Effect of recent prior infection on influenza vaccine immunogenicty

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A) Aims and Objectives The primary aim is to determine the impact of prior influenza infection and cross-reactive memory B cells on neutralizing antibody titers to the prevailing infecting or vaccine strain. We hypothesize that responses dominated by cross-reactive memory B cells are inferior to responses with less memory cell involvement. B) Key Question(s) 1) Does influenza infection history affect prevailing strain titer? 2) Are prevailing strain titers related to the magnitude of memory-type humoral responses, defined as early, cross-reactive IgG responses? 3) What proportion of acutely responding B cells (plasmablasts) are memory-derived, what proportion adapt to the prevailing strain, and how do these relate to titers to the prevailing strain? C) Research Design This prospective study will investigate immune responses to influenza vaccination and infection in an existing cohort. The Ha Nam cohort includes 270 households, and is unique in that participants have been actively monitored for influenza illness or infection defined by seroconversion, since 2007, a period including eleven influenza seasons. This provides a rare opportunity to understand how prior influenza infections and immune memory influence antibody responses to new strains, and the protection that is generated. Responses to influenza vaccine will be compared between participants with divergent influenza infection histories. Responses to vaccination and natural infection will also be compared. Blood samples will be collected before and after vaccination or infection to determine peak and sustained levels of protective antibodies to the prevailing strain, to compare the evolution of antibody responses to prevailing and past strains in the two groups, and to characterize antibody producing B cells. We have developed key resources to facilitate these analyses including a computational tool (antibody landscapes) to analyse titers in the context of antigenic difference between strains; and high throughput BCR sequencing and analysis that can indicate whether acutely responding cells are naïve- or memory-B cell derived.

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