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

Abstract

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 in humans remains unclear. Here, we used a multilevel 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 in humans 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 19% 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 to 2015), and 20% were estimated to have 3 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 analysed using appropriate inference methods, and adds to our understanding of the life course epidemiology of influenza A/H3N2.

Fig 1. Proportion of individuals seropositive and seroconverted to 20 A/H3N2 strains circulating from 1968 to 2014 stratified by age.

Solid black line divides age groups that were alive or not at the time of strain circulation. Seropositivity was defined as having an HI titre of ≥1:40 (a log titre of 3). (A) First serum sample. (B) Second serum sample. (C) Seroconversion between samples, defined as a ≥4-fold increase in HI titre. The data underlying this figure can be found at https://doi.org/10.5281/zenodo.12795911.

Fig 2. Quarterly incidence and individual infection histories from the Fluscape data set.

(A) Model predicted per-capita incidence per quarter. Attack rates were estimated by dividing the number of inferred infections by the number alive in each 3-month period. Red line shows the posterior median estimate from 1,000 posterior samples. Dark and light red shaded regions show 50% and 95% credible intervals respectively from 1,000 posterior samples. Grey shaded box shows duration of the Fluscape study—the improved precision is due to the inclusion of sera bracketing this time period. Asterisks mark times from which a strain included in the HI panel was first isolated. (B) Inferred infection histories for each individual. Each row represents an individual ordered by increasing age in years. Each column represents the time of a potential infection. Cells are shaded based on the proportion of posterior samples with an infection at that time. The grey areas show time periods prior to each individual’s birth. The data underlying this figure can be found at https://doi.org/10.5281/zenodo.12795911.

Fig 3. Age-specific patterns of infection.

(A) Pointrange plot shows posterior median and 95% CrI on the total number of lifetime infections for each individual in the Fluscape cohort, ordered by increasing age at time of sampling. (B) Distribution of the total number of infections across all individuals based on the posterior median total number of infections. (C) Posterior median number of infections per 10 year period stratified by age group at the time of infection, excluding individuals who spent less than 2 years in that age group and including only time periods prior to the first serum sample in Q4-2009 (see S11 Fig for explanation and comparison using all time periods). Text shows sample size within each age group—note this does not sum to the number of individuals in the sample, as individuals contribute to multiple age groups during their lifetime. (D) Distribution of individual posterior median number of infections per 10 years alive. The data underlying this figure can be found at https://doi.org/10.5281/zenodo.12795911.

Fig 4. Model predicted titres against circulating strains since birth.

Each subplot shows one randomly selected individual. X-axis shows time since birth. Blue line and shaded region show model-predicted, true latent titre against the strain assumed to be circulating at each time period (posterior median and 95% CrI). Note that titres are continuous and represent latent, true values, not observations. Orange lines indicate times of high posterior probability of infection. Grey regions show times before birth and after the last serum sample. The data underlying this figure can be found at https://doi.org/10.5281/zenodo.12795911.

Fig 5. Estimated relationship between HI titre and probability of infection.

Top left panel shows the relative risk of infection at all time points stratified by model-predicted HI titre against the circulating strain just before infection for all age groups. Remaining plots show the same relationship but stratified by age group in 10-year bands at the time of infection. Solid lines and shaded regions show posterior median and 95% CrI. Note that the uncertainty intervals reflect uncertainty in the imputed infection states and latent antibody titres; the relationships shown here are empirically calculated from the serosolver estimates. Wide uncertainty intervals at higher titres reflect limited data as few individuals reach such high titres; the posterior median for number of individuals with HI titre of 1:640 or greater at the time of infection was less than 10 for all but the youngest age group. Vertical dashed line shows HI titre 1:40. Horizontal grey dashed line shows 50% protective titre. The data underlying this figure can be found at https://doi.org/10.5281/zenodo.12795911.