Bidirectional Synergistic Interaction Between Influenza Virus and SARS-CoV-2 in the Postpandemic Era: A Modeling...

Influenza and COVID-19 are major respiratory diseases whose co-circulation dynamics are not fully understood. Surveillance data from the postpandemic period, free from the confounding effects of nonpharmaceutical interventions (NPIs), provide a unique opportunity to study their interactions. This study aimed to (1) estimate the direction and strength of the epidemiological interactions between influenza virus and SARS-CoV-2 and (2) quantify the impact of these interactions on the cumulative disease burden.

We developed a deterministic influenza virus × SARS-CoV-2 12-compartmental model SIR × SEIR using weekly laboratory surveillance data from Hong Kong between 2023 and 2025. Interaction parameters were introduced across multiple pathways to quantify the effect of one virus on the transmission of the other. Model parameters were estimated via maximum likelihood estimation (MLE), with uncertainty assessed using bootstrap resampling. Counterfactual simulations were conducted to evaluate the impact of interactions on cumulative infection incidence. Sensitivity analyses were performed to evaluate the robustness of our findings.

The model identified a significant bidirectional synergistic interaction. Specifically, prior exposure to SARS-CoV-2 was associated with a relative risk of influenza virus infection that was 1.24 (95% CI: 1.13, 1.35) times higher compared to the scenario without interaction, while SARS-CoV-2 infection and recovery from it were associated with relative risks of influenza virus infection that were 2.43 (2.20, 2.66) and 12.04 (10.93, 13.17) times higher, respectively. Additionally, influenza virus infection was associated with a relative risk of SARS-CoV-2 infection that was 2.39 (2.17, 2.62) times higher, and recovery from influenza was associated with a relative risk of SARS-CoV-2 infection that was 9.92 (9.00, 10.84) times higher. Counterfactual analysis demonstrated that this interaction substantially amplified epidemic sizes.

This study provides strong epidemiological evidence that influenza virus and SARS-CoV-2 exhibit a bidirectional synergistic interaction at the population level, which significantly elevates the total disease burden. These findings underscore the urgent need for multifaceted public health preparedness, including enhanced clinical management and multiplex testing, optimized vaccination strategies, and integrated multipathogen surveillance to mitigate the amplified burden from influenza virus-SARS-CoV-2 synergy.