Dynamics of Influenza Protection and Infection: Implications for Vaccination Development

Abstract

Influenza is a major contributor to respiratory morbidity and mortality worldwide and is a particular concern for high-risk populations including children. Although influenza has been studied for over 100 years, major gaps remain in our understanding of influenza transmission and infection. In particular, how individuals respond to natural influenza infection (including those individuals who do not form a traditional response) and the effect of repeated influenza infection on patterns of response across seasons are not well-characterized. In chapter 2 of this dissertation we investigate humoral immune response to influenza A(H1N1)pdm infection among Nicaraguan households. In chapters 3 and 4 we examine the impacts of repeated influenza infections over a nearly ten-year period among a cohort of Nicaraguan children aged 0-14 years. To examine these questions of immunity to natural infection and patterns of repeated infection we utilize data from the Nicaraguan Pediatric Influenza Cohort Study (NPICS) from 2011-2019, as well as data collected as part of the Household Influenza Transmission Study (HITS) from 2013-2015. In chapter 2 of we found that a group of the infected individuals identified by PCR failed to produce a ≥4-fold hemagglutinin inhibition assay (HAI) response; a subset of these individuals produced an alternate antibody response (against full-length HA, HA stalk, or neuraminidase). These individuals had lower pre-existing HAI antibody titers and showed a pattern of milder illness. An additional subset did not produce an alternate antibody response, had higher pre-existing antibody titers against full-length & stalk HA, and were less sick. These findings demonstrate that some individuals mount an alternate antibody response to influenza infection. In chapters 3 and 4 we investigate the periods of protection from repeat infection following symptomatic influenza. We examine the effects of natural influenza virus infection on subsequent infection with homotypic and heterotypic influenza virus subtypes/lineages across multiple seasons. We observed homotypic protection from repeat infection in children infected with influenza A/H1N1pdm, A/H3N2, and B/Victoria. Overall, protection waned as time or antigenic distance increased. Individuals infected with one subtype or lineage of influenza virus have significantly lower odds of homologous reinfection for the following one to two years; after two years this protection waned. While we found no significant protection from heterotypic/heterosubtypic infection within influenza seasons, we did find that individuals infected with a given type or subtype of influenza in a season where two types/subtypes circulated were at increased risk for the other circulating type/subtype in the subsequent season. This heightened risk was present for both older and younger children and held true even after adjustments were made for healthcare-seeking behavior and pre-exposure antibody titer levels. Better understanding these dynamics of varied immune response and repeated infection and exposure is critical to addressing future risk patterns for individuals and populations and will allow for improvements in influenza vaccine design.