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Principal Investigator: CHRISTOPHER EDWARDS
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $48,974
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
The humoral immune system relies on the rich diversity of the antibody binding repertoire to generate targeted
responses to the vast array of antigens one may encounter, and much work has been done to characterize the
factors generating this diversity. However, allelic variation at the highly polymorphic immunoglobulin heavy chain
(IGH) gene locus has remained largely unexplored as a factor impacting the specificity of antibody responses to
both infection and vaccination. While many antigens are capable of eliciting strong neutralizing responses across
the population regardless of IGH haplotype, recent studies have shown that certain alleles encoding IGH gene
segments impact the magnitude of neutralizing antibody responses to viral antigens in humans. Differential
development of neutralizing antibody titers in response to HIV immunogens across individuals is well
documented, with only around 20% of HIV infected individuals developing broadly neutralizing antibodies
(bNAbs). Similarly, BG505.SOSIP.664, a tier 2 HIV envelope glycoprotein (env) immunogen, has been shown
to elicit a wide range of humoral responses in rhesus macaques (RM), with some developing high titers of nAbs
capable of protection against autologous SHIV challenge, while others develop very low nAb titers not capable
of such protection. We hypothesize that germline IGH polymorphisms and allelic representation within the
antigen specific B cell repertoire contribute to the variation in Nab titers observed in response to BG505
SOSIP.664 vaccination. The goal of this project is to determine how allelic variation at IGH genes in rhesus
macaques affects the development of nAbs, in the following two Specific Aims: (1) to identify IGH polymorphisms
in RM vaccinated with BG505SOSIP.644 associated with differential development of nAb titers (2) to identify the
epitope specificity of the antibody repertoire encoded by alleles associated most strongly with high nAb titers.
These experiments will uncover a factor contributing to the diversity of humoral immune responses at the
population level, and in doing so we will contribute to the establishment of a non-human primate model for
studying the effects of genotype on antibody responses to vaccines against various human pathogens. Our
results will greatly enhance the rational design and development of germline targeting vaccines.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Diversity><Antibody Repertoire><Antibody Response><Antibody Specificity><Antibody titer measurement><Antigenic Determinants><Antigens><Assay><Autologous><B blood cells><B cell><B cell receptor><B cell repertoire><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Bar Codes><Binding><Binding Determinants><Bioassay><Biological Assay><COVID-19 virus><COVID19 virus><Cell Body><Cells><Clinical Trials><CoV-2><CoV2><Development><ELISA><Envelope Protein><Enzyme-Linked Immunosorbent Assay><Epitopes><Exhibits><Frequencies><Gene variant><Genes><Genetic><Genetic Diversity><Genetic Polymorphism><Genetic Variation><Genotype><Germ Lines><Glycoproteins><Goals><HIV><HIV Infections><HIV envelope><HIV envelope protein><HIV vaccine><HIV/AIDS Vaccines><HTLV-III Infections><HTLV-III-LAV Infections><Haplotypes><Health><Heavy-Chain Immunoglobulins><Heterogeneity><Human><Human Genome><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Humoral Immunities><IGH><IGH@ gene cluster><Ig Genes><IgH locus><Immune Globulins><Immune response><Immune system><Immunoglobulin Genes><Immunoglobulin Heavy Chain Genes><Immunoglobulin Heavy Gene><Immunoglobulin Heavy Locus><Immunoglobulins><Immunological response><Individual><Infection><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Knowledge><LAV-HTLV-III><Link><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Memory B Cell><Memory B-Lymphocyte><Modern Man><Molecular Interaction><Mutate><NGS Method><NGS system><Orthomyxovirus Type A><PBMC><Peripheral Blood Mononuclear Cell><Persons><Population><Pre-Clinical Model><Preclinical Models><Preventative vaccine><Preventive vaccine><Prophylactic vaccine><Proteins><Protocol><Protocols documentation><Research><Rhesus Macaque><Rhesus Monkey><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SHIV><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Single cell seq><Sorting><Specificity><Staining method><Stains><Study models><Techniques><Testing><Transcript><Type A Influenza><Vaccinated><Vaccination><Vaccines><Variant><Variation><Viral Antigens><Virus-HIV><Work><Wuhan coronavirus><adaptive immune response><allele variant><allelic variant><antibody titering><antibody-based immunity><antigen binding><antigen bound><barcode><clinical relevance><clinically relevant><combat><coronavirus disease 2019 virus><coronavirus disease-19 virus><design><designing><developmental><env Antigens><env Gene Products><env Polyproteins><env Protein><enzyme linked immunoassay><experiment><experimental research><experimental study><experiments><gene locus><genetic locus><genetic variant><genomic location><genomic locus><genomic variant><hCoV19><host response><human immunodeficiency virus vaccine><human pathogen><human whole genome><immune system response><immunogen><immunoglobulin heavy chain locus><immunoresponse><model of animal><nCoV2><neutralizing antibody><next gen sequencing><next generation sequencing><nextgen sequencing><non-human primate><nonhuman primate><polymorphism><preference><rational design><response><simian HIV><simian human immunodeficiency virus><single cell next generation sequencing><single cell sequencing><social role><tool><vaccination study><vaccination trial><vaccine response><vaccine responsiveness><vaccine study><vaccine trial><vaccine-induced response><virus antigen>