FcRn-targeted mucosal vaccination protects the respiratory tract from influenza virus infection

Authors: OCHSNER, SUSAN - University Of Maryland; LI, WEIZHONG - University Of Maryland; PALANIYANDI, SENTHILKUMAR - University Of Maryland; RAJENDRAKUMA, ARUNRAJ - Non ARS Employee; LIU, XIAOYANG - University Of Maryland; GEFEI, WANG - University Of Maryland; KRAMMER, FLORIAN - The Icahn School Of Medicine At Mount Sinai; SHI, MEIQING - University Of Maryland; Tuo, Wenbin; PAUZA, C DAVID - University Of Maryland School Of Medicine; XIAOPING, ZHU - University Of Maryland

Submitted to: Science Translational Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/2/2021
Publication Date: N/A
Citation: N/A

Interpretive Summary: The respiratory tract is constantly exposed to various airborne pathogens. Current vaccines against respiratory infections are designed for non-respiratory route administration, resulting in minimal protection. A vaccination strategy to induce optimal immunity in respiratory tract is needed. The neonatal Fc receptor (FcRn) transports immunoglobulin G (IgG) across epithelial cells in respiratory tract. This study investigates whether FcRn delivers IgG-Fc-vaccine complex to induce immunity to respiratory infection. IgG-Fc fused to the influenza virus vaccine, hemagglutinin (HA), was designed and constructed. Mice carrying intact FcRn immunized with IgG-Fc-HA fusion vaccine conferred significant protection against infection by influenza virus. Further, mice immunized with IgG-Fc-HA fusion lacking FcRn binding or HA alone succumbed to lethal infection. Protection was positively correlated with high levels of neutralizing antibodies and long-lasting B- and T-cell responses. Our results demonstrate for the first time that FcRn can effectively deliver a vaccine in the respiratory tract and induce protection against infection. This study further supports development of a universal vaccine delivery platform against common respiratory or mucosal pathogens. The results of the present study will benefit vaccine research and development in both medical and veterinary fields.

Technical Abstract: The respiratory tract is constantly exposed to various airborne pathogens. Most vaccines against respiratory infections are designed for the parenteral routes of administration, consequently, they provide relatively minimal protection in the respiratory tract. A vaccination strategy that aims to induce the optimal mucosal immune responses in the respiratory tract is urgently needed. The neonatal Fc receptor (FcRn) mediates IgG antibody transport across the epithelial cells lining the respiratory tract. By mimicking this natural IgG transfer, we tested whether FcRn delivers vaccine antigens to induce a protective immunity to respiratory infection. In this study, we designed a monomeric IgG Fc fused to influenza virus hemagglutinin (HA) antigen with a T4 fibritin foldon trimerization domain. The soluble trimeric HA-Fc proteins were characterized by their binding with conformation-dependent HA antibodies or FcRn. In wild-type but not FcRn-knockout mice, immunized intranasally (i.n.) with HA-Fc proteins plus CpG adjuvant, conferred significant protection against lethal i.n challenge with influenza A/PR/8/34 virus. Further, mice immunized with a mutant HA-Fc protein lacking FcRn binding sites or HA alone succumbed to lethal infection. Protection was attributed to high levels of neutralizing antibodies, robust and long-lasting B- and T-cell responses, the presence of lung-resident memory T cells and bone marrow plasma cells, and a remarkable reduction of virus-induced lung inflammation. Our results demonstrate for the first time that FcRn can effectively deliver a trimeric viral vaccine antigen in the respiratory tract and elicit potent protection against respiratory infection. This study further supports our view that FcRn-mediated mucosal immunization can be a universal delivery platform for vaccines against common respiratory pathogens.