Project 2: Current Good Manufacture Practices (CGMP) Production of Nucleoside-Modified mRNAs Encoding HIV-1 Envelopes
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Principal Investigator: Frederick Porter Organization: DUKE UNIVERSITY Fiscal Year: 2021 Award: $1,280,922 Funding agency: National Institute of Allergy and Infectious Diseases Project 2: Current Good Manufacture Practices (CGMP) Production of Nucleoside-Modified mRNAs Encoding HIV-1 Envelopes This IPCAVD grant seeks to develop and evaluate mRNA as an HIV-1 vaccine platform. Project 2 will oversee the manufacture of two nucleoside-modified mRNAs by current good manufacturing practices (CGMP) for a Phase I clinical trial to begin in year 5. To execute this project, we will select contract development and manufacturing organizations (CDMOs) as commercial partners to manufacture two mRNA immunogens to induce V3-glycan envelope site-targeted bnAb precursors. The scope of this work will span knowledge transfer to the selected CDMO through successful IND filing for the final vaccine candidate. A technical CDMO management team, including Drs. Haynes, Weissman and Porter will be assembled to oversee the process and ensure successful delivery of the program. The following specific aims are proposed for the project. • Aim 1. Facilitate knowledge transfer for selected mRNA immunogens to CDMOs. • Aim 2. Deliver final drug substances and drug products for toxicology studies and clinical testing. • Aim 3. Develop and deliver regulatory strategy to enable Phase I proof of concept clinical studies. Project 2 will advance modified mRNA as a platform for HIV immunization and establish the regulatory framework for its use. CGMP production of an mRNA V3-glycan mimetope vaccine will allow this vaccine platform to be evaluated in humans for comparison to other vaccination strategies and to assess the induction of V3-glycan bnAb precursors. Once developed, this platform could be rapidly applied to other HIV-1 immunogens with little additional development since the production process and the majority of release methods are not sequence dependent. These features of modified mRNA position the platform to address the complexity, safety, and cost effectiveness of HIV-1 vaccine regimens. Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Categories><Cell Lineage><Characteristics><Chemicals><Clinic><Clinical Evaluation><Clinical Research><Clinical Study><Clinical Testing><Clinical Trials><Complex><Consumption><Contracting Opportunities><Contracts><Custom><Development><Dose><Drugs><Early-Stage Clinical Trials><Ensure><Envelope Protein><Formulation><Glycans><Glycopeptides><Goals><Grant><HIV><HIV immunization><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><Immunity><Knowledge><LAV-HTLV-III><Lymphadenopathy-Associated Virus><Medication><Messenger RNA><Methods><Modern Man><Modification><Mosaicism><Non-Polyadenylated RNA><Nucleic Acids><Nucleosides><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Polysaccharides><Position><Positioning Attribute><Pre-Clinical Model><Preclinical Models><Process><Production><Proteins><RNA><RNA Gene Products><RNA vaccine><RNA-based vaccine><Recombinants><Regimen><Ribonucleic Acid><Rivers><Safety><Site><System><T cell response><Techniques><Technology><Testing><Time><TimeLine><Toxic effect><Toxicities><Toxicology><Vaccine Design><Vaccines><Viral Vector><Virus-HIV><Work><ZIKV><Zika Virus><base><clinical test><cost effectiveness><design><designing><developmental><drug/agent><env Antigens><env Gene Products><env Polyproteins><env Protein><expectation><falls><flexibility><flexible><human immunodeficiency virus vaccine><immunogen><immunogenicity><mRNA><mRNA vaccine><mRNA-based vaccine><model of animal><model organism><mosaic disorders><neutralizing antibody><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel><novel vaccines><phase I protocol><plasmid DNA><pre-clinical study><preclinical study><programs><protein expression><research clinical testing><stability testing><vaccination strategy><vaccine candidate><vector><zikav>