Characterization of seasonal CoV immunity and operationalization of a novel controlled human infection model for the betacoronavirus OC43

Project Summary Coronaviruses (CoVs) are large RNA viruses with a well-demonstrated potential for jumping host species. The persistent threat of novel emergent CoVs necessitates a thorough understanding of CoV immunity and preparedness for outbreak response. Four CoVs circulate seasonally, and SARS-CoV-2 has further demonstrated the ability of coronaviruses to re-infect the same individual multiple times over a lifetime. Whether CoV reinfections occur due to evolving viral epitopes or waning immunologic memory, and the role of within host immunity for selection of novel variants remains a critical gap in understanding CoV immunity. My long-term career goal is to become an independent and productive investigator in CoV and influenza vaccinology, with a focus on controlled human infection models (CHIMs). A CHIM using the seasonal CoV OC43, with low pathogenicity and structural similarity to the severe CoVs, will advance our understanding of CoV immunology and provide a foundation for pan-CoV vaccine and therapeutic development in preparation for future outbreaks. Under the mentorship of Dr. Frieman, an expert in coronaviruses, and Dr. Neuzil, an expert in vaccine development and controlled human infection models, I will pursue this goal of developing a CHIM with the seasonal CoV OC43. A 2022 isolate of OC43 is undergoing ongoing development for use in a CHIM. However, the assays to evaluate immunity to seasonal CoVs such as OC43 have historically been limited by relatively poor growth in cell culture and lack of specificity by binding assays. Therefore, in Aim 1 I will use pseudoviruses to develop a functional neutralization assay to assess immunity to seasonal CoVs, evaluating the ability of sera from the past four decades to neutralize both recent and older OC43 pseudotyped viruses. This will provide a mechanism to rapidly evaluate seasonal CoV neutralization with greater accuracy than antibody binding alone. In Aim 2 I will build on a recent influenza CHIM conducted at the University of Maryland to explore the diversity of influenza mutations occurring within individuals after a controlled infection, providing novel explorations of the host factors that affect viral diversity. The viral genome analysis platform that we develop in aim 2 will be essential for evaluating the viral diversity that develops during an OC43 CHIM. In Aim 3 I will develop the protocol for a seasonal CoV CHIM, with careful consideration for safety and endpoints that will allow us to evaluate the effect of pre-existing immunity on symptomatic infection, viral shedding, and duration of immune response. A seasonal CoV CHIM has not been conducted for over 40 years, and today would allow us to characterize the cellular and humoral correlates of protection, define host mediators of susceptibility, and directly assess durability of immunity. This model system will be an essential tool for assessing variant-proof pan-coronavirus interventions and will provide preparedness for the emergence of future novel coronaviruses.