Vaccine development and production

疫苗研发及生产

• 批准号: 10401880
• 负责人: Sylvain FLEURY
• 金额: $ 152.92万
• 依托单位: UNIVERSITY OF LOUISIANA AT LAFAYETTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401880
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Adult; Agonist; Agreement; Antigens; Biomedical Research; CD4 Positive T Lymphocytes; Child; Cold Chains; Collaborations; Contracts; Development; Distant; Dosage Forms; Enteral; Epidemic; Epithelial; Formulation; GMP lots; Generations; Genital; Genitalia; Goals; Gut associated lymphoid tissue; HIV; HIV Antigens; HIV Envelope Protein gp41; HIV Vaccine Trials Network; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Immunization; Infant; Infection; Influenza; Intestinal Mucosa; Intestines; Intramuscular; Label; Lead; Liquid substance; Macaca mulatta; Membrane; Modeling; Mucosal Immune System; Mucous Membrane; Needles; Nose; Oral; Play; Polymers; Population; Powder dose form; Preventive vaccine; Process; Research Institute; Research Personnel; Route; Safety; Site; Small Intestines; Solid; Structure; Subunit Vaccines; Surface; TLR7 gene; Tablets; Teenagers; Temperature; Testing; Texas; Tissues; Toxicology; Vaccine Production; Vaccines; Viral Antibodies; Virosome Vaccines; Virosomes; Virus; Woman; Work; analytical method; base; capsule; clinical development; cold temperature; dosage; draining lymph node; efficacy study; ileum; immune activation; immunogenic; immunogenicity; improved; in vivo; innovation; manufacturing process; men; migration; mucosal site; mucosal vaccine; nonhuman primate; novel; novel vaccines; particle; phase I trial; prevent; programs; reconstitution; rectal; research clinical testing; response; sexual HIV transmission; thermostability; vaccine candidate; vaccine delivery; vaccine development; vaccine formulation; viral transmission

ABSTRACT – PROJECT 1 The induction of frontline defenses in genital and rectal tissues to prevent sexual HIV transmission is challenging, particularly with standard liquid subunit vaccines generally given intramuscularly. This multi-PI application is a collaboration between Mymetics (Dr. Sylvain Fleury, Project 1 Lead) and the Texas Biomedical Research Institute (Dr. Ruth Ruprecht, Project 2 Lead) that seeks to bring a promising mucosal HIV/AIDS vaccine approach into clinical development. Mymetics had inserted HIV gp41 antigens into the membranes of influenza virosomes, which have an excellent safety record in humans. These earlier, unadjuvanted liquid virosomal HIV gp41 vaccines were >80% efficacious in two independent nonhuman primate (NHP) studies. One of the gp41 vaccines, termed virosome-P1, was also safe and immunogenic in a Phase I trial in healthy women. To improve mucosal immunogenicity in the genital and intestinal tracts, Mymetics has adjuvanted the HIV vaccine formulation with the 3M-052 adjuvant that activates the toll-like receptor (TLR) 7/8; the 3M-052 adjuvant was active in infants, children, teenagers and adults. New, promising “all-in-one” HIV gp41 vaccines were specifically developed for various mucosal administration sites, with the aim to induce more efficient mucosal tissue coverage. A key innovation is the development of needle-free, solid-dosage vaccine formulations that are thermostable: nasal powder spray, sublingual tablets, or oral enteric-coated capsules filled with vaccine powder. All of these new vaccine formulations can withstand high/low temperatures outside the recommended cold-chain conditions without compromising product bioactivity. These novel, solid-form vaccines contain no free-form adjuvant; the HIV gp41-derived antigens as well as the 3M-052 adjuvant are physically bound to surface of the same particle. This prevents systemic adjuvant spread and thus avoids non-specific immune activation. Mymetics and its network of Contract Manufacturing Organizations (CMOs) will manufacture these different vaccines to test the hypothesis that the novel, cold chain-independent, needle-free, adjuvanted solid virosome forms are significantly more immunogenic than the earlier liquid form in NHPs, particularly when administered by mucosal routes. The Specific Aims for Project 1 are to: 1. Select a suitable enteric-coated capsule for vaccine delivery to the small intestine in rhesus macaques 2. Manufacture non-GMP batches of the different solid dosage forms for the NHP studies 3. Optimize the analytical methods and GMP manufacturing processes for the selected vaccine solid forms 4. Perform toxicology studies to show good safety profiles of the solid-form, adjuvanted virosomal vaccines given by mucosal routes – and to generate GMP vaccine for a Phase I trial to be conducted with the HVTN. This Project is significant because thermostable, solid-dosage forms of HIV gp41 virosomal vaccines offering mucosal protection could play a key role in preventing the further spread of HIV in the developing world, where the AIDS epidemic remains a serious problem.

摘要-项目1