FcRn-Targeted Mucosal Vaccination against Influenza Virus Infection

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 protective mucosal immune responses in the airway is urgently needed. The FcRn mediates IgG Ab transport across the epithelial cells lining the respiratory tract. By mimicking this natural IgG transfer, we tested whether FcRn delivers vaccine Ags to induce a protective immunity to respiratory infections. In this study, we designed a monomeric IgG Fc fused to influenza virus hemagglutinin (HA) Ag with a trimerization domain. The soluble trimeric HA-Fc were characterized by their binding with conformation-dependent HA Abs or FcRn. In wild-type, but not FcRn knockout, mice, intranasal immunization with HA-Fc plus CpG adjuvant conferred significant protection against lethal intranasal challenge with influenza A/PR/8/34 virus. Further, mice immunized with a mutant HA-Fc lacking FcRn binding sites or HA alone succumbed to lethal infection. Protection was attributed to high levels of neutralizing Abs, 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, to our knowledge, that FcRn can effectively deliver a trimeric viral vaccine Ag in the respiratory tract and elicit potent protection against respiratory infection. This study further supports a view that FcRn-mediated mucosal immunization is a platform for vaccine delivery against common respiratory pathogens.

An FcRn-targeted mucosal vaccine against SARS-CoV-2 infection and transmission

“…immunized by S-Fc developed high levels of IgA Abs in the nasal washes and BAL. These results are consistent with the findings of previous studies where FcRn-targeted respiratory immunizations against viral mucosal infections 9, 28, 29 and adenovirus-vectored SARS-CoV-2 nasal vaccine 32, 33 elicit high Ab responses. In addition, the mice or hamsters i.m.…”

“…The FcRn-targeted nasal vaccine can be used for an unimmunized first dose or booster for those who have been immunized, even previously infected by SARS-CoV-2. The combination of mucosal and parenteral vaccines has been proven effective at mucosal entry against SARS-CoV-2 infections 7, 9, 44, 45 .…”

“…Nasal-spray vaccines can elicit local secretory IgA antibodies and resident T and B cell responses in the upper respiratory tract and the lungs 6,9,10 .…”

“…This ongoing evolution of SARS-CoV-2 necessitates a safe and protective mucosal vaccine to block the viral entry and reduce or eliminate the viral spread, thus, prevent lung and systemic infection and breakthrough infection. Nasal-spray vaccines can elicit local secretory IgA antibodies and resident T and B cell responses in the upper respiratory tract and the lungs 6, 9, 10 .…”

A needle-free subunit vaccine platform inducing mucosal and systemic antibody immunity

“…At mucosal surfaces FcRn mediates pH-dependent transport of IgG antibodies and immune complexes (8,11,12), as well as albumin, which has an FcRn binding site that is distal and non-overlapping with that of IgG (13)(14)(15)(16). While studies have shown bidirectional transport of IgG and IgG Fc-fused antigens (17)(18)(19) in an FcRn-dependent manner, more recent studies have revealed a profound ability of albumin and albumin-fused antigens to cross epithelial cell barriers, followed by induction of antigen-specific antibody responses (20,21). This is highly interesting, as we have demonstrated that human albumin is transported more efficiently than IgG across mucosal surfaces after intranasal administration to human FcRn-expressing mice.…”