Neutralizing antibody pressure on the evolution of SARS-CoV-2 variants."

PROJECT SUMMARY / ABSTRACT: Rationale: SARS-CoV-2 evolution has led to the emergence of viral variants that evade existing immunity in the human population, which continue to pose a threat to global public health. It has proven challenging to predict which mutations will arise in future dominant viral variants, and, as a result, it is difficult to design vaccines that provide adequate protection against viruses that will circulate in future waves of infections. Our preliminary data show that viral variant evolution is most closely correlated with evasion of serum neutralizing antibodies, and that serum neutralizing antibody responses are shaped by immune imprinting to the ancestral D614G strain. This mentored career project aims to leverage these observations to develop an in vitro model for predicting where mutations will appear in the virus and to use that information to design updated vaccines. Candidate: As a Transfusion Medicine fellow with a PhD in Genomics and Computational Biology and two years of experience in virology and immunology research, I bring a unique complement of perspectives and skills to the analysis of viral and antigenic evolution and to vaccine design strategies. Further training in advanced BSL-2-compatible pseudovirus culture, mouse immunization, and computational structural biology will be central to the completion of the proposed project and to my development as an independent physician-scientist aiming to improve our understanding and mitigation of pathogen evolution. My primary mentor, Dr. David Ho, an international leader in virology, and my complementary multidisciplinary advisory team, will ensure my research and career development progress. Environment: The Ho laboratory at the Columbia University Irving Medical Center (CUIMC) is a world leader in the study of pandemic viruses, including SARS-CoV-2, with expertise in the characterization of viral variants and serum antibody analysis. The Ho lab has access to abundant resources and many collaborators, including leaders in pseudovirus construction, structural biology, and vaccine design. CUIMC also has a long track record of supporting junior physician-scientists on their paths to successful independent careers in academic medicine. Approach: We will test the central hypothesis that widespread early exposure to ancestral SARS-CoV-2 shapes the evolutionary trajectory of the virus and that such a trajectory can be modeled in vitro. In Aim 1 we will assess the impact of mouse serum neutralizing antibodies elicited by different immunization histories on mutational profiles in cultured BSL-2-rated pseudoviruses and correlate mutations with historical public health databases. In Aim 2, we will identify whether particular epitopes on the spike protein are particularly susceptible to the emergence of mutations under serum antibody selective pressure. In Aim 3, we will design and test novel COVID-19 vaccine candidates in mice based on observed mutations that arise in pseudoviruses. This project will enhance our understanding of SARS-CoV-2, provide a framework for in vitro modeling of antigenically variable pathogens, and contribute to vaccine design strategies.