Vaccine development and production

疫苗研发及生产

• 批准号: 10624799
• 负责人: Sylvain FLEURY
• 金额: $ 9.71万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624799
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Adult; Agonist; Agreement; Antigens; Binding; Biomedical Research; CD4 Positive T Lymphocytes; Child; Cold Chains; Collaborations; Contracts; Development; Distant; Dosage Forms; Enteral; Epidemic; Epithelium; Formulation; GMP lots; Generations; Genital; Genitalia; Goals; Good Manufacturing Process; Gut associated lymphoid tissue; HIV; HIV Antigens; 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; Qualifying; Recommendation; Rectum; 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; capsule; clinical development; cold temperature; dosage; draining lymph node; efficacy study; ileum; immune activation; immunogenic; immunogenicity; improved; in vivo; innovation; manufacture; manufacturing organization; 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 在生殖器和直肠组织中诱导前线防御以防止性HIV传播是具有挑战性的， 特别是使用标准的液体亚基疫苗通常给予肌肉内。此多PI应用程序是 Mymetics（Sylvain Fleury博士，Project 1 Lead）与德克萨斯生物医学研究之间的合作 试图带来有希望的粘膜艾滋病毒/艾滋病疫苗方法的研究所（Ruth Ruprecht博士，项目2负责人） 进入临床发展。 Mymetics已将HIV GP41抗原插入了影响Za病毒体的膜中， 在人类中具有出色的安全记录。这些较早的，无抗的液体病毒体HIV GP41 在两项独立的非人类灵长类动物（NHP）研究中，疫苗效率> 80％。 GP41之一 在健康女性的I期试验中，称为病毒体P1的疫苗也是安全且免疫原性的。 为了改善生殖器和肠道中的粘膜免疫原性，Mymetics调整了HIV 3M-052调整疫苗公式，以激活Toll样接收器（TLR）7/8; 3M-052调整 活跃于婴儿，儿童，青少年和成人。新的，承诺的“多合一” HIV GP41疫苗是 专门为各种粘膜给药部位开发，目的是诱导更有效的粘膜 组织覆盖范围。一个关键的创新是开发无针，固体剂量疫苗的公式 热稳定性：鼻粉喷雾，舌下片剂或装有疫苗粉末的口服肠涂层胶囊。 所有这些新的疫苗配方都可以承受推荐冷链之外的高/低温 没有损害产品生物活性的条件。这些新颖的固体形式疫苗不含自由形式 调整; HIV GP41衍生的抗原以及3M-052调整在物理上与表面结合 同一粒子。这样可以防止系统性调整扩散，从而避免了非特异性免疫激活。 Mymetics及其合同制造组织网络（CMO）将制造这些不同的 疫苗测试了新型，冷链独立的，无针，调整的固体病毒体的假设 与NHP中的早期液体形式相比，形式的免疫原性要高得多，尤其是当给药时 通过粘膜路线。项目1的具体目标是： 1。选择一个合适的肠涂层胶囊，以将疫苗传递到恒河猕猴中的小肠 2。用于NHP研究的不同固体剂型的非GMP批次 3。优化选定疫苗固体形式的分析方法和GMP制造过程 4。进行毒理学研究以显示固体形式调整的病毒体疫苗的良好安全概况 由粘膜途径给出 - 并生成GMP疫苗以使用HVTN进行的I期试验。 该项目很重要，因为HIV GP41病毒体疫苗的热稳定，固体剂量形式 粘膜保护可能在防止艾滋病毒在发展中国家进一步传播方面发挥关键作用 艾滋病流行仍然是一个严重的问题。