Characteristics of included studies

In total, 17 studies met the inclusion criteria ^{Reference Bajema, Dahl and Prill23–Reference Tartof, Slezak and Fischer33,Reference Braeye, Cornelissen and Catteau37–Reference Thompson, Stenehjem and Grannis42} and were included in the final review (Table 1). Almost all of these studies were nonrandomized (16 studies), and of these, 12 were retrospective cohort studies. ^{Reference Bajema, Dahl and Prill23,Reference Bozio, Grannis and Naleway24,Reference Cohn, Cirillo, Murphy, Krigbaum and Wallace26–Reference Embi, Levy and Naleway28,Reference Nanduri, Pilishvili and Derado30–Reference Tartof, Slezak and Fischer33,Reference Braeye, Cornelissen and Catteau37,Reference Self, Tenforde and Rhoads39,Reference Tande, Pollock, Shah, Binnicker and Berbari40} Also, 1 study was a prospective cohort study ^{Reference Fowlkes, Gaglani, Groover, Thiese, Tyner and Ellingson29} and 3 studies were case–control studies. ^{Reference Chemaitelly, Tang and Hasan25,Reference Kissling, Hooiveld and Sandonis Martín38,Reference Thompson, Stenehjem and Grannis42} Only 1 study was a randomized clinical trial. ^{Reference Thomas, Moreira and Kitchin41} All but 1 of these studies evaluated the Pfizer/BioNTech vaccine (16 studies). ^{Reference Bajema, Dahl and Prill23–Reference Cohn, Cirillo, Murphy, Krigbaum and Wallace26,Reference Embi, Levy and Naleway28–Reference Tartof, Slezak and Fischer33,Reference Braeye, Cornelissen and Catteau37,Reference Self, Tenforde and Rhoads39–Reference Thompson, Stenehjem and Grannis42} Of these studies, 13 analyzed the Moderna vaccine ^{Reference Bajema, Dahl and Prill23,Reference Bozio, Grannis and Naleway24,Reference Cohn, Cirillo, Murphy, Krigbaum and Wallace26,Reference Embi, Levy and Naleway28–Reference Nunes, Rodrigues and Kislaya32,Reference Braeye, Cornelissen and Catteau37,Reference Self, Tenforde and Rhoads39,Reference Tande, Pollock, Shah, Binnicker and Berbari40,Reference Thompson, Stenehjem and Grannis42} ; 7 studies analyzed the Janssen vaccine, ^{Reference Cohn, Cirillo, Murphy, Krigbaum and Wallace26,Reference Corchado-Garcia, Zemmour and Hughes27,Reference Fowlkes, Gaglani, Groover, Thiese, Tyner and Ellingson29,Reference Braeye, Cornelissen and Catteau37–Reference Self, Tenforde and Rhoads39,Reference Thompson, Stenehjem and Grannis42} 1 of which evaluated only the Janssen vaccine ^{Reference Corchado-Garcia, Zemmour and Hughes27} ; and 3 studies analyzed the AstraZeneca vaccine, ^{Reference Nordström, Ballin and Nordström31,Reference Braeye, Cornelissen and Catteau37,Reference Kissling, Hooiveld and Sandonis Martín38} 1 of which evaluated mixing COVID-19 vaccines. ^{Reference Nordström, Ballin and Nordström31}

Table 1. Summary of Characteristics of Studies Included in the Systematic Literature Review

Note. A, asymptomatic; S, symptomatic; SD, standard deviation; IQR, interquartile range; IRR, incidence rate ratio; HR, hazard ratio [HR]; RR’, relative risk; OR, odds ratio; 95% CI, 95% confidence interval; VE, vaccine effectiveness; NR, not reported; N, number reported; RCT, randomized controlled trial.

Table 2. Subset Analyses Evaluating Long-Term COVID-19 Vaccine Effectiveness Among Fully Vaccinated Individuals

Note. CI, confidence interval; mRNA, Pfizer/BioNTech and Moderna; viral vector, AstraZeneca, and Janssen.

^a Vaccine effectiveness was estimated as 100% × (1 − DOR).

