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: 10158409
• 负责人: Sylvain FLEURY
• 金额: $ 171.95万
• 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/10158409
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Address; Adjuvant; Affect; Animal Model; Animals; Antibodies; Antibody Response; Biomedical Research; Chinese People; Clinic; Clinical; Cold Chains; Collaborations; Data; Development Plans; Dosage Forms; Dose; Double-Blind Method; Epidemic; Experimental Designs; Female; Formulation; HIV; HIV Envelope Protein gp41; HIV Vaccine Trials Network; 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; Vaccines; Viremia; Virion; Virosomes; Virus-like particle; Woman; antibody-dependent cell cytotoxicity; base; capsule; design; 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; virus envelope; 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.

项目摘要 - 总体 该多PI应用程序是Mymetics与德克萨斯生物医学研究所之间的合作 （txbiomed），dr。 Sylvain Fleury（项目1领导； Mymetics）和Ruth Ruprecht（项目2领导； TXBIOMED） 用作pis。我们寻求将有希望的艾滋病毒/艾滋病疫苗接种方法带到诊所。疫苗是基于的 在影响扎病毒体上，在其表面伸长的HIV GP41上显示的包蛋白样颗粒 肽（Virosome-P1）或重组截短的HIV GP41（Virosome-RGP41）。 Mymetics的I期临床试验 健康女性中的病毒体P1显示出安全性和免疫原性。两个独立的非人类灵长类动物 （NHP）研究证明了Virosome-P1 +毒子组RGP41的组合的安全性和高效率 反对反复使用中文和印度恒河的2级R5 SHIV的重复低剂量脑室挑战 猕猴（RMS）。在后者中，当SHIV挑战剂量约为7x104倍时，效率为78-87％ 男性到女性艾滋病毒传播中的艾滋病毒中位数接种物。但是，当这种HIV接种物超过105-时 通过更高的SHIV接种物折叠，丢失了印度RMS的保护，这意味着阈值效果 疫苗诱导的粘膜抗体无法抵消更多入侵的SHIV颗粒。这 两项NHP研究中使用的可溶性疫苗均未进行。为了提高免疫原性，Mymetics具有 嵌入类似收费的接收器（TLR）7/8将3M-052调整为病毒体信封中。此外，Mymetics具有 开发了一种不再依赖冷链的病毒体的粉末状病毒体形式，可以用作 鼻内喷雾剂，舌下（SL）片剂或包装到口腔胶囊中。我们假设这些小说 固体病毒体配方明显更加免疫原性，尤其是通过粘膜给药 路线，而不是NHP中早期使用的非补充液体形式。该IPCAVD项目的具体目的是： 1。评估新疫苗候选物的免疫原性，新近佐剂的HIV病毒体P1 和Virosome-rgp41，以固体剂型的形式以SL或口头为印度RMS，以选择 两种最免疫原性的配方，用于随后的粘膜素/粘膜增强免疫化。 2。评估粘膜联合粘膜传递的冷链独立的病毒体疫苗的效率 与异源R5进化枝B SHIVSF162P3反复进行直肠内挑战的免疫途径。 受保护的RMS将用R5 Tier 2进化枝C S SHIV重新收获。 3。优化用于粘膜递送的选定病毒体配方的GMP制造过程，并 4.进行毒理学研究以显示由 选定的粘膜路线 - 并生成GMP疫苗，以使用HVTN进行I期试验。 我们的疫苗开发计划代表了主要的进步，作为新颖的无针固体疫苗剂型 是独立的冷链，并且将是粘膜交付的 - 独特的方面使新颖的病毒体形成 疫苗对发展中国家特别有吸引力，艾滋病流行仍然是一个严重的问题。