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Review

Effectiveness of BNT162b2 and mRNA-1273 Vaccines against COVID-19 Infection: A Meta-Analysis of Test-Negative Design Studies

by
Shuailei Chang
1,†,
Hongbo Liu
2,†,
Jian Wu
1,
Wenwei Xiao
1,
Sijia Chen
3,
Shaofu Qiu
2,
Guangcai Duan
1,
Hongbin Song
2,* and
Rongguang Zhang
1,4,*
1
Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
2
Chinese PLA Center for Disease Control and Prevention, Beijing 100071, China
3
Department of Epidemiology, College of Public Health, China Medical University, Shenyang 110122, China
4
Department of Epidemiology, College of Public Health, Hainan Medical University, Haikou 571199, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Vaccines 2022, 10(3), 469; https://doi.org/10.3390/vaccines10030469
Submission received: 16 February 2022 / Revised: 10 March 2022 / Accepted: 12 March 2022 / Published: 18 March 2022
(This article belongs to the Special Issue Prevention of SARS-CoV-2 Infection and COVID-19: Safety, Immunogenicity and Effectiveness of Available Vaccines)
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Abstract

:
Although numerous COVID-19 vaccines are effective against COVID-19 infection and variants of concern (VOC) in the real world, it is imperative to obtain evidence of the corresponding vaccine effectiveness (VE). This study estimates the real-world effectiveness of the BNT162b2 and mRNA-1273 vaccines against COVID-19 infection and determines the influence of different virus variants on VE by using test-negative design (TND) studies. We systematically searched for published articles on the efficacy of BNT162b2 and mRNA-1273 against COVID-19 infection. Two researchers independently selected and extracted data from eligible studies. We calculated the VE associated with different vaccine types, SARS-CoV-2 variants, and vaccination statuses, using an inverse variance random-effects model. We selected 19 eligible studies in the meta-analysis from 1651 records. For the partially vaccinated group, the VE of BNT162b2 and mRNA-1273 was 61% and 78% against COVID-19 infection, respectively. For the completely vaccinated group, the VE of BNT162b2 and mRNA-1273 was 90% and 92% against COVID-19 infection, respectively. During subgroup analyses, the overall VE of BNT162b2 and mRNA-1273 against the Delta variant was 53% and 71%, respectively, for the partially vaccinated group; the respective VE values were 85% and 91% for the fully vaccinated group. Irrespective of the BNT162b2 or mRNA-1273 vaccines, the Delta variant significantly weakened vaccine protection for the partially vaccinated group, while full vaccination was highly effective against COVID-19 infection and various VOC. The mRNA-1273 vaccine is more effective against COVID-19 infection and VOC than the BNT162b2 vaccine, especially for the partially vaccinated group. Overall, the results provide recommendations for national and regional vaccine policies.

1. Introduction

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 255 million confirmed cases and more than 5 million deaths as of 19 November 2021. In addition, the global COVID-19 situation remains severe, with the number of new novel coronavirus cases going up 0.5 million per day. The advent of COVID-19 vaccines and widespread vaccination across the globe have offered glimmers of hope for the eradication of COVID-19, and more than 7.3 billion dose of vaccine have been administered as of 17 November 2021 [1]. Both BNT162b2 and mRNA-1273 vaccines have been shown to be highly effective in multiple randomized clinical trials (RCTS) [2,3,4,5,6].
However, clinical trials may not simulate the real-world mass vaccination of COVID-19 vaccines because these studies were conducted in highly controlled environments. In contrast, the emerging variants defined as variants of concern (VOC), including the Alpha, Beta, Gamma, and Delta variants, were associated with increased transmission, more severe outcomes, reduced antibody neutralization from previous infection or vaccination, and lower vaccine effectiveness [7,8,9,10]. Thus, it is urgent and necessary to synthesize evidence of the vaccine effectiveness (VE) of COVID-19 vaccines against COVID-19 infection and VOC in the real world.
Because of feasibility and ethical issues, observational studies will replace randomized controlled trials as the preferred method of assessing the efficacy of COVID-19 vaccines. Test-negative design—one of the main methods for assessing the effectiveness of influenza vaccines—has increasingly been used by researchers as a convenient and effective way to assess the efficacy of COVID-19 because it reduces the bias due to infection misclassification and confusion in care-seeking behavior compared to other observational studies [11,12,13,14]. More importantly, when a large randomized controlled trial is impossible, the design can detect changes in vaccine effectiveness or measure VE against VOC [15].
Global mass vaccination requires a synthesis of evidence on SARS-CoV-2 VE to drive global health policy strategies. Especially, the VE against VOC may influence the choices of policy makers with regard to vaccine supply, procurement, deployment, and vaccination. We conducted a meta-analysis using TND studies to assess the VE of BNT162b2 and mRNA-1273 vaccines against COVID-19 infection and VOC.

