Mechanisms and Duration of Immunity to SARS-CoV-2

Primary immune deficiency disorders (PID) affect 1 in 2,000 individuals in the U.S., twice the prevalence of non-Hodgkin lymphoma. PID patients are at risk for severe COVID-19 and impaired responses to vaccination. Research into vaccine boosting in these individuals is clearly of importance for public health. Study of these patients, many of which have single-gene inborn causes for their phenotype, offers the valuable opportunity to correlate genotypes with immunological phenotypes in humans. Dr. Boyd will collaborate with Dr. Charlotte Cunningham-Rundles, a world expert in PID at the Mount Sinai School of Medicine in New York, to analyze the serological and B and T lymphocyte responses to vaccination and boosting using previously-collected plasma and peripheral blood mononuclear cells from a cohort of 142 PID patients whose disorders affect adaptive immune responses with a range of severity, and whose immunological phenotypes can include autoreactivity in addition to impaired protective immunity. The most common diagnosis in this cohort is Common Variable Immune Deficiency, (CVID). These patients generate suboptimal vaccine responses, but some can still mount specific antibody titers after vaccination. We will carry out an in-depth systemsimmunology characterization of serological responses and B cell and T cell populations in these patients, characterizing the frequencies, cellular phenotypes, B cell and T cell receptor sequences, and antigen epitopes targeted by antigen-specific B cells, using a panel of 14 different DNA-tagged SARS-CoV-2 variant antigen tetramers. Examination of T cell responses in the PID patients will include analysis of vaccine antigen-stimulated T cell frequencies and TCR sequences, and detailed flow cytometric immunophenotyping. These data will provide clinically relevant information about SARS-CoV-2 vaccination and boosting responses in PID patients to potentially contribute to clinical guidance as new Omicron variant-containing vaccine boosters are implemented, and should provide insights into the immunological genes, pathways and cell populations that contribute to adaptive immune responses and memory formation after mRNA vaccination in human patients.