Th170 - Mapping the Impact of Vaccination and Viral Strain on sars-cov-2 Infection and Host Response in the Human Nasal Mucosa

Vincent Miao; Joshua Bromley; Samuel Kazer; Ying Tang; Anna Owings; Erica Langan; Alex Shalek; Sarah Glover; Bruce Horwitz; Arlene Sharpe; Jose Ordovas-Montanes

Abstract Text: SARS-CoV-2 vaccines have been shown to ameliorate COVID-19 disease and reduce transmission suggesting their ability to shape host-viral dynamics at the site of infection. However, detailed knowledge as to how vaccines, novel variants, and their intersection shift host responses in the human nasal mucosa remains unclear. We performed scRNA-seq on nasopharyngeal swabs from 124 adult patients collected during the original, Delta, and Omicron waves of the COVID-19 pandemic in Mississippi, resulting in a dataset of 73,000 diverse cell types. To understand the impact of mRNA vaccination, we compared the cellular composition and transcriptional response in the nasal mucosa between vaccinated and unvaccinated patients. We identified signatures of macrophage recruitment and activation in vaccinated patients regardless of strain, suggesting that stimulation of mucosal myeloid cells may play a role in vaccine-induced protection. To investigate why some patients still become critically ill despite vaccination, we compared mild and severe cases. We found that an impaired epithelial-intrinsic interferon response is persistent in vaccinated patients with severe disease, emphasizing the need to further understand why some patients fail to mount this response. By aligning to a joint host-viral genome, we mapped which cell types and subsets are likely actively infected with SARS-CoV-2. We found that Delta samples have an increased abundance of viral RNA that was independent of ACE2 expression. These results will inform the identification of patients at risk of severe disease from SARS-CoV-2 infection, our understanding of how to optimally design novel mucosal vaccines, and potential therapeutic pathways for COVID-19.