Mucosal vaccine-elicited IgA is protective against zoonotic Betacoronavirus challenge

Current vaccines for respiratory viruses are primarily administered intramuscularly. Messenger RNA-lipid nanoparticle (LNP)-based intramuscular vaccination for respiratory coronaviruses induces strong systemic IgG antibody responses; they do not consistently elicit IgA in the upper and lower respiratory tracts. Using a synthetic consensus spike protein aimed to broadening immunity against SARS-like viruses, SarbConS, coupled to ferritin nanoparticles co-delivered with mastoparan-7 and an FDA-approved CpG adjuvant, we intranasally boost SARS-CoV-2-immune animals. This intranasal boosting strategy elicits durable mucosal IgA responses in the respiratory tract, along with robust systemic IgG responses, and demonstrates durable protection against SARS-CoV-2 and zoonotic SARS-like viruses from bats and pangolins. Intranasal delivery of mastoparan-7 and CpG with MERS-CoV spike protein similarly elicits MERS-CoV-specific mucosal IgA and protects against MERS-CoV challenge in mice. Moreover, we observe durable protection against these genetically divergent zoonotic SARS-like viral challenges compared to intramuscular mRNA-LNP or unadjuvanted intranasal spike boosters. Intranasal SarbConS-ferritin nanoparticle intranasal vaccination similarly elicited durable mucosal IgA and antigen-specific memory B cell responses in the airways. The protective efficacy of M7-CpG adjuvanted SarbConS ferritin nanoparticle intranasal boosters was abolished in IgA knockout mice, suggesting a requirement for IgA in mediating respiratory mucosal vaccine-mediated protection against coronavirus infection. Altogether, our results demonstrate that respiratory mucosal vaccination can elicit durable and cross-protective mucosal IgA responses against genetically diverse zoonotic coronaviruses with implications for improved mucosal vaccines for highly transmissible respiratory viral pathogens.