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

Background Prior infection with SARS-CoV-2 can provide protection against infection and severe COVID-19. In settings with high pre-existing immunity, vaccine effectiveness (VE) should decrease with higher levels of immunity among unvaccinated individuals. Here, we conducted a systematic review and meta-analysis to understand the influence of prior infection on VE. Methods We included test-negative design (TND) studies that examined VE against infection or severe disease (hospitalization, ICU admission, or death) for primary vaccination series. To determine the impact of prior infections on VE estimates, we compared studies that excluded or included people with prior COVID-19 infection. We also compared VE estimates by the cumulative incidence of cases before the start of and incidence rates during each study in the study locations, as further measures of prior infections in the community. Findings We identified 67 studies that met inclusion criteria. Pooled VE among studies that included people with prior COVID-19 infection was lower against infection (pooled VE: 77%; 95% confidence interval (CI): 72%, 81%) and severe disease (pooled VE: 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 the cumulative incidence of cases before the start of the study and VE estimates against infection (spearman correlation ( ρ ) = −0.32; 95% CI: −0.45, −0.18) and severe disease ( ρ = −0.49; 95% CI: −0.64, −0.30). There was also a negative correlation between the incidence rates of cases during the study period and VE estimates against infection ( ρ = - 0.48; 95% CI: −0.59, −0.34) and severe disease ( ρ = −0.42; 95% CI: −0.58, −0.23). Interpretation Based on a review of published VE estimates we found clear empirical evidence that higher levels of pre-existing immunity in a population were associated with lower VE estimates. Excluding previously infected individuals from VE studies may result in higher VE estimates with limited generalisability to the wider population. Prior infections should be treated as confounder and effect modificatory when the policies were targeted to whole population or stratified by infection history, respectively. ### Competing Interest Statement BJC reports honoraria from AstraZeneca, Fosun Pharma, GSK, Haleon, Moderna, Pfizer, Roche and Sanofi Pasteur. JN was previously employed by and owns stocks in Sanofi. The authors report no other potential conflicts of interest. ### Funding Statement This project was supported by the National Institute of General Medical Sciences (grant no. R01 GM139926), and the Theme-based Research Scheme (Project No. T11-712/19-N) of the Research Grants Council of the Hong Kong SAR Government. BJC is supported by an RGC Senior Research Fellowship (grant number: HKU SRFS2021-7S03) and the AIR@innoHK program of the Innovation and Technology Commission of the Hong Kong SAR Government. The WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health and Aged Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript