Mucosal SARS-CoV-2 S1 adenovirus-based vaccine elicits robust systemic and mucosal immunity and protects against disease in animals

The COVID-19 pandemic has emphasized the importance and need for accessible safe, effective, and versatile vaccine platforms. While approved SARS-CoV-2 vaccines have been instrumental in saving lives and reducing healthcare and economic burdens, the induction of mucosal immunity remains an unmet need. Here, we engineered and evaluated a non-replicating adenovirus 5 (rAd5)-based vaccine expressing the SARS-CoV-2 S1 subunit (rAd5-SARS2-S1). We assessed the immunogenicity, durability, and protective efficacy of intramuscular (IM) and intranasal (IN) administration of rAd5-SARS2-S1 in mice and Syrian hamsters. Two IM or IN doses of rAd5-SARS2-S1 elicited robust and sustained Th1-skewed S1-specific serum IgG, neutralizing antibodies (nAbs) against several SARS-CoV-2 variants and systemic antigen-specific memory T cell responses in mice. Additionally, IN vaccination induced potent and long-lasting mucosal S1-specific IgG, IgA, and nAbs and pulmonary memory T cells. Importantly, while IM vaccine significantly ameliorated disease severity in hamsters by reducing viral burden, lung pathology, and, to some extent, weight loss, IN immunization significantly reduced viral replication and provided superior protection against disease and weight loss. Together, our study demonstrates that the rAd5-SARS2-S1 vaccine is immunogenic in both mice and hamsters when administered intramuscularly or intranasally, with IN administration providing better protection. These findings suggest that IN delivery of rAd5-SARS2-S1 could be a promising approach for inducing mucosal and systemic immunity, offering enhanced protection against SARS-CoV-2 and emerging variants.