Breakthrough infections by SARS-CoV-2 variants boost cross-reactive hybrid immune responses in mRNA-vaccinated Golden Syrian hamsters

Hybrid immunity (vaccination + natural infection) to SARS-CoV-2 provides superior protection to re-infection. We performed immune profiling studies during breakthrough infections in mRNA-vaccinated hamsters to evaluate hybrid immunity induction. The mRNA vaccine, BNT162b2, was dosed to induce binding antibody titers against ancestral spike, but inefficient serum virus neutralization of ancestral SARS-CoV-2 or variants of concern (VoCs). Vaccination reduced morbidity and controlled lung virus titers for ancestral virus and Alpha but allowed breakthrough infections in Beta, Delta and Mu-challenged hamsters. Vaccination primed for T cell responses that were boosted by infection. Infection back-boosted neutralizing antibody responses against ancestral virus and VoCs. Hybrid immunity resulted in more cross-reactive sera, reflected by smaller antigenic cartography distances. Transcriptomics post-infection reflects both vaccination status and disease course and suggests a role for interstitial macrophages in vaccine-mediated protection. Therefore, protection by vaccination, even in the absence of high titers of neutralizing antibodies in the serum, correlates with recall of broadly reactive B- and T-cell responses. Hybrid immunity to SARS-CoV-2, defined as the immunity provided by the combination of vaccination and natural infection has been shown to provide superior protection to re-infection. To assess the induction of hybrid immunity, we vaccinated hamsters with a single-dose of the mRNA BNT162b2 vaccine and challenged them with different SARS-CoV-2 variants of concern. This vaccine dose induced ELISA binding antibody titers against the virus spike, but these antibodies were not able to neutralize ancestral or drifted viruses. Vaccination reduced morbidity and controlled lung virus titers for ancestral virus and Alpha variant but allowed breakthrough infections with the other antigenically more distant variants of concern. Nevertheless, vaccination primed for more cross-reactive B and T cell responses after infection. Whole lung transcriptomics after infection suggests a role for innate immune cells, such as interstitial macrophages, in vaccine-mediated protection. Our study sheds light on the early phases of induction of protective immune responses during infection with SARS-CoV-2 variants of concern in vaccinated hosts, even before the onset of neutralizing antibodies through recall of cross-reactive B- and T-cell responses.