Correlates of Protection for IAV, RSV, and SARS-CoV-2

Abstract

Influenza A virus (IAV), respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are responsible for over 17.2 billion infections annually, cause severe respiratory disease, and continue to pose public health threats that disproportionately affect households with mothers and infants. Protection from infection is provided by antibodies, with increasing levels correlating with greater protection. The most efficient way to acquire antibodies is via vaccination. To develop and improve vaccinations, Correlates of Protection (CoPs), measured in a laboratory, are used to assess immune responses toward respiratory virus infections and the effectiveness of vaccines. This dissertation harnesses multiple laboratory and statistical approaches to explore antibody CoPs for three common respiratory viruses: IAV, RSV, and SARS-CoV-2. The goal of this dissertation is to elucidate the relevant CoPs for these viruses to better assess the effectiveness of vaccinations in household and maternal infant populations. These settings provide a strong foundation for evaluating antibody responses in more generalizable settings compared to clinical trials. Ultimately, this research will strengthen evidence for the identification of CoPs for IAV, RSV, and SARS-CoV-2, which will aid in vaccine development and infection mitigation in high-risk populations. In the first chapter I provide relevant pathophysiologic, epidemiologic, and immunologic background on research surrounding IAV, RSV, and SARS-CoV-2. In the second chapter of this dissertation, I investigate Immunoglobulin A (IgA) and Immunoglobulin G (IgG) as antibody CoPs, from nasal mucosal and serum environments against symptomatic SARS-CoV-2 infection in a household population. I established nasal IgA as an independent strain-specific CoP against symptomatic SARS-CoV-2 infection. In addition, I evaluate post-vaccination antibody responses in the nasal mucosa and serum among all participants vaccinated with the seasonal SARS-CoV-2 vaccine. This investigation did not show substantial boosts in nasal IgA; instead, notable increases were seen for both ancestral and XBB.1.5 spike serum IgG. In the third chapter, I describe RSV antibody dynamics following RSV infection and exposures in a household cohort over an eight-year period. I show that lower concentrations of RSV pre-fusion F (pre-F) IgG increase the susceptibility to mild or moderate RSV disease in community settings. Utilizing a predictive model, I demonstrate that RSV pre-F IgG mediated protection derived from RSV infection starts to wane 6 months after the infection event. Furthermore, I apply a case-based antibody boost cutoff to identify probable asymptomatic RSV infections among exposed household contacts of those with confirmed RSV infection. From this, I identified a small number of household contacts with serologic evidence of asymptomatic infection. In chapter four, I evaluate the efficiency of IAV and RSV transplacental antibody transfer in pregnant individuals and their infants and how that efficiency is impacted by maternal influenza vaccination and preterm birth. I demonstrate that IAV- and RSV-specific maternal antibody is readily transferred across the placenta. The total antibody concentration in infants is significantly increased for IAV Hemagglutinin 1 (H1) and Hemagglutinin 3 (H3) subtypes following maternal influenza vaccination. This is especially true for infants born preterm who have higher IAV IgG following maternal influenza vaccination and are at higher risk of lower IgG transfer ratios without vaccination. The findings from this dissertation highlight the importance of advancing ongoing and future antibody CoP research to better understand susceptibility to respiratory virus infections and to evaluate vaccination schedules and novel immunotherapeutics more effectively.