2. Materials and Methods

2.1. Data Sources and Search Strategies

We systematically searched for articles published from 2020, when the first vaccine against COVID-19 was released, to October 26, 2021, in the following electronic databases: PubMed, Cochrane Library, Web of Science, Embase, Scopus, and preprint servers (Biorxiv and Medrxiv). We employed literature management with EndNote-X9. This meta-analysis used the following combinations as search terms: “SARS-CoV-2, COVID-19, 2019nCoV, Pfizer, BNT162b2, Comirnaty, mRNA-1273, Spikevax, Moderna, mRNA vaccine, effectiveness, efficacy, test-negative case-control, test-negative design.” Terms could appear in either the title or abstract of the article. There were no restrictions on the language of the articles that were reviewed, and the reference lists of related articles were also browsed to retrieve additional studies.
Results were screened independently by two reviewers, and disputes were resolved in consultation with a third reviewer. Only TND studies evaluating the effectiveness of BNT162b2 or mRNA-1273 vaccine against SARS-CoV-2 infection were included. Studies eligible for inclusion should meet the following criteria: definition of case is people testing positive for SARS-CoV-2 confirmed by PCR and control is people testing negative for SARS-CoV-2 confirmed by PCR [14]; the efficacies of BNT162b2 and mRNA-1273 vaccines were reported separately, and measurements used to assess the VE were adjusted. This meta-analysis excluded studies if they contained exclusively mRNA vaccine VE data (or mixed BNT162b2 and mRNA-1273 VE data which could not be separated). Studies where the outcome was not COVID-19 infection, such as hospitalization, severe illness, death, and other severe outcomes, were excluded.

2.2. Data Extraction and Study Quality Assessment

Two research personnel extracted data independently from selected studies, and a third author was consulted when consensus was lacking. The following data from selected articles were extracted: first author’s surname, country, sample, total number of participants, number of vaccinated and unvaccinated individuals in the cases and controls, type of vaccine, variants of COVID-19, adjusted VE estimate, and adjustment factors. We only extracted data related to SARS-CoV-2 infection when both the results of SARS-CoV-2 infection and symptomatic infection were reported. Quality assessment of researches was conducted with the Newcastle–Ottawa scale (NOS) [16] by a researcher independently, and the second researcher was responsible for inspection and verification. The score >7 was considered high quality, 5–6 was medium, <5 was low, and a study with a score of 5 or greater was included in the meta-analysis.

2.3. Data Synthesis and Analysis

Relevant study characteristics were synthesized in a tabular format. VE against SARS-CoV-2 infection and VOC with different vaccination situations were evaluated with the odds rate (OR) of vaccination between cases and controls and were calculated using the following formula: VE = (1 − OR) × 100%. One-dose vaccination and two-dose vaccination were defined as partial and full vaccination, respectively. Meta-analysis with the random-effects model was employed to calculate the pooled OR and 95% confidence intervals, and statistical heterogeneity between the studies was assessed using I2. We performed subgroup analysis stratifying by different times after vaccination, VOC, and vaccine situation. All analyses were conducted using Stata 11.2 (StataCorp, College Station, TX, USA). A two-tailed p value < 0.05 was considered to be statistically significant.

3. Results

3.1. Literature Research and Study Characteristics

The flow diagram of the literature screening in this research is shown in Figure 1. We identified 1681 publications or preprints, after excluding duplicates and irrelevant literature, 52 documents were reviewed in full text for eligibility, and the remaining 19 articles [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35] were included in the present meta-analysis.
The study characteristics of the selected articles are shown in Table 1, Table 2 and Table 3 (more details are provided in Table A1 andTable A2). In total, six articles were produced in Canada [18,19,22,30,31,32], five in the United States (US) [21,23,24,25,26], four in the United Kingdom (UK) [20,29,34], three in Qatar [17,28,35], and one from multiple-centers from UK, France, Ireland, the Netherlands, Portugal, Scotland, Spain, and Sweden [33] among the eligible research. The numbers of documents that reported the VE of BNT162b2 and mRNA-1273 against infection was 11, only mRNA-1273, 2, and only BNT162b2, 6. A total of 12 articles [17,18,20,22,23,24,27,28,29,32,34,35] reported the VE against VOC (Alpha, Beta, Gamma, and Delta), of which five mentioned only the BNT162b2 vaccine [20,27,28,29,35], one only the mRNA-1273 vaccine [24], and six compared the BNT162b2 and mRNA-1273 vaccines [17,18,22,23,32,35]. The quality assessment for the included studies was implemented by NOS, and all research had scores greater than 5, meeting the criteria for inclusion in the meta-analysis.

