Direct and Indirect Effects of Influenza Vaccination on the Risk of Infection with Multiple Respiratory Pathogens in Children

The interaction between influenza virus and other respiratory pathogens is increasingly recognized, yet the extent to which influenza vaccination alters the dynamics remains to be fully elucidated. Here we evaluate the associations between influenza vaccination and subsequent infection risk of 11 respiratory pathogens using a test-negative case-control study. Additionally, a dynamic “SVIRS×SIRS” model considering both direct and indirect pathways was constructed to explore the primary mechanisms underlying the observed associations. Among the 52,725 paediatric patients included, 11,895 (22.6%) had been vaccinated against influenza within 2 years of the test date. We identified robust associations between influenza vaccination and subsequent infection with influenza A virus (OR 0.52, 95% CI 0.47–0.58), influenza B virus (OR 0.22, 95% CI 0.19–0.26), and Mycoplasma pneumoniae (MP) (OR 1.24, 95% CI 1.20–1.27). The potential increase in human adenovirus and human metapneumovirus infection risk following influenza vaccination, in contrast to the decreased risk of human coronavirus and human respiratory syncytial virus, necessitates further research. No statistically significant associations were detected for the other four pathogens: chlamydia, human rhinovirus, human parainfluenza, and human bocavirus. Simulations using the dynamic model indicated that associations on MP was predominantly mediated by indirect pathway, i.e., the suppression of the influenza virus leaves a void for MP, rather than the direct side effect of the vaccine. These findings underscore that distinguishing between the direct and indirect impacts of vaccination is extremely important considering the currently fragile global confidence in vaccines. Furthermore, understanding these vaccine-pathogen interactions helps strengthen integrated prevention systems for multiple respiratory infectious diseases.