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.