Journal Article

Impact of variants and vaccination on nasal immunity across three waves of SARS-CoV-2

Guo, Yanglin, Ordovas-Montanes, Jose, Navia, Andrew W., Diamond, Gill, Wichman, T. Grant, Long, Jaclyn M., Lyons, Jonathan J., Tang, Ying, Laird, Hannah, Kimler, Kyle, Tarugu, Spurthi, Glover, Sarah C., Parker, Adam, Shalek, Alex K., Miao, Vincent N., Horwitz, Bruce H., Ibrahim, Samira, Kota, Sai K., Billingsley, Benjamin C., Garrett, Michael, Pride, Yilianys, Jivanjee, Tasneem, Senitko, Michal, Owings, Anna H., Drake, Riley S., Dotherow, Paul, Bates, John T., Davis, Yesenia T., Robinson, Tanya O., Frame, I.J., Bromley, Joshua D., Dhaliwal, Neha S., Kazer, Samuel W., Ziegler, Carly G. K., Harvey, Jessie, George, Micayla

2025

Overview

SARS-CoV-2 infection and COVID-19 disease vary with respect to viral variant and host vaccination status. However, how vaccines, emergent variants, and their intersection shift host responses in the human nasal mucosa remains uncharacterized. We and others have shown during the first SARS-CoV-2 wave that a muted nasal epithelial interferon response at the site of infection underlies severe COVID-19. We sought to further understand how upper airway cell subsets and states associate with COVID-19 phenotypes across viral variants and vaccination. Here, we integrated new single-cell RNA-sequencing (scRNA-seq) data from nasopharyngeal swabs collected from 67 adult participants during the Delta and Omicron waves with data of 45 participants collected during the original (Ancestral) wave from our prior study. By characterizing detailed cellular states during infection, we identified changes in epithelial and immune cells that are both unique and shared across variants and vaccination status. By defining SARS-CoV-2 RNA+ cells for each variant, we found that Delta samples had a marked increase in abundance of viral RNA+ cells. Despite this dramatic increase in viral RNA+ cells, the nasal cellular landscapes of Delta and Omicron exhibit greater similarity, driven partly by myeloid subsets, than the Ancestral landscapes associated with specialized epithelial subsets. We found that vaccination was surprisingly associated with nasal macrophage recruitment and activation rather than adaptive immune cell signatures. While patients with severe disease caused by Ancestral or Delta variants had muted interferon responses, Omicron-infected patients had equivalent interferon responses regardless of disease severity. Our study defines the evolution of cellular targets and signatures of disease severity in the upper respiratory tract across SARS-CoV-2 variants, and suggests that intramuscular vaccines shape myeloid responses in the nasal mucosa upon SARS-CoV-2 infection.