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Principal Investigator: Beatrice H Hahn
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $879,161
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY (See instructions):
A central goal in HIV/AIDS vaccine research is the elicitation of broadly neutralizing antibodies
(bNAbs). Here, we leverage three recent discoveries from our groups to generate more effective V2 apex
immunogens. Having found that unshielded regions (“glycan holes”) in Env are negatively associated with
bNAb development, we have created bioinformatic tools to identify and mask these unwanted epitopes. We
have also used our Signature-based Epitope Targeted (SET) immunogen design strategy to generate
germline targeting Envs that engage multiple V2 apex bNAb precursors. Finally, by studying bNAb
development in ~150 rhesus macaques (RMs) infected with 16 different SHIVs, we have identified 25 animals
(17%) with heterologous breadth, 15 of which developed V2 apex bNAbs. Based on these data, we
hypothesize that by (i) minimizing distracting glycan hole epitopes, (ii) increasing Env affinity for V2 apex
bNAb precursors, (iii) increasing relevant epitope diversity in vaccine boosts, and (iv) incorporating B cell
lineage designs, we will improve V2 bNAb germline engagement and bNAb lineage maturation. During the
first 3 years of this R37 application, we have made significant progress toward all Specific Aims. In
Aim 1, we optimized the glycan shield and improved the germline targeting properties of several SIVcpz and
HIV-1 Envs, which allowed us to down-select the CAP256 Env as the most promising platform. In Aim 2, we
cloned members of 12 new rhesus V2 apex bNAb lineages and inferred their unmutated common ancestors
(UCAs), thereby tripling the number of V2 bNAb lineages for novel lineage-based immunogen design. SHIVs
expressing the best performing germline targeting CAP256 Envs are being generated and envelope-antibody
coevolution pathways are being determined for all SHIV infected animals that developed V2 neutralization
breadth. In Aim 3, we generated nucleoside-modified mRNA containing lipid nanoparticle (mRNA/LNP)
vaccines that express germline targeting, stabilized, membrane bound CAP256 Envs. The best performing
constructs have been shown to express well and to bind multiple human and macaque V2 bNAb UCAs. In
this five-year MERIT extension application, we propose to extend these studies and complete the rhesus
macaque infection and immunization studies that were delayed by the COVID lockdown. Since the last
competitive renewal, our group has been highly productive, publishing 38 papers relevant to HIV vaccine
development. In this MERIT extension application, we will apply multiple vaccine improvement strategies to
induce V2 apex bNAbs in RMs and then translate these findings to humans.
Terms: <AIDS Virus><Ab-mediated immunity><Ab-mediated protection><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affinity><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><Antibody immunity><Antibody protection><Antibody-mediated protection><Antigenic Determinants><Antigens><Apical><Autologous><B blood cells><B cell><B cells><B-Cell Receptor Binding><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID-19><CV-19><Cell Lineage><Characteristics><Clinical Treatment Moab><Coronavirus Infectious Disease 2019><Data><Development><Dose><Epitopes><Event><Evolution><Genes><Germ Lines><Glycans><Goals><HIV><HIV vaccine><HIV-1><HIV-1 vaccine><HIV-I><HIV/AIDS Vaccines><HIV1><HIV1 vaccine><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Immunization><Immunize><Infection><Instruction><LAV-HTLV-III><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Maps><Masks><Membrane><Messenger RNA><Modern Man><Molecular Interaction><Monkeys><Monoclonal Antibodies><Nucleosides><Paper><Pathway interactions><Pattern><Polysaccharides><Primates><Primates Mammals><Productivity><Property><Publishing><Regimen><Reproducibility><Rhesus><Rhesus Macaque><Rhesus Monkey><SHIV><T4 Cells><T4 Lymphocytes><Testing><Translating><Transmission><Vaccination><Vaccine Design><Vaccine Research><Vaccines><Variant><Variation><Virus><Virus-HIV><Work><antibody-mediated immunity><bio-informatics tool><bioinformatics tool><booster dose><booster shot><booster vaccine><breakthrough infection><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><env Glycoproteins><human immunodeficiency virus vaccine><immunogen><immunogenicity><improved><in vivo><lipid based nanoparticle><lipid nanoparticle><mAbs><mRNA><member><membrane structure><model of animal><monoclonal Abs><neutralizing antibody><neutralizing mAb><neutralizing monoclonal antibodies><novel><pathway><pre-clinical><preclinical><protective efficacy><rational design><response><simian HIV><simian human immunodeficiency virus><transmission process><vaccine boost><vaccine development><vaccine-related research><vector>