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: 9919543
• 负责人: Sylvain FLEURY
• 金额: $ 185.55万
• 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/9919543
• 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 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.

项目总结-整体