Repeated vaccination with homologous influenza hemagglutinin broadens human antibody responses to unmatched flu viruses

The ongoing diversification of influenza virus necessitates annual vaccine updating. The vaccine antigen, the viral spike protein hemagglutinin (HA), tends to elicit strain-specific neutralizing activity, predicting that sequential immunization with the same HA strain will boost antibodies with narrow coverage. However, repeated vaccination with homologous SARS-CoV-2 vaccine eventually elicits neutralizing activity against highly unmatched variants, questioning this immunological premise. We evaluated a longitudinal influenza vaccine cohort, where each year the subjects received the same, novel H1N1 2009 pandemic vaccine strain. Repeated vaccination gradually enhanced receptor-blocking antibodies (HAI) to highly unmatched H1N1 strains within individuals with no initial memory recall against these historical viruses. An in silico model of affinity maturation in germinal centers (GCs) integrated with a model of differentiation and expansion of memory cells outside GCs during a recall response provides insight into the potential mechanisms underlying these results and shows how repeated exposure to the same immunogen can broaden the antibody response against diversified targets.