Characteristics of included studies

Overall, 16 studies met the inclusion criteria ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18–Reference Walsh, Skally and Traynor33} and were included in the final review (Table 1). All of these studies were nonrandomized: 8 were retrospective cohort studies, ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18,Reference Angel, Spitzer and Henig19,Reference Cavanaugh, Fortier and Lewis21–Reference Garvey, Wilkinson and Holden23,Reference Jones, Rivett and Seaman26,Reference Swift, Breeher and Tande30,Reference Walsh, Skally and Traynor33} 6 were prospective cohort studies, ^{Reference Bianchi, Germinario and Migliore20,Reference Hall, Foulkes and Saei25,Reference Pryor, Cooper and Britton28,Reference Sansone, Tiraboschi and Sala29,Reference Tang, Hijano and Gaur31,Reference Thompson, Burgess and Naleway32} and 2 were case–control studies. ^{Reference Gras-Valentí, Chico-Sánchez and Algado-Sellés24,Reference Pilishvili, Fleming-Dutra and Farrar27} All of the studies evaluated the Pfizer/BioNTech mRNA COVID-19 vaccine, ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18–Reference Walsh, Skally and Traynor33} 2 studies also analyzed the Moderna mRNA COVID-19 vaccine, ^{Reference Pilishvili, Fleming-Dutra and Farrar27,Reference Tang, Hijano and Gaur31} and another study also analyzed the AstraZeneca COVID-19 vaccine ^{Reference Hall, Foulkes and Saei25} (but this study was not considered in the vaccine effectiveness analysis). No study evaluated the vaccine effectiveness for the Johnson & Johnson/Janssen vaccine. Nearly all HCWs (99.9%) were vaccinated with the Pfizer/BioNTech COVID-19 mRNA vaccine. ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18–Reference Walsh, Skally and Traynor33}

Table 1.

Summary of Characteristics of Studies Included in the Systematic Literature Review

* Genomic investigation about the new variants: (Cavanaugh 2021: R.1 lineage variant; Jones 2021: B.1.1.7 [alpha] variant; Sansone 2021: B.1.1.7 [α] variant)

Note. S/A, symptomatic and asymptomatic; S, symptomatic; SD, standard deviation; IQR, interquartile range; IRR, incidence rate ratio; RRed, rate reduction; HR, hazard ratio; RR’, relative risk; OR, odds ratio; CI, confidence interval; VE, vaccine effectiveness; D&B, Downs and Black scale; NR, not reported, N, no. reported.

Most of the studies included in our review were conducted in the United States (6 studies) ^{Reference Cavanaugh, Fortier and Lewis21,Reference Pilishvili, Fleming-Dutra and Farrar27,Reference Pryor, Cooper and Britton28,Reference Swift, Breeher and Tande30–Reference Thompson, Burgess and Naleway32} ; 3 studies were performed in Italy ^{Reference Bianchi, Germinario and Migliore20,Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22,Reference Sansone, Tiraboschi and Sala29} ; 3 were performed in the United Kingdom ^{Reference Garvey, Wilkinson and Holden23,Reference Hall, Foulkes and Saei25,Reference Jones, Rivett and Seaman26} ; 2 studies were performed in Israel ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18,Reference Angel, Spitzer and Henig19} ; 1 was conducted in Spain ^{Reference Gras-Valentí, Chico-Sánchez and Algado-Sellés24} ; and 1 was conducted in Ireland. ^{Reference Thompson, Burgess and Naleway32} All studies were performed between December 2020 and April 2021. ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18–Reference Walsh, Skally and Traynor33}

