Mechanisms of superior respiratory IgA responses against SARS-CoV-2 after mucosal vaccination 2158

Description Mucosal immunization and respiratory IgA responses offer significant promise in protecting against airborne pathogens, including SARS-CoV-2. However, However, the conditions and mechanisms that lead to the robust induction of respiratory IgA responses following mucosal vaccination remain poorly understood. It is also currently debatable whether mucosal vaccination is still warranted given that most individuals in developed countries have established a hybrid immunity from vaccination and infection. Here, we analyzed respiratory immune responses in humans following SARS-CoV-2 infection, vaccination, or both. We found that hybrid immunity resulted in moderately increased respiratory IgA and neutralizing antibody responses compared to infection or vaccination alone. However, a direct comparison of hybrid immunity and a mucosal adenovirus-based booster vaccination in animal models revealed that respiratory booster immunization elicited markedly stronger and more durable respiratory IgA, T cell response and protective immunity, supporting the promise of respiratory vaccination. Mechanistically, mucosal boosters prompted IgA-secreting cells in the respiratory mucosa with help from local IL-21-producing Blimp1+ Th1 cells. Furthermore, lung macrophages were important for this respiratory IgA response via TGF-β. Our findings highlight a local network for robust respiratory IgA responses, supporting mucosal vaccination strategies against SARS-CoV-2 and other respiratory pathogens. Funding Sources AI147394, AG069264, AI112844, HL170961, and AI154598 to J.S, AI176171 to W.G.T. and J.S.; U54CA260582 to S.L.L; R01AI168684 to G. Z.