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

## TL;DR

Boosting immune monkeys with a bivalent vaccine improves lung immunity, reducing Omicron reinfection despite waning antibodies.

## Contribution

Demonstrates that lung-specific immune cell infiltration, not just antibodies, is key to protection against SARS-CoV-2.

## Key findings

- Boost vaccination increases cross-reactive S-specific antibodies and B cells, not new BA.5-specific responses.
- Animals with complete protection show stronger immune cell influx into the lungs and CD8 T cell expansion.
- Localized lung immunity correlates with reduced Omicron replication after reinfection.

## 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.

Vaccination-induced antibody responses wane, but protection from infection often lasts longer. Here the authors boost-immunize rhesus macaques with pre-existing hybrid immunity using new bivalent SARS-CoV-2 vaccine, and find that protection from subsequent infection correlates with immune infiltration in the lung.