Fully vaccinated is defined as receiving 2 doses of Pfizer/BioNTech, Moderna, or AstraZeneca vaccine, or 1 dose of Janssen vaccine.

Most of the studies included in our review were conducted in the United States (12 studies) ^{Reference Bajema, Dahl and Prill23,Reference Bozio, Grannis and Naleway24,Reference Cohn, Cirillo, Murphy, Krigbaum and Wallace26–Reference Nanduri, Pilishvili and Derado30,Reference Tartof, Slezak and Fischer33,Reference Self, Tenforde and Rhoads39–Reference Thompson, Stenehjem and Grannis42} ; 1 study was a multicenter study performed in Europe (assembling data from England, France, Ireland, Netherlands, Portugal, Scotland, Spain, and Sweden) ^{Reference Kissling, Hooiveld and Sandonis Martín38} ; and 1 study was performed in each of these countries: Belgium, ^{Reference Braeye, Cornelissen and Catteau37} Qatar, ^{Reference Chemaitelly, Tang and Hasan25} Sweden, ^{Reference Nordström, Ballin and Nordström31} and Portugal. ^{Reference Nunes, Rodrigues and Kislaya32} All studies were performed between December 2020 and October 2021. ^{Reference Bajema, Dahl and Prill23–Reference Tartof, Slezak and Fischer33,Reference Braeye, Cornelissen and Catteau37–Reference Thompson, Stenehjem and Grannis42}

Moreover, 10 studies evaluated long-term vaccine effectiveness for COVID-19, ^{Reference Chemaitelly, Tang and Hasan25–Reference Corchado-Garcia, Zemmour and Hughes27,Reference Fowlkes, Gaglani, Groover, Thiese, Tyner and Ellingson29–Reference Nordström, Ballin and Nordström31,Reference Tartof, Slezak and Fischer33,Reference Kissling, Hooiveld and Sandonis Martín38,Reference Tande, Pollock, Shah, Binnicker and Berbari40,Reference Thomas, Moreira and Kitchin41} 8 studies evaluated long-term vaccine effectiveness for COVID-19 hospitalizations, ^{Reference Bajema, Dahl and Prill23–Reference Chemaitelly, Tang and Hasan25,Reference Embi, Levy and Naleway28,Reference Nordström, Ballin and Nordström31,Reference Nunes, Rodrigues and Kislaya32,Reference Self, Tenforde and Rhoads39,Reference Thompson, Stenehjem and Grannis42} with 2 studies overlapping. ^{Reference Chemaitelly, Tang and Hasan25,Reference Nordström, Ballin and Nordström31} The study duration varied from 5 to 14 months. ^{Reference Bajema, Dahl and Prill23–Reference Tartof, Slezak and Fischer33,Reference Braeye, Cornelissen and Catteau37–Reference Thompson, Stenehjem and Grannis42}

Furthermore, 13 studies reported genomic surveillance data. ^{Reference Bajema, Dahl and Prill23–Reference Cohn, Cirillo, Murphy, Krigbaum and Wallace26,Reference Embi, Levy and Naleway28–Reference Tartof, Slezak and Fischer33,Reference Braeye, Cornelissen and Catteau37,Reference Kissling, Hooiveld and Sandonis Martín38} Also, 11 studies reported detecting the new SARS-CoV-2 B.1.617.2 δ (delta) variant ^{Reference Bajema, Dahl and Prill23–Reference Tartof, Slezak and Fischer33} ; 7 studies reported only δ variant during the long-term vaccine effectiveness evaluation ^{Reference Bajema, Dahl and Prill23,Reference Bozio, Grannis and Naleway24,Reference Cohn, Cirillo, Murphy, Krigbaum and Wallace26,Reference Embi, Levy and Naleway28–Reference Nordström, Ballin and Nordström31} ; 2 studies reported the B.1.1.7 α (alpha) variant and δ variant ^{Reference Corchado-Garcia, Zemmour and Hughes27,Reference Nunes, Rodrigues and Kislaya32} ; 1 study reported the B.1.351 β (beta) variant and δ variant, ^{Reference Chemaitelly, Tang and Hasan25} and 1 study reported α, β, γ (gamma or P.1), and δ variants. ^{Reference Chemaitelly, Tang and Hasan25}

Studies varied with regards to the type of statistical analysis performed. Nine studies used logistic regression ^{Reference Bajema, Dahl and Prill23–Reference Chemaitelly, Tang and Hasan25,Reference Embi, Levy and Naleway28,Reference Braeye, Cornelissen and Catteau37–Reference Self, Tenforde and Rhoads39,Reference Thomas, Moreira and Kitchin41,Reference Thompson, Stenehjem and Grannis42} ; 5 studies used Cox proportional hazard analysis ^{Reference Cohn, Cirillo, Murphy, Krigbaum and Wallace26,Reference Fowlkes, Gaglani, Groover, Thiese, Tyner and Ellingson29,Reference Nordström, Ballin and Nordström31–Reference Tartof, Slezak and Fischer33} ; 1 study used propensity matched scoring ^{Reference Corchado-Garcia, Zemmour and Hughes27} ; 1 study used Poisson distribution for adjusted logistic regression ^{Reference Nanduri, Pilishvili and Derado30} ; and 1 study used mixed-effects modeling. ^{Reference Tande, Pollock, Shah, Binnicker and Berbari40}

Regarding the quality assessment scores of the 17 included studies, >75% of the studies (13 studies) were considered good quality (ie, 19–23 of 28 possible points) per the Downs and Black quality tool. ^{Reference Bajema, Dahl and Prill23,Reference Chemaitelly, Tang and Hasan25–Reference Fowlkes, Gaglani, Groover, Thiese, Tyner and Ellingson29,Reference Nordström, Ballin and Nordström31–Reference Tartof, Slezak and Fischer33,Reference Kissling, Hooiveld and Sandonis Martín38–Reference Tande, Pollock, Shah, Binnicker and Berbari40,Reference Thompson, Stenehjem and Grannis42} Also, 3 studies were considered fair quality (ie, 14–18 points) ^{Reference Bozio, Grannis and Naleway24,Reference Nanduri, Pilishvili and Derado30,Reference Braeye, Cornelissen and Catteau37} and 1 study was considered high quality (ie, >24 points). ^{Reference Thomas, Moreira and Kitchin41}

Results pooled by COVID-19 vaccine type and COVID-19 outcome

Overall, we included 17,939,172 individuals from 16 studies in the meta-analysis. ^{Reference Bajema, Dahl and Prill23–Reference Tartof, Slezak and Fischer33,Reference Kissling, Hooiveld and Sandonis Martín38–Reference Thompson, Stenehjem and Grannis42} Among them, 10 studies evaluated the long-term vaccine effectiveness of mRNA or viral vector vaccines (ie, AstraZeneca or Janssen). ^{Reference Chemaitelly, Tang and Hasan25–Reference Corchado-Garcia, Zemmour and Hughes27,Reference Fowlkes, Gaglani, Groover, Thiese, Tyner and Ellingson29–Reference Nordström, Ballin and Nordström31,Reference Tartof, Slezak and Fischer33,Reference Kissling, Hooiveld and Sandonis Martín38,Reference Tande, Pollock, Shah, Binnicker and Berbari40,Reference Thomas, Moreira and Kitchin41} The estimated long-term vaccine effectiveness for COVID-19 was 84.2% (95% CI, 84.0%–84.3%). Also, 5 studies evaluated the long-term vaccine effectiveness of the Pfizer/BioNTech vaccine, ^{Reference Chemaitelly, Tang and Hasan25,Reference Cohn, Cirillo, Murphy, Krigbaum and Wallace26,Reference Nanduri, Pilishvili and Derado30,Reference Tartof, Slezak and Fischer33,Reference Thomas, Moreira and Kitchin41} and 2 studies evaluated the Moderna vaccine. ^{Reference Cohn, Cirillo, Murphy, Krigbaum and Wallace26,Reference Nanduri, Pilishvili and Derado30} The estimated long-term vaccine effectiveness against COVID-19 of the Pfizer/BioNTech COVID-19 vaccine was 81.5% (95% CI, 81.3%–81.6%). Furthermore, 4 studies evaluated vaccine effectiveness of the mRNA or viral vector vaccines during the δ variant period ^{Reference Chemaitelly, Tang and Hasan25,Reference Fowlkes, Gaglani, Groover, Thiese, Tyner and Ellingson29,Reference Nanduri, Pilishvili and Derado30,Reference Tande, Pollock, Shah, Binnicker and Berbari40} ; 2 studies evaluated vaccine effectiveness of the Pfizer/BioNTech COVID-19 vaccine only ^{Reference Chemaitelly, Tang and Hasan25,Reference Nanduri, Pilishvili and Derado30} , and 2 studies reported vaccine effectiveness of the Moderna COVID-19 vaccine only. ^{Reference Chemaitelly, Tang and Hasan25,Reference Nanduri, Pilishvili and Derado30} The estimated long-term vaccine effectiveness for COVID-19 with mRNA or viral vector vaccines during the δ variant–dominant period was 61.2% (95% CI, 59.0%–63.3%).

