Project Summary/Abstract: There is an urgent need to develop new approaches to induce broadly protective immunity against rapidly mutating viruses. The induction of protective immunity requires the development of memory lymphocytes that can rapidly recognize and neutralize the virus upon re-infection. Virus-specific memory B cells are long-lived cells that are critical for the establishment of protective immunity by vaccines. Memory B cells mediate protective immunity by rapidly differentiating into antibody secreting cells upon antigen re-encounter. Memory B cells that re-encounter antigen can also undergo further mutation of their B cell receptor to increase their affinity for viral antigen. Induction of broadly reactive memory B cells through iterative exposure to cross- reactive viral antigens is an emerging vaccination strategy designed to protect against rapidly mutating viruses. However, efforts to induce broadly reactive memory B cells have been hindered by the relative inefficiency with which memory B cells diversify their B cell receptor following antigen re-encounter. Better understanding of the mechanisms governing memory B cell development is necessary to facilitate the design of vaccines capable of eliciting a broadly protective memory B cell response. Additionally, effective harnessing of memory B cells to protect against mucosal viruses requires understanding how memory B cells develop and function in barrier tissues. Memory cells are critical for the establishment of barrier immunity, with lung-resident memory B cells recently identified as essential to elicit a rapid and robust local antibody response following influenza challenge. However, a lack of clarity regarding the pathways regulating memory B cells development in barrier tissues remains a significant barrier to designing vaccines capable of inducing tissue-resident memory B cells. This project proposes to characterize how the tissue microenvironment shapes the development of memory B cells following viral infection. This project will first determine how viral- and tissue-specific cues influence the transcriptional profile of memory B cells. This proposal will then identify key transcriptional regulators of memory B cell development in barrier tissues and investigate the mechanisms by which these regulators function. Transcriptional regulators are essential in facilitating memory lymphocyte development and function in barrier tissues. By revealing the developmental pathway of memory B cells in barrier tissues, this study will provide important insight into how vaccines can overcome existing challenges in order to elicit broadly protective immunity against mucosal viruses. The development of vaccines specifically designed to induce tissue-resident memory B cells would mark an important paradigm shift away from traditional vaccination approaches focused on inducing a systemic virus-specific B cell response.

Project Narrative: The COVID-19 pandemic has demonstrated the immense risk posed by the emergence of novel viral strains. There is an urgent need to develop new vaccination approaches to induce broadly protective immunity against highly mutable mucosal viruses, which are likely sources of future pandemics. In this proposal, I will explore how the tissue microenvironment shapes the development of memory B cells following viral infection in order to better understand how vaccines can enhance the antiviral memory B cell response and establish broadly protective immunity against mucosal viruses.