imaging data gathered by the Yale team to build computational simulations of the entire process.

The cutting-edge imaging technique combined with the computer models allowed the team to take images of the spike-ACE2 interaction and the following fusion intermediates that had not been seen before with that level of detail. For example, they were able to see new details of the spike protein’s dramatic shape change—it looks somewhat like a jackknife folding shut, as Grunst described it.

“This is the first time we’ve seen the structure of the intermediate stages of the spike during fusion,” said Wenwei Li, PhD , associate research scientist in the Mothes Laboratory, who led the study along with Mothes and Paul Whitford , PhD, associate professor of physics at Northeastern. “We found that this region is even more dynamic than what we thought before.”

Imaging to inform vaccine design

They also captured images of the two proteins together with antibodies that bind to the shape-changing region of the spike protein. With the computer simulations, the team was able to show that the antibody blocks the spike protein from folding in on itself, preventing it from pulling the virus and cell membranes close enough to fuse.

They also found that antibodies bind to a transient folded form of the spike protein, perhaps explaining why these antibodies are naturally relatively rare—our immune systems only have a short window of time of exposure to this particular shape of the protein. The details about the shapes the spike protein undergoes as it folds could help vaccine developers pick the ideal part of the virus to stimulate the production of more of these antibodies, Mothes said.

“COVID variants can escape our immune systems and vaccines by mutating, but these fusion machines have only one pattern of how to do their job,” he said. “It’s a hardwired, conserved machine; you can’t change them. So this is why understanding more about how that mechanism works means we can learn more about their vulnerability, to [use vaccines to] block this process with antibodies.”

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Better safety studies could restore America’s confidence in vaccines

By Gregory A. Poland Aug. 14, 2024

I n February 2021, I received my second Covid-19 shot — the newly developed vaccine that would eventually save millions of lives worldwide — with great anticipation. It proved to be a life-changing event: Two hours later as I was driving home, the shock of a sudden loud and high-pitched whistling nearly caused me to veer off the road. It was as if an audible dog whistle began blaring right next to me. But it wasn’t a dog whistle. It was the acute onset of tinnitus , a ringing in the ear with no external source.

For several years I had lived with minimal, intermittent tinnitus, but never anything like this, so loud and unrelenting.

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Could the Covid-19 vaccine have amplified my tinnitus, or was this just a coincidence? I was suspicious, but at that time no data had demonstrated any relationship between the mRNA Covid-19 vaccines and tinnitus.

When I got my third dose in November 2021, the sound became even louder and more bothersome. This new noise level has continued to this day, nonstop, often keeping me from sleep and sometimes bringing me to tears.

Related: Covid-19 vaccine safety and the public trust: lessons from Paul Meier and polio

As someone who has studied vaccines for 40 years, I know that the mRNA Covid-19 vaccines, and other vaccines, have saved millions upon millions of lives. For the vast majority of people, the benefits of getting vaccinated far exceed the risks.

But some people, like me, have unexpected effects from vaccines that affect our health and well-being. I say “some” because no one really knows how often vaccine-related injuries occur. Understanding that would be a first step toward reducing these rare risks even further. Are such adverse events predictable, and can they be prevented by identifying risk factors for the onset of a vaccine injury? I believe the answer is yes, but it won’t be achievable without increased funding for vaccine safety research.

Americans’ trust in vaccines has been slowly eroding. It accelerated with the advent of the World Wide Web in the 1990s and has been declining ever since. The Covid-19 outbreak temporarily obscured the problem, as many expressed the desire for a vaccine against this plague and millions got it once it became available.

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Covid-19 also obscured the problem another way: lockdowns and sheltering in place reduced people’s normal activities and movements, and with it the spread of all viruses, not just SARS-CoV-2. But as people once again gathered and shopped and worshipped together, as well as traveled from country to country, measles — one of the most infectious viruses — has returned. In the first three months of 2024, the United States has had 17 times more measles cases than during the same time period for the past three years. The United States is now on the verge of losing its status as a nation in which measles has been eliminated.

Increasing vaccine hesitancy and rejection has contributed to ongoing outbreaks of measles in the U.S. Last year, the number of parents in the U.S. seeking exemptions to vaccinate their children increased in 41 states , and similar trends are being seen with the flu, pneumonia, and HPV vaccines.

Although the Covid-19 vaccines were a huge public health success, politicization and opposition to them became weaponized through disinformation for political gain. Whether or not to receive a Covid-19 vaccine became an expression of opinion, rather than an informed health decision, and this has had a trickle-down effect to other vaccines.

A renewed and well-funded focus on the study of vaccine safety is among the critical measures needed to stop the return of vaccine-preventable infectious diseases like measles and to reverse the loss of public confidence in vaccines. While the system to evaluate vaccine safety is extensive, it must be strengthened. Researchers and public health experts need to know which events are caused by vaccines, who is at increased risk for them, and why. With that information in hand they can move forward to reduce such risk.

Related: Empathy should be the first response to people with vaccine injury, fears

To be sure, systems are in place for vaccine safety monitoring. The national Vaccine Adverse Event Reporting System (VAERS) collects reports of possible side effects after vaccinations. It’s an important tool for spotting potential safety issues, but it has limitations. VAERS mainly captures problems that are obvious, lead to doctor visits, or show up on medical tests. This means it might not catch all types of side effects, especially those that are less visible or don’t prompt immediate medical attention.

Large and ongoing studies using real-world data are also needed to fully understand vaccine safety. Once vaccine-related injuries have been identified, federal entities overseeing vaccine safety must take them seriously and investigate thoroughly, publishing the method and data used.

Myocarditis following mRNA Covid-19 vaccination is an example of a rare vaccine adverse reaction that can be detected only after the vaccine has been administered to millions of people — it would almost never show up in clinical trials testing the vaccine. Once a rare adverse reaction is discovered, understanding its biological mechanism is necessary to prevent it. This hasn’t yet been done for vaccine-induced myocarditis, which will require a significant scientific investment.

Compensating people who have been injured by vaccines is another dimension of the issue. The National Vaccine Injury Compensation Program has been in place since the 1980s. Through it, individuals who file a petition and are found to have been injured by a covered vaccine can receive financial compensation.

Vaccine injury reporting and compensation have worked adequately for routine vaccines. For vaccines provided under emergency use authorization, however, such as vaccines against H1N1 in 2009 and now Covid-19, safety science and compensation programs have been chronically underfunded. While the Centers for Disease Control and Prevention has an annual vaccine budget of up to $5 billion to purchase and promote vaccines, the study of vaccine safety at the CDC has been limited to $20 million per year since the time when Dr. Louis Cooper, former president of the American Academy of Pediatrics, warned of the vaccine confidence crisis more than 20 years ago. Since then, many new vaccines have been developed, including some intended for children, pregnant people, and older Americans, who can require different preparations and protocols.

Related: How will people act after getting vaccinated? The complex psychology of safety

While federal budgets are under intense scrutiny, there is a budget-neutral solution for vaccine safety science. The law that created the National Vaccine Injury Compensation Program provided liability protection to pharmaceutical companies and no-fault compensation to people who are injured by a vaccine. The law also focused on vaccine safety monitoring and the prevention of adverse reactions. Funding was created from a separate tax law by adding a 75-cent excise tax to childhood vaccines for any disease the vaccine was intended to prevent. This law, however, allowed the excise tax money to be used only for compensation. Vaccine safety science and prevention of vaccine injuries, as intended by the initial law, were not allowed.

As recently published in The New England Journal of Medicine , the compensation program currently has an excess of more than $4 billion. Congress should amend this tax law to allow these revenues — a budget-neutral approach — to fund vaccine safety science and prevent rare vaccine injuries.

Americans’ confidence in vaccines will improve only if the vaccine safety system is trusted, transparent, and credible. The independent National Academies of Sciences, Engineering, and Medicine should be asked to review the current vaccine safety system and develop an optimal structure and governance for an adequately funded vaccine safety and compensation system.

Because of the difficulty of eradicating infectious diseases, vaccines will always be needed. The United States needs a robust, sustainable, and well-funded vaccine safety system to help overcome the crisis in vaccine confidence. For too many Americans, confidence in vaccines is truly a matter of life and death.

Gregory A. Poland, M.D., is a virologist who studies the immunogenetics of vaccine responses in adults and children, the editor of the academic journal Vaccine , and president of the Atria Academy of Science and Medicine . He reports being chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories, has been a consultant for various vaccine and pharmaceutical companies, and is an adviser to the White House on Covid-19 vaccines and the World Health Organization on mpox.

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The rapid progress in COVID vaccine development and implementation

• Alan D. T. Barrett   ORCID: orcid.org/0000-0003-3740-7448 1 ,
• Richard W. Titball   ORCID: orcid.org/0000-0002-0162-2077 2 ,
• Paul A. MacAry   ORCID: orcid.org/0000-0002-1139-8996 3 ,
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npj Vaccines volume  7 , Article number:  20 ( 2022 ) Cite this article

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January 2022 is the second anniversary of the identification of Coronavirus disease 2019 (COVID-19) 1 caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2). Scientifically, during the COVID pandemic, we have come a very long way in a very short period of time and demonstrated the power of twenty-first century science and technology when a pandemic situation catalyzed the adoption of novel vaccine technologies at record speed. Rapid sequencing of the virus genome allowed initial development to start in January 2020 2 and we had our first authorized vaccines by December 2020 3 .

NPJ Vaccines has published over 65 papers on SARS-CoV-2 that cover the entire breadth of vaccinology from basic science to attitudes of the public to COVID vaccines. With this in mind, the editors of NPJ Vaccines have selected 17 articles that exemplify the rapid progress made with COVID vaccine development in the last 2 years.

Our first COVID paper described the outbreak of SARS-CoV-2 pneumonia in China with the first confirmed cases on December 29, 2019, and the urgent need for vaccines 4 . The scientific and medical community quickly realized that a vaccine would be essential for controlling the disease. Work started on developing inactivated, live attenuated, nucleic acid, subunit and vectored vaccines, and the various potential technologies and their advantages and drawbacks were summarized briefly in a Comment 4 . As laboratories around the world shifted to studying the virus, its biology and interactions with the immune system were also clarified.

SARS-CoV-2 is typical of many RNA viruses being enveloped with a major surface glycoprotein (in this case the Spike (S) protein) that is involved in binding to the cell receptor of the virus, angiotensin-converting enzyme 2 (ACE2), and is the major target for neutralizing antibodies. In particular, the receptor binding domain (RBD) of the S-protein is the target of the most potent neutralizing antibodies 5 . Importantly, immunization can achieve higher levels of antibody to the S-protein than natural exposure to the virus 6 . However, like many RNA viruses SARS-CoV-2 has a low-fidelity replication complex that allows the viral genome to mutate rapidly as it adapts to new conditions. Many SARS-CoV-2 laboratory isolates have been made in monkey kidney Vero cells. A very important study by Funnell et al. (2021) 7 showed that Vero cell culture passaging of isolates must be undertaken carefully, as this can lead to the generation of virus variants with critical changes in the region of the S-protein furin cleavage site, affecting the use of such viruses in in vitro neutralization tests and in vivo challenge studies. Similarly, there are a number of different neutralization assays used to measure neutralizing antibodies and there is a need to standardize such assays using the World Health Organization standard that measures neutralization titers in International Units 8 . Mutations in the S-protein have proved to be particularly important for vaccine development, as they can result in changes in the interaction of the protein with both ACE2 and antibodies. The first major mutation identified in the S-protein was the D614G substitution, which became the dominant variant by June 2020. A range of studies reported in NPJ Vaccines have shown that antibodies to the Wuhan spike protein are able to neutralize a range of variants, including the Omicron variant, albeit with reduced potency towards some variants 9 , which is mostly due to mutations in the RBD of variants 5 . The reduced neutralizing activity of antibodies towards variants can, to some extent, be addressed using a third immunizing dose 10 .

Although vaccines depend on the native S-protein for inducing potent neutralizing antibody responses alongside T-cell responses, the presentation of the S-protein to the immune system differs substantially between the different vaccine platform technologies 11 . It is clear that differences in the presentation of the S-protein to the immune system can have a profound effect on the nature of the immune response 11 . This is elegantly illustrated in a study on the immune responses to a human adenovirus 26-vectored vaccine encoding modified forms of the S-protein 12 . A wide range of other approaches have been proposed, including using the anti-tuberculosis vaccine Bacille Calmette-Guérin (BCG), which has inherent immunostimulatory properties 13 . This might provide ways of re-programming the innate response to achieve single-dose protective immunity and could be of great value in both high- and low-income countries.

One of the intriguing features of the immune response induced by many coronavirus infections is the lack of a long-lived protective immune response, in particular the waning antibody responses. Bachmann et al. (2021) 14 suggest this is due, in part, to the topography of SARS-CoV-2 virus, where S-protein is perpendicular to the surface of virions and embedded in a fluid membrane, such that neutralizing epitopes are loosely “floating.” Another feature of the S-protein is the N-linked glycosylation sites, which can mask epitopes. In the case of SARS-CoV-2, it was found that glycans masked epitopes on the S2 subunit domain of the S-protein, but not the S1 subunit domain, which includes the RBD 15 . These findings highlight the importance of understanding the basic biology of the virus to enable the development of effective vaccines.

Meanwhile vaccine development continued apace, and by February 2021 Kyriakidis et al. (2021) 16 described 64 candidate vaccines, developed using different technologies (mRNA, replication-defective viral vector, virus-like particle, inactivated virus and protein subunit), as they entered phase III clinical trials. By May 2021 McDonald et al. (2021) 17 were able to compile a systematic review and meta-analysis that compared reactogenicity, immunogenicity, and efficacy of 18 candidate vaccines based on studies in non-human primates and humans. Not surprisingly, the different vaccines varied in their abilities to induce antibodies (including neutralizing antibodies), T-cell responses, and their reactogenicity and efficacy.

Following the authorization or licensing of a vaccine, implementation becomes the critical issue, especially with respect to vaccine hesitancy. Kreps et al. (2021) 18 investigated attitudes of the general public towards COVID-19 vaccination and identified that the public were confused in their understanding of the differences between “Emergency Use Authorization” and conventional “licensure.” The findings of studies such as this one have implications regarding public health strategies for implementation of many vaccines, not only COVID, to increase levels of vaccination in the general public. Another concern of the public is around the safety and efficacy of vaccines in special populations. For example, Low et al. (2021) 19 undertook an important study that demonstrated codominant IgG and IgA expression with minimal vaccine mRNA in milk of lactating women, who received the Pfizer-BioNTech BNT162b2 and no adverse events in infants who breastfed from these vaccinees.

Finally, the COVID pandemic has identified the need for pandemic preparedness in the future for other pathogens and Monrad et al. (2021) 20 discuss the important issues of how we could finance such activities moving forward.

We hope that you will find these papers interesting and informative, they are representative of the work we have published in NPJ Vaccines . We encourage you to look at these other equally interesting reports, which collectively provide an incomparable breadth of information and a resource for everyone interested in this field.

Li, Q. et al. Early transmission dynamics in Wuhan, China, of novel coronavirus–infected pneumonia. New Engl. J. Med. 382 , 1199–1207 (2020).

Article   CAS   Google Scholar  

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Medicines and Healthcare products Regulatory Agency. Regulatory approval of Pfizer/BioNTech vaccine for COVID-19. https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19 (Medicines and Healthcare products Regulatory Agency, 2020).

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Richard W. Titball

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Barrett, A.D.T., Titball, R.W., MacAry, P.A. et al. The rapid progress in COVID vaccine development and implementation. npj Vaccines 7 , 20 (2022). https://doi.org/10.1038/s41541-022-00442-8

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Study: COVID vaccines saved 1.6 million lives in Europe

Simen Stromme / iStock

New estimates published in The Lancet Respiratory Medicine show that at least 1.6 million European lives have been directly saved by COVID-19 vaccinations, with 60% of those lives saved when Omicron became the dominant strain of the virus—and those numbers may be an undercount.  

As of March 2023, 2.2 million COVID-19–related deaths have been reported across Europe.  

The data come from The World Health Organization European Respiratory Surveillance Network, which analyzed vaccination efforts from December 2020 to March 2023, a period that encompasses both initial vaccine rollouts in the European region and booster doses. A total of 34 of 54 countries in the region were included in the study.

In the 34 countries, total vaccine overage in all adults aged 25 years or older was 87% for the primary vaccine series, 82% for the second dose, 71% for the first booster, 24% for the second booster, and 5% for the third booster by March of 2023.

The study looked at deaths divided by age-groups (25 to 49 years, 50 to 59, 60 and older, 60 to 69, 70 to 79, and 80 and older). Countries that reported weekly data for both COVID-19 vaccination and mortality by age-group for 90% or more of study weeks or more were included.

First booster dose saved most lives

Each week was also associated with a variant of concern (VOC), which accounted for 50% or more sequences per week.

In 29 countries there were 1,064,165 COVID-19–related deaths in people aged 25 years or older; of these deaths, 454,131 (43%) were in people aged 80 years or older, the authors said. By contrast, 40,788 (4%) and 19,831 (2%) of COVID-19–related deaths were in people aged 50 to 59 years and 25 to 49 years, respectively.

Most reported deaths were during the Omicron period.

"When considering each VOC mortality per variant month (PVM), regardless of age, most reported deaths were during the Omicron period (390,358 deaths); however, the Delta period had the highest number of reported deaths PVM (33,234 deaths)," the authors said.  

Overall, those aged 60 years or older accounted for 96% of the total lives saved; whereas, people aged 80 years or older represented 52% of the total lives saved.

In temporal analysis, the first booster saved the most lives (51% of all lives saved) aligning with 60% of lives saved during the Omicron period. The administration of the first booster doses started around week 30 of 2021 in Europe.

In an editorial on the study, Oliver Watson, PhD, and Alexandra Hogan, PhD, of Imperial College London, write that the number of lives saved as reported by the authors is probably an underestimation.  

"This study does not consider the additional herd effects of COVID-19 vaccination, whereby the population-level reduction in transmission indirectly reduces exposures, and therefore deaths, in the unvaccinated population," they write.  

"Second, the estimate of averted deaths is based on the reported COVID-19 mortality by each country, which is known to underestimate the true burden of COVID-19."

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School of Economics

How a bristol economist helped covax get the world back on track from the pandemic.

Vaccine allocation method designed for COVID-19.

13 August 2024

A new study from the School of Economics’ Battal Doğan details the vaccine allocation method he designed for the COVID-19 vaccine initiative, COVAX, in 2022.

The method ensured COVAX fairly distributed 250 million units of COVID-19 vaccines across 150+ countries – and despite political restrictions on who received them.  

Cast your mind back to January 2022. We were amidst a record-breaking global surge in COVID-19 cases, fuelled by the highly contagious Omicron variant.  

At this point in the pandemic, mass vaccination shielded many wealthier countries from the disease’s worst effects – driving down death rates and re-energising economies. But low- and middle-income countries still struggled. The previous year, G20 nations had claimed over 80% of the world’s vaccines for themselves.  

This imbalance denied poorer countries the protection and newfound freedoms enjoyed by wealthier nations. It further threatened to prolong the pandemic globally. As widely quoted at the time: “No-one is safe, until everyone is safe.”  

Dr Battal Doğan , Associate Professor in Economics at the University of Bristol, has now published the vaccine allocation method he designed in 2022 to narrow this gap and help the world find its way out of the pandemic ( view the method here ).  

Overcoming earmarks on COVID-19 vaccines  

Doğan designed the method for COVAX – the global initiative that aimed to provide vaccines regardless of a country's wealth.   

In early 2022, COVAX faced a growing problem. Around 60% of its doses had been donated by wealthy countries with (often politically motivated) restrictions on which other countries could receive them.  

These earmarks hindered COVAX's ability to distribute vaccines based on need. They also violated its ‘no dose left idle’ principle, which demanded minimal waste of the vaccines.   

It was in January 2022 that Madhav Raghavan, an economist and technical officer on the COVAX allocation team, contacted Doğan with a plea. He needed help designing a new method for allocating vaccines.  

Raghavan worked for GAVI, the Vaccine Alliance, who co-led COVAX with the World Health Organization (WHO), the Coalition for Epidemic Preparedness Innovations (CEPI) and UNICEF.  

The standard method for allocating vaccines, serial priority (SP), was ineffective under earmarking. Doğan’s expertise in market design positioned him as an ideal candidate to co-create a new method. Doğan's previous work on resource allocation explored the theoretical basis for deciding ‘who gets what’, and tackled thorny problems, including school admissions.  

Re-distributing vaccines  

Together with Raghavan, Doğan created the SPIP (serial priority improvement pathways) mechanism. This provides precise, systematic tools for sharing out vaccines in the face of restrictions.   

SPIP builds on the standard SP method. SP ranks countries by their current vaccine coverage and prioritises countries with the lowest coverage for doses. With earmarks, however, countries further down the list could get more than they need and leave more vulnerable countries short.  

Doğan introduced improvement pathways (IP) to manage earmarks. IP allowed COVAX to transfer excess vaccines from earmarked recipients to countries in greater need.   

Doğan and Raghavan made sure that SPIP would allocate vaccines fairly, with high-priority countries getting what they need, and it would minimise waste. Doğan calculates that, if 40-60% of doses are earmarked, 8% more are distributed under SPIP, compared with SP alone.  

SPIP in action  

The first version of SPIP was ready within just a few weeks of Raghavan’s initial call to Doğan. And two months later, COVAX put it into action.  

Between March and June 2022, COVAX allocated over 250 million units of vaccines across 150+ countries. Each unit contained multiple doses. Although levels of earmarking turned out to be lower than first feared, SPIP's flexibility allowed COVAX to manage these restrictions effectively.   

SPIP ultimately strengthened COVAX’s efforts to close the vaccine gap and bring the pandemic under control.    

For Doğan, the project brought dual rewards: “I enjoyed the intellectual parts of designing SPIP a lot, the theoretical side of things. But I was also very happy that we provided a practical solution to an important real-life problem and helped save lives.   

“In the field of market design, we care a lot about practical impact. It’s a subject that can really change the world.”   

Further information

Explore the SPIP method in full in the Working Paper : Equitable Allocation of Vaccines in a Supply Network: Application to COVAX.

Article written by Michelle Kilfoyle.

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• COVID-19 in babies and children

Anyone can get COVID-19 , also called coronavirus disease 2019, including children. Find out about the symptoms, testing and medical issues linked to COVID-19 in children. And learn how to help prevent COVID-19, especially in children at high risk of serious illness.

How likely is it for a child to become sick with coronavirus disease 2019 (COVID-19)?

Data tracking between 2020 and 2023 found that children made up about 18% of all people with reported COVID-19 in the United States.

While children are as likely as adults to catch the virus that causes COVID-19, kids are less likely to become seriously ill. From 2020 to the end of March 2024, children up to age 17 accounted for about 1.5% of people who needed to be treated for COVID-19 in the hospital.

But some children with COVID-19 need to be hospitalized, treated in the intensive care unit or placed on a machine to help them breathe, called a ventilator. Very rarely, COVID-19 can cause death.

Some health issues might raise a child's risk of serious illness with COVID-19, such as:

• Having more than one chronic disease, including those of the heart, lung or nervous system.
• Not being up to date with COVID-19 vaccination.
• Having a weakened immune system.
• Being born before the due date, called prematurity.
• Having obesity.
• Having type 1 or type 2 diabetes.

This is not a complete list. Other health issues, such as sickle cell disease, may be linked to more-serious COVID-19.

Having more than one risk factor raises the chance of serious COVID-19. Age younger than 1 year or older than 12 also raises the risk. And if a medical condition isn't under control, that can raise the risk of serious COVID-19.

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

How are babies affected by COVID-19?

Babies under age 1 might be at higher risk of serious illness with COVID-19 than are older children. This may be mostly due to the fact that babies born prematurely have the highest risk.

In general, the virus that causes COVID-19 doesn't spread from the pregnant person to the unborn baby. Infants typically get COVID-19 from a sick caregiver after delivery.

Pregnant people can help lower an infant's risk by getting the COVID-19 vaccine during pregnancy. Some evidence suggests protection can pass to the unborn baby and continue after birth.

What are the symptoms of COVID-19 in children?

Children with COVID-19 may have serious or mild symptoms or no symptoms at all. Symptoms may show up from 2 to 14 days after contact with the virus that causes COVID-19.

The most common symptoms are fever and a cough, including a barking cough linked to croup. For many children, symptoms are like those of other lung and breathing illnesses, called respiratory illnesses, and may include:

• Sore throat.
• Stuffy or runny nose.
• Feeling very tired, called fatigue.
• Nausea, vomiting or loose stools, called diarrhea.
• Muscle aches and pain.

Testing can help figure out if the virus that causes COVID-19 is the cause.

COVID-19 symptoms also may include problems breathing or shortness of breath, as well as new loss of taste or smell.

