Low levels of post-vaccination hemagglutination inhibition antibodies and their correlation with influenza protection among healthcare workers during the 2024/2025 A/H1N1 outbreak in Japan

Background After the prolonged COVID-19 pandemic, during which the seasonal influenza epidemic was suppressed, Japan experienced a record-breaking influenza A/H1N1 outbreak in the 2024/2025 season. This situation also raises a concern about the immunogenicity of the annual inactivated influenza vaccine. This study evaluated post-vaccination hemagglutination inhibition (HI) antibody titers and their association with influenza infection risk among healthcare workers. Methods A serosurvey was conducted among staff at a national medical and research center in Tokyo in December 2024, one month after staff received the inactivated influenza vaccine. HI antibody titers against vaccine strains were measured, and participants were followed for influenza infection until January 2025. Seroprotection was defined as an HI titer ≥40. A Cox proportional hazards model assessed the association between HI titers and infection risk among vaccinated participants. Results Among 1,507 vaccinated participants, only 12.7% had seroprotective HI titers against A/H1N1. Around 90% had no influenza history for at least four seasons and had received repeated vaccinations over two seasons. Participants with HI titers <40 had a 4-fold higher infection risk than those with titers ≥40. A dose-response association was observed, even within the range below the titer of 40. Relative to titers <10, titers of 10 and 20 conferred 47.3% and 57.9% protection, respectively. Conclusions After a prolonged period without a major influenza epidemic, HI titers against A/H1N1 were extremely low in vaccinated healthcare workers. Nonetheless, higher post-vaccination HI titers, even at relatively low levels, were associated with protection, supporting the benefit of vaccines.