3.2. Pooled VE of BNT162b2 and mRNA-1273 against COVID-19 Infection

In the meta-analyses of VE against COVID-19 infection, we grouped the studies by four different vaccination situations: BNT162b2, partially vaccinated; BNT162b2, fully vaccinated; mRNA-1273, partially vaccinated and mRNA-1273, fully vaccinated. The meta-analysis of twelve articles that used OR as VE evaluation indicated the prominent role against confirmed COVID-19 infection by RT-PCR after partial vaccination of BNT162b2 vaccine (pooled OR = 0.39; 95% CI: 0.33–0.45, I2 = 96.7%), where the pooled estimate showed a VE of 61% (95% CI: 55–67%) (Figure 2). Additionally, the meta-analysis of eight articles which used OR as the VE evaluation indicated the prominent role against confirmed COVID-19 infection by RT-PCR after partial vaccination with the mRNA-1273 vaccine (pooled OR = 0.22; 95% CI: 0.17–0.27, I2 = 88.1%), where the pooled estimate showed a VE of 78% (95% CI: 73–83%) (Figure 2).
The vaccine effectiveness was further improved after the subjects had been fully vaccinated. Higher vaccine effectiveness was observed after full vaccination with the BNT162b2 vaccine, where the meta-analysis of 15 articles which used OR reported a pooled OR of 0.10 (95% CI: 0.09–0.12; I2 = 98.8%) and a VE of 90% (95% CI: 88–91%) (Figure 2). Similarly, the phenomenon of higher vaccine effectiveness was also observed after full vaccination with the mRNA-1273 vaccine, where the meta-analysis of 10 articles which used OR reported a pooled OR of 0.08 (95% CI: 0.06–0.09; I2 = 94.7%) and VE of 92% (95% CI: 91–94%) (Figure 2).

3.3. Pooled VE against VOC

To assess the vaccine effectiveness of BNT162b2 and mRNA-1273 vaccines against VOC, we performed a subgroup analysis for VOC in partially vaccinated and fully vaccinated individuals of BNT162b2 and mRNA-1273 vaccine. In the partial vaccination groups, the summary VE of the BNT162b2 vaccine against the Delta, Alpha, Beta and Gamma variants was 53% (OR = 0.47, 95% CI: 0.36–0.61), 37% (OR = 0.37, 95% CI: 0.27–0.52), 36% (OR = 0.64, 95% CI: 0.44–0.93) and 72% (OR = 0.28, 95% CI: 0.16–0.49), respectively, and the results of the pooled estimate showed that the VE of the mRNA-1273 vaccine against Delta, Alpha and Gamma variants was 71% (OR = 0.29, 95% CI:0.24–0.35), 85% (OR = 0.15, 95% CI: 0.11–0.21) and 87% (OR = 0.13, 95% CI: 0.08–0.22) (Figure 3), respectively. In the full vaccination groups, the total VE of BNT162b2 against Delta, Alpha and Gamma variants was 85% (OR = 0.15, 95% CI: 0.11–0.20), 94% (OR = 0.06, 95% CI: 0.04–0.10) and 92% (OR = 0.08, 95% CI: 0.05–0.14), respectively (Figure 3), whereas the pooled VE of the mRNA-1273 vaccine against Delta, Alpha and Gamma was 91% (OR = 0.09, 95% CI: 0.06–0.13), 95% (OR = 0.05, 95% CI: 0.02–0.12) and 93% (OR = 0.07, 95% CI: 0.04–0.13), respectively (Figure 3), respectively.

3.4. Pooled VE by Different Time Points after Vaccination

In the subgroup analysis of VE by different time points after vaccination, we conducted studies on the following groups: 14 or more days and 21 or more days after partial vaccination with BNT162b2 vaccine and mRNA-1273 vaccine and 7 or more days and 14 or more days after full vaccination with BNT162b2 vaccine and mRNA-1273 vaccine. The results indicated that the summary VE of 14 or more days after partial vaccination with BNT162b2 vaccine was 58% (OR = 0.42, 95% CI: 0.35–0.50), while that of the mRNA-1273 was 77% (OR = 0.23, 95% CI: 0.17–0.30) (Figure 4). Of the people with partial vaccination with BNT162b2 or mRNA-1273 after 21 or more days, the pooled VE was 67% (OR = 0.33, 95% CI: 0.23–0.47) and 80% (OR = 0.20, 95% CI: 0.15–0.26) (Figure 4), respectively. Studying the fully vaccinated individuals showed that the total VE of full vaccination with BNT162b2 or mRNA-1273 after 7 or more days was 89% (OR = 0.11, 95% CI: 0.10–0.13) and 94% (OR = 0.06, 95% CI: 0.04–0.08), and that after 14 or more days was 90% (OR = 0.10, 95% CI: 0.08–0.13) and 92% (OR = 0.08, 95% CI: 0.06–0.10) (Figure 4), respectively.

4. Discussion

In this meta-analysis of the VE against COVID-19 infection and VOC from TND studies, in both BNT162b2 and mRNA-1273, partial vaccination had low VE against COVID-19 infection with VE of 61% and 78%, respectively, and full vaccination had significantly higher efficacy against COVID-19 infection than the partial vaccine with VE of 90% and 92%, respectively, which was consistent with, but slightly less effective than the phase 3 randomized controlled trials of BNT162b2 [5] and mRNA-1273 [4] vaccines. The differences in vaccine effectiveness between clinical trials and real-world studies may result from differences in the definition of COVID-19. In clinical trials, the presence of symptoms and a positive SARS-CoV-2 RT-PCR test was defined as confirmed COVID-19, whereas in the studies included in our meta-analyses, only a positive SARS-CoV-2 RT-PCR test confirmed COVID-19. In addition, some studies have reported that vaccines are less effective in protecting older adults against COVID-19 infection, and four articles (Skowronski et al. [18], Thompson et al. [21], Bernal et al. [27] and Kissling et al. [33]) included in our analysis studied vaccine effectiveness in adults over the age of 50, which could reduce the overall vaccine protection. Furthermore, a low sensitivity or specificity of PCR tests in TND may lead to misclassification of cases and controls, which would also weaken estimates of vaccine effectiveness [20].
Similar to the results of the vaccine for preventing infection, full vaccination was significantly more effective for preventing hospitalization than partial vaccination. The difference is that the effectiveness of vaccines in preventing hospitalization is slightly higher than that of preventing infection under the same vaccine status (Table A3, Figure A1). Our findings also showed that partial vaccination of both BNT162b2 and mRNA-1273 vaccines significantly reduced the effect on Delta compared with the Alpha variant, but the difference was significantly reduced after full vaccination. The same phenomenon was observed in two U.S. CDC reports [36,37] and an observational study on the efficacy of vaccines against Delta infection [38]. In this analysis, the estimated vaccine effectiveness of partial BNT162b2 and mRNA-1273 vaccines for the Delta variant was 53% and 71%, respectively, and that of full vaccination for the Delta variant was 85% and 91%, respectively. In the subgroup analysis, the VE of mRNA-1273 was slightly higher at 7 or more days after full vaccination than at 14 or more days, which we believed was caused by the significantly higher proportion of studies on Delta in the group of 14 or more days than in the group of 7 or more days.
The Delta variant, first identified in India in December 2020 [39,40], quickly became the dominant reported variant in the country in just a few months and is now the most common variant of COVID-19 infections globally, making universal vaccination undoubtedly the best protection against COVID-19 infection in the current situation. The included studies [28,35] showed that partial vaccination had the lowest efficacy against the Beta variants, with BNT162b2 and mRNA-1273 vaccines having efficacies of only 36% and 61%, respectively. However, the number of studies on vaccine efficacy against the Beta variants included in this analysis was too small (less than 3) to provide valuable evidence of vaccine efficacy against Beta as well as Gamma variants.
We also found that mRNA-1273 seemed to be better than BNT162b2 against COVID-19 infection and the VOC after both partial and full vaccination, which is consistent with the results of several other articles [41,42,43]. In particular, when partial vaccination was given, the efficacy of mRNA-1273 against COVID-19 infection (78%) was 17 percentage points higher than that of BNT162b2 (61%). The efficacy of mRNA-1273 against Delta (71%) was 18 percentage points higher than that of BNT162b2 (53%). Differences in VE between the mRNA-1273 and BNT162b2 vaccines might be due to higher mRNA content in mRNA-1273 compared with BNT162b2 and the longer interval between priming and boosting for mRNA-12733 (4 weeks vs. 3 weeks for BNT162b2) [44,45]. Self W.H. also indicated that the VE of mRNA-1273 (VE = 93%) against COVID-19 hospitalization was higher than that of the BNT162b2 vaccine (VE = 88%) (p = 0.011) [46]. We believe that prioritizing the mrNA-1273 vaccine may be a better option in countries and regions where vaccine stocks are insufficient for full vaccination.
There are some limitations in our meta-analysis because TDN studies lack a detailed protocol for consensus, in terms of experimental design. There were six articles involving individuals with COVID-19 symptoms, two articles involving health care workers, and other articles involving individuals or community residents undergoing tests among the 19 articles analyzed, and samples from different sources might have skewed the VE of the vaccines. Each study was not exactly the same in terms of adjustment factors; however, key factors such as age and gender were adjusted for all the literature. In addition, nine articles did not report the strains of COVID-19, and almost all the research was conducted in four countries (US, UK, Canada, and Qatar). These differences may have contributed to the heterogeneity observed in some of the pooled analyses. Due to inconsistent grouping of age, risk factors, and severe disease events in the included studies, we did not extract sufficient data for subgroup analysis of these factors. This analysis also does not analyze the efficacy of long periods after vaccination and protection efficiency against severe illness and death in hospital. Despite the limitations described above, our analyses contribute significantly to the evidence base and highlights the spots that may exist in VE across type of vaccine, status of vaccination, and against VOC.

5. Conclusions

Irrespective of the BNT162b2 or mRNA-1273 vaccine, the Delta variant significantly weakened vaccine protection after partial vaccination, and full vaccination is highly effective against COVID-19 infection and the VOC. The mRNA-1273 vaccine is more effective against COVID-19 infection and VOC than the BNT162b2 vaccine, both after partial and full vaccination. The evidence in this study provides recommendations for national and regional vaccine policies.

Author Contributions

Research design, S.C. (Shuailei Chang) and H.L.; software, J.W. and W.X.; data extract, S.C. (Shuailei Chang) and S.C. (Sijia Chen); writing—original draft preparation, S.C. (Shuailei Chang); writing—review and editing, H.L. and S.Q.; supervision, G.D.; project administration, R.Z. and H.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by National key research and development program, grant number 2017YFC1600105, 2019YFC1200702 and 2021YFC2301102 and the National Nature Science Foundation of China, grant number 81873968, 81673237 and 32141003.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A

