SARS-CoV-2 mucosal vaccine protects against clinical disease with sex bias in efficacy.

Intranasal mucosal vaccines can more effectively induce mucosal immune responses against SARS-CoV-2. Here, we show in hamsters that an intranasal subunit mucosal vaccine boost with the beta variant S1 can prevent weight loss, in addition to reducing viral load, which cannot be studied in macaques that don't develop COVID-like disease. Protective efficacy against both viral load and weight loss correlated with serum antibody titers. A sex bias was detected in that immune responses and protection against viral load were greater in females than males. We also found that priming with S1 from the Wuhan strain elicited lower humoral immune responses against beta variant and led to less protection against beta viral challenge, suggesting the importance of matched antigens. The greater efficacy of mucosal vaccines in the upper respiratory tract and the need to consider sex differences in vaccine protection are important in the development of future improved COVID-19 vaccines.