Serological Assessment and Transcriptional Instruction of Durable Antibody Responses to Viral Infections and Vaccinations

Abstract

Antibody responses serve a fundamental role in the clearance of active infections and the establishment of immunity post-infection or vaccination. Following either infection or vaccination, the presence or absence of neutralizing antibody titers is considered the most reliable immunological correlate of protection. As such, the production of durable post-vaccination antibody responses has long been an essential criterion in modern vaccine design. Nonetheless, much variability exists among commonly administered vaccines in their ability to generate stable, protective antibody titers.In the Winter of 2019-2020, the novel coronavirus SARS-CoV-2 began circulating in human populations and soon initiated a global pandemic. Development of reliable serological assays capable of detecting post-infection anti-SARS-CoV-2 antibody responses became a chief focus of public health and basic research efforts. Determining the dominant viral antigens targeted by the immune system, how quickly neutralizing titers were established, and the longevity of anti-SARS-CoV-2 responses, were all pressing topics. Moreover, these questions remained pertinent in the context of vaccination as the pandemic progressed and novel anti-SARS-CoV-2 vaccines became widely distributed. In many ways, the pandemic thrust these basic immunological processes into the everyday minds of both researchers and the general public. Antibody responses are mounted by terminally differentiated lymphocyte called plasma cells, which arise from activated B cell precursors. Plasma cells emerge in two waves of the B cell response. An early burst is generated within the first week post-exposure; these cells aim to clear an active infection and persist for a matter of days. A second wave of plasma cells are formed over a period of weeks as the B cell response matures. These cells secrete superior antibodies to their early plasma cell counterparts and ideally provide long-term protection. Two features are most critical for durable antibody-mediated immunity. First, plasma cells must aim at least some of their antibodies against regions of the pathogen that are essential for its infection or pathogenesis. Second, these plasma cells must also possess the intrinsic genetic properties for long-term persistence. When both conditions are met, durable, protective antibody titers are observed. Despite the public health relevance, much remains unknown about the genetic and molecular underpinnings that support the longevity of durable, protective, antibody responses. A deeper understanding of the fundamental drivers of longevity across B cell to plasma cell differentiation is crucial for successful future vaccine design. Furthermore, this knowledge could uncover properties of B cell responses that predict their prospective durability. Taken together this dissertation displays the utility of translational serological research, as well as pursuing a better understanding of the basic machinery that drives plasma cell longevity. In this work, I will detail efforts executed by myself and our tremendous SARS-CoV-2 pandemic response team here at the University of Arizona that demonstrate the production of durable, neutralizing antibody responses to SARS-CoV-2 following infection and vaccination. I will also describe at length my work aimed to better understand the basic transcriptional drivers of plasma cell longevity. I will begin with an introductory chapter summarizing the core properties and molecular drivers of B cell to plasma cell differentiation, followed by individual chapters regarding the research topics described above.