Date of Award

2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Scott E. Hensley

Abstract

Antigenic drift, the sequential accumulation of substitutions that enable escape from population immunity, is a constant problem for RNA viruses that circulate in the human population. Developing effective vaccines against such pathogens is challenging and requires extensive knowledge of virological and antigenic properties of circulating strains. Here we complete studies on seasonal influenza viruses of distinct lineages to evaluate recent changes in these viruses. We show that H3N2 and influenza B viruses have recently acquired substitutions in the receptor binding protein, hemagglutinin (HA). We demonstrate that these viruses maintain binding to human-type receptors, and maintain efficient growth in primary human airway cells. Additionally, one of these novel virus variants encoded for changes that significantly altered the antigenicity of the HA protein, which led to a major vaccine mismatch in 2021. These data highlighted the plasticity of the influenza HA protein in maintaining its essential functions for continued circulation in the human population. Next, we study monoclonal antibodies expressed as the different IgG subclasses to evaluate the role of IgG constant domains in altering binding and neutralization of antibodies. We found that many influenza virus-specific mAbs have altered binding and neutralization potency depending on the IgG subclass encoded, and that these differences result from unique avidity differences among the subclasses. Importantly, subclass differences in antibody binding and neutralization were greatest when the affinity for the target antigen was reduced through antigenic mismatch. We found that antibodies expressed as IgG3 bound and neutralized antigenically drifted influenza viruses more effectively. We obtained similar results using a panel of SARS-CoV-2-specific mAbs and an antigenically drifted strain of SARS-CoV-2. These data highlight the utility of IgG3 as a molecule with increased breadth, which could prove useful for therapeutic antibodies. Overall, the work presented here provides granularity to the problem of antigenic drift of viruses, and provides a potential solution in eliciting or utilizing mAbs with a natural propensity for increased breadth.

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