Repeated influenza vaccination results in blunting rather than back-boosting of antibody responses against A(H3N2) antigens.

Hemagglutination inhibiting (HI) antibody responses against influenza A(H3N2) vaccine strains decline with increasing years of vaccination. It is hypothesized that memory B cell dominance may direct antibody responses towards epitopes conserved with previously-encountered vaccine strains, including non-HI epitopes. To investigate this, we compared healthcare workers with zero versus five consecutive years of vaccination prior to enrolment in 2020 or 2021. We evaluated HI antibody reactivity across 25 A(H3N2) viruses spanning 2007-2022 and antibody binding to recombinant hemagglutinins (HA). HI antibody responses were poor across strains for participants vaccinated five compared to zero of five prior years, independent of pre-vaccination titre. HA and HA-stem binding antibody titre-rises were likewise attenuated in the repeatedly vaccinated group. These results provide no evidence that repeated vaccination promotes antibodies targeting conserved epitopes, rather, repeated vaccination broadly attenuates antibody responses. Work is ongoing to investigate whether attenuation reflects deficient memory B cell differentiation into plasmablasts.