Human influenza viruses rapidly acquire mutations in their hemagglutinin (HA) protein that erode neutralization by antibodies from prior exposures. Here, we use a sequencing-based assay to measure neutralization titers for 78 recent H3N2 HA strains against a large set of children and adult sera, measuring ~10,000 total titers. There is substantial person-to-person heterogeneity in the titers against different viral strains, both within and across age cohorts. The growth rates of H3N2 strains in the human population in 2023 are highly correlated with the fraction of sera with low titers against each strain. Notably, strain growth rates are less correlated with neutralization titers against pools of human sera, demonstrating the importance of population heterogeneity in shaping viral evolution. Overall, these results suggest that high-throughput neutralization measurements of human sera against many different viral strains can help explain the evolution of human influenza.
Keywords: antigenic drift; evolutionary biology; infectious disease; influenza; microbiology; seqneut; sequencing-based neutralization assay; vaccine; viruses.
Pathogens are in a constant evolutionary battle to outwit the immune system. For example, influenza viruses rapidly mutate their hemagglutinin protein to evade antibody proteins generated by past infections or vaccinations. This is one reason why people can be repeatedly infected by influenza viruses throughout their lives. Understanding this process is crucial for selecting the right viral strains for the annual flu vaccine. However, interpreting the evolution of the flu virus is challenging because individuals vary greatly in their exposure histories, resulting in diverse antibody repertoires that target the virus in different ways. Kikawa et al. developed a new method to measure antibody levels against 78 recent flu strains in both children and adults. They discovered that individuals differed significantly in their ability to neutralize various strains. Furthermore, in 2023, viral strains with a higher proportion of people having lower antibody levels appeared to grow much more rapidly in the human population. This suggests that measuring antibody levels against current viral strains can help identify which ones should be included in next year’s vaccine. Overall, the study by Kikawa et al. shows that experimental approaches capturing the complexity of human immune responses can provide valuable insights into the evolution of flu viruses. Such insights can improve the selection of strains for the annual flu vaccine.
© 2025, Kikawa, Loes et al.