Breathing trouble

Get emergency help right away if your child is working hard to breathe. Symptoms of breathing trouble include grunting, flaring the nostrils, or having the chest pull at the collarbone and rib with a breath. Other symptoms of trouble breathing are shortness of breath at rest; rapid breathing; or wheezy, noisy or raspy breathing. In babies, this may show as not being able to cry or feed.

Get emergency help for other symptoms of serious illness, such as:

• Fever higher than 100.4 degrees Fahrenheit (38 degrees Celsius) in a child younger than 3 months old.
• Problems swallowing, for example, drooling in children younger than age 3 and in older children, not being able to swallow or open the mouth fully.
• Skin, lips or nail beds that are gray or blue.
• New confusion.
• Trouble staying awake or waking up.
• Chest pain or pressure that is constant.
• Vomiting or diarrhea that doesn't stop.
• Dehydration, which in babies younger than 3 month means fewer than three wet diapers in 24 hours.

This list doesn't include every emergency symptom. If the child you're taking care of has symptoms that worry you, get help. Let the healthcare team know about a positive test for COVID-19 or symptoms of the illness.

Testing for COVID-19

Testing for COVID-19 can help you quickly figure out if the COVID-19 virus is the cause of your child's illness. Testing helps you act quickly to prevent serious illness in kids who are at higher than average risk. It also helps protect others who may be at high risk.

Test for COVID-19 if you know you or your child was exposed to the virus or if you have symptoms. Testing during times when many people in your area have COVID-19 can help stop the spread of the virus that causes the illness.

Supporting Your Child During COVID-19 Nasal Swab Testing

The purpose of this video is to help children get ready for a COVID-19 nasal swab test. Knowing what to expect may help ease any fears they may have. When children know about the medical test they're about to take, the test is easier for them to take. Children as young as 4 years old can watch this video.

Jennifer Rodemeyer, Child Life Program Manager, Mayo Clinic: Hi, I'm Jennifer and I am a child life specialist at Mayo Clinic. My job is to help kids like you prepare for medical tests.

You may have heard there is a virus going around that can make people feel sick. A virus is a germ and it is so tiny you can't even see it.

Some people who get this virus can have a fever or a cough and may feel achy and tired, while some people can have this virus and not feel sick at all. People may get this virus from touching things. That's why it's important to wash your hands often with soap and water. The virus also can spread through a cough or a sneeze. So it's important to always cover your cough or sneeze.

Today, even though you may or may not be feeling sick, we will need to give you a test so we know how to best proceed with your medical care. This medical test will tell us if you have the virus.

When you go to take your test, the health care provider will wear special protective clothing. They wear this clothing to keep themselves and you safe from getting germs. They will wear a mask to cover their nose and mouth and a clear plastic shield to protect their eyes.

The most important thing you can do during your test is to sit perfectly still like a statue. To help make sure you don't move, your parent or caregiver will help keep you still and calm during your test. The health care provider needs to touch the inside of the back of your nose with a long, skinny Q-tip. To do this, you need to hold your chin up, then the health care provider will put the Q-tip in your nose for a short time to collect a sample.

While this happens you may feel like you want to push the Q-tip away, but it's really important to stay as still as possible so the health care provider can finish the test. The Q-tip will be in and out of your nose in a few seconds.

Some kids tell me that counting to 3 or taking a deep breath relaxes them before the test happens, and some tell me they like to hold on to their favorite stuffed animal or blanket. Maybe you have your own way to relax.

Remember that during the test, the most important thing to do is to keep your body perfectly still.

You may have many feelings seeing the health care provider wearing different clothing, but know this person is caring and wants to help you.

Thank you for helping us get this test done, so we know how to proceed with your medical care.

What is multisystem inflammatory syndrome in children (MIS-C)?

Multisystem inflammatory syndrome in children (MIS-C) is a serious condition linked to infection with the virus that causes COVID-19.

With MIS-C, children have fever, blood markers of inflammation and serious disease throughout the body. Organs such as the brain, eyes, heart, lungs, kidneys, digestive system and skin may become inflamed. MIS-C symptoms are treated in the hospital as the illness runs its course.

MIS-C is rare. In 2023, the U.S. Centers for Disease Control and Prevention received 117 reports of MIS-C. Most of these children had no medical issues before getting MIS-C.

Symptoms usually show up in about 2 to 6 weeks after infection with the virus that causes COVID-19.

Symptoms of MIS-C include a fever that doesn't go away, along with other symptoms:

• Belly pain.
• Bloodshot eyes.
• Dizziness or lightheadedness.

Emergency warning signs of MIS-C include:

• Difficulty breathing.
• Gray or blue skin, lips or nail beds.
• Terrible belly pain.

If your child shows any emergency warning signs or is severely sick with other symptoms, take your child to the nearest emergency department or call 911 or your local emergency number. If your child isn't seriously ill but shows other symptoms of MIS-C, contact your child's healthcare professional right away for advice.

Most children get better quickly and don't have any medical issues caused by MIS-C.

Staying up to date with COVID-19 vaccination offers protection against MIS-C. And most children who have had MIS-C can get a COVID-19 vaccine on schedule.

Can children who get COVID-19 experience long-term effects?

Anyone who has had COVID-19 can develop a post-COVID-19 syndrome. New symptoms or conditions that develop after infection with the virus that causes COVID-19 is more often linked to serious COVID-19 illness. But anyone who catches the COVID-19 virus can develop a post-COVID-19 syndrome.

Symptoms often include a high level of tiredness that affects day-to-day life. And some symptoms may get worse after certain activities.

Symptoms may relate to trouble with:

• Trouble with thinking.
• Fast heartbeat.
• Sleep problems
• Digestive issues.
• Pain in the joints or muscles.

Depending on their age, children may have trouble explaining some of these issues, which may be difficult for healthcare teams to diagnose.

These symptoms could affect your child's ability to attend school or do typical activities. If your child has post-COVID-19 symptoms that aren't getting better, talk with your healthcare professional. Working with your child's school, it may be possible to compensate for these symptoms.

Staying up to date with COVID-19 vaccines offers protection against post-COVID-19 syndrome.

What COVID-19 vaccines are available to kids in the U.S.?

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

• 2023-2024 Pfizer-BioNTech COVID-19 vaccine, available for people age 6 months and older.
• 2023-2024 Moderna COVID-19 vaccine, available for people age 6 months and older.
• 2023-2024 Novavax COVID-19 vaccine, available for people age 12 years and older.

In general, people older than age 4 with typical immune systems can get any vaccine that is approved or authorized for their age. And people usually don't need to get vaccines from the same vaccine maker each time.

Some people should get all their vaccine doses from the same vaccine maker, including:

• Children age 6 months to 4 years.
• People age 5 years and older with weakened immune systems.
• People age 12 and older who have had one shot of the Novavax vaccine. They should get the second Novavax shot in the two-dose series.

Talk with your healthcare professional if you have any questions about the vaccines for you or your child. Your healthcare team can help you if:

• The vaccine you or your child got earlier isn't available.
• You don't know which vaccine you or your child received.
• You or your child started a vaccine series but couldn't finish it due to side effects.

What can I do to prevent my child from getting COVID-19?

There are many steps you can take to prevent your child from getting the COVID-19 virus and spreading it to others.

• Get vaccinated. If the timing works out, a COVID-19 vaccine can be given to eligible children on the same day as other vaccines.
• Keep hands clean. Encourage frequent hand-washing with soap and water for at least 20 seconds. Teach your kids to keep washing their hands until they have sung the entire "Happy Birthday" song twice, which takes about 20 seconds. Or use an alcohol-based hand sanitizer that contains at least 60% alcohol. Have your child cover the mouth and nose with an elbow or a tissue when coughing or sneezing. Remind your child to avoid touching the eyes, nose and mouth.
• Clean and disinfect your home. Clean high-touch surfaces and objects regularly and after you have visitors in your home. Also, regularly clean areas that easily get dirty, such as a baby's changing table, and surfaces and items that your child often touches.
• Get the air flowing. Use fans, open windows or doors, and use filters to keep air and germs moving out of your indoor space.
• Keep some distance. If possible, avoid close contact with anyone who is sick or has symptoms. Spread out in crowded indoor places, especially in places with poor airflow.
• Wear face masks. If you are in an area with a high number of people in the hospital with COVID-19, the CDC recommends wearing a well-fitted mask indoors in public. Don't place a face mask on a child younger than age 2 or a child with a disability who can't safely wear a mask.

Keep up with well-child visits and your child's other vaccines. COVID-19 is just one of many illnesses that can be prevented with vaccination. Vaccines for children are timed carefully. Vaccines are given when protection inherited from the mother fades and the child's immune system is ready, but before kids are likely to come in contact with the germs that cause real infections.

Following guidelines to protect against the COVID-19 virus can be difficult for kids. Stay patient. Be a good role model and your child will be more likely to follow your lead.

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• Children and COVID-19: State data report. American Academy of Pediatrics. https://www.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/children-and-covid-19-state-level-data-report/. Accessed April 3, 2024.
• Information for pediatric healthcare providers. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/hcp/pediatric-hcp.html. Accessed April 3, 2024.
• COVID data tracker. Centers for Disease Control and Prevention. https://covid.cdc.gov/covid-data-tracker/#pediatric-data. Accessed April 3, 2024.
• Willis ZI, et al. Guidance for prevention and management of COVID-19 in children and adolescents: A consensus statement from the Pediatric Infectious Diseases Society Pediatric COVID-19 Therapies Taskforce. Journal of the Pediatric Infectious Diseases Society. 2024; doi:10.1093/jpids/piad116.
• Stay up to date with your vaccines. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html. Accessed April 4, 2024.
• Hughes BL, et al. COVID-19: Antepartum care of pregnant patients with symptomatic infection. https://www.uptodate.com/contents/search. Accessed April 4, 2024.
• AskMayoExpert. COVID-19: Pregnancy. Mayo Clinic; 2024.
• Halasa NB, et al. Effectiveness of maternal vaccination with mRNA COVID-19 vaccine during pregnancy against COVID-19-associated hospitalization in infants aged <6 months — 17 states, July 2021-January 2022. MMWR Morbidity and Mortality Weekly Report. 2022; doi:10.15585/mmwr.mm7107e3.
• AskMayoExpert. COVID-19: Outpatient and inpatient management (child). Mayo Clinic; 2024.
• Symptoms of COVID-19. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html. Accessed April 4, 2024.
• Testing and respiratory viruses. Centers for Disease Control and Prevention. https://www.cdc.gov/respiratory-viruses/prevention/testing.html. Accessed April 4, 2024.
• Information for healthcare providers about multisystem inflammatory syndrome in children (MIS-C). Centers for Disease Control and Prevention. https://www.cdc.gov/mis/mis-c/hcp_cstecdc/index.html. Accessed April 4, 2024.
• Notes from the field: Surveillance for multisystem inflammatory syndrome in children, United States, 2023. MMWR Morbidity and Mortality Weekly Report. 2024; doi:10.15585/mmwr.mm7310a2.
• For parents: Multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. Centers for Disease Control and Prevention. https://www.cdc.gov/mis/mis-c.html. Accessed April 4, 2024.
• Long COVID or post-COVID conditions. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html. Accessed April 3, 2024.
• Caring for people with long COVID. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/care-post-covid.html. Accessed April 4, 2024.
• Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html. Accessed April 3, 2024.
• How to protect yourself and others. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed April 4, 2024.
• When and how to wash your hands. Centers for Disease Control and Prevention. https://www.cdc.gov/handwashing/when-how-handwashing.html. Accessed April 4, 2024.
• Everyday cleaning. Centers for Disease Control and Prevention. https://www.cdc.gov/hygiene/cleaning/index.html. Accessed April 4, 2024.
• Taking steps for cleaner air for respiratory virus prevention. Centers for Disease Control and Prevention. https://www.cdc.gov/respiratory-viruses/prevention/air-quality.html. Accessed April 4, 2024.
• Masks and respiratory viruses prevention. Centers for Disease Control and Prevention. https://www.cdc.gov/respiratory-viruses/prevention/masks.html. Accessed April 4, 2024.
• Timing and spacing of immunobiologics. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/timing.html. Accessed April 4, 2024.
• Infants and children birth through age 6. U.S. Department of Health and Human Services. https://www.hhs.gov/immunization/who-and-when/index.html. Accessed April 4, 2024.
• Your child's first vaccines. Centers for Disease Control and Prevention. http://www.cdc.gov/vaccines/hcp/vis/vis-statements/multi.html. Accessed April 4, 2024.

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• Introduction
• Conclusions
• Article Information

ARI indicates acute respiratory infection; CDC, Centers for Disease Control and Prevention; ED, emergency department; UC, urgent care.

Models are adjusted for week of encounter, age, sex, self-reported race and ethnicity, body mass index, Charlson Comorbidity Index, prior SARS-CoV-2 infection, and health care utilization history (ie, influenza and pneumococcal vaccination; inpatient, emergency department, and outpatient encounters in the prior year). Error bars indicate 95% CIs.

Models are adjusted for week of encounter, age, sex, self-reported race and ethnicity, body mass index, Charlson Comorbidity Index, prior SARS-CoV-2 infection, and health care utilization history (ie, influenza and pneumococcal vaccination; inpatient, emergency department, and outpatient encounters in prior the year). The dashed line indicates the effectiveness of 0, which serves as a reference of no effect, and the error bars indicate 95% CIs.

eTable 1. Acute Respiratory Infection Codes, October 10, 2023 through December 10, 2023

eAppendix. Approach to medical chart review validation of hospital admissions

eTable 2. Adjusted and unadjusted relative effectiveness of BNT162b2 XBB vaccine against COVID-19 outcomes, by comparison group and age among adults ≥18 years of age

eTable 3. Adjusted absolute effectiveness of prior (non-XBB) vaccines compared to unvaccinated individuals, by age group among adults ≥18 years of age

eTable 4. Sensitivity analyses of adjusted effectiveness of BNT162b2 XBB vaccine against COVID-19 outcomes, by comparison group, after including those who received antiviral or monoclonal antibody treatment in the 30 days prior to their COVID-19 encounter, among adults ≥18 years of age

eTable 5. Covariate estimates from adjusted risk model of COVID-19 outcome among those who received a BNT162b2 XBB vaccine versus those that did not receive a BNT162b2 XBB vaccine among adults ≥18 years of age

Data Sharing Statement

• Evaluating COVID-19 Vaccines in the Era of Endemicity—Recency vs Reformulation JAMA Internal Medicine Invited Commentary August 1, 2024 Gopi S. Mohan, MD, PhD; Michael J. Mina, MD, PhD; Pierre O. Ankomah, MD, PhD

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Tartof SY , Slezak JM , Frankland TB, et al. Estimated Effectiveness of the BNT162b2 XBB Vaccine Against COVID-19. JAMA Intern Med. 2024;184(8):932–940. doi:10.1001/jamainternmed.2024.1640

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Estimated Effectiveness of the BNT162b2 XBB Vaccine Against COVID-19

• 1 Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena
• 2 Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California
• 3 Kaiser Permanente Hawaii Center for Integrated Health Care Research, Honolulu
• 4 Pfizer Inc, New York, New York
• 5 Southern California Permanente Medical Group, Harbor City
• Invited Commentary Evaluating COVID-19 Vaccines in the Era of Endemicity—Recency vs Reformulation Gopi S. Mohan, MD, PhD; Michael J. Mina, MD, PhD; Pierre O. Ankomah, MD, PhD JAMA Internal Medicine

Question   Does receiving the BNT162b2 XBB vaccine offer additional protection against COVID-19 hospital admissions and ambulatory visits for US adults compared with not receiving a BNT162b2 XBB vaccine of any kind, and do older versions of the COVID-19 vaccine still provide any protection compared with being unvaccinated?

Findings   In this case-control study among 2854 cases and 15 345 controls, the BNT162b2 XBB vaccine provided statistically significant additional protection against a range of COVID-19 outcomes during the early part of the 2023 to 2024 viral respiratory season. Older versions of COVID-19 vaccines offered little, if any, additional protection compared with being unvaccinated, including against COVID-19 hospital admissions, regardless of the number or type of prior doses received.

Meaning   These findings reaffirm current recommendations for broad age-based use of annually updated COVID-19 vaccines.

Importance   Data describing the early additional protection afforded by the recently recommended BNT162b2 XBB vaccine (Pfizer-BioNTech; 2023-2024 formulation) are limited.

Objective   To estimate the association between receipt of the BNT162b2 XBB vaccine and medically attended COVID-19 outcomes among US adults 18 years and older.