Table
Table A1. Characteristics of BNT162b2 vaccine vaccinated participants.
Table A1. Characteristics of BNT162b2 vaccine vaccinated participants.
Study14 or More Days after 1 Dose21 or More Days after 1 Dose7 or More Days after 2 Doses14 or More Days after 2 DosesVariant
CasesControlsCasesControlsCasesControlsCasesControls
V*UV*VUVVUVVUVVUVVUVVUVVUV
Chung [17]63651,2207483251,541 5151,220327525,154 NA
Bernal [20] 4507313864196,371 49731315,74996,371Alpha
1374043864196,371 122404315,74996,371Delta
Pilishvili [23]NANANANA NANANANA
Thompson [21]8828478248965 105284734848965NA
Tenforde [26] 2845469144NA
Bernal [27] 4237,32067289,377
Sheikh [29] 208367253,471113,591Delta
104582853,471113,591Alpha
752439432638,065Delta
343977439438,065Alpha
Chemaitelly [35]23583567111,472110,263 NA
271581501558 Alpha
723000952977 Beta
272134722089 Delta
Skowronski [31] 21547554084067 NA
Nascreen [22]248437,62160,775440,391 13837,62132,292440,391 Alpha
1733160,758373,364 --32,292373,364 Beta
104167860,758373,364 --32,292373,364 Gamma
657183254,770155,232 87183228,335155,232 Delta
Skowronski [32] 487618,809168,83176,621NA
250111,500168,83176,621Delta
10728168,83176,621Alpha
24708168,83176,621Gamma
370711,366387,968212,918NA
24896349397,968212,918Delta
321589387,968212,918Alpha
Carazo [30]1202342424,58918,663 483424195418,663 NA
Kissling [33]305054332345 145055122345 NA
Skowronski [18] 2995258795935,358 NA
93580277412,194 Alpha
64580259112,194 Gamma
958025012,194 Delta
Tang [17] Delta
Andrews [34] ----Alpha
----Delta
Olson [25] 617393192NA
V*: The number of people vaccinated. UV*: The number of people unvaccinated.
Table
Table A2. Characteristics of mRNA-1273 vaccine vaccinated participants.
Table A2. Characteristics of mRNA-1273 vaccine vaccinated participants.
Study14 or More Days after 1 Dose21 or More Days after 1 Dose7 Or More Days After 2 Doses14 or More Days after 2 DosesVariant
CasesControlsCasesControlsCasesControlsCasesControls
V *UV *VUVVUVVUVVUVVUVVUVVUV
Chung [19]4951,220962251,541 651,220542251,541 NA
Pilishvili [23]---- ---- NA
Thompson [21] 49284724278965NA
Tenforde [26] 1745446144NA
Skowronski [31] 284759134067 NA
Narseen [22]28237,62113,750440,391 -37,6218608440,391 Alpha
6167813,750373,364 Gamma
117183212,955155,232 1418327807155,232 Delta
Skowronski [32] 120918,80941,88976,621NA
57311,50041,88976,621Delta
372841,88976,621Alpha
370841,88976,621Gamma
79611,366109,861212,918NA
5176349109,861212,918Delta
91589109,861212,918Alpha
Carazo [30]643424152918,663 2342412618,663 NA
Bruxvoort [24] 13140917345376Alpha
232179545885547Delta
93405521193Gamma
Tang [17] 1502797156810,583Delta
Andrews [34] ----Delta
Chemaitelly [28]4423,86036523,539 Alpha
41947,872106747,224 644,73116544,572Beta
V*: The number of people vaccinated. UV*: The number of people unvaccinated.
Table
Table A3. Effectiveness of vaccines against COVID-19 hospitalization after 1 dose and after 2 doses.
Table A3. Effectiveness of vaccines against COVID-19 hospitalization after 1 dose and after 2 doses.
StudyVaccine TypeAfter 1 Dose
(days)		ORAfter 2 Doses
(days)		ORVariants
Tang et al. [17]BNT162b2≥140.203 (0.026–1.595)≥140.066 (0.03–0.146)Delta
mRNA-1273≥140.133 (0.017–1.014)≥140.039 (0.005–0.284)Delta
Nasreen et al. [22]BNT162b2≥140.14 (0.13–0.16)≥70.32 (0.25–0.41)Alpha
mRNA-1273≥140.116 (0.13–0.20)≥70.04 (0.02–0.07)Alpha
BNT162b2≥140.28 (0.13–0.63)≥70.122 (0.01–0.94)Beta
BNT162b2≥140.14 (0.09–0.22)≥70.10 (0.02–0.40)Gamma
mRNA-1273≥140.07 (0.02–0.27)——Gamma
BNT162b2≥140.17 (0.09–0.30)≥70.05 (0.01–0.21)Non-VOC
mRNA-1273≥140.17 (0.05–0.56)——Non-VOC
Bruxvoort et al. [24]mRNA-1273——≥140.025 (0.008–0.073)Delta
mRNA-1273——≥140.034 (0.011–0.105)NA
Skiwronski et al. [32]BNT162b2——≥140.02 (0.02–0.03)Delta
BNT162b2——≥140.04 (0.01–0.17)Alpha
BNT162b2——≥140.03 (0.01–0.07)Gamma
mRNA-1273——≥140.03 (0.02–0.04)Delta
BNT162b2——≥140.03 (0.02–0.04)Delta
mRNA-1273——≥140.02 (0.01–0.04)Delta
mRNA-1273——≥140.13 (0.04–0.44)Alpha
Skiwronski et al. [31]BNT162b2≥210.19 (0.15–0.25)——NA
mRNA-1273≥210.15 (0.09–0.24)——NA
Andrews et al. [34]BNT162b2——≥140.021 (0.005–0.086)Alpha
BNT162b2——≥140.033 (0.03–0.037)Delta
Vaccines 10 00469 g0a1 550
Figure A1. Forest plot odds ratio (OR) against hospitalization. (a): OR with 95% confidence intervals (CI) against COVID-19 hospitalization after being vaccinated (BNT162b2); (b): OR with 95% confidence intervals (CI) against COVID-19 hospitalization after being vaccinated (mRNA-1273).
Figure A1. Forest plot odds ratio (OR) against hospitalization. (a): OR with 95% confidence intervals (CI) against COVID-19 hospitalization after being vaccinated (BNT162b2); (b): OR with 95% confidence intervals (CI) against COVID-19 hospitalization after being vaccinated (mRNA-1273).
Vaccines 10 00469 g0a1

