Broad beta-CoV immunity and transmission blockade by a single-dose live-attenuated vaccine with atypical codon usage

Current COVID-19 vaccines have saved countless lives but primarily aim to induce immunity to the spike or its RBD protein and often fail to confer broad or durable protection against rapidly evolving variants and prevent transmission. Here, we invented a live-attenuated broad-spectrum coronavirus vaccine (cb1) by changing the codon usage bias of SARS-CoV-2 genome, which maintained amino acid conservation but reduced virulence. A single intranasal dose of cb1 vaccine elicits remarkably broad and potent immunity that overcomes existing parenteral vaccine’s limitations. cb1 induced robust neutralizing antibody and T cell responses that translated into complete protection in animal models, including prevention of viral transmission to unvaccinated contacts. Notably, cb1 provided cross-protection not only against diverse SARS-CoV-2 variants of concern but also against more divergent SARS-CoV-1 and hCoV-OC43, a breadth of immunity unparalleled by current vaccines. These findings highlight the potential of cb1 to address urgent needs for next-generation COVID-19 vaccines that elicit mucosal immunity with broad, long-lasting efficacy, eliminating the necessity for frequent updates.