Vaccine immunogenicity and efficacy in the rhesus macaque/SHIV model

恒河猴/SHIV 模型中疫苗的免疫原性和功效

• 批准号: 10158413
• 负责人: Ruth Margrit Ruprecht
• 金额: $ 50.76万
• 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/10158413
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; African; Animal Model; Animals; Antibody Formation; Antigens; Autopsy; Cells; Characteristics; Chinese People; Cold Chains; Control Groups; Detection; Developing Countries; Dose; Enteral; Epidemic; Female; Follow-Up Studies; Formulation; Generations; HIV; HIV Envelope Protein gp41; HIV-1; Hand; Immunization; Immunize; Intramuscular; Isotopes; Label; Lead; Liquid substance; Macaca mulatta; Membrane; Microscopy; Modeling; Monitor; Morbidity - disease rate; Mucous Membrane; Needles; Oral; Peptides; Plant Resins; Powder dose form; Radioactive Tracers; Recombinants; Refrigeration; Regimen; Route; SIV; Scanning; Small Intestines; Solid; Stomach; Surface; Systemic infection; TLR7 gene; Tablets; Testing; Time; Tissues; Tracer; Vaccination; Vaccines; Virosomes; Virus; Virus-like particle; Woman; Work; capsule; combat; design; efficacy study; efficacy testing; experimental study; human male; ileum; immunogenic; immunogenicity; improved; influenzavirus; innovation; liquid formulation; man; mortality; novel; novel strategies; novel vaccines; parenteral administration; particle; prevent; programs; rectal; simian human immunodeficiency virus; transmission process; uptake; vaccine delivery; vaccine development; vaccine efficacy; vaccine evaluation

Project 2 seeks to test virosomal vaccine immunogenicity and efficacy in the rhesus macaque (RM)/SHIV model. Mymetics has improved virosomal vaccines built from empty influenza virus-like particles that display an elongated HIV gp41 peptide on their surface (virosome-P1) or recombinant truncated HIV gp41 (virosome- rgp41). Earlier, Chinese RMs given two intramuscular (IM) primes followed by two intranasal (IN) boosts were 100% protected from persistent systemic infection and did not seroconvert to SIV Gag after low-dose intravaginal SHIV challenges. A follow-up study in Indian RMs showed 78% to 87% protection as long as the SHIV dose was ~7x104 times the median HIV inