Background: In the 2023-24 influenza season, adults born in the 1957-1985 birth cohort had the lowest vaccine effectiveness (VE) against A(H1N1)pdm09 viruses than other age groups, including those in the 1986-2005 birth cohort. Here, we investigated A(H1N1)pdm09 antibody levels in sera collected from influenza cases and controls to explain the birth cohort effect of the low VE.

Methods: Acute sera within 7 days and convalescent sera at 28 days post-symptom onset were collected from adult patients (18-66 years, 1986-2005 and 1957-1985 birth cohorts) enrolled in the US Influenza VE Network study during the 2023-2024 season. Hemagglutination inhibiting (HI) antibodies and binding antibodies in sera were assessed against representative A(H1N1) viruses and hemagglutinin antigens.

Results: A(H1N1)pdm09-infected cases in the 1957-1985 birth cohort had significantly lower HI antibodies in the acute sera against circulating A(H1N1)pdm09 viruses in 2023-24 season than those born in 1986-2005. Over 60% of the cases in the 1957-1985 birth cohort had HI antibodies ≤10 to the circulating A(H1N1)pdm09 viruses. Nonetheless, vaccinated cases in the same 1957-1985 birth cohort were able to mount robust antibody responses to A(H1N1)pdm09 virus infection, suggesting low vaccine immunogenicity. Antibody landscape analysis by both HI and binding antibodies revealed that these patients born in 1957-1985 with the lowest VE were likely primed with USSR/77-like A(H1N1) viruses.

Conclusion: HI antibody levels in the acute sera around the time of encountering influenza viruses were associated with protection against influenza A(H1N1)pdm09 infection. Improving immunogenicity of the vaccines could help improve VE and overcome the birth cohort effects.