Investigating the Legacy of the 1918 Influenza Pandemic in Age-Related Seroepidemiology and Immune Responses to Subsequent Influenza A(H1N1) Viruses Through a Structural Equation Model

A(H1N1) strains of Influenzavirus were responsible for 2 pandemics in the last 100 years. Because infections experienced early in life may have a long-lasting influence on future immune response against other influenza strains, we drew on previously collected seroincidence data from Singapore (n = 2,554; June–October 2009) to investigate whether the 1918 pandemic influenza virus and its early descendants produced an age-related signature in immune responses against the A/California/7/2009(H1N1)pdm09 virus of 2009. Hemagglutination inhibition assays revealed a J-shaped relationship; the oldest birth cohort (born in 1911–1926) had the highest titers, followed by the youngest (born in 1987–1992). Differential response by vaccination history was also observed, with seasonal influenza vaccine being associated with higher titers mainly in the oldest birth cohort. On the assumption that antibody titers are a correlate of protection, structural equation modeling predicted that a titer-mediated effect by the vaccine could, on its own, account for a negative association with seroconversion equivalent to a risk reduction of 23% (relative risk = 0.77, 95% confidence interval: 0.60, 0.99) in the oldest birth cohort. A subset of 503 samples tested against the A/Brisbane/59/2007(H1N1) and A/Puerto Rico/8/1934(H1N1) strains also revealed different age-related antibody profiles. The effectiveness of seasonal influenza vaccines against future pandemic strains could thus be age-dependent and related to early-life exposures.