Vaccine development and production

摘要-项目1 在生殖器和直肠组织中诱导一线防御以防止性传播艾滋病毒是具有挑战性的， 特别是对于通常肌肉注射的标准液体亚单位疫苗。此多PI应用程序是一个 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 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艾滋病毒/艾滋病疫苗方法 进入临床开发阶段。Mymetics将HIV gp41抗原插入流感病毒小体的膜中， 它们在人类身上有很好的安全记录。这些早期的，未经佐剂的液体病毒体HIV gp41 在两项独立的非人灵长类(NHP)研究中，疫苗的有效率为80%。Gp41中的一位 在健康女性的第一阶段试验中，被称为病毒小体-P1的疫苗也是安全的和免疫原性的。 为了提高生殖器和肠道的粘膜免疫原性，Mymetics已经对HIV进行了佐剂 具有激活Toll样受体(TLR)7/8的3M-052佐剂的疫苗制剂 在婴儿、儿童、青少年和成人中很活跃。新的，有前途的“一体式”HIV gp41疫苗 专门为不同的粘膜给药部位开发的，旨在诱导更有效的粘膜 纸巾覆盖。一项关键的创新是开发无针、固体剂量的疫苗配方，这些配方 耐热性：疫苗粉鼻粉喷雾剂、舌下含片或口服肠溶胶囊。 所有这些新疫苗配方都可以承受推荐冷链之外的高/低温。 在不影响产品生物活性的条件下。这些新型固体形式的疫苗不含自由形式 佐剂；HIV gp41来源的抗原以及3M-052佐剂物理上结合到 相同的粒子。这防止了全身佐剂的扩散，从而避免了非特异性免疫激活。 Mymetics及其合同制造组织(CMO)网络将制造这些不同的 疫苗来测试这种新型的、不依赖冷链的、无针的、有佐剂的固体病毒体的假设 在NHP中，形式明显比早期的液体形式更具免疫原性，特别是在给药时 通过粘膜途径。项目1的具体目标是： 1.选择适合恒河猴小肠注射疫苗的肠溶胶囊 2.为NHP研究生产不同固体剂型的非GMP批次 3.优化选定疫苗固体形式的分析方法和GMP制造工艺 4.进行毒理学研究，以显示固体形式佐剂病毒体疫苗的良好安全性 通过粘膜途径给予-并为将与HVTN一起进行的I期试验生成GMP疫苗。 该项目意义重大，因为耐热、固体剂型的HIV gp41病毒体体疫苗可提供 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，在发展中国家 艾滋病流行仍然是一个严重的问题。

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.