Overall, we included 195,801 HCWs in the qualitative analysis. Moreover, 6 studies evaluated vaccine effectiveness >7 days after the second dose, ^{Reference Angel, Spitzer and Henig19,Reference Bianchi, Germinario and Migliore20,Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22,Reference Hall, Foulkes and Saei25,Reference Pilishvili, Fleming-Dutra and Farrar27,Reference Sansone, Tiraboschi and Sala29} 3 studies evaluated vaccine effectiveness >14 days after the second dose, ^{Reference Cavanaugh, Fortier and Lewis21,Reference Swift, Breeher and Tande30,Reference Thompson, Burgess and Naleway32} 1 study evaluated vaccine effectiveness after HCWs received the second dose on day 21 or day 22 after the first dose, ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18} and the other 6 studies did not report the time the vaccine was considered effective. ^{Reference Garvey, Wilkinson and Holden23,Reference Gras-Valentí, Chico-Sánchez and Algado-Sellés24,Reference Jones, Rivett and Seaman26,Reference Pryor, Cooper and Britton28,Reference Tang, Hijano and Gaur31,Reference Walsh, Skally and Traynor33} Of the HCWs included that received the first dose, 6 studies evaluated the effectiveness of COVID-19 vaccine >14 days after the first dose, ^{Reference Bianchi, Germinario and Migliore20,Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22,Reference Pilishvili, Fleming-Dutra and Farrar27,Reference Pryor, Cooper and Britton28,Reference Swift, Breeher and Tande30,Reference Thompson, Burgess and Naleway32} 2 studies evaluated the vaccine effectiveness >12 days after the first dose, ^{Reference Gras-Valentí, Chico-Sánchez and Algado-Sellés24,Reference Jones, Rivett and Seaman26} 1 study evaluated the vaccine effectiveness >10 days after the first dose, ^{Reference Garvey, Wilkinson and Holden23} and 1 study evaluated >21 days after the first dose. ^{Reference Bianchi, Germinario and Migliore20} Also, 1 study evaluated vaccine effectiveness from day 1 to day 14 after the first dose. ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18} Another study evaluated vaccine effectiveness from day 7 to day 28 after the first dose, ^{Reference Cavanaugh, Fortier and Lewis21} and another study evaluated vaccine effectiveness up 39 days after the first dose: 0−7 days, 8−14 days, 15−21 days, 22−30 days, and 39 days. ^{Reference Walsh, Skally and Traynor33} Furthermore, 3 studies did not report the period after vaccination ^{Reference Pilishvili, Fleming-Dutra and Farrar27,Reference Sansone, Tiraboschi and Sala29} and 5 studies reported asymptomatic cases in vaccinated and unvaccinated HCWs. ^{Reference Angel, Spitzer and Henig19,Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22,Reference Hall, Foulkes and Saei25,Reference Swift, Breeher and Tande30,Reference Tang, Hijano and Gaur31}

The studies we reviewed varied regarding the reportage of the infection rates and the type of statistical analyses performed. To determine vaccine effectiveness, 4 studies used Poisson distribution for adjusted logistic regression, ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18,Reference Angel, Spitzer and Henig19,Reference Hall, Foulkes and Saei25,Reference Swift, Breeher and Tande30} 3 studies used adjusted regression and Cox proportional hazard models, ^{Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22,Reference Garvey, Wilkinson and Holden23,Reference Thompson, Burgess and Naleway32} and 3 studies used unadjusted odds ratio calculation. ^{Reference Pryor, Cooper and Britton28,Reference Sansone, Tiraboschi and Sala29,Reference Walsh, Skally and Traynor33} In addition, 2 studies used conditional logistical regression, ^{Reference Gras-Valentí, Chico-Sánchez and Algado-Sellés24,Reference Pilishvili, Fleming-Dutra and Farrar27} 2 studies used survival curves for the vaccinated and unvaccinated groups using Kaplan-Meier, ^{Reference Bianchi, Germinario and Migliore20,Reference Tang, Hijano and Gaur31} 1 study used the Fisher exact test, ^{Reference Jones, Rivett and Seaman26} and 1 study used the risk ratio calculation to determine the vaccine effectiveness. ^{Reference Cavanaugh, Fortier and Lewis21}

Among the studies we reviewed, genomic surveillance detection of the new SARS-CoV-2 B.1.1.7 or α variant ^{Reference Jones, Rivett and Seaman26,Reference Sansone, Tiraboschi and Sala29} was conducted in 2 studies, and 1 outbreak study identified a new SARS-CoV-2 variant (R.1 lineage variant). ^{Reference Cavanaugh, Fortier and Lewis21} Genomic surveillance was not performed in most of the studies we reviewed. ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18–Reference Bianchi, Germinario and Migliore20,Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22–Reference Hall, Foulkes and Saei25,Reference Pilishvili, Fleming-Dutra and Farrar27,Reference Pryor, Cooper and Britton28,Reference Swift, Breeher and Tande30–Reference Walsh, Skally and Traynor33}

