SARS-COV-2 Surveillance, Evolution, and Immune Responses: Insights for Pandemic Mitigation

Abstract

Zoonotic viral spillover events pose a constant threat to human health. A multitude of factors such as climate change and increased population density have expanded the human-animal interface, leading to increased opportunities for viral spillover from animals to humans. Much of the work in this dissertation was done in response to the COVID-19 pandemic and to understand the human immune response to SARS-CoV-2 infection, however, the advances in knowledge and technology can be applied for future pandemic prevention and management. Initially, widespread testing of the population was difficult and placed a large burden on healthcare workers, who were already overextended due to demands of patient care. We validated a massively scalable alternative to the gold-standard, nasopharyngeal swab sample collection method, called saline gargle. This collection method was implemented as part of the University of Arizona’s Test, Trace, Treat program to facilitate a safe return to in-person instruction. Not only did this expand testing capacity, but it enabled the University to perform comprehensive whole-viral genome sequencing and monitor for the presence of more transmissible and pathogenic variants on campus, and in turn, provided the opportunity for policies to be implemented in response to the shifting pandemic landscape. During the initial mRNA vaccine rollout, we identified immunocompromised individuals as an important population that had been excluded from mRNA clinical trials. We recruited individuals undergoing immunosuppressive therapy for cancer treatment and interrogated their cellular and humoral immune responses to the recommended two-dose mRNA vaccine series. We determined that these individuals derived great benefit from a third mRNA dose, leading to a recommended three-dose primary series for immunocompromised individuals. Immunocompromised people have been shown to be susceptible to prolonged SARS-CoV-2 infections. I present a case-study where an individual has a prolonged ≥63-day infection. After deep sequencing of three timepoints throughout the infection, I present analysis of within-host viral evolution, where the virus evolved both immune-evasive properties and likely, increased transmissibility. To assess the impacts of antigenic imprinting after multiple SARS-CoV-2 exposures, we recruited individuals with post-vaccination Delta or Omicron BA.1 infections. Additionally, we recruited individuals whose first SARS-CoV-2 exposure was to Delta or Omicron BA.1. We find a larger role for changing immunodominance hierarchies in variants, compared to the role of antigenic imprinting in suppressing de novo memory B cell responses. This dissertation contributes valuable immunological insights for the continued management of the COVID-19 pandemic, as well as techniques for viral surveillance both within human populations and at the human-animal interface.