Immune Priming and the Risk of COVID-19, Influenza, and Other Acute Respiratory Infections: Insights From an N3C Cohort

Background: The emergence of SARS-CoV-2 and introduction of COVID-19 vaccines into immunologically naïve populations may alter the dynamics of other acute viral respiratory infections (viral ARIs) and vice versa. Competing forces, including viral interference, cross-reactive immunity, shared susceptibility, and immune dysregulation, may affect the risk. The potential net impact of various immune-priming events and their timing on the risk of viral ARIs is largely unknown. Methods: Using data from the National Clinical Cohort Collaborative (N3C) COVID-19 Enclave, this retrospective population-based cohort study investigated the relationship between immune-priming events (COVID-19 and influenza vaccinations, and SARS-CoV-2, influenza, other, and unspecified viral ARIs) between January 2018 and September 2021 and the risk of viral ARIs during October 2021–April 2022. The sample included N = 608,725 individuals from seven data partners with well-ascertained COVID-19 and influenza vaccination data. Results: Early COVID-19 vaccination (December 2020–March 2021) and SARS-CoV-2 infection during the overlapping period (October 2020–March 2021) were associated with a lower risk of all outcomes, including non-SARS-CoV-2 infections. Off-season influenza vaccination (January–June 2021) was associated with a lower risk of SARS-CoV-2 and any viral ARI. Other priming events showed mixed associations, with a lack of evidence of stronger protection from more recent immune-priming events. Conclusions: This exploratory analysis suggests potential crossprotection between viral ARIs that may inform vaccination strategies. While ascertainment and healthcare-seeking biases in electronic health records may inflate positive associations between infection outcomes and immune priming, negative (i.e., protective) associations are of potential public health significance and warrant further investigation.