The roles of pre-season immunity, age, viral shedding, and community exposures in shaping influenza household transmission dynamics

Our understanding of influenza transmission remains imperfect due to the high prevalence of asymptomatic infections that often go undetected. To address this challenge, we leveraged uniquely resolved data from a household cohort study spanning three consecutive years in rural and urban South Africa. The study incorporated pre-season serum collection and twice-weekly virological testing during the influenza season, regardless of symptom presence. We developed a subtype/lineage-specific influenza household transmission model that accounts for time-resolved viral shedding across the full clinical spectrum of infections, allowing us to disentangle the role of household and community exposures, pre-season immunity, and age on transmission. Our analysis revealed that viral shedding intensity, as measured by the cycle threshold (Ct) values of infected household members, significantly correlated with the risk of transmission for all four influenza subtypes/lineages. After adjusting for viral shedding, pre-season hemagglutination inhibition (HAI) titers greater than 1:40 were associated with a significantly lower risk of infection acquisition for A(H1N1)pdm09, A(H3N2), and B/Victoria, but not for B/Yamagata. Notably, children exhibited higher susceptibility, longer viral shedding durations, and higher peak viral loads compared to adults across all subtypes/lineages, even after adjusting for pre-season HAI titers. While our findings support that HAI titers correlate with protection, the strong residual effects of age on susceptibility and viral shedding may reflect the accumulation of additional immune responses shaped by repeated exposures over time. Our study underscores the need to explore immune mechanisms beyond HAI titers that modulate influenza susceptibility and transmission.