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Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram of the process of study selection.
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram of the process of study selection.
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Figure 2. Forest plot odds ratio (OR) against COVID-19 infection (a): OR with 95% confidence intervals (CI) against COVID-19 infection (partially vaccinated BNT162b2); (b): OR with 95% confidence intervals (CI) against COVID-19 infection (fully vaccinated BNT162b2); (c): OR with 95% confidence intervals (CI) against COVID-19 infection (partially vaccinated mRNA-1273); (d): OR with 95% confidence intervals (CI) against COVID-19 infection (fully vaccinated mRNA-1273).
Figure 2. Forest plot odds ratio (OR) against COVID-19 infection (a): OR with 95% confidence intervals (CI) against COVID-19 infection (partially vaccinated BNT162b2); (b): OR with 95% confidence intervals (CI) against COVID-19 infection (fully vaccinated BNT162b2); (c): OR with 95% confidence intervals (CI) against COVID-19 infection (partially vaccinated mRNA-1273); (d): OR with 95% confidence intervals (CI) against COVID-19 infection (fully vaccinated mRNA-1273).
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Figure 3. Forest plot odds ratio (OR) against VOC (a): OR with 95% confidence intervals (CI) against VOC (partially vaccinated BNT162b2); (b): OR with 95% confidence intervals (CI) against VOC (fully vaccinated BNT162b2); (c): OR with 95% confidence intervals (CI) against VOC (partially vaccinated mRNA-1273); (d): OR with 95% confidence intervals (CI) against VOC (fully vaccinated mRNA-1273).
Figure 3. Forest plot odds ratio (OR) against VOC (a): OR with 95% confidence intervals (CI) against VOC (partially vaccinated BNT162b2); (b): OR with 95% confidence intervals (CI) against VOC (fully vaccinated BNT162b2); (c): OR with 95% confidence intervals (CI) against VOC (partially vaccinated mRNA-1273); (d): OR with 95% confidence intervals (CI) against VOC (fully vaccinated mRNA-1273).
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Figure 4. Forest plot odds ratio (OR) against COVID-19 by time (a): OR with 95% confidence intervals (CI) against COVID-19 infection of 14 or more days after being partially vaccinated (BNT162b2); (b): OR with 95% confidence intervals (CI) against COVID-19 infection of 14 or more days after being fully vaccinated (BNT162b2); (c): OR with its 95% confidence intervals (CI) against COVID-19 infection of 14 or more days after being partially vaccinated (mRNA-1273); (d): OR with its 95% confidence intervals (CI) against COVID-19 infection of 14 or more days after being fully vaccinated (mRNA-1273).
Figure 4. Forest plot odds ratio (OR) against COVID-19 by time (a): OR with 95% confidence intervals (CI) against COVID-19 infection of 14 or more days after being partially vaccinated (BNT162b2); (b): OR with 95% confidence intervals (CI) against COVID-19 infection of 14 or more days after being fully vaccinated (BNT162b2); (c): OR with its 95% confidence intervals (CI) against COVID-19 infection of 14 or more days after being partially vaccinated (mRNA-1273); (d): OR with its 95% confidence intervals (CI) against COVID-19 infection of 14 or more days after being fully vaccinated (mRNA-1273).
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Table
Table 1. Main characteristics of the included articles.
Table 1. Main characteristics of the included articles.
Study/CountryStudy
Period		Study PopulationNumber of Cases/ControlsAge (Years)Female
(%)		Vaccine
Type		Point Time of Assessing VE VariantsNOS
Days after 1 DoseDays after 2 Dose
