SARS-CoV-2 infection and COVID-19 mRNA vaccination in aged and diet-induced obese mouse models

Abstract

People with advanced age or obesity are clinically known to be more susceptible to infectious diseases. Recently, they were reported to have a higher risk of developing severe outcomes from Coronavirus Disease 2019 (COVID-19). However, the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in aged or obese individuals, as well as the host immune responses to infection remain incompletely understood. Importantly, the efficacy of COVID-19 vaccination in these two populations is largely unexplored. In this project, we investigated the pathogenicity of SARS-CoV-2 and host immune responses to infection, re-infection and vaccination using aged mice and diet-induced obese (DIO) mice models. We found that SARS-CoV-2 variants including Omicron BA.1 and Alpha replicated to comparable levels in the lungs of DIO mice which developed more severe pneumonia, though Omicron BA.1 caused much milder lung damage than Alpha in lean mice. We further demonstrated that the innate antiviral responses such as type I interferons are not mounted upon SARS-CoV-2 infection in aged and DIO mice when compared to young and lean mice respectively. The subsequent adaptive antibody responses in SARS-CoV-2 infected aged or DIO mice are also impaired. The impairment of interferon responses and antibody responses as well as T cell functions may contribute to the higher virus replication thus leading to more severe lung damage in aged and DIO mice. Importantly, both aged and DIO mice demonstrated enhanced susceptibility to SARS-CoV-2 re-infection. Two doses of COVID-19 mRNA vaccination provided limited T cell and B cell-mediated adaptive immune response to SARS-CoV-2 in aged and DIO mice which explained the lower vaccine efficacy. However, in DIO mice, mRNA vaccination offered partial protection in the lung upon Omicron BA.1 challenge which was accompanied by increased production of IFN-α and IFN-β. DIO mice RNAseq of lung tissues indicated that vaccination could activate the antiviral innate immune responses when compared to the unvaccinated controls. Overall, our results support tailored and optimized strategies for the prevention and treatment of SARS-CoV-2 infection in elderly and obese individuals.