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Principal Investigator: SANDHYA VASAN
Organization: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
Fiscal Year: 2023
Award: $619,289
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
An HIV-1 (HIV) vaccine capable of eliciting broad and potent neutralizing antibody (Ab) response to HIV envelope
(Env) remains elusive. HIV has a high mutation rate, Env is highly glycosylated as well as conformationally
dynamic and, well-characterized broadly neutralizing responses reported to date have been generated after
chronic HIV infection, rather than by candidate HIV vaccines. Recently, we reported that precursor broadly
neutralizing antibodies (bNAbs) can develop during early HIV infection and neutralization breadth was more
frequent when multiple HIV variants established infection in an individual, defined here as multiple-founder
variant (MFV) infection. Furthermore, Env diversity during initial infection was higher in individuals who
developed neutralization breadth. We concluded that Env-specific B cell development within one month of initial
HIV infection can predict neutralization breadth years later; this phenomenon highlights the critical importance
of these initial interactions, which prime B cells at the earliest stages of HIV infection. To determine the
immunogenicity of an HIV vaccine design based on the MFV concept, we formulated a cocktail of five Env trimer
proteins derived from MFV in acute infection. The Env sequences corresponded to 5 founder lineages in one
participant. They were further optimized by stabilizing them in a closed conformation using the ’Repair and
Stabilize’ strategy developed by Janssen Pharmaceuticals. The cocktail of minimally distant, stabilized Env
proteins were formulated with the novel vaccine adjuvant, Army Liposome Formulation plus QS-21 (ALFQ).
Preliminary immunogenicity data in rabbits demonstrated that this vaccine candidate elicited a greater breadth
of neutralizing Ab responses than an equivalent total dose of a single stabilized Env trimer protein. These
minimally distant immunogens also elicited a higher magnitude of IgM responses to HIV; a predictor of
subsequent neutralization breadth in our studies of early infection. Therefore, we propose to select an optimal
combination of minimally distant HIV Env immunogens that mimic the diversity and development of neutralizing
Ab breadth seen in acute infections with MFV in vitro and in vivo. We will optimize the antigenicity of the HIV Env
trimer immunogens by comparing native stabilized trimers with Env trimers that have shortened hypervariable
(HV) loops and glycan modifications in an attempt to improve their antigenicity (Aim 1). We will optimize
immunogen delivery and display strategies, including multivalent trimeric Envs delivered as messenger RNA
(mRNA) and, multivalent immunogen display on self-assembling liposomal cobalt porphyrin phospholiposomes
(CoPoP) that afford Env base shielding (Aim 2). We will utilize pre-specified Go/No-Go criteria to downselect the
optimal vaccine regimen of optimized minimally distant HIV vaccine candidates, to evaluate protective immune
responses in non-human primate SHIV challenge studies (Aim 3). Our long-term goal is to develop a multivalent
HIV vaccine candidate that elicits protective broadly neutralizing Ab responses for subsequent manufacture and
evaluation in human clinical trials.
Terms: <19S Gamma Globulin><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adjuvant><Antibodies><Antibody Response><Antibody titer measurement><Antigenic Determinants><Antigens><Armed Forces Personnel><B blood cells><B cell><B cells><B-Cell Activation><B-Cell Development><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Cell Communication and Signaling><Cell Maturation><Cell Signaling><Chronic><Clinical><Clinical Evaluation><Clinical Testing><Clinical Trials><Cobalt><Cohort Studies><Complementarity Determining Regions><Complex><Complimentarity Determining Region><Concurrent Studies><Data><Development><Distant><Domestic Rabbit><Dose><Engineering><Envelope Protein><Epitopes><Evaluation><Frequencies><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Germinal Center><Glycans><Goals><Grant><Growth><HIV><HIV Infections><HIV Vaccine Trials Network><HIV envelope><HIV envelope protein><HIV vaccine><HIV-1><HIV-1 vaccine><HIV-I><HIV/AIDS Vaccines><HIV1><HIV1 vaccine><HTLV-III Infections><HTLV-III-LAV Infections><HVTN><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Hypervariable Loop><Hypervariable Regions><IgM><Immune><Immune response><Immunes><Immunization><Immunochemical Immunologic><Immunoglobulin Hypervariable Region><Immunoglobulin M><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><In Vitro><Individual><Infection><Intracellular Communication and Signaling><Knowledge><LAV-HTLV-III><Lead><Length><Liposomal><Liposomes><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Messenger RNA><Metabolic Glycosylation><Military><Military Personnel><Modeling><Modern Man><Modification><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mutation><Oryctolagus cuniculus><Participant><Pb element><Persons><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Phosphatides><Phospholipids><Polysaccharides><Porphyrins><Preventative strategy><Prevention strategy><Preventive><Preventive strategy><Process><Proteins><QS 21><QS-21 Adjuvant><QS21><RNA vaccine><RNA-based vaccine><Rabbits><Rabbits Mammals><Regimen><Reporting><Research><Rhesus Macaque><Rhesus Monkey><SHIV><Sampling><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Specific qualifier value><Specified><Stimulon QS-21 Adjuvant><Structure of germinal center of lymph node><T cell response><Testing><Tissue Growth><Vaccination><Vaccine Adjuvant><Vaccine Design><Vaccines><Variant><Variation><Virus><Virus-HIV><activated B cells><acute infection><antibody titering><base><bases><biological signal transduction><clinical test><cohort><conformation><conformational><conformational state><conformationally><conformations><deliver vaccines><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><efficacy trial><env Antigens><env Gene Products><env Polyproteins><env Protein><genome mutation><glycosylation><heavy metal Pb><heavy metal lead><host response><human immunodeficiency virus vaccine><immune system response><immunogen><immunogenicity><immunoresponse><improved><in silico><in vivo><liposomal formulation><liposomal preparation><mRNA><mRNA vaccine><mRNA-based vaccine><manufacture><manufacturing test><military population><mosaic><neutralizing antibody><neutralizing mAb><neutralizing monoclonal antibodies><new approaches><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel approaches><novel strategies><novel strategy><novel vaccines><ontogeny><pharmaceutical><pre-clinical study><preclinical study><prevent><preventing><programs><protective efficacy><repair><repaired><research clinical testing><response><self assembly><simian HIV><simian human immunodeficiency virus><vaccine candidate><vaccine delivery><vaccine development><vaccine formulation><vaccine platform><vaccine strategy>