Cold Chain-Independent, Needle-Free Mucosal Virosomal Vaccine to Prevent HIV-1 Acquisition at Mucosal Levels

不依赖冷链、无针粘膜病毒体疫苗，可预防粘膜水平的 HIV-1 感染

• 批准号: 10072724
• 负责人: Sylvain FLEURY
• 金额: $ 72.72万
• 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/10072724
• 关键词: Cold; Chain; Independent; Needle; Free

PROJECT SUMMARY – OVERALL This multi-PI application is a collaboration between Mymetics and the Texas Biomedical Research Institute (TxBiomed), with Drs. Sylvain Fleury (Project 1 Lead; Mymetics) and Ruth Ruprecht (Project 2 Lead; TxBiomed) serving as PIs. We seek to bring a promising HIV/AIDS vaccine approach to the clinic. The vaccine is based upon influenza virosomes, enveloped virus-like particles that display on their surface elongated HIV gp41 peptides (virosome-P1) or recombinant truncated HIV gp41 (virosome-rgp41). Mymetics' Phase I clinical trial with virosome-P1 in healthy women showed safety and immunogenicity. Two independent nonhuman primate (NHP) studies demonstrated the safety and high efficacy of the combination of virosome-P1 + virosome rgp41 against repeated low-dose intravaginal challenges with a tier 2 R5 SHIV in Chinese and Indian-origin rhesus macaques (RMs). In the latter, 78-87% efficacy was noted when the SHIV challenge dose was ~7x104 times the median HIV inoculum in male-to-female HIV transmission. However, when this HIV inoculum was exceeded 105- fold by an even higher SHIV inoculum, protection in Indian RMs was lost, implying a threshold effect whereby vaccine-induced mucosal antibodies were unable to ward off the higher number of invading SHIV particles. The soluble vaccine used in both NHP studies was unadjuvanted. To improve immunogenicity, Mymetics has embedded the toll-like receptor (TLR)7/8 adjuvant 3M-052 into virosomal envelopes. Moreover, Mymetics has developed a powdered form of virosomes that is no longer cold-chain dependent and can be administered as intranasal (IN) spray, sublingual (SL) tablets, or packaged into oral capsules. We hypothesize that these novel solid virosome formulations are significantly more immunogenic, particularly when administered via mucosal routes, than the unadjuvanted liquid form used earlier in NHPs. The Specific Aims of this IPCAVD project are to: 1. Assess the immunogenicity of the new vaccine candidates, the newly 3M-052-adjuvanted HIV virosome-P1 and virosome-rgp41, under solid dosage forms delivered IN, SL, or orally to Indian RMs in order to select the two most immunogenic formulations for subsequent mucosal prime/mucosal boost immunization. 2. Assess the efficacy of the cold-chain independent virosomal vaccine delivered by combined mucosal immunization routes against repeated intrarectal challenges with the heterologous R5 clade B SHIVSF162P3. Protected RMs will be rechallenged with an R5 tier 2 clade C SHIV. 3. Optimize the GMP manufacturing process for the selected virosomal formulations for mucosal delivery, and 4. Perform toxicology studies to show good safety profiles of the adjuvanted, solid-form vaccines given by selected mucosal routes – and generate GMP vaccine for a Phase I trial to be conducted with the HVTN. Our vaccine development plans represent major advances, as the novel needle-free, solid vaccine dosage forms are cold-chain independent and will be mucosally delivered – unique aspects that make the novel virosomal vaccines especially attractive for the developing world, where the AIDS epidemic remains a serious problem.

项目总结--总体 这个多PI应用程序是Mymetics和德克萨斯生物医学研究所之间的合作 作者：Sylvain Fleury博士(项目1的负责人；Mymetics)和Ruth Ruprecht(项目2的负责人；TxBimed) 担任私家侦探。我们寻求将一种有前途的艾滋病毒/艾滋病疫苗方法引入临床。疫苗是基于 在流感病毒小体上，表面显示的被包裹的病毒样颗粒拉长了HIV gp41 多肽(病毒体-P1)或重组截短HIV gp41(病毒体-rgp41)。Mymetics的I期临床试验 病毒小体-P1在健康女性中表现出安全性和免疫原性。两个独立的非人灵长类 (NHP)研究证实了病毒小体-P1+病毒小体rgp41组合的安全性和高效性 中国恒河猴和印度恒河猴使用第2层R5 SHV预防反复低剂量阴道内感染 猕猴(RMS)。在后者中，当SHIV攻击剂量为~7x104倍时，有78-87%的有效率 男性向女性传播的艾滋病毒接种量中位数。然而，当艾滋病毒接种量超过105时- 在更高的SIV疫苗的作用下，印度RMS的保护作用丧失，这意味着阈值效应 疫苗诱导的粘膜抗体不能抵挡更多数量的入侵SIV颗粒。这个 在两项NHP研究中使用的可溶性疫苗都没有佐剂。为了提高免疫原性，Mymetics已经 将Toll样受体(TLR)7/8佐剂3M-052嵌入病毒体膜。此外，Mymetics已经 开发了一种粉末状的病毒小体，不再依赖冷链，可以作为 鼻腔喷雾(IN)、舌下(SL)片剂或包装成口服胶囊。我们假设这些小说 固体病毒体制剂具有更强的免疫原性，特别是通过粘膜给药时。 与早先在卫生保健方案中使用的无辅助剂液体形式相比，它更适合于其他途径。IPCAVD项目的具体目标是： 1.评估新的候选疫苗，新的3M-052佐剂HIV病毒体-P1的免疫原性 和病毒体-rgp41，在固体剂型中、SL或口服给印度RMS，以选择 两种最具免疫原性的配方，用于随后的粘膜基础/粘膜强化免疫。 2.联合粘膜接种冷链非依赖病毒体苗的效果评价 用异源R5分支B SHIVSF162P3免疫抵抗重复直肠内攻击的途径。 受保护的RM将使用R5第2层分支C Shiv进行重新质询。 3.优化用于粘膜递送的选定病毒体制剂的GMP制造工艺，以及 4.进行毒理学研究，以显示由以下公司提供的佐剂固体疫苗具有良好的安全性 选定的粘膜路线--并为将与HVTN一起进行的I期试验生成GMP疫苗。 我们的疫苗开发计划代表着重大进展，因为新型无针固体疫苗剂型 是冷链独立的，并将通过粘膜递送--这是使新的病毒体具有独特的方面 疫苗对发展中国家特别有吸引力，因为那里的艾滋病流行仍然是一个严重的问题。