Document text
Principal Investigator: Richard Thomas Wyatt
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2023
Award: $503,260
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
Circulating (tier 2) HIV-1 variants are highly resistant to antibody-mediated neutralization, making broadly
effective vaccine design a major challenge. Encouragingly, work in our previous HIVRAD program
demonstrated that Ab responses capable of cross-neutralizing multiple heterologous tier 2 viruses were
elicited by targeted N-glycan deletion priming and heterologous glycan restorative Env trimer-liposome
boosting. The isolation of two monoclonal antibodies with broadly neutralizing activity from these studies
and high-resolution structures in complex with native-like trimers revealed that one mAb targeted the
conserved CD4 binding site (CD4bs) and the other targeted the gp41:gp120 interface region,
substantiated this result. In the current application, we will build on these efforts by evaluating responses
elicited by well-ordered, novel, trimer-based immunogens inoculated into Indian origin rhesus macaques.
In addition to the use pf protein-based trimers, we will test trimer platforms based on administration of
mRNA lipid nanoparticles as described in Project 1.
In Project 2, we will characterize B cell responses elicited by vaccine regimens evaluated in Indian origin
rhesus macaques in Core B by rapid, high-throughput monoclonal antibody (mAb) isolation to
define the targeted epitopes and guide both the choice of boosting immunogens and, if needed, trimer
redesign by eliminating or masking unwanted non-neutralizing immunodominant responses for
subsequent immunization studies. We will interact with the investigators in Core C, who also will generate
information about immunodominant Ab responses through their negative stain electron microscopy
(nsEM)-based method for evaluation of vaccine-induced serum responses. Using the Env-specific mAbs,
we will further determine how Env-specific antibody lineages evolve over time using Next Generation
Sequencing (NGS) and IgDiscover, a computational tool optimized for use in rhesus macaques. We will
generate individualized databases of macaque germline VDJ alleles for precise gene assignments, which
is necessary for correct conclusions about Ab affinity maturation and SHM levels. We will further use
the IgDiscover results and the new haplotype module to investigate if certain alleles, or combinations of
alleles, predispose to elicitation of neutralizing Ab responses in either adult of juvenile macaques. We
will investigate the level of expansion of neutralizing and non-neutralizing Ab lineages over time and
ask if vaccine-induced neutralizing Ab lineages persist in long-lived immune compartments such
as memory B cells and plasma cells, which are critical for the long-term protective effects of vaccines.
Terms: <21+ years old><AIDS Virus><Ab response><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adolescent><Adolescent Youth><Adult><Adult Human><Affinity><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antigenic Determinants><Antigens><B blood cells><B cell><B cell repertoire><B cells><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Binding Sites><Blood><Blood Plasma Cell><Blood Reticuloendothelial System><Blood Serum><Cell Isolation><Cell Lineage><Cell Segregation><Cell Separation><Cell Separation Technology><Cell surface><Characteristics><Clinical Treatment Moab><Combining Site><Communities><Complex><Data Bases><Databases><Development><Domestic Rabbit><Electron Microscopy><Epitopes><Evaluation><Evolution><FNA><Fine Needle Aspirate><Fine needle aspiration biopsy><Fine-Needle Aspiration><Framework Regions><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Germinal Center><Glycans><Goals><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV-1><HIV-I><HIV1><HTLV-III gp120><Haplotypes><Heterozygote><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Ig Somatic Hypermutation><Immune><Immunes><Immunity><Immunization><Immunize><Immunoglobulin Somatic Hypermutation><Individual><Investigators><LAV-HTLV-III><Laboratories><Light><Liposomal><Liposomes><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Mediating><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Methods><Modern Man><Monoclonal Antibodies><Mutation><NGS Method><NGS system><Negative Staining><Oryctolagus cuniculus><Photoradiation><Plasma Cells><Plasmacytes><Polysaccharides><Primates><Primates Mammals><Property><Proteins><Rabbits><Rabbits Mammals><Reactive Site><Recombinants><Regimen><Research><Research Personnel><Researchers><Resistance><Resolution><Rhesus Macaque><Rhesus Monkey><Sampling><Serum><Shapes><Specificity><Structure><Structure of germinal center of lymph node><Testing><Time><Vaccination><Vaccine Design><Vaccines><Variant><Variation><Virus><Virus-HIV><Work><adult animal><adulthood><antibody biosynthesis><cell sorting><chronic infection><computational tools><computerized tools><data base><design><designing><developmental><draining lymph node><evaluate vaccines><experiment><experimental research><experimental study><experiments><gene corrected><gene correction><genome mutation><gp120><gp120 ENV Glycoprotein><gp120(HIV)><heterozygosity><immunogen><immunoglobulin biosynthesis><improved><innovate><innovation><innovative><interest><juvenile><juvenile animal><juvenile human><lipid based nanoparticle><lipid nanoparticle><mAbs><mRNA><mature animal><model of animal><monoclonal Abs><neutralizing antibody><next gen sequencing><next generation sequencing><nextgen sequencing><non-human primate><nonhuman primate><novel><persistent infection><plasmocyte><programs><protective effect><regional lymph node><resistant><resolutions><response><somatic hypermutation><time use><tool><vaccine evaluation><vaccine screening><vaccine testing><young animal>