Vaccine development and production

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传播艾滋病毒是具有挑战性的， 特别是通常肌肉内给予的标准液体亚单位疫苗。这个多PI应用程序是一个 Mymetics（Sylvain Fleury博士，项目1负责人）和德克萨斯州生物医学研究中心之间的合作 该研究所（Ruth Ruprecht博士，项目2负责人）寻求带来一种有前途的粘膜HIV/AIDS疫苗方法 临床开发。Mymetics将HIV gp 41抗原插入流感病毒体的膜中， 在人体内有很好的安全记录。这些早期的无佐剂液体病毒体HIV gp 41 在两项独立的非人灵长类动物（NHP）研究中，疫苗的有效性>80%。GP 41之一 被称为病毒体-P1的疫苗在健康女性的I期试验中也是安全和免疫原性的。 为了提高生殖器和肠道的粘膜免疫原性，Mymetics已经辅助了HIV 具有激活Toll样受体（TLR）7/8的3 M-052佐剂的疫苗制剂; 3 M-052佐剂 在婴儿、儿童、青少年和成人中很活跃。新的，有前途的“一体化”艾滋病毒gp 41疫苗， 专为各种粘膜给药部位开发，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制剂， 耐热：鼻用粉末喷雾剂、舌下片剂或填充有疫苗粉末的口服肠溶胶囊。 所有这些新的疫苗配方都可以承受推荐冷链以外的高/低温 在不损害产品生物活性的条件下。这些新型固体疫苗不含游离形式的 佐剂; HIV gp 41衍生抗原以及3 M-052佐剂物理地结合至免疫球蛋白的表面。 相同的粒子。这防止了全身性佐剂扩散，从而避免了非特异性免疫激活。 Mymetics及其合同制造组织（CMO）网络将生产这些不同的 新的、不依赖于冷链的、无针的、佐剂化的固体病毒体 在NHP中，形式比早期的液体形式具有显著更高的免疫原性，特别是当施用时 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用于恒河猴小肠递送疫苗 2.生产用于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，以显示固体形式、含佐剂病毒体疫苗的良好安全性特征 通过粘膜途径给药-并产生GMP疫苗用于将用HVTN进行的I期试验。 该项目意义重大，因为热稳定的HIV gp 41病毒体疫苗固体剂型提供了 粘膜保护在防止艾滋病毒在发展中国家进一步传播方面发挥着关键作用， 艾滋病流行病仍然是一个严重问题。

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.