Date of Award

January 2026

Document Type

Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Albert Ko

Second Advisor

Nathan Grabaugh

Abstract

Immunocompromised individuals have been proposed as important reservoirs for SARS-CoV-2evolution, since chronic infections in these individuals may extend viral replication and facilitate the accumulation of adaptive mutations. Although chronic SARS-CoV-2 infections in immunocompromised individuals have been linked to within-host viral evolution and the emergence of adaptive mutations, much less is known about whether immune-depleting therapies shape viral evolution during acute infections. This distinction is important because acute infections are far more common than chronic infections and may therefore represent a broader, but less well-characterized, setting in which immune status could influence viral diversity. In this thesis, I linked electronic health record data with high-depth SARS-CoV-2 sequencing data from the Yale New Haven Hospital System to assess the association between B-cell-depleting and combined B- and T-cell-depleting therapies and within-host viral diversity during acute SARS- CoV-2 infection. I compared individuals receiving B-cell-depleting or combined B- and T-cell- depleting therapies with matched controls without any recorded exposure to B-cell-depleting or T-cell-depleting therapies, and assessed overall within-host diversity as measured by the frequency of intra-host Single Nucleotide Variants (iSNVs), mutation patterns across genomic regions, and gene-level selection signals. Although overall within-host diversity remained low across groups, B-cell-depleting therapy was associated with higher odds of nonsynonymous iSNVs in the spike region. I found positive selection in the nucleocapsid gene in the B-cell- depleting group, indicating that gene-level selection differs across exposure groups during acute infection. Together, my findings suggest that immune depletion during acute SARS-CoV-2 infection may not increase total counts of iSNVs but instead shift the distribution and types of mutations observed. My results extend prior work on SARS-CoV-2 evolution in less frequent chronic infections and suggest that signals consistent with adaptive evolution are already detectable during acute infection in individuals receiving B-cell- or T-cell-depleting therapies.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 09/16/2028

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