Persistent Antibody Clonotypes Dominate the Serum Response to Influenza over Multiple Years and Repeated Vaccinations

Humans are repeatedly exposed to influenza virus via infections and vaccinations. Understanding how multiple exposures and pre-existing immunity impact antibody responses is essential for vaccine development. Given the recent prevalence of influenza H1N1 A/California/7/2009 (CA09), we examined the clonal composition and dynamics of CA09 hemagglutinin (HA)-reactive IgG repertoire over 5 years in a donor with multiple influenza exposures. The anti-CA09 HA polyclonal response in this donor comprised 24 persistent antibody clonotypes, accounting for 72.6% ± 10.0% of the anti-CA09 HA repertoire over 5 years. These persistent antibodies displayed higher somatic hypermutation relative to transient serum antibodies detected at one time point. Additionally, persistent antibodies predominantly demonstrated cross-reactivity and potent neutralization toward a phylogenetically distant H5N1 A/Vietnam/1203/2004 (VT04) strain, a feature correlated with HA stem recognition. This analysis reveals how “serological imprinting” impacts responses to influenza and suggests that once elicited, cross-reactive antibodies targeting the HA stem can persist for years. [Display omitted] •Longitudinal profiling of anti-H1N1 serum antibodies (Abs) reveals persisting Abs•The persistent Abs on average account for >70% of the serum responses over 5 years•Most persistent Abs bind and neutralize a highly divergent H5N1 viral strain•Cross-neutralizing anti-influenza Abs can persist in the circulation In recent years, there has been a great interest in understanding how repeated exposures to influenza can change the already established host antibody repertoire. Lee et al. quantitatively demonstrate that over multiple years and repeated vaccinations, the serum response to influenza is dominated by a small number of persistent antibodies.