Tang et al./Qatar [17]23 March 2021
–
7 July 2021		Resident population12,357/50,6160–70+21,095
(33.4)		BNT162b2, mRNA-1273≥14 ≥14 Delta8
Skowronski et al./Canada [18]4 April 2021
–
2 October 2021		Adults in British Columbia3040/49,47750–6927,877
(53)		BNT162b2, mRNA-1273≥21—NA
Alpha,
Gamma,
Delta		6
Chung et al./Canada [19]14 December 2020
–
19 April 2021		Community dwelling people who had symptoms of COVID-19 53,270/270,763≥18185,539
(57.3)		BNT162b2, mRNA-1273≥14 ≥7 NA8
Bernal et al./UK [20]October 2020
–
May 2021		Symptomatic persons who underwent
COVID-19 testing in England 		11,356/96,371≥16NABNT162b2≥21≥14Alpha, Delta8
Thompson et al./US [21]1 January 2021
–
22 June 2021		Laboratory-confirmed SARS-CoV-2 and COVID-19-like illness3251/18,271≥50NABNT162b2, mRNA-1273≥14≥14NA8
Nasreen et al./Canada [22]14 December 2020
–
3 August 2021		Symptomatic community-dwelling individuals82,880/599,591≥16376,607
(55)		BNT162b2, mRNA-1273≥14≥7Alpha, Beta, Gamma, Delta7
Pilishvili et al./US [23]28 December 2020
–
19 May 2021		Health care personnel across 25 U.S. states 1482/3449≥184107
(83)		BNT162b2, mRNA-1273≥14≥7Delta6
Bruxvoort et al./US [24]1 March 2021
–
27 September 2021		KPSCa membership2027/10,135≥185364
(44.1)		mRNA-1273—≥14Alpha,
Gamma,
Delta		7
Olson et al./US [25]1 June2021
–
30 September 2021		Adolescent patients179/28512–18210
(45.3)		BNT162b2—≥14NA6
Tenforde et al./US [26]11 March 2021
–
5 May 2021		US adults590/620≥18613
(50.7)		BNT162b2, mRNA-1273—≥14NA6
Bernal et al./UK [27]8 December 2020
–
19 February 2021		Adults who reported symptoms 44,590/112,340≥7087,066
(55.5)		BNT162b2—≥14Alpha7
Chemaitelly et al./Qatar [28]1 February 2021
–
10 May 2021		Resident population66,042/66,04219–3940,298
(30.5)		mRNA-1273≥14≥14Alpha,
Beta		8
Sheikh et al./UK [29]1 April 2021
–
6 June 2021		Individuals who have a PCR test for SARS-CoV-2 in study period10,827/195,0000–90+NABNT162b2—≥14Alpha,
Delta		8
Carazo et al./Canada [30]17 January 2021
–
5 June 2021		Healthcare workers5316/53,16018–7448,513
(83)		BNT162b2, mRNA-1273≥14≥7NA6
Skowronski et al./Canada [31]4 April 2021
–
1 May 2021		Community-dwelling adults in British Columbia1226/15,767≥708657
(50.9)		BNT162b2, mRNA-1273≥21—NA6
Skowronski et al./Canada [32]3 May 2021
–
2 October 2021		Community-dwelling adults in British Columbia and QuebecBritish:27,439/353,093
Quebec:17,234/837,681		≥18British:211,999
(56)
Quebee:511,620
(60)		BNT162b2, mRNA-1273—≥14NA,
Alpha,
Gamma,
Delta		7
Kissling et al. [33]10 December 2021
–
31 May 2021		Adults in 8 European countries592/4372≥652933
(60)		BNT162b2≥14≥7NA6
Andrews et al./UK [34]8 December 2020
–
3 September 2021		Symptomatic adults1475,391/3757,981≥162,928,972
(56)		BNT162b2, mRNA-1273—≥14Alpha,
Delta		8
Chemaitelly et al./Qatar [35]1 January 2021
–
5 September 2021		Resident population142,300/848,2400–70+NABNT162b2≥21—NA
Alpha,
Beta,
Delta		8
a. KPSC: integrated healthcare system with 15 hospitals and associated medical offices across Southern California.
Table
Table 2. Effectiveness of the BNT162b2 vaccine against SARS-CoV-2 infection after 1 dose and after 2 doses.
Table 2. Effectiveness of the BNT162b2 vaccine against SARS-CoV-2 infection after 1 dose and after 2 doses.
First AuthorBNT162b2 OR 1Variant
14 Days after 1 Dose21 Days after 1 Dose7 Days after 2 Doses14 Days after 2 Doses
Chung et al. [19]0.41 (0.38–0.45)—0.09 (0.02–0.12)NANA
Bernal et al. [20]—0.525 (0.472–0.584)—0.063 (0.047–0.084)Alpha
—0.644 (0.536–0.773)—0.12 (0.099–0.147)Delta
Pilishvili et al. [23]0.161 (0.121–0.213)—0.085 (0.06–0.121)—Delta
Thompson et al. [21]0.42 (0.32–0.54)——0.11 (0.09–0.15)NA
Tenforde et al. [26]———0.155 (0.091–0.262)NA
