Graduation Date

Spring 5-9-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Interdisciplinary Graduate Program in Biomedical Sciences

First Advisor

M. Jana Broadhurst

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease-2019 (COVID-19), has been responsible for millions of deaths and hundreds of millions of confirmed infections around the globe. Despite the continuous evolution of SARS-CoV-2 variants, booster vaccination rates for SARS-CoV-2 are trending down year-over-year. In the face of decreasing vaccination rates and waning population immunity we developed a multiplexed, bead-based immunoassay (HumorX) that can quantify IgG, IgA, and IgM antibodies against both ancestral and variant strain SARS-CoV-2. Antibody-mediated immunity against SARS-CoV-2 has been observed, with neutralizing antibodies (nAb) representing the most robust currently identified correlate of protection (CoP) against severe disease. Current methods to discern nAb from binding antibodies (bAb) are both time-consuming and, for SARS-CoV-2, require a BSL-3 laboratory space to grow live virus. We addressed these limitations by employing a surrogate virus neutralization test (svNT) which allows us to perform neutralization experiments in a BSL-2 laboratory space. Between the svNT and HumorX we aim to determine the relationship between bAb and nAb in the current era of SARS-CoV-2 in both longitudinal cohorts as well as cross-sectional studies. To further assess functionality of bAb we employed a urea gradient to uncover antibody avidity. Through this method we identified bAb thresholds that correspond to >90% inhibition, likely indicating protection from severe disease. We found that cross-reactive antibodies against emergent SARS-CoV-2 Omicron variants were surprisingly functional as measured by nAb and avidity, and these species gained significant durability upon repeated exposures to non-Omicron strains as well as Omicron infection. Finally, we have deployed this tool for a community-based study to assess the local population’s immune resilience to future SARS-CoV-2 outbreaks. In urban and rural settings in Nebraska, we identified functionally lacking humoral responses to emergent SARS-CoV-2 variants. These data highlight the importance of continuous vaccination against SARS-CoV-2 to protect the health of our communities. Identifying ways to improve booster vaccination rates will be critical to maintaining protection from severe COVID-19.

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