SARS-CoV-2 Ancestral and Variant of Concern Breakthrough Infections Boost Both Cross-Reactive Cellular and Humoral Immune Responses in Mrna-Vaccinated Hamsters.

When mRNA vaccines were rolled out under EUA, it was observed that a single vaccination, already protected vaccinees from severe disease, even before neutralizing antibodies appearded. To better understand the underlying mechanism of protection, we vaccinated hamsters once with a suboptimal dose of Pfizer/BioNTech COVID-19 mRNA vaccine (5mg/animal). Four weeks post vaccination, animals were challenged with different variants of SARS-CoV-2. Vaccination resulted in antibody ELISA titers against SARS-CoV-2 spike protein, but antibody titers were too low for efficient neutralization of antigenically matching USA-WA1/2020 (WA1) or drifted variants of concern (Alpha, Beta, Delta and Mu). Nevertheless, suboptimal vaccination resulted in reduced morbidity for WA1 and Alpha-challenged animals and complete control of lung virus titers for WA1, Alpha and Delta but with breakthrough infection for the antigenically more distant Beta and Mu. Moreover, T cell responses were higher in vaccinated animals compared to unvaccinated ones at 5 days post infection, suggesting a recall of vaccine-primed T cells. Infection with different SARS-CoV-2 variants also back-boosted neutralizing antibody responses against the challenge virus and in the case of the variants of concern, against the antigenically distant but vaccine-matched WA1. Transcriptomic analysis of host immune responses to infection reflects both vaccination status and disease course, is further compared with lung pathology and suggests a role for interstitial lung macrophages in vaccine-mediated protection. In summary, protection after suboptimal vaccination against SARS-CoV-2 challenge in hamsters correlates with recall of both vaccine-induced B- and T-cell responses. This study was also partly funded by CRIPT (Center for Research on Influenza Pathogenesis and Transmission), a NIH NIAID funded Center of Excellence for Influenza Research and Response (CEIRR, contract number 75N93021C00014) to A.G.S and M.S. and by R01 AI160706 to M.S.