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Principal Investigator: DREW WEISSMAN
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2019
Award: $836,210
Funding agency: National Institute of Allergy and Infectious Diseases
DESCRIPTION (provided by applicant): A single HIV vaccine in human clinical trials demonstrated low level and short-term effectiveness, RV144. This vaccine used Pox virus prime - protein boost methodology, which because of the live virus prime, presents difficulties for large
scale production and safety. We have developed a new approach to the prime portion of an HIV vaccine that uses nucleoside modified mRNA composed entirely of physiologic components that is simple and cost effective to produce, does not require a cold chain, and should have no adverse events due to the mRNA. The mRNA is complexed in a lipid nanoparticle (LNP) whose formulation has entered phase 3 clinical trials for siRNA with no adverse events due to the lipids and is delivered by the intradermal route. To complement this novel method of priming an immune response, we have also developed a new immunogen that is an HIV envelope that does not require CD4 binding to infect a cell (CD4 independent). This envelope has a more open conformation, and we have demonstrated that it induces higher levels of Env-specific IgG, Tier-1 and 2 neutralization, and V1/V2 directed responses compared to their parents. In 3 specific aims, we will developed a new CD4 independent immunogen from a transmitted/founder clade C virus, compare it to already produced CD4i immunogens in the rabbit model and downselect for study in Rhesus macaques. We will also analyze boost proteins, comparing gp120 monomers to SOSIP trimers, in rabbits for use as a boost in macaques. We will then compare single immunogen prime-boost to multi-genic vaccination. We believe this new vaccine approach will be effective, in that it will develop high levels of Env-specific IgG, Tier-1 and 2 neutralization, and V1/V2 directed responses. In addition, we have demonstrated that the nucleoside modified mRNA-LNP prime induces very high levels (half of the total antigen-specific CD4+ T cell response) of antigen-specific T follicular helper (Tfh) cell that are critical in both the generation of high avidity IgG and long term memory, both of which are critical elements in the development of an effective HIV vaccine. This grant will move a new approach to vaccine priming and optimize immunogens for the prime and boost for testing in rabbits and Rhesus macaques. The data generated will be capable of moving this vaccine approach to clinical trial development with a minority of additional experiments.
Terms: <7S Gamma Globulin><AIDS Virus><ATGN><Ab response><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adverse Experience><Adverse event><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antigenic Determinants><Antigens><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Avidity><Binding><Binding Determinants><Binding Sites><Bioassay><Biologic Assays><Biological Assay><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Carbohydrates><Cell Body><Cell surface><Cells><Cellular biology><Clinical Trials><Cold Chains><Collaborations><Combining Site><Complement><Complement Proteins><Complex><DNA Molecular Biology><Data><Development><Domestic Rabbit><Effectiveness><Elements><Entropy><Envelope Protein><Epidemic><Epitopes><Formulation><General Viruses><Generations><Genes><Goals><Grant><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV Infections><HIV env Protein gp120><HIV envelope protein><HIV vaccine><HIV/AIDS Vaccines><HTLV-III Infections><HTLV-III gp120><HTLV-III-LAV Infections><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><I-RNA><IgG><Immune response><Immunochemical Immunologic><Immunoglobulin G><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunology><Inducer Cells><Inducer T-Lymphocytes><LAV-HTLV-III><Lipids><Lymphadenopathy-Associated Virus><Macaca><Macaca mulatta><Macaque><Mediating><Membrane><Messenger RNA><Methodology><Methods><Mice><Mice Mammals><Minority><Modeling><Modern Man><Modification><Molecular Biology><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Murine><Mus><Non-Polyadenylated RNA><Nucleic Acids><Nucleosides><Oryctolagus cuniculus><Parents><Phase 3 Clinical Trials><Phase III Clinical Trials><Physiologic><Physiological><Poxviridae><Poxviruses><Production><Proteins><Protocol><Protocols documentation><RNA><RNA Gene Products><Rabbits><Rabbits Mammals><Reactive Site><Rhesus><Rhesus Macaque><Rhesus Monkey><Ribonucleic Acid><Route><Safety><Short interfering RNA><Small Interfering RNA><Structure><System><T cell response><T4 Cells><T4 Lymphocytes><Testing><Thermodynamic><Thermodynamics><Translations><V3 Loop><V3 Loop of HIV-1><Vaccination><Vaccines><Viral><Viral Activity><Viral Function><Viral Physiology><Virus><Virus-HIV><Work><anti-viral agents><anti-viral drugs><anti-virals><antibody biosynthesis><base><cell biology><conformation><conformational state><cost><cost effective><developmental><env Antigens><env Gene Products><env Polyproteins><env Protein><experience><experiment><experimental research><experimental study><gp120><gp120 ENV Glycoprotein><gp120(HIV)><host response><human immunodeficiency virus vaccine><immune RNA><immunogen><immunogenicity><immunoglobulin biosynthesis><immunoresponse><improved><in vivo><large scale production><lipid nanoparticle><long term memory><longterm memory><mRNA><membrane structure><monomer><native protein drug><neutralizing antibody><new approaches><new vaccines><next generation vaccines><novel><novel approaches><novel strategies><novel strategy><novel vaccines><pharmaceutical protein><phase 3 trial><phase III protocol><plasmid vaccine><pox virus><pre-clinical study><preclinical study><product development><protein drug agent><public health relevance><response><sensor><siRNA><siRNA therapy><siRNA-based therapeutic><therapeutic protein><therapeutic siRNA><vaccine response><vaccinology><vector vaccine><virology>