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Principal Investigator: Barton F. Haynes
Organization: DUKE UNIVERSITY
Fiscal Year: 2020
Award: $942,168
Funding agency: National Institute of Allergy and Infectious Diseases
Vaccine trials in non-human primates challenged with R5, tier 2 SHIVs have shown protection in the
presence of high levels of non-neutralizing antibodies (NNAbs), and one of the 5 Phase IIb HIV-1 vaccine
efficacy trials using alum (ALVAC/AIDSVAX in RV144) showed an estimated vaccine efficacy of 31%, with a
correlate of decreased transmission risk of V2 and other FcR-mediated anti-HIV antibodies. NNAbs are
polyfunctional antibodies capable of mediating a number of FcR-mediated or complement-mediated functions
such as ADCC, antibody dependent cellular phagocytosis (ADCP) or NK cytokine production. A new efficacy
trial is ongoing to follow-up on RV144, called HVTN702, using ALVAC-C, a bivalent clade C gp120 boost, and
the adjuvant MF59. We have demonstrated that a multivalent wildtype (WT) Env ALVAC/protein vaccine
protected macaques by ~55% from robust (12 intrarectal challenges) challenge with R5, tier 2 SHIV. In this
study, the immune correlates of protection were NNAbs that mediated infected cell antibody binding, ADCC,
ADCP of challenge SHIV and MIP1β expression by NK cells. The overall hypothesis of project 1 is that the
efficacy of RV144 and the current HVTN 702 efficacy trial will be improved upon by use of mRNAs encoding
trivalent ADCC mosaic Envs that are specifically designed to overcome NNAb epitope diversity. This will be
accomplished by the following Specific Aims:
Specific Aim 1. Design and produce multivalent nucleoside-modified mRNAs encoding either
polyvalent WT or ADCC mosaic Env gp120s.
Specific Aim 2. Determine the induction of NNAbs induced by trivalent ADCC mosaic vs. WT Envs in
bnAb VH + VL UCA knock-in (KI) mice that express the RV144-derived V2 ADCC-mediating antibody,
CH58.
Specific Aim 3. Test ALVAC-C/trivalent ADCC Env gp120s in rhesus macaques (RMs) for ability to
protect against an R5, tier 2 transmitted/founder SHIV for use in a phase I clinical trial in year 5.
Terms: <AIDS Virus><ALVAC><ALVAC Canarypox Vector><Ab-dependent cellular cytotoxicity><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Active Follow-up><Adjuvant><Affinity><Alum Adjuvant><Antibodies><Antibody Response><Antibody titer measurement><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><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><Cell Body><Cells><Class Switching><Class Switchings><Complement><Complement Proteins><Complex><Cytotoxic cell><Data><Development><Early-Stage Clinical Trials><Elements><Epitopes><Germinal Center><Grant><HIV><HIV Antibodies><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV Vaccine Trials Network><HIV env Protein gp120><HIV vaccine><HIV-1><HIV-1 vaccine><HIV-Associated Antibodies><HIV-I><HIV/AIDS Vaccines><HIV1><HIV1 vaccine><HTLV-III Antibodies><HTLV-III gp120><HTLV-III-LAV Antibodies><HVTN><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antibodies><Human immunodeficiency virus 1><I-RNA><Immune><Immunes><Immunization><Immunize><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunostimulation><Inducer Cells><Inducer T-Lymphocytes><Infectious Agent><Inflammatory><Interferon Type I><Intramuscular><Isotype Switching><Isotype Switchings><K lymphocyte><KI mice><Knock-in Mouse><LAV Antibodies><LAV-HTLV-III><Lymphadenopathy-Associated Antibodies><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><MF59><Macaca><Macaca mulatta><Macaque><Maintenance><Mediating><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Mice><Mice Mammals><Modern Man><Molecular Interaction><Mosaicism><Murine><Mus><NK Cells><Natural Killer Cells><Nucleosides><Phagocytosis><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Plasma><Plasma Serum><Production><Proteins><RNA vaccine><Reticuloendothelial System, Serum, Plasma><Rhesus Macaque><Rhesus Monkey><Risk><SHIV><Safety><Structure of germinal center of lymph node><T cell response><T4 Cells><T4 Lymphocytes><Testing><Translations><Transmission><Vaccine Design><Vaccines><Virus-HIV><Wild Type Mouse><ZIKV><Zika Virus><active followup><alum><aluminum sulfate><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody titering><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><comparative><cost><cytokine><design><designing><develop a vaccine><development of a vaccine><developmental><efficacy trial><expectation><follow up><follow-up><followed up><followup><gp120><gp120 ENV Glycoprotein><gp120(HIV)><human immunodeficiency virus vaccine><immune RNA><immunogen><improved><infectious organism><innovate><innovation><innovative><knockin mice><lipid nanoparticle><mRNA><mRNA vaccine><mosaic disorders><native protein drug><neutralizing antibody><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel vaccines><pharmaceutical protein><phase I protocol><protein drug agent><response><sensor><simian HIV><simian human immunodeficiency virus><therapeutic protein><transmission process><vaccination study><vaccination trial><vaccine candidate><vaccine development><vaccine efficacy><vaccine formulation><vaccine study><vaccine trial><wildtype mouse><zikav>