Immunogenetics of COVID-19 Immune Response

PROJECT SUMMARY/ABSTRACT This application is a request for funding of a vaccine immunogenetics research program focused on identifying critical genetic and phenotypic determinants of COVID-19 infection and/or vaccination-induced immunity by examining associations between gene polymorphisms, HLA allelic variation, and clinical phenotypes and inter-

individual variations in immune response to COVID-19. Our laboratory has done significant work delineating the effect of gene polymorphisms on mumps, measles, rubella, influenza, and smallpox vaccine immune responses. Our research demonstrates that variations in immune responses to viral vaccines are multigenic

and not a single dominant allele model and that the genetic contribution to such variations in immune responses can be quantified. Informed by insights from these studies and given the public health importance of the ongoing SARS-CoV-2 pandemic, we now turn our attention to understanding genetic associations with

COVID-19-induced immune responses (regardless of whether they are vaccine or infection-induced, or a result of hybrid immunity). The most thorough and efficient study for such purposes is a comprehensive discovery/replication genome-wide association study (GWAS), to which we will add a phenome association

study (PheWAS) followed by a more complete characterization of distinct immune effector mechanisms believed to contribute to protective immunity. Our studies will identify gene polymorphisms and pathways having the largest or most critical impact on inter-individual variations in immunity among subjects, and how

comorbidities (phenotypes) contribute to these variations. Our Specific Aims are to 1) perform a large, genome-wide association study to identify novel genetic associations between SNPs and HLA alleles and inter-individual variations in the humoral immune response to COVID-19 infection or vaccination; identify

polygenic risk scores predictive of antibody response; replicate the findings in an independent cohort; evaluate significant findings in a cohort with documented infection and no vaccination; 2) conduct a phenome-wide association study to quantify the effect of additional subject characteristics (e.g., age, sex, race, ethnicity,

BMI), comorbidities, and phecodes (clusters of ICD10 codes) on the antibody response to COVID-19 vaccines; and 3) Evaluate the effect of genetic variation and host factors on T cell and B cell markers of immune response following vaccination. These aims will allow us to comprehensively define how inter-individual

variations in immune responses to COVID-19 vaccine are influenced by gene polymorphisms and host characteristics. Notably, despite the public health implications, there are no population-based studies identifying associations between COVID-19 vaccine immune response and genome-wide SNPs or clinical phenotypes. Our study is carefully designed to be rigorous and produce robust, unbiased, and reproducible

results applicable to the US population.