Design, Setting, and Participants   This test-negative case-control study was performed to estimate the effectiveness of the BNT162b2 XBB vaccine against COVID-19–associated hospitalization and emergency department (ED) or urgent care (UC) encounters among adults in the Kaiser Permanente Southern California health system between October 10, 2023, and December 10, 2023. Cases were those presenting with an acute respiratory illness and who had a positive SARS-CoV-2 polymerase chain reaction test; controls had an acute respiratory illness but tested negative for SARS-CoV-2.

Exposure   The primary exposure was receipt of the BNT162b2 XBB vaccine compared with not receiving an XBB vaccine of any kind, regardless of prior COVID-19 vaccination or SARS-CoV-2 infection history. Receipt of prior (non-XBB) versions of COVID-19 vaccines was also compared with being unvaccinated to estimate remaining protection from older vaccines.

Main Outcomes and Measures   Analyses for cases and controls were conducted separately for COVID-19 hospital admissions and ED/UC encounters. Adjusted odds ratios and 95% CIs were estimated from multivariable logistic regression models that were adjusted for patient demographic and clinical characteristics. Estimation of vaccine effectiveness was calculated as 1 − odds ratio × 100%.

Results   Among 2854 cases and 15 345 controls (median [IQR] age, 56 [37-72] years; 10 658 [58.6%] female), adjusted estimation of effectiveness of the BNT162b2 XBB vaccine received a median of 34 days prior vs not having received an XBB vaccine of any kind was 62% (95% CI, 32%-79%) against COVID-19 hospitalization and 58% (95% CI, 48%-67%) for ED/UC visits. Compared with being unvaccinated, those who had received only older versions of COVID-19 vaccines did not show statistically significant reduced risk of COVID-19 outcomes, including hospital admission.

Conclusions and Relevance   Findings of this case-control study reaffirm current recommendations for broad age-based use of annually updated COVID-19 vaccines given that (1) the BNT162b2 XBB vaccine provided statistically significant additional protection against a range of COVID-19 outcomes and (2) older versions of COVID-19 vaccines offered little, if any, long-term protection, including against hospital admission, regardless of the number or type of prior doses received.

XBB and its sublineages were the predominant circulating SARS-CoV-2 strains in the US between January and December 2023. 1 XBB sublineages are antigenically and phylogenetically distinct from the Omicron BA.4 and BA.5 sublineages that were predominant in late 2022. Thus, on September 11, 2023, the US Food and Drug Administration authorized or approved updated monovalent messenger RNA (mRNA) COVID-19 vaccines targeting the XBB sublineage for individuals aged 6 months through 11 years and 12 years and older, respectively. 2 This included use of XBB vaccines for all recommended doses, including primary series and booster doses. XBB vaccines were made broadly available in the US on September 15, 2023, following Centers for Disease Control and Prevention (CDC) recommendations for use in all individuals 6 months and older in preparation for the winter respiratory virus season. 3 Studies evaluating the association between receipt of XBB vaccines and the development of clinically relevant COVID-19 end points are needed.

Similar to our previous reports, 4 - 8 we performed a test-negative case-control study to estimate the effectiveness of the BNT162b2 XBB vaccine (Pfizer-BioNTech; 2023-2024 formulation). We included patients 18 years and older at Kaiser Permanente Southern California (KPSC) who were diagnosed with acute respiratory infection (ARI; eTable 1 in Supplement 1 ) and tested for SARS-CoV-2 using polymerase chain reaction (PCR) during a (1) hospital admission or (2) emergency department (ED) or urgent care (UC) encounter without a subsequent hospital admission for the same index encounter from October 10, 2023, through December 10, 2023. The study start date corresponded to 14 days after the date that XBB vaccines were made available in KPSC (September 25, 2023).

Participants were required to have 1 year or more of health plan membership (allowing for a 31-day gap in membership to account for delays in membership renewal) to determine comorbidities and medical history. Encounters in which the patient had the following were excluded: (1) another positive SARS-CoV-2 test within 90 days, (2) received any type of XBB vaccine other than the BNT162b2 XBB vaccine, (3) received a BNT162b2 XBB vaccine within 2 months after a prior COVID-19 dose, (4) received a BNT162b2 XBB vaccine within 14 days prior to the encounter, (5) received any other non-XBB booster doses (eg, BA.4/5 bivalent or wild-type boosters) outside of CDC-recommended dosing intervals (recommendations were defined as receipt of any mRNA BA.4/5 bivalent dose between August 31, 2022, and September 11, 2023, with ≥8 weeks [≥56 days] since their most recent dose of original wild-type COVID-19 mRNA vaccine received with a minimal required interval of ≥28 days between a second and subsequent wild-type dose), (6) received nirmatrelvir/ritonavir or any other COVID-19 outpatient antiviral or monoclonal antibody (ie, molnupiravir, remdesivir, bebtelovimab, bamlanivimab, casirivimab, cilgavimab, sotrovimab, tixagevimab) in the 30 days prior to a COVID-19 encounter, or (7) a hospital admission that, despite having an ARI diagnosis with a positive SARS-CoV-2 test, was determined to be likely unrelated to COVID-19 or clearly related to another cause based on medical record review conducted by trained research staff who were blinded to vaccination status and later validated by a blinded physician investigator (B.K.A.; eAppendix in Supplement 1 ). For patients who had multiple encounters, we included only the first encounter to maintain independence of outcome events. This study was approved by the KPSC institutional review board, which waived the requirement for informed consent in accordance with the Common Rule (45 CFR §46.116).

Cases were those with a positive SARS-CoV-2 PCR test associated with a hospital admission or ED/UC encounter with ARI. Controls had ARI and a negative SARS-CoV-2 PCR test result. Hospital admission and ED/UC outcomes were mutually exclusive. SARS-CoV-2 PCR tests among cases and controls were restricted to those administered within 14 days prior to the initial ARI encounter through no more than 3 days after the encounter.

All KPSC members were eligible for COVID-19 vaccines at no cost based on indications authorized or approved by the US Food and Drug Administration. KPSC electronic health records captured all vaccinations administered within the health system. Records were supplemented with vaccine administration data from the California Immunization Registry, to which all health care professionals are required by law to report COVID-19 vaccinations within 24 hours. To be considered vaccinated, the dose had to occur more than 14 days before testing for SARS-CoV-2.

For the primary analysis, the odds of receipt of a BNT162b2 XBB vaccine were compared with the odds of not receiving a XBB vaccine of any kind (including unvaccinated persons) across cases and controls, regardless of prior COVID-19 vaccination or SARS-CoV-2 infection history. Secondary analyses compared the odds of receipt of a BNT162b2 XBB vaccine vs the odds of (1) receipt of 1 or more doses of a BA.4/5 bivalent vaccine but no XBB vaccine of any kind, (2) receipt of 3 or more or 2 or more doses of an original wild-type mRNA vaccine but no variant-adapted vaccines of any kind (eg, XBB or BA.4/5 bivalent doses), and (3) being unvaccinated across cases and controls. Among those who did not receive an XBB vaccine of any kind, we also compared the odds of receiving 1 or more doses of a BA.4/5 bivalent vaccine or receiving 3 or more or 2 or more original wild-type COVID-19 vaccine doses without a bivalent vaccine of any kind with the odds of being unvaccinated across cases and controls. These comparisons were used to estimate remaining protection from prior non-XBB vaccines (ie, either BA.4/5 or wild-type doses) during the study period.

Odds ratios and 95% CIs calculated using the Wald method were derived from multivariable logistic regression models that included week of encounter, age (18-49, 50-64, and ≥65 years), sex (female, male), self-reported race and ethnicity (non-Hispanic African American or Black, non-Hispanic Asian or Pacific Islander, Hispanic or Latinx, non-Hispanic White, other [including individuals who identified as American Indian or multiple or other races and ethnicities], and unknown), body mass index (calculated as weight in kilograms divided by height in meters squared; <18.5, 18.5-24.9, 25.0-29.9, 30.0-34.9, ≥35.0, and unknown), Charlson Comorbidity Index (0, 1, 2, 3, and ≥4), receipt of influenza vaccine in the year before admission (yes or no), receipt of pneumococcal vaccine in the 5 years before admission (yes or no), health care utilization in the year before admission (ie, number of hospital admissions and ED or outpatient visits), and documentation of previous SARS-CoV-2 infection confirmed by PCR or antigen test (ever vs never) for pre-Delta, Delta, and Omicron periods. Missing values were treated as separate categories for all variables in all analyses.

