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预防艾滋病毒性传播具有挑战性， 特别是通常肌肉注射的标准液体亚单位疫苗。这个多 PI 应用程序是 Mymetics（Sylvain Fleury 博士，项目 1 负责人）与德克萨斯生物医学研究中心之间的合作 研究所（Ruth Ruprecht 博士，项目 2 负责人）致力于带来一种有前景的粘膜 HIV/艾滋病疫苗方法 进入临床开发。 Mymetics 将 HIV gp41 抗原插入流感病毒体的膜中， 对人类有良好的安全记录。这些早期的、未加佐剂的液体病毒体 HIV gp41 在两项独立的非人灵长类动物 (NHP) 研究中，疫苗的有效性 >80%。 gp41之一 被称为病毒体-P1 的疫苗在健康女性的 I 期试验中也具有安全性和免疫原性。 为了提高生殖器和肠道的粘膜免疫原性，Mymetics 已对 HIV 进行佐剂 含有可激活 Toll 样受体 (TLR) 7/8 的 3M-052 佐剂的疫苗制剂； 3M-052佐剂 在婴儿、儿童、青少年和成人中都很活跃。新的、有前途的“一体式”HIV gp41 疫苗已上市 专为各种粘膜给药部位而开发，旨在诱导更有效的粘膜给药 组织覆盖。一项关键的创新是开发无针固体剂量疫苗配方， 耐热：鼻粉喷雾剂、舌下含片或填充疫苗粉的口服肠溶胶囊。 所有这些新疫苗配方都可以承受推荐冷链之外的高温/低温 条件下不影响产品的生物活性。这些新型固体疫苗不含游离形式 佐剂； HIV gp41 衍生抗原以及 3M-052 佐剂物理结合到表面 相同的粒子。这可以防止全身佐剂扩散，从而避免非特异性免疫激活。 Mymetics 及其合同制造组织 (CMO) 网络将制造这些不同的产品 疫苗来检验以下假设：新型、不依赖冷链、无针、带佐剂的固体病毒体 NHP 中的形式比早期的液体形式具有更高的免疫原性，特别是在施用时 通过粘膜途径。项目 1 的具体目标是： 1. 选择合适的肠溶胶囊将疫苗输送至恒河猴小肠 2. 为 NHP 研究生产不同固体剂型的非 GMP 批次 3. 优化所选疫苗固体剂型的分析方法和 GMP 生产工艺 4. 进行毒理学研究以显示固体佐剂病毒体疫苗的良好安全性 通过粘膜途径给予——并生产 GMP 疫苗，用于与 HVTN 进行的 I 期试验。 该项目意义重大，因为提供了热稳定的固体剂型 HIV gp41 病毒体疫苗 粘膜保护可以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，其中 艾滋病流行仍然是一个严重的问题。