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

Authors: LI, WEIZHONG - University Of Maryland; WANG, TAO - University Of Maryland; RAJENDRAKUMAR, ARUNRAJ - University Of Maryland; MIAO, ZIZHEN - University Of Maryland; YU, HAILIANG - University Of Maryland; ACHARYA, GYANADA - University Of Maryland; Tuo, Wenbin; ZHU, XIAOPING - University Of Maryland

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/21/2023
Publication Date: 11/6/2023
Citation: Li, W., Wang, T., Rajendrakumar, A.M., Miao, Z., Yu, H., Acharya, G., Tuo, W., Zhu, X. 2023. An FcRn-targeted mucosal vaccine against SARS-CoV-2 infection and transmission. Nature Communications. 14(1). Article e7114. https://doi.org/10.1038/s41467-023-42796-0.
DOI: https://doi.org/10.1038/s41467-023-42796-0

Interpretive Summary: SARS-CoV-2 and its variants cause the COVID-19 pandemic and the transmission is primarily through droplets and airborne aerosols. We studied a vaccination strategy to elicit a protective immunity in the respiratory tract and block initial infection of the inhaled viruses and reduce viral spread. The neonatal Fc receptor (FcRn) can bind to the tail region (Fc) of immunoglobulin G antibodies (IgG) and transfer IgG across the epithelial barrier. The FcRn is present on the respiratory mucosal surfaces in high density. Here we explore the potential to use FcRn as a vehicle shuttling the SARS-CoV-2 spike protein (S) genetically engineered to the Fc (S-Fc, which is the anti-Covid vaccine) across the mucosal membrane. We first demonstrated that S-Fc had the ability to specifically engage S-specific antibodies and FcRn. Then, we immunized mice through the nasal cavity with the S-Fc in CpG adjuvant and showed the S-Fc vaccine can induce high levels of immune responses. Further, we immunized nasally the hamsters and mice carrying the human angiotensin converting enzyme 2 (ACE2, a Covid receptor) with the S-Fc vaccine and demonstrated protection against challenge infections by SARS-CoV-2 and its variants. Importantly, viral transmission was also significantly reduced between the immunized and naive hamsters, indicating that this vaccine can stop break-through infections. The results of the present study clearly showed that the IgG antibody receptor, FcRn, can deliver the Covid Spike protein in the airway and achieve protection against infection and transmission. This strategy can be potentially used to deliver vaccines against any mucosal pathogens. The successful us of this strategy will encourage development of new vaccine delivery systems in livestock species. This research is beneficial to the cattle producers, general public and researchers with focuses on the mucosal pathogens.

Technical Abstract: SARS-CoV-2 is primarily transmitted through droplets and airborne aerosols, and in order to prevent infection and reduce viral spread vaccines should elicit protective immunity in the airways. The neonatal Fc receptor (FcRn) transfers IgG across epithelial barriers and can enhance mucosal delivery of antigens. Here we explore FcRn-mediated respiratory delivery of SARS-CoV-2 spike (S). A monomeric IgG Fc was fused to a stabilized spike; the resulting S-Fc bound to S-specific antibodies and FcRn. Intranasal immunization of mice with S-Fc and CpG significantly induced antibody responses compared to the vaccination with S alone or PBS. Furthermore, we intranasally immunized mice or hamsters with S-Fc. A significant reduction of virus replication in nasal turbinate, lung, and brain was observed following nasal challenges with SARS-CoV-2 and its variants. Intranasal immunization also significantly reduced viral airborne transmission in hamsters. Nasal IgA, neutralizing antibodies, lung-resident memory T cells, and bone-marrow S-specific plasma cells mediated protection. Hence, FcRn delivers an S-Fc antigen effectively into the airway and induces protection against SARS-CoV-2 infection and transmission.