Prior infections and effectiveness of SARS-CoV-2 vaccine in test-negative studies: a systematic review and meta-analysis

Abstract

Prior infection with SARS-CoV-2 can provide protection against infection and severe COVID-19. We aimed to determine the impact of preexisting immunity on vaccine effectiveness (VE) estimates. We systematically reviewed and meta-analyzed 66 test-negative design studies that examined VE against infection or severe disease (hospitalization, intensive care unit admission, or death) for primary vaccination series. Pooled VE among studies that included people with prior COVID-19 infection was lower against infection (77%; 95% CI, 72-81) and severe disease (86%; 95% CI, 83-89) compared with studies that excluded people with prior COVID-19 infection (pooled VE against infection: 87% [95% CI, 85-89]; pooled VE against severe disease: 93% [95% CI, 91-95]). There was a negative correlation between VE estimates against infection and severe disease, and the cumulative incidence of cases before the start of the study or incidence rates during the study period. We found clear empirical evidence that higher levels of preexisting immunity were associated with lower VE estimates. Prior infections should be treated as both a confounder and effect modificatory when the policies target the whole population or are stratified by infection history, respectively.

Keywords: COVID-19; SARS-CoV-2; preexisting immunity; test-negative design; vaccination; vaccine effectiveness.

Figure 1

Selection of studies for the systematic review. VE, vaccine effectiveness.

Figure 2

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Figure 2

Estimates of vaccine effectiveness (VE) against infection from identified studies that excluded (A) or included (B) participants with COVID-19 infection history. Multiple estimates could be due various factors. These are labeled as follows: for vaccine, a(1) for Pfizer, a(2) for Moderna, a(3) for ChAdOx1, or a(4) for rAd26-rAd5 (Sputnik V); as for the control, b(1) for syndrome-negative), and (b2) for test-negative control; and for different duration between first and second dose: (c1) for 19-29 days, (c2) for 30-44 days, (c3) for 45-64 days, (c4) for 65-84 days, and (c5) for ≥85 days. VOC, variant of concern.

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Figure 3

Estimates of vaccine effectiveness (VE) against severe disease from identified studies that excluded (A) or included (B) participants with COVID-19 infection history. Multiple estimates could be due to various factors. These are labeled as follows: for vaccine, a(1) for Pfizer, a(2) for Moderna, a(3) for ChAdOx1, or a(4) for rAd26-rAd5 (Sputnik V); as for the control, b(1) for syndrome-negative), and (b2) for test-negative control; and for different duration between first and second dose: (c1) for 19-29 days, (c2) for 30-44 days, (c3) for 45-64 days, (c4) for 65-84 days, and (c5) for ≥85 days. VOC, variant of concern.

Figure 4

Vaccine effectiveness (VE) point estimates from identified studies based on prior infection (A), predominant circulating virus (B) and vaccine type (C). Each point represents the VE point estimate. Estimates are jittered to enable visualization. Black points represent the pooled VE estimate from meta-analysis, with black lines representing the 95% CI around the pooled estimate. The shaded area is the violin plot, showing the smoothed density of the VE point estimates. VE estimates against infection and severity disease (D) vs the cumulative incidence of cases before the study (in log scale) (I) in the study regions are shown; VE estimates against infection and severity disease (E) vs the incidence rate of cases during study (in log scale) (J) in the study regions are shown. Pearson (r) and spearman (ρ) correlation coefficients are provided.

Figure 5

Pooled vaccine effectiveness (VE) estimates against infection and severe disease by circulating virus, vaccine types, and the inclusion or exclusion of participants with prior COVID-19 infection from random-effect meta-analysis.

Figure 6

Predicted vaccine effectiveness (VE) for a group of individuals based on the estimated ratio of odds ratios estimated from meta-regression, and the VE for the individuals in the reference group. Predicted VE against infection (A) and severe disease (B) are shown. Prior COVID-19 infection, cumulative incidence of cases before the study, and the incidence rate of cases during study are considered. Models adjusted for age group, type of vaccine, predominant circulating virus, and enrolment criteria, corresponding to the estimate in model 1.