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: 10624796
• 负责人: Sylvain FLEURY
• 金额: $ 162.98万
• 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/10624796
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Address; Adjuvant; Affect; Animal Model; Animals; Antibodies; Antibody Response; Biomedical Research; Chinese; Clinic; Clinical; Cold Chains; Collaborations; Data; Development Plans; Dosage Forms; Dose; Double-Blind Method; Epidemic; Experimental Designs; Female; Formulation; HIV; HIV Vaccine Trials Network; HIV envelope protein; HIV vaccine; HIV-1; Human; Immunization; Immunoglobulin A; Immunoglobulin G; Influenza; Intramuscular; Invaded; Lead; Link; Liquid substance; Macaca mulatta; Membrane; Mucous Membrane; Needles; Nose; Oral; Peptides; Phase; Phase I Clinical Trials; Pilot Projects; Plasma; Powder dose form; Program Development; Publishing; Recombinants; Refrigeration; Reporting; Research Institute; Route; SIV; Safety; Solid; Surface; Systemic infection; TLR7 gene; Tablets; Texas; Time; Toxicology; Vaccinated; Vaccination; Vaccinee; Vaccines; Viremia; Virion; Virosome Vaccines; Virosomes; Virus-like particle; Woman; antibody-dependent cell cytotoxicity; capsule; design; efficacy evaluation; human male; immunogenic; immunogenicity; improved; male; manufacturing process; neutralizing antibody; nonhuman primate; novel; novel vaccines; particle; phase I trial; pre-clinical; prevent; response; seroconversion; sexual HIV transmission; simian human immunodeficiency virus; transcytosis; transmission process; vaccine candidate; vaccine delivery; vaccine development; vaginal fluid; ward

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.

项目概要-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 Sylvain Fleury博士（项目1负责人; Mymetics）和Ruth Ruprecht博士（项目2负责人; TxBiomed） 作为PI。我们寻求将一种有希望的艾滋病毒/艾滋病疫苗方法引入临床。疫苗是基于 在流感病毒体上，在其表面展示的包膜病毒样颗粒延长了HIV gp 41 肽（病毒体-P1）或重组截短的HIV gp 41（病毒体-rgp 41）。Mymetics的I期临床试验 结果表明，病毒体P1在健康女性中的安全性和免疫原性均较好。两个独立的非人类灵长类动物 (NHP)研究证明了病毒体-P1+病毒体rgp 41的组合的安全性和高效性 在中国和印度恒河猴中对抗2级R5 SHIV的重复低剂量阴道内攻毒 猕猴（RM）。在后者中，当SHIV攻击剂量为约7 × 104倍于对照组时，观察到78-87%的疗效。 男性对女性艾滋病毒传播中的艾滋病毒接种中位数。然而，当这种艾滋病毒接种超过105- 倍，甚至更高的SHIV接种物，在印度RM的保护丢失，这意味着阈值效应， 疫苗诱导的粘膜抗体不能抵御更多数量的SHIV颗粒的入侵。的 在两个NHP研究中使用的可溶性疫苗是无佐剂的。为了提高免疫原性，Mymetics 将Toll样受体（TLR）7/8佐剂3 M-052包埋到病毒体包膜中。此外，Mymetics 开发了一种粉末状的病毒体，不再依赖于冷链， 鼻内（IN）喷雾剂、舌下（SL）片剂或包装成口服胶囊。我们假设这些小说 固体病毒体制剂的免疫原性显著更高，特别是当通过粘膜给药时， 途径，而不是在NHP早期使用的无佐剂液体形式。该IPCAVD项目的具体目标是： 1.评估新候选疫苗（新添加3 M-052佐剂的HIV病毒体-P1）的免疫原性 和病毒体-rgp 41，以IN、SL或口服递送给印度RM的固体剂型， 两种最具免疫原性的制剂用于随后的粘膜初免/粘膜加强免疫。 2.评估通过联合粘膜递送的非冷链依赖性病毒体疫苗的效力 针对用异源R5进化枝B SHIVSF 162 P3的重复直肠内攻击的免疫途径。 受保护的RM将使用R5 2级进化枝C SHIV进行再攻毒。 3.优化用于粘膜递送的选定病毒体制剂的GMP生产工艺，以及 4.进行毒理学研究，以显示通过以下方式给予的含佐剂固体疫苗的良好安全性 选择的粘膜途径-并产生GMP疫苗的I期试验将与HVTN进行。 我们的疫苗开发计划代表了重大进展，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-独特的方面，使新的病毒体 疫苗对发展中国家特别有吸引力，因为艾滋病流行病仍然是一个严重的问题。