Influenza and pneumococcal vaccination and the risk of COVID-19: A systematic review and meta-analysis

A number of studies have investigated the potential non-specific effects of some routinely administered vaccines (e.g. influenza, pneumococcal) on COVID-19 related outcomes, with contrasting results. In order to elucidate this discrepancy, we conducted a systematic review and meta-analysis to assess the association between seasonal influenza vaccination and pneumococcal vaccination with SARS-CoV-2 infection and its clinical outcomes. PubMed and medRxiv databases were searched, up until November 2021. Random effects model was used in the meta-analysis to pool odds ratio (OR) and adjusted estimates with their 95% confidence intervals (CIs). Heterogeneity was quantitatively assessed using the Cohrans Q and the I2 index. Sub-group analysis, sensitivity analysis and assessment of publication bias were performed for all outcomes. In total 38 observational studies were included in the meta-analysis and there was substantial heterogeneity. Influenza and pneumococcal vaccination were associated with lower risk of SARS-Cov-2 infection (OR: 0.80, 95% CI: 0.75-0.86 and OR: 0.70, 95% CI: 0.57-0.88, respectively). Regarding influenza vaccination, it seems that the majority of studies did not properly adjust for all potential confounders, so when the analysis was limited to studies that adjusted for age, sex, comorbidities and socioeconomic indices, the association diminished. This is not the case regarding the pneumococcal vaccination, for which even after adjustment for such factors the association persisted. Regarding harder endpoints such as ICU admission and death, current data do not support the association. Possible explanations are discussed, including trained immunity, inadequate matching for socioeconomic indices and possible coinfection.