Among the 3 studies that reported the presence of underlying medical conditions, ^{Reference Hall, Foulkes and Saei25,Reference Pilishvili, Fleming-Dutra and Farrar27,Reference Thompson, Burgess and Naleway32} 1 study showed that 75% of participants had no underlying medical condition, ^{Reference Hall, Foulkes and Saei25} 1 study showed that ∼70% had no medical condition but that ∼30% had at least 1 chronic condition. ^{Reference Thompson, Burgess and Naleway32} In 1 case–control study, 75% of the case patients (symptomatic COVID-19) and the controls (non–COVID-19 patients) had at least 1 underlying condition or risk factor associated with increased risk for severe COVID-19. ^{Reference Pilishvili, Fleming-Dutra and Farrar27} Proportions of immunocompromised HCWs were reported in only 2 studies with a rate at 2% ^{Reference Hall, Foulkes and Saei25} to 5%. ^{Reference Pilishvili, Fleming-Dutra and Farrar27} None of the included studies reported rates of adverse events after vaccination. ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18–Reference Walsh, Skally and Traynor33}

Regarding the quality assessment scores of the 16 included studies, 9 studies were considered good quality (19–23 of 28 possible points) on the Downs and Black quality tool, ^{Reference Amit, Regev-Yochay, Afek, Kreiss and Leshem18–Reference Bianchi, Germinario and Migliore20,Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22,Reference Gras-Valentí, Chico-Sánchez and Algado-Sellés24,Reference Hall, Foulkes and Saei25,Reference Pilishvili, Fleming-Dutra and Farrar27,Reference Swift, Breeher and Tande30,Reference Thompson, Burgess and Naleway32} 5 studies were considered fair quality (14–18 points), ^{Reference Cavanaugh, Fortier and Lewis21,Reference Pryor, Cooper and Britton28,Reference Sansone, Tiraboschi and Sala29,Reference Tang, Hijano and Gaur31,Reference Walsh, Skally and Traynor33} and 2 studies were considered poor quality (<14). ^{Reference Garvey, Wilkinson and Holden23,Reference Jones, Rivett and Seaman26}

Results pooled by each COVID-19 vaccination dose and COVID-19 status

The review included 13 studies in which 173,742 HCWs were evaluated for vaccine effectiveness and were included in the meta-analysis. ^{Reference Angel, Spitzer and Henig19–Reference Hall, Foulkes and Saei25,Reference Pilishvili, Fleming-Dutra and Farrar27–Reference Tang, Hijano and Gaur31,Reference Walsh, Skally and Traynor33} The pooled DOR for symptomatic COVID-19 among HCWs vaccinated with at least 1 dose was 0.072 (95% CI, 0.028–0.184), with an estimated the vaccine effectiveness of 92.8% (95% CI, 81.6%–97.2%). Among 13 studies, 7 studies evaluated vaccine effectiveness of 2 doses in HCWs. ^{Reference Angel, Spitzer and Henig19–Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22,Reference Pilishvili, Fleming-Dutra and Farrar27,Reference Sansone, Tiraboschi and Sala29,Reference Swift, Breeher and Tande30} The pooled DOR for this group of studies was 0.065 (95% CI, 0.024–0.175) and the estimated vaccine effectiveness was 93.5% (95% CI, 82.5%–97.6%). Also, 6 studies evaluated vaccine effectiveness of 1 dose of vaccine in HCWs. ^{Reference Angel, Spitzer and Henig19,Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22,Reference Pilishvili, Fleming-Dutra and Farrar27,Reference Pryor, Cooper and Britton28,Reference Swift, Breeher and Tande30,Reference Thompson, Burgess and Naleway32} The pooled DOR for these studies was 0.179 (95% CI, 0.059–0.539) and the estimated vaccine effectiveness was 82.1% (95% CI, 46.1%–94.1%).

