Project Summary/Abstract To date, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) has caused over 32 million cases of coronavirus disease (COVID-19), with ~1 million associated deaths. Multiple vaccine trials have begun in an effort to stop this pandemic, yet the correlates of viral clearance and immune protection from SARS-CoV-2 remain unknown. In fact, there are no licensed vaccines to any human coronavirus, as we have not yet discovered the immunologic correlates of a successful coronavirus vaccine. In his brief tenure in the Iwasaki lab, Dr. Goldman-Israelow has already developed a highly adaptable mouse model of SARS-CoV-2 infection that can be applied to mice of any genotype. He published this work as co-first author in the Journal of Experimental Medicine. He also showed that innate immune activation drives acute pathology. However, the extent to which innate immune signals drive adaptive immunity remains to be explored. This proposal will address how: (1) type I interferon signaling and (2) cGAS signaling control antibody development to SARS- CoV-2. This work is critical for characterizing the fundamental rules that govern adaptive immunity to SARS- CoV-2, which will promote the development of highly effective vaccines. This proposal describes a rigorous five-year career development training program for Benjamin Goldman- Israelow, M.D., Ph.D., with the goal of preparing him for an independent research career as an academic physician-scientist. The principal investigator is a physician scientist who completed his M.D. and Ph.D. training in Biomedical Sciences at the Icahn School of Medicine at Mount Sinai, where he studied molecular virology. Dr. Goldman-Israelow continued his training by joining the Physician Scientist Research Pathway at Yale New Haven Hospital, a combined residency and fellowship program, and is currently an infectious diseases fellow. He has embarked on an intensive training program to broaden his expertise in viral immunology under the mentorship of Dr. Akiko Iwasaki, a pioneer and world leader in deciphering the complex interplay among viruses, innate immune recognition, and adaptive immunity. Dr. Iwasaki is not only a world- class scientist, but also a world-class mentor with a very productive track record of mentoring physician- scientists. In addition to the intellectual grooming and practical laboratory-based training that Dr. Goldman- Israelow will continue to receive in Dr. Iwasaki’s lab, he has developed a training program built on high-yield didactic coursework. He has also carefully crafted an advisory committee comprising translational scientists with a broad range of scientific expertise relevant to this proposal and impressive records of mentorship. Yale School of Medicine, along with its Departments of Internal Medicine and Immunobiology, will provide the resources, support, and infrastructure to assist Dr. Goldman-Israelow in achieving the aims described in this proposal and his long-term goal of developing into an independent physician-scientist studying the rules that govern antibody development to both viral infection and vaccination.

Project Narrative Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused over 32 million cases of Coronavirus disease (COVID-19), with greater than 1 million associated deaths to date. Though vaccine trails are ongoing, the correlates of viral clearance and immune protection from SARS-CoV-2 are unknown. This proposal seeks to understand how innate immune signals drive adaptive immunity to SARS-CoV-2, with the goal of identifying fundamental immunologic rules that govern SARS-CoV-2 immunity to promote development of highly effective vaccines.