Analyses were completed separately for ARI-associated hospital admissions and ED/UC encounters, as well as separately by the exposure comparisons defined herein. Estimation of vaccine effectiveness (VE) was calculated as 1 − odds ratio × 100%. Primary analyses were further stratified by age group (18-64 years vs ≥65 years). In sensitivity analyses, we examined the effect on the primary analysis by including patients who received COVID-19 antiviral or monoclonal antibody treatment. Analyses were performed using SAS, version 9.4 (SAS Institute).

Of 20 015 ARI encounters among adults 18 years and older with continuous enrollment and an eligible SARS-CoV-2 PCR test, 18 199 met study selection criteria (2977 [16.4%] hospital admissions and 15 222 [83.6%] ED/UC encounters; Figure 1 ). Overall, 148 of 592 (25.0%) hospitalizations with a positive SARS-CoV-2 test were determined to be unrelated to COVID-19 on physician medical record review and were excluded. The median (IQR) age among patients was 56 (37-72) years. Of the 18 199 included patients, 2854 (15.7%) tested positive for SARS-CoV-2 and 1146 (6.3%) received the BNT162b2 XBB vaccine ( Table and Figure 1 ). In analyses of hospital admissions among 391 cases and 2586 controls, 13 (3.3%) and 169 (6.5%), respectively, received the BNT162b2 XBB vaccine. Of 2463 cases and 12 759 controls in analyses of ED/UC encounters, 95 (3.9%) and 869 (6.8%), respectively, received the BNT162b2 XBB vaccine. A total of 17 053 patients (93.7%) never received an XBB COVID-19 vaccine of any kind and 2140 (11.8%) never received a COVID-19 vaccine of any kind. Among those who received the BNT162b2 XBB vaccine, the median (range) time since receipt of their most recent previous dose of a COVID-19 vaccine was 363 (63-956) days. Overall, median (IQR) time since receipt of a BNT162b2 XBB vaccine was 34 (23-49) days. Median (IQR) time since last dose for those who received a bivalent booster but no XBB dose was 358 (311-392) days. Median (IQR) times since last dose for those with more than 3 and more than 2 doses with no variant-adapted boosters were 627 (425-691) days and 675 (513-763) days, respectively.

Adjusted estimation of VE of the BNT162b2 XBB vaccine (vs not having received an XBB vaccine of any kind) was 62% (95% CI, 32%-79%) against COVID-19 hospital admission and 58% (95% CI, 48%-67%) against ED/UC visits ( Figure 2 and eTables 2 and 5 in Supplement 1 ). In secondary analyses, the estimation of VE of the BNT162b2 XBB vaccine was similar regardless of comparison group, including those who (1) received 1 or more doses of the BA.4/5 bivalent vaccine and no XBB vaccine, (2) received 3 or more or 2 or more doses of the original wild-type vaccine without any variant-adapted boosters of any kind (eg, BA.1 or BA.4/5 bivalent vaccines or XBB vaccines), and (3) were unvaccinated, across all settings of care (ie, hospital admission and ED/UC visits) ( Figure 2 and eTable 2 in Supplement 1 ). With the exception of hospitalization outcomes among the 18- to 64-year olds, for which 95% CIs were wide, estimation of VE appeared generally similar across age groups 18 to 64 years and 65 years and older (eTables 2 and 3 in Supplement 1 ). In sensitivity analyses, results were similar when patients who received antiviral or monoclonal antibody treatment in the 30 days prior to their COVID-19 encounter (n = 950) were included (eTable 4 in Supplement 1 ). Finally, compared with unvaccinated individuals, those who had not received an XBB vaccine of any kind but had received older versions of COVID-19 vaccines (ie, ≥1 BA.4/5 bivalent dose or ≥3 or ≥2 original wild-type doses and no variant-adapted vaccines of any kind) did not show a statistically significant reduced risk of COVID-19 outcomes, including hospital admission, during the study period ( Figure 3 ).

In this test-negative case-control study conducted in a large US health care system during the early part of the 2023 to 2024 viral respiratory season, the estimation of VE for the BNT162b2 XBB vaccine was 62% (95% CI, 32%-79%) against COVID-19 hospital admission and 58% (95% CI, 48%-67%) against COVID-19 ED/UC encounters after a median of 34 days since receipt of the BNT162b2 XBB dose compared with those who did not receive an XBB vaccine. For the week ending December 9, 2023, there were 23 432 new COVID-19 hospital admissions in the US—the highest rate since winter 2022. 9 This still represents a large public health burden and is roughly 3 times higher than the number of new weekly influenza hospitalizations that occurred during the same period (n = 7090), 10 albeit fewer than the approximately 150 000 weekly hospitalizations seen at the peak of the Omicron BA.1 wave. 9 With this context, the present findings help reaffirm current recommendations for broad age-based use of annually updated COVID-19 vaccines in the US to improve protection against COVID-19 each year prior to likely winter peaks in disease activity. 11

The BNT162b2 XBB vaccine provided similar additional protection in adults regardless of age group and the number of prior COVID-19 vaccine doses received for all COVID-19 outcomes. This latter finding was consistent with results suggesting that prior receipt of only older versions of COVID-19 vaccines (ie, receipt of a BA.4/5 bivalent vaccine or ≥3 or ≥2 original wild-type doses but no XBB vaccine) provided little, if any, current additional protection compared with being unvaccinated against COVID-19 outcomes, including hospital admission. Median time since administration of these older vaccines was between 1 and 2 years ago, whereas median time since receipt of a BNT162b2 XBB vaccine was 1 month. Thus, analogous to influenza, although older versions of COVID-19 vaccines once provided high levels of protection, the combination of waning vaccine-induced immunity and continuous SARS-CoV-2 strain evolution eventually renders prior versions of vaccines ineffective. This, in turn, warrants routine updates to COVID-19 vaccines—also like influenza—so long as SARS-CoV-2 continues to circulate and cause disease. 9 - 11

An earlier study showed that among adults 65 years and older in Denmark, receipt of an XBB vaccine (90% of which were the BNT162b2 XBB vaccine in the study population) led to a 76% (95% CI, 62%-85%) reduction in risk of COVID-19 hospital admission over an average follow-up time of 10 days compared with those who did not receive an XBB vaccine 12 —an estimate that was comparable to the present, albeit slightly higher, against the same outcome and comparison group. However, this study had shorter follow-up time and included data only through the end of October 2023, which was prior to the emergence and rapid growth of the JN.1 strain. Another recent study conducted in the Netherlands also showed similar reductions in risk of hospital admission (71%; 95% CI, 67%-74%) among adults 60 years and older who were previously vaccinated. 13 The present study helps confirm these early global findings but also describes the association between BNT162b2 XBB vaccine receipt and the development of COVID-19 across a broader range of outcomes and age groups, in a more diverse study population, and during a more recent time period that included when the JN.1 strain was rapidly increasing in prevalence in the US.

Uptake of XBB vaccines in the US to date has been low. As of December 22, 2023, only 19% and 37% of all adults 18 years and older and 65 years and older, respectively, had received an XBB vaccine. 14 Current COVID-19 vaccine coverage considerably lags that of seasonal influenza vaccines, despite both vaccines being made available during the autumn and winter and current CDC guidelines that support co-administration of the 2 vaccines. 15 Reasons for low COVID-19 vaccine uptake likely include reduced concern about COVID-19 in the general population over time and, as pandemic declarations ended, annual COVID-19 vaccination not yet being seen as a routine health activity, confusion about risk level regarding COVID-19, and continued skepticism in some populations about the safety and effectiveness of mRNA vaccines. 16 In addition, XBB vaccines were not made available until the latter half of September 2023, which is notably later than when influenza vaccines are made available each year. Thus, there may have been missed opportunities for co-administering COVID-19 vaccines with influenza vaccines during the month of September—a time when many influenza vaccines are given.

