Rabies virus-based oral and inactivated vaccines protect minks against SARS-CoV-2 infection and transmission

Minks are highly susceptible to SARS-CoV-2, and have transmitted SARS-CoV-2 to humans. Oral immunization is one of the most promising strategies to prevent SARS-CoV-2 infection and transmission in minks. Here, we generated 3 recombinant rabies viruses (RABV), rERAG333E/S6P, rERAG333E/DS6P and rERAG333E/BA2S6P, expressing the prefusion-stabilized SARS-CoV-2 spike protein of wild-type (S6P), delta (DS6P) or BA.2 (BA2S6P) strain based on an oral rabies vaccine candidate (rERAG333E). Oral or inactivated immunization of the 3 RABVs monovalent or trivalent were safe, and induced robust RABV neutralizing antibody and cross-antibody responses against the three SARS-CoV-2 in mice and minks. The challenge tests showed that 2 doses of rERAG333E-S6P as an oral or inactivated vaccine completely protected mice against mouse-adapted SARS-CoV-2 infection in the upper and lower respiratory tracts, and largely prevented viral replication and lung damage caused by wild-type SARS-CoV-2 infection in minks. Notably, we also confirmed that 2 doses of rERAG333E-S6P as an oral or inactivated vaccine can largely protect minks against wild-type SARS-CoV-2 transmission via respiratory droplets. Our findings suggest that rERAG333E-based COVID-19 vaccines appear to be suitable oral candidates to protect minks from SARS-CoV-2 infection and transmission, and may serve as inactivated vaccines for further investigation in humans.