Influenza remains a major killer worldwide, with most deaths occurring in the elderly. Even when influenza does not kill directly, it may aggravate comorbidities, pave the way for bacterial infections or increase frailty. Hence, the influenza immunity may have a more profound impact on survival than we realize. While older individuals have the highest risk of death from influenza infection, their immune response may differ in other ways due to a lifetime of influenza exposure. Several studies have suggested that over multiple exposures individuals will develop antibodies to highly conserved regions of the hemagglutinin (HA) stalk protein, leading to broad cross-strain immunity. Such cross reactive antibodies have long been a target in the search for a universal influenza vaccine. Measuring and explaining the complex, varying patterns of influenza immunity that develop over a lifetime could alter long-held notions of how influenza immunity develops and impacts health. In a study of influenza immunity in Southern China we found a significant increase in neutralizing antibody titers strains of H3N2 influenza in the oldest study participants. These results mirror patterns seen in studies of influenza antibody titers in Japan and elsewhere. This observation suggests that either (1) influenza immunity confers a greater survival advantage than previously thought; (2) levels of circulating antibodies against influenza are a marker of robust immune health, which confers a survival advantage; or (3) the nature of the immune response to influenza changes as we age, eventually leading to a broadly elevated antibody response. Here we propose to use data from two ongoing studies, the Guangzhou Biobank Cohort Study (GBCS) and Fluscape, to address these hypotheses and gain insight into the development, maintenance and impact of influenza immunity over a lifetime of exposure. Specifically we aim to: (1) determine whether high influenza antibody titers are associated with increased survival among older individuals in Guangdong province, China; (2) characterize the diversity of age-specific influenza antibody profiles and response to antigen challenges (infection and vaccination) among participants in the Fluscape study; and (3) Evaluate the extent to which broadly cross- reactive antibodies play a role in individuals with homogenously high immunity across strains. This study leverages two existing studies and will attempt to explain patterns of influenza immunity that have been previously underappreciated and have important implications for vaccination and health in the elderly. Efficient study designs and innovative methods will be used to address the study hypotheses: a nested case-control study will look for survival effects; existing samples will be used to characterize the immune response using cutting edge analytic techniques; and in depth laboratory testing will be performed to explain these patterns. Successful completion of these aims will yield insights into the epidemiologic and immunologic factors that give rise to patterns of immunity as we age. The results of this study have the potential to expand our understanding of the role that influenza plays over a lifetime, thereby impacting vaccine development, public health and clinical care.
Each person experiences multiple infections with influenza virus over their lifetime, and the risks from these infections increase as we age. Recent studies suggest that the oldest individuals, with a lifetime of influenza exposure behind them, have elevated antibody titers to influenza across strains. This study aims to understand how and why this increase in antibody titers occurs, and what role survival effects, patterns of infection and the biology of the immune response play in creating patterns of immunity over a lifetime of influenza exposure.