Bernal et al. [27]———0.17 (0.12–0.23)Alpha
Sheikh et al. [29]———0.21 (0.18–0.25)Delta
———0.08 (0.07–0.10)Alpha
———0.17 (0.13–0.22)Delta
———0.08 (0.06–0.12)Alpha
Chemaitelly et al. [35]0.632 (0.598–0.668)———NA
0.521 (0.321–0.845)———Alpha
0.742 (0.539–1.02)———Beta
0.366 (0.234–0574)———Delta
Skowronski et al. [31]NA0.36 (0.29–0.43)——NA
Nasreen et al. [22]0.33 (0.32–0.35)—0.11 (0.10–0.13)—Alpha
0.5 (0.30–0.85)—0.13 (0.02–0.92)—Beta
0.37 (0.30–0.46)—0.12 (0.06–0.27)—Gamma
0.43 (0.39–0.47)—0.08 (0.06–0.10)—Delta
Skowronski et al. [32]———0.09 (0.08–0.09)Delta
———0.04 (0.02–0.07)Alpha
———0.07 (0.05–0.11)Gamma
———0.12 (0.11–0.12)NA
———0.11 (0.11–0.12)Delta
———0.02 (0.02–0.03)Alpha
Carazo et al. [30]0.297 (0.276–0.319)—0.145 (0.107–0.196)—NA
Kissling et al. [33]0.39 (0.25–0.61)—0.13 (0.07–0.13)—NA
Skowronski et al. [18]NA0.25 (0.22–0.28)——NA
NA0.23 (0.19–0.29)——Alpha
NA0.21 (0.16–0.27)——Gamma
NA0.26 (0.12–0.55)——Delta
Tang et al. [17]0.547 (0.384–0.78)——0.481 (0.436–0.53)Delta
Andrews et al. [34]———0.05 (0.041–0.062)Alpha
———0.165 (0.164–0.167)Delta
Olson et al. [25]———0.07 (0.03–0.17)NA
OR 1: odds ratio (OR) against COVID-19 infection confirmed by PCR test.
Table
Table 3. Effectiveness of the mRNA-1273 vaccine against SARS-CoV-2 infection after 1 dose and after 2 doses.
Table 3. Effectiveness of the mRNA-1273 vaccine against SARS-CoV-2 infection after 1 dose and after 2 doses.
First AuthormRNA-1273 OR 1Variants
14 Days after 1 Dose21 Days after 1 Dose7 Days after 2 Doses14 Days after 2 Doses
Chung et al. [19]0.28 (0.20–0.37)—0.06 (0.03–0.14)—NA
Pilishvili et al. [23]0.163 (0.124–0.214)—0.08 (0.057–0.113)—Delta
Thompson et al. [21]0.27 (0.21–0.36)——0.08 (0.06–0.11)NA
Tenforde et al. [26]———0.113 (0.059–0.215)NA
Skowronski et al. [31]—0.29 (0.19–0.44)——NA
Nasreen et al. [22]0.18 (0.16–0.20)—0.08 (0.02–0.15)—Alpha
0.11 (0.05–0.24)———Gamma
0.30 (0.24–0.36)—0.05 (0.03–0.09)—Delta
Skowronski et al. [32]———0.09 (0.09–0.10)NA
———0.10 (0.09–0.10)Delta
———0.08 (0.07–0.09)Alpha
———0.09 (0.08–0.10)Gamma
———0.05 (0.02–0.15)NA
———0.03 (0.01–0.05)Delta
———0.05 (0.01–0.15)Alpha
Carazo et al. [30]0.313 (0.241–0.405)—0.159 (0.039–0.651)—NA
Bruxvoort et al. [24]———0.016 (0.009–0.031)Alpha
———0.133 (0.113–0.157)Delta
———0.045 (0.022–0.091)Gamma
Skowronski et al. [18]—0.18 (0.13–0.24)——NA
—0.15 (0.08–0.26)——Alpha
—0.15 (0.08–0.29)——Gamma
—0.27 (0.06–1.14)——Delta
Tang et al. [17]0.263 (0.165–0.419)——0.269 (0.222–0.325)Delta
Andrews et al. [34]———0.052 (0.048–0.056)Delta
Chemaitelly et al. [28]0.119 (0.085–0.163)———Alpha
0.387 (0.345–0.455)——0.036 (0.013–0.081)Beta
OR 1: odds ratio (OR) against COVID-19 infection confirmed by PCR test.
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Chang, S.; Liu, H.; Wu, J.; Xiao, W.; Chen, S.; Qiu, S.; Duan, G.; Song, H.; Zhang, R. Effectiveness of BNT162b2 and mRNA-1273 Vaccines against COVID-19 Infection: A Meta-Analysis of Test-Negative Design Studies. Vaccines 2022, 10, 469. https://doi.org/10.3390/vaccines10030469

AMA Style

Chang S, Liu H, Wu J, Xiao W, Chen S, Qiu S, Duan G, Song H, Zhang R. Effectiveness of BNT162b2 and mRNA-1273 Vaccines against COVID-19 Infection: A Meta-Analysis of Test-Negative Design Studies. Vaccines. 2022; 10(3):469. https://doi.org/10.3390/vaccines10030469

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Chang, Shuailei, Hongbo Liu, Jian Wu, Wenwei Xiao, Sijia Chen, Shaofu Qiu, Guangcai Duan, Hongbin Song, and Rongguang Zhang. 2022. "Effectiveness of BNT162b2 and mRNA-1273 Vaccines against COVID-19 Infection: A Meta-Analysis of Test-Negative Design Studies" Vaccines 10, no. 3: 469. https://doi.org/10.3390/vaccines10030469

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