Reconstructed influenza A/H3N2 infection histories reveal variation in incidence and antibody dynamics over the life course.

Humans experience many influenza infections over their lives, resulting in complex and varied immunological histories. Although experimental and quantitative analyses have improved our understanding of the immunological processes defining an individual's antibody repertoire, how these within-host processes are linked to population-level influenza epidemiology remains unclear. Here, we used a multi-level mathematical model to jointly infer antibody dynamics and individual-level lifetime influenza A/H3N2 infection histories for 1,130 individuals in Guangzhou, China, using 67,683 haemagglutination inhibition (HI) assay measurements against 20 A/H3N2 strains from repeat serum samples collected between 2009 and 2015. These estimated infection histories allowed us to reconstruct historical seasonal influenza patterns and to investigate how influenza incidence varies over time, space and age in this population. We estimated median annual influenza infection rates to be approximately 18% from 1968 to 2015, but with substantial variation between years. 88% of individuals were estimated to have been infected at least once during the study period (2009-2015), and 20% were estimated to have three or more infections in that time. We inferred decreasing infection rates with increasing age, and found that annual attack rates were highly correlated across all locations, regardless of their distance, suggesting that age has a stronger impact than fine-scale spatial effects in determining an individual's antibody profile. Finally, we reconstructed each individual's expected antibody profile over their lifetime and inferred an age-stratified relationship between probability of infection and HI titre. Our analyses show how multi-strain serological panels provide rich information on long term, epidemiological trends, within-host processes and immunity when analyzed using appropriate inference methods, and adds to our understanding of the life course epidemiology of influenza A/H3N2.

Using serological measures to estimate influenza incidence in the presence of secular trends in exposure and immuno-modulation of antibody response.

BACKGROUND: Influenza infection is often measured by a fourfold antibody titer increase over an influenza season (ie seroconversion). However, this approach may fail when influenza seasons are less distinct as it does not account for transient effects from recent infections. Here, we present a method to determine seroconversion for non-paired sera, adjusting for changes in individuals' antibody titers to influenza due to the transient impact of recent exposures, varied sampling times, and laboratory processes. METHODS: We applied our method using data for five H3N2 strains collected from 942 individuals, aged 2-90 years, during the first two study visits of the Fluscape cohort study (2009-2012) in Guangzhou, China. RESULTS: After adjustment, apparent seroconversion rates for non-circulating strains decreased while we observed a 20% increase in seroconversion rates to recently circulating strains. When examining seroconversion to the most recently circulating strain (A/Brisbane/20/2007) in our study, participants aged under 18, and over 64 had the highest seroconversion rates compared to other age groups. CONCLUSIONS: Our results highlight the need for improved methods when using antibody titers as an endpoint in settings where there is no clear influenza "off" season. Methods, like those presented here, that use titers from circulating and non-circulating strains may be key.

Life course exposures continually shape antibody profiles and risk of seroconversion to influenza.

Complex exposure histories and immune mediated interactions between influenza strains contribute to the life course of human immunity to influenza. Antibody profiles can be generated by characterizing immune responses to multiple antigenically variant strains, but how these profiles vary across individuals and determine future responses is unclear. We used hemagglutination inhibition titers from 21 H3N2 strains to construct 777 paired antibody profiles from people aged 2 to 86, and developed novel metrics to capture features of these profiles. Total antibody titer per potential influenza exposure increases in early life, then decreases in middle age. Increased titers to one or more strains were seen in 97.8% of participants during a roughly four-year interval, suggesting widespread influenza exposure. While titer changes were seen to all strains, recently circulating strains exhibited the greatest titer rise. Higher pre-existing, homologous titers at baseline reduced the risk of seroconversion to recent strains. After adjusting for homologous titer, we also found an increased frequency of seroconversion against recent strains among those with higher immunity to older previously exposed strains. Including immunity to previously exposures also improved the deviance explained by the models. Our results suggest that a comprehensive quantitative description of immunity encompassing past exposures could lead to improved correlates of risk of influenza infection.