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

Klara Lenart, Hendrik Feuerstein, Mariana Prado Marmorato, Laura Perez Vidakovics, Gerald McInerney, Mimi Guebre-Xabier, Jessica F. Trost, Bengt Eriksson, Gale Smith, Nita Patel and Karin Loré ()
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Klara Lenart: Karolinska Institutet
Hendrik Feuerstein: Karolinska Institutet
Mariana Prado Marmorato: Karolinska Institutet
Laura Perez Vidakovics: Karolinska Institutet
Gerald McInerney: Karolinska Institutet
Mimi Guebre-Xabier: Novavax Inc
Jessica F. Trost: Novavax Inc
Bengt Eriksson: Karolinska Institutet
Gale Smith: Novavax Inc
Nita Patel: Novavax Inc
Karin Loré: Karolinska Institutet

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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-naïve 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 CD69+CD103+ 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.

Date: 2025
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DOI: 10.1038/s41467-025-60885-0

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