Project 1: Development of Nucleoside-Modified mRNAs Encoding Sequential HIV-1 Envelopes for Initiation of V3-glycan Neutralizing Antibody Lineages
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Principal Investigator: Barton F. Haynes Organization: DUKE UNIVERSITY Fiscal Year: 2021 Award: $96,745 Funding agency: National Institute of Allergy and Infectious Diseases Project 1: Development of Nucleoside-Modified mRNAs Encoding Sequential HIV-1 Envelopes for Initiation of V3-glycan Neutralizing Antibody Lineages A major goal of HIV-1 vaccine development is to induce broadly neutralizing antibodies (bnAbs). This IPCAVD team has immunogens that can trigger unmutated common ancestors (UCAs) of bnAb B cell lineages, a key approach for an HIV vaccine. One such sequential Env immunogen termed, EnvSeq-3, is derived from the study of the CH848 HIV-1-infected individual who made the DH270 HIV V3-glycan-targeted bnAb. We hypothesize that use of priming immunogens that bind to the UCA of the DH270 B cell lineage followed by sequential modified mRNA gp160 or gp140 trimer-based immunogens will result in the initiation of V3-glycan bnAb B cell lineages in humans. • Specific Aim 1. Design and formulate sequential nucleoside-modified mRNAs encoding two gp160s or soluble chimeric, stabilized trimers that bind to intermediate antibodies of the DH270 B cell lineage. Nucleoside-modified mRNA encoding the first 2 trimeric lineage immunogens after the V3-glycopeptide will be optimized for high level expression using established techniques. • Specific Aim 2. Determine if synthetic UCA-binding glycopeptides combined with GLA/SE adjuvant will prime DH270 UCA B cells for boosting with Env trimer-encoding mRNAs in DH270 UCA VH and VL knock-in mice. Glycopeptide and mRNA immunogens will be analyzed including combinations to confirm in DH270 UCA VH + VL knock-in (KI) mice their induction of Tfh cells and selection of antibodies that target the V3-glycan bnAb site. The two selected mRNAs will be produced CGMP in Project 2. • Specific Aim 3. Test sequential immunogens in outbred rhesus macaques to optimize immunization schemes for use in a phase I clinical trial in year 5. We believe that modified mRNA-LNPs encoding V3-glycan lineage immunogens will generate potent CD4+ Tfh and antibody responses, and will initiate V3-glycan bnAb lineages in bnAb KI mice and in humans. This project will use a promising sequential immunogen design in the form of nucleoside-modified mRNAs to overcome barriers to bnAb development. If successful, the use of nucleoside-modified mRNAs will transform HIV-1 vaccine development. Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adjuvant><Affinity><Antibodies><Antibody Affinity><Antibody Response><Antigenic Determinants><Antigens><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Blood Plasma><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Carbohydrates><Cell Lineage><Cell surface><Complex><Development><Dose><Early-Stage Clinical Trials><Elements><Epitopes><Germinal Center><Glycans><Glycopeptides><Goals><HIV><HIV envelope protein><HIV vaccine><HIV-1><HIV-1 vaccine><HIV-I><HIV/AIDS Vaccines><HIV1><HIV1 vaccine><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Homolog of Drosophila TOLL><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><I-RNA><Ig Somatic Hypermutation><Immune Tolerance><Immunization><Immunize><Immunoglobulin Somatic Hypermutation><Immunologic Sensitization><Immunologic Stimulation><Immunologic Tolerance><Immunological Sensitization><Immunological Stimulation><Immunostimulation><Individual><Inducer Cells><Inducer T-Lymphocytes><Infectious Agent><Interferon Type I><Intramuscular><KI mice><Knock-in Mouse><LAV-HTLV-III><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Mice><Mice Mammals><Modern Man><Molecular Interaction><Murine><Mus><Nucleosides><Phase 1 Clinical Trials><Phase I Clinical Trials><Plasma><Plasma Serum><Poly ICLC><Polysaccharides><Production><Provider><Regimen><Reticuloendothelial System, Serum, Plasma><Rhesus Macaque><Rhesus Monkey><Route><Safety><Scheme><Site><Structure of germinal center of lymph node><T cell response><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TLR3><TLR3 gene><TLR4><TLR4 gene><Techniques><Testing><Toll Homologue><Toll-Like Receptor 3><Translations><Vaccine Design><Vaccines><Virus-HIV><ZIKV><Zika Virus><antigen antibody affinity><base><cost><cytokine><design><designing><develop a vaccine><development of a vaccine><developmental><expectation><gp160><human immunodeficiency virus vaccine><immune RNA><immune system tolerance><immune unresponsiveness><immunogen><immunogenicity><immunological paralysis><in vivo><infectious organism><knockin mice><lipid nanoparticle><long term memory><longterm memory><mRNA><native protein drug><neutralizing antibody><new vaccines><next generation vaccines><novel vaccines><pharmaceutical protein><phase I protocol><protein drug agent><sensor><somatic hypermutation><therapeutic protein><thymus derived lymphocyte><toll-like receptor 4><vaccine development><vaccine formulation><zikav>