Among the 16 studies, 8 studies evaluated the long-term vaccine effectiveness of mRNA or viral vector vaccines for COVID-19 hospitalization. ^{Reference Bajema, Dahl and Prill23–Reference Chemaitelly, Tang and Hasan25,Reference Embi, Levy and Naleway28,Reference Nordström, Ballin and Nordström31,Reference Nunes, Rodrigues and Kislaya32,Reference Self, Tenforde and Rhoads39,Reference Thompson, Stenehjem and Grannis42} The estimated long-term vaccine effectiveness against COVID-19 was 88.7% (95% CI, 55.8%–97.1%). In stratified analyses, 6 studies evaluated long-term vaccine effectiveness for COVID-19 hospitalization with the Pfizer/BioNTech vaccine, ^{Reference Bajema, Dahl and Prill23–Reference Chemaitelly, Tang and Hasan25,Reference Embi, Levy and Naleway28,Reference Self, Tenforde and Rhoads39,Reference Thompson, Stenehjem and Grannis42} and 5 studies with the Moderna vaccine. ^{Reference Bajema, Dahl and Prill23,Reference Bozio, Grannis and Naleway24,Reference Embi, Levy and Naleway28,Reference Self, Tenforde and Rhoads39,Reference Thompson, Stenehjem and Grannis42} The estimated long-term vaccine effectiveness for COVID-19 hospitalization with the Pfizer/BioNTech vaccine was 85.4% (95% CI, 84.8%–86.0%). The estimated long-term vaccine effectiveness for COVID-19 hospitalization with the Moderna vaccine was 89.8% (95% CI, 89.2%–90.4%). Only 1 study evaluated COVID-19 hospitalization during the δ variant period with mRNA vaccines. ^{Reference Bozio, Grannis and Naleway24} This study did not report the COVID-19 vaccine effectiveness but reported that the adjusted odds of COVID-19 was higher among unvaccinated and previously infected patients compared with fully vaccinated individuals (adjusted odds ratio, 5.49; 95% CI, 2.75–10.99). ^{Reference Bozio, Grannis and Naleway24}

The results of meta-analyses were homogeneous for COVID-19 with mRNA or viral vector vaccines (heterogeneity P = .76; I² = 0%); studies evaluating individuals vaccinated with the Pfizer/BioNTech vaccine alone (heterogeneity P = .55; I² = 0%); and studies evaluating individuals vaccinated with mRNA or viral vector vaccines during the δ variant period (heterogeneity P = .50; I² = 0%).

Meta-analysis results were also homogeneous for COVID-19 hospitalization (studies evaluating individuals vaccinated with mRNA or viral vector vaccines (heterogeneity P = .67; I² = 0%); and studies evaluating individuals vaccinated with the Moderna vaccine alone (heterogeneity P = .28; I² = 20%). However, results were not homogenous for studies of COVID-19 hospitalization only evaluating individuals vaccinated with the Pfizer/BioNTech vaccine alone (heterogeneity P = .07; I² = 51%) or for studies of COVID-19 hospitalization only evaluating individuals vaccinated with the Moderna vaccine alone (heterogeneity P = .21; I² = 32%).