Altered germinal center responses in mice vaccinated with highly pathogenic avian influenza A(H5N1) virus

Highly pathogenic avian influenza (HPAI) H5N1 virus vaccines typically yield lower neutralizing antibody titers in animals than influenza A virus (IAV) vaccines derived from other viral subtypes. To understand these differences, we compared the cellular immune responses in the draining lymph nodes (dLNs) of mice vaccinated with an inactivated whole H5N1 vaccine to those in mice vaccinated with seasonal H1N1pdm09, H7N9, or H9N2 IAV vaccines. H5N1-vaccinated mice exhibited reduced serum neutralizing antibody titers, despite the hemagglutinin-binding immunoglobulin production being similar to that with other IAV vaccines. Although bulk RNA sequencing showed no differences in B-cell populations after H5N1 and H1N1pdm09 vaccination, H5N1 vaccination resulted in fewer, but larger, dLN germinal centers and significantly more extrafollicular B cells, which are known to produce lower neutralizing antibody titers. Furthermore, H5N1-vaccinated mice had significantly more follicular helper and regulatory T cells. Therefore, differences in neutralizing antibody production in mice after IAV vaccination correlate with subtype-dependent germinal center reactions in the dLNs.