Abstract
Mucosal immunity may be required to prevent the ongoing transmission of SARS-CoV-2 emerging variants of concern. To define the most efficient way to induce protective mucosal immunity, we compared three different forms of mucosal antigen exposure in mRNA pre-immunized rhesus macaques. Two vaccine groups received an oropharyngeal spray immunization with either an adenoviral vector or a live-attenuated SARS-CoV-2 vaccine (LAV). A third group was infected with SARS-CoV-2 Delta variant as a comparator group representing the exposure history of most humans. Profound levels of SARS-CoV-2-specific IgA antibodies and mucosal T cell responses in the bronchoalveolar lavage next to systemic IgG antibodies were induced after the adenoviral vector boost and the delta infection, but not after LAV immunization. Consequently, these two groups were better protected against a challenge infection with an immune-escape variant of the Omicron lineage EG.5.1.1 showing almost no upper and lower respiratory tract infection. The adenoviral vector vaccine would be a promising candidate for booster vaccinations to interrupt ongoing viral transmission and could generate similar levels of protection as a natural encounter with heterologous SARS-CoV-2.