Regulation and Function of respiratory mucosal immunity post SARS-CoV-2 vaccination and infection

Current intramuscular COVID-19 vaccines, despite eliciting robust systemic immune responses, generate suboptimal neutralizing antibody (nAb), IgA Ab, and cellular responses in the respiratory mucosal. This is likely why current vaccines are less effective at preventing infection and transmission. The role of mucosal immunity in protecting against respiratory viral infection remains largely unexplored. The long-term goal of this research is to comprehensively understand the differentiation, function, regulation, and interaction of respiratory immune cells. Pilot data revealed that people with hybrid immunity from SARS-CoV-2 infection and vaccination exhibit significantly high levels of antigen-specific IgA and nAbs in the respiratory mucosa, compared to those who got vaccinated or infected alone. Further, recent research and our initial findings suggest that mucosal IgA is locally produced by lung-resident B cells during both primary infection and reinfection, yet the specific role and development of mucosal IgA are not fully understood. Therefore, the overall objectives of this application are to a) understand systemic and mucosal immunity in people with hybrid immunity, b) define immune compartments that confer protection and transmission in animal models, and c) unravel the mechanisms underlying the respiratory protection of mucosal immunity. The central hypothesis is that respiratory IgA provides neutralization and protection against heterologous infection, facilitated by an orchestrated interaction between macrophages, CD4 Th1 cells, and IgA+ B cells in the respiratory mucosa. This hypothesis will be tested by pursuing three specific aims: 1) To identify the respiratory mucosal immunity in people with hybrid immunity, 2) To study protection and transmission following SARS-CoV-2 breakthrough infection or mucosal vaccine booster in animal models primed with mRNA vaccines, and 3) To elucidate the mechanisms underlying the mucosal protection of respiratory immunity. Aim 1 will systematically profile the immune signatures in the blood, nasal cavity, and lower airway in children with hybrid immunity. Aim 2 will utilize mouse and hamster models of hybrid immunity and mucosal vaccine booster to study protection and transmission. Under Aim 3, we will investigate the mechanism of mucosal protection in both humans and mice. This research will advance our understanding of respiratory immunology and vaccinology, potentially impacting the global fight against SARS-CoV-2 and future respiratory viruses. This project will provide the applicant, Dr. Jinyi Tang, with experimental and conceptual training to develop his research program and ensure his transition to an independent tenure- track position. Dr. Tang will be mentored by a committee of experienced immunologist, virologist and clinician-scientist specializing in mucosal viral immunology, led by primary mentor Dr. Jie Sun. The planned career development activities will ensure Dr. Tang achieves his long-term goals of consistent manuscript publishing, achieving independent funding, and training of the next generation of scientists.