This study has limitations. Although we controlled for key sociodemographic and clinical characteristics, there may be residual confounding associated with unaccounted-for differences in the likelihood of exposure or severity of SARS-CoV-2 infection between vaccinated and unvaccinated individuals. Although individuals who are more likely to get vaccinated against COVID-19 may also be more likely to seek care or testing for SARS-CoV-2, the test-negative design of this study and the focus on ARI events occurring in the hospital and ED/UC settings help mitigate against bias caused by differences in health care–seeking behavior, including the propensity to test. 17 - 19 We also controlled for prior health care utilization, age, and underlying comorbid illness to help mitigate the potential for healthy vaccinee bias. A second limitation is that median time since receipt of a BNT162b2 XBB vaccine was only 34 days, and future studies are needed to evaluate durability of protection. In addition, this study was conducted during a period when XBB sublineages were predominant but JN.1 was also co-circulating and rapidly increasing in prevalence across the US and California. 1 However, we did not have genotype information available for all of the included cases, nor were we able to estimate sublineage-specific estimates. Thus, future studies describing the association between receipt of XBB vaccines and development of strain-specific BA2.86 sublineage-related disease (eg, JN.1) are needed. While high health care utilization in this study population may mitigate underascertainment of prior infections, misclassification of previous infections is likely, particularly as home testing has increased and overall rates of testing have gone down compared with earlier in the pandemic. If undocumented previous infection was more likely in unvaccinated individuals, for example, this could contribute to underestimation of vaccine protection. It remains possible that some health care encounters were “with COVID-19” rather than “for COVID-19,” and this could lead to underestimation of the protective effects of vaccination against medically attended disease. To help mitigate this bias, we (1) used medical record review to exclude hospital admissions that were unrelated to COVID-19 and (2) restricted the analyses to patients presenting with ARI for all outcomes. Lastly, uptake of the BNT162b2 XBB vaccine was low overall and was most frequent in individuals who were older and who had comorbidities, which may affect the generalizability of the findings, lead to the underestimation of VE, or both.

In this case-control study, individuals who did not receive an XBB vaccine and had received only older versions of COVID-19 vaccines had little, if any, additional protection compared with unvaccinated individuals against COVID-19 end points, including hospital admission, regardless of the number or type of prior doses received. Receipt of a BNT162b2 XBB vaccine, however, was associated with statistically significant reduced risk of developing a range of COVID-19 outcomes during the early part of the 2023 to 2024 viral respiratory season—with the strongest protective effects seen against hospital admission. These 2 findings help reaffirm current recommendations for broad age-based use of annually updated COVID-19 vaccines. Uptake of this 2023-2024 formulation of COVID-19 vaccines, however, remains low, and targeted and tailored interventions to continuously improve annual COVID-19 uptake are warranted.

Accepted for Publication: March 22, 2024.

Published Online: June 24, 2024. doi:10.1001/jamainternmed.2024.1640

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License . © 2024 Tartof SY et al. JAMA Internal Medicine .

Corresponding Author: Sara Y. Tartof, PhD, MPH, Department of Research & Evaluation, Kaiser Permanente Southern California, 100 S Los Robles, 2nd Floor, Pasadena, CA 91101 ( [email protected] ).

Author Contributions: Dr Slezak and Ms Hong 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: Tartof, Slezak, Puzniak, Simmons, Jodar, McLaughlin.

Acquisition, analysis, or interpretation of data: Tartof, Slezak, Frankland, Puzniak, Hong, Ackerson, Stern, Zamparo, Jodar, McLaughlin.

Drafting of the manuscript: Tartof, Frankland, Puzniak, McLaughlin.

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

Statistical analysis: Slezak, Frankland, Hong.

Obtained funding: Tartof, Puzniak, Zamparo, Jodar, McLaughlin.

Administrative, technical, or material support: Frankland, Ackerson, Stern, Zamparo, Simmons, Jodar, McLaughlin.

Supervision: Tartof, Ackerson, Zamparo, Jodar, McLaughlin.

Conflict of Interest Disclosures: Dr Tartof reported institutional grants from Pfizer and GSK outside the submitted work. Dr Slezak reported institutional grants from Pfizer and Dynavax outside the submitted work. Mr Frankland reported a research contract with Pfizer and previous stock in Pfizer. Dr Puzniak reported personal fees from Pfizer during the conduct of the study. Ms Hong reported institutional grants from Pfizer during the conduct of the study. Dr Ackerson reported institutional grants from Pfizer, Moderna, GSK, and Dynavax outside the submitted work. Dr Stern reported grants from GSK, Sanofi, and Moderna outside the submitted work. Dr Jodar reported salary from and stock in Pfizer outside the submitted work. Dr McLaughlin reported salary from and stock in Pfizer during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was sponsored by Pfizer.

Role of the Funder/Sponsor: The study design was jointly developed by Kaiser Permanente Southern California and Pfizer. Kaiser Permanente Southern California collected and analyzed the data. Pfizer did not participate in the collection or analysis of data. Kaiser Permanente Southern California and Pfizer participated in the interpretation of data, the writing of the report, and the decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: We thank Harpreet Takhar, MPH, from the Kaiser Permanente Southern California Department of Research & Evaluation for administrative support during this study. No additional compensation was provided.

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Aug. 16, 2024

Researchers make breakthrough in fight against covid-19.

A team led by Jose Onuchic at Rice University and Paul Whitford at Northeastern University, both researchers at the National Science Foundation Physics Frontiers Center at the Center for Theoretical Biological Physics ( CTBP ) at Rice, has made a discovery in the fight against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for COVID-19.

The team, in partnership with an experimental effort led by Yale University researchers Walter Mothes and Wenwei Li, has uncovered new insights into how the virus infects human cells and how it can be neutralized. Their findings were published in the journal Science on Aug. 15.

SARS-CoV-2 uses its spike protein to attach to the angiotensin-converting enzyme 2 on human cells, initiating a process that allows it to enter the cell. The spike protein has two main parts: the S1 domain, which varies greatly among different strains of the virus, and the S2 domain, which is highly conserved across different coronaviruses. This similarity makes the S2 domain a promising target for vaccines and therapies that could work against many virus strains.

By combining simulations and theoretical predictions with structural information from their experimental collaborators, including initial and final configurations as well as intermediate states during the viral invasion, the researchers obtained a detailed picture of the infection process at an atomic level.

“Understanding these intermediate states of the spike protein creates new opportunities for treatment and prevention,” said Onuchic, the Harry C. and Olga K. Wiess Chair of Physics, professor of physics and astronomy, chemistry and biosciences and co-director of CTBP. “Our work demonstrates the importance of combining theoretical and experimental approaches to tackle complex problems such as viral infections.”

Using an advanced imaging technique called cryo-electron tomography, the experimental researchers at Yale captured detailed snapshots of the spike protein as it changes during the fusion process.

They discovered antibodies targeting a specific part of the S2 domain, called the stem-helix, which can bind to the spike protein and stop it from refolding into a shape necessary for fusion. This prevents the virus from entering human cells.

“Our study provides a detailed understanding of how the spike protein changes shape during infection and how antibodies can block this process,” Onuchic said. “This molecular insight opens up new possibilities for designing vaccines and therapies targeting a wide range of coronavirus strains.”

The researchers used a combination of theoretical modeling and experimental data to achieve their findings. By combining simulations of the spike protein with experimental images, they captured intermediate states of the protein that were previously unseen. This integrated approach allowed them to understand the infection process at an atomic level.

“The synergy between theoretical and experimental methods was crucial for our success,” said Whitford, a professor in the Department of Physics at Northeastern. “Our findings highlight new therapeutic targets and strategies for vaccine development that could be effective against most variants of the virus.”

The team’s discovery is significant in the ongoing efforts to combat COVID-19 and prepare for future outbreaks of related viruses. By targeting the conserved S2 domain, scientists can develop vaccines and therapies that remain effective even as the virus mutates.

“This research is a step forward in the fight against COVID-19 and other coronaviruses that may emerge in the future,” said Saul Gonzalez, director of the U.S. National Science Foundation’s Physics Division. “Understanding the fundamental physical workings within intricate biological mechanisms is essential for developing more effective and universal treatments that can protect our health and save lives.”

This work was supported by the National Science Foundation, National Institutes of Health, Canadian Institutes of Health Research, Canada Research Chairs and Welch Foundation.

Other researchers include Michael Grunst and Zhuan Qin at the Department of Microbial Pathogenesis and Shenping Wu at the Department of Pharmacology at Yale; Esteban Dodero-Rojas at CTPB; Shilei Ding, Jérémie Prévost and Andrés Finzi at the Centre de Recherche du CHUM; Yaozong Chen and Marzena Pazgier in the Infectious Disease Division in the F. Edward Hebert School of Medicine at Uniformed Services University of the Health Sciences; and Yanping Hu and Xuping Xie in the Department of Biochemistry and Molecular Biology at the University of Texas Medical Branch at Galveston.