Stratifying the analysis for studies reporting both symptomatic and asymptomatic COVID-19, 10 studies evaluated vaccine effectiveness among vaccinated HCWs who had received 1 and 2 doses. ^{Reference Angel, Spitzer and Henig19–Reference Garvey, Wilkinson and Holden23,Reference Hall, Foulkes and Saei25,Reference Sansone, Tiraboschi and Sala29–Reference Tang, Hijano and Gaur31,Reference Walsh, Skally and Traynor33} The pooled DOR for this group of studies was 0.082 (95% CI, 0.030–0.223) and the estimated vaccine effectiveness was 91.8% (95% CI, 77.7−97.0%). In 3 studies evaluating vaccine effectiveness among HCWs with 2 doses, ^{Reference Angel, Spitzer and Henig19,Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22,Reference Swift, Breeher and Tande30} the pooled DOR was 0.035 (95% CI, 0.013−0.100) and the estimated vaccine effectiveness was 96.5% (95% CI, 90.0−98.7%). In 6 studies evaluating vaccine effectiveness among HCWs who had received only 1 dose of vaccine, ^{Reference Angel, Spitzer and Henig19,Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22–Reference Hall, Foulkes and Saei25,Reference Swift, Breeher and Tande30} the pooled DOR was 0.213 (95% CI, 0.040−1.138) and the estimated vaccine effectiveness was 78.7% (95% CI, −13.8% to 96.0%). Stratifying the analysis for only asymptomatic COVID-19, 4 studies evaluated vaccine effectiveness among HCWs who had received 2 doses of vaccine. ^{Reference Angel, Spitzer and Henig19,Reference Cavanaugh, Fortier and Lewis21,Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22,Reference Swift, Breeher and Tande30} The pooled DOR for this group of studies was 0.089 (95% CI, 0.029−0.274) and the estimated vaccine effectiveness was 85.3% (95% CI, 47.7%−95.9%). In 3 studies evaluating vaccine effectiveness among HCWs who had received only 1 dose of vaccine, ^{Reference Angel, Spitzer and Henig19,Reference Fabiani, Ramigni, Gobbetto, Mateo-Urdiales, Pezzotti and Piovesan22,Reference Swift, Breeher and Tande30} the pooled DOR for this group of studies was 0.364 (95% CI, 0.104−1.276) and the estimated vaccine effectiveness was 63.3% (95% CI, −27.6% to 89.6%).

The results of both meta-analyses were homogeneous for symptomatic COVID-19 (all studies evaluating vaccinated HCWs: heterogeneity P = .86, I ^{Reference Hodgson, Mansatta, Mallett, Harris, Emary and Pollard2} = 0%; 2 doses: heterogeneity P = 0.70, I ^{Reference Hodgson, Mansatta, Mallett, Harris, Emary and Pollard2} = 0%; 1 dose: heterogeneity P = 0.43, I ^{Reference Hodgson, Mansatta, Mallett, Harris, Emary and Pollard2} = 0%). The results were homogeneous for symptomatic and asymptomatic COVID-19 (all studies evaluating vaccinated HCWs: heterogeneity P = .78, I ^{Reference Hodgson, Mansatta, Mallett, Harris, Emary and Pollard2} = 0%; 2 doses: heterogeneity P = .49, I ^{Reference Hodgson, Mansatta, Mallett, Harris, Emary and Pollard2} = 0%; 1 dose: heterogeneity P = .56, I ^{Reference Hodgson, Mansatta, Mallett, Harris, Emary and Pollard2} = 0%). The results were also homogenous for only asymptomatic COVID-19 in 2 doses and 1 dose: heterogeneity P = .25, I ^{Reference Hodgson, Mansatta, Mallett, Harris, Emary and Pollard2} = 27.0%; heterogeneity P = .43, I ^{Reference Hodgson, Mansatta, Mallett, Harris, Emary and Pollard2} = 0%, respectively. The reasons for not including the other 3 COVID-19 vaccine HCW studies in the meta-analysis are summarized in Supplementary Appendix 2 .