FcRn-mediated mucosal vaccination with hemagglutinin stalk confers broad protection from influenza virus infections 4198

Abstract Description The current seasonal influenza vaccines are designed to match the circulating strains of the virus and are updated yearly to align with changes in the HA antigen. However, the HA stalk remains conserved across strains and may induce cross-reactive Abs. Since the FcRn facilitates IgG transport across the airway barrier, we explored whether intranasal delivery of the HA stalk via FcRn could induce broad immunity against various influenza subtypes. To target the HA stalk to FcRn, we produced HA Stalk-Fc antigen, mimicking the prefusion conformation of the HA stalk. The soluble Stalk-Fc proved stable and bound to stalk-specific Abs, FcRn, and FcγRI. Wild-type mice immunized intranasally with HA stalk-Fc were significantly protected against lethal doses of H1N1, H5N1, and H6N2 influenza viruses, compared to those immunized with a HA stalk alone. The protection was attributed to long-lasting HA stalk-specific IgG and IgA Abs in blood, BAL, and nasal washes, significant reduction of viral replication in the lung, the presence of lung-resident memory T cells, and long-lasting Ab-secreting plasma cells in the bone marrow. The HA stalk-specific Abs were found to mediate ADCC, CDC, and phagocytosis and displayed cross-reactivity against different influenza strains. These results showed that FcRn-targeted mucosal delivery of HA stalk induces strong, cross-protective immunity against distinct influenza viruses, suggesting the potential of developing universal influenza mucosal vaccine. Funding Sources This work was supported in part by NIH R01 grants AI146063 and the intramural research program of the USDA ARS. Topic Categories Vaccines and Immunotherapy (VAC)