Nucleocapsid Vaccine Elicits Spike-Independent SARS-CoV-2 Protective Immunity

Matchett, William E; Joag, Vineet; Stolley, J Michael; Shepherd, Frances K; Quarnstrom, Clare F; Mickelson, Clayton K; Wijeyesinghe, Sathi; Soerens, Andrew G; Becker, Samuel; Thiede, Joshua M; Weyu, Eyob; O'Flanagan, Stephen D; Walter, Jennifer A; Vu, Michelle N; Menachery, Vineet D; Bold, Tyler D; Vezys, Vaiva; Jenkins, Marc K; Langlois, Ryan A; Masopust, David

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Neutralizing Abs target the receptor binding domain of the spike (S) protein, a focus of successful vaccine efforts. Concerns have arisen that S-specific vaccine immunity may fail to neutralize emerging variants. We show that vaccination with a human adenovirus type 5 vector expressing the SARS-CoV-2 nucleocapsid (N) protein can establish protective immunity, defined by reduced weight loss and viral load, in both Syrian hamsters and K18-hACE2 mice. Challenge of vaccinated mice was associated with rapid N-specific T cell recall responses in the respiratory mucosa. This study supports the rationale for including additional viral Ags in SARS-CoV-2 vaccines, even if they are not a target of neutralizing Abs, to broaden epitope coverage and immune effector mechanisms.