Coordinated early immune response in the lungs is required for effective control of SARS-CoV-2 replication.

Publication date: Jun 25, 2025

Despite waning of virus-neutralizing antibodies, protection against severe SARS-CoV-2 in the majority of immune individuals remains high, but the underlying immune mechanisms are incompletely understood. Here, rhesus macaques with pre-existing immunity from Novavax WA-1 and/or P. 1 vaccines and WA-1 or P. 1 infection are immunized with a bivalent WA-1/Omicron BA. 5 Novavax vaccine ten months after the last exposure. The boost vaccination primarily increases the frequency of cross-reactive spike (S)-specific antibodies and B cells instead of inducing de novo BA. 5-specific responses. Reinfection with heterologous Omicron XBB. 1.5 six months after the boost vaccination results in low levels of virus replication in the respiratory tract compared with virus-nacEFve results from other studies. Whereas systemic S-specific immunity remains largely unchanged in all animals, the animals with complete protection from infection exhibit a stronger influx of S-specific IgG, monocytes, B cells and T cells into the bronchioalveolar space combined with expansion of CD69CD103 lung tissue-resident, S-specific CD8 T cells compared to actively infected animals. Our results underscore the importance of localized respiratory immune responses in mediating protection from Omicron reinfection and provide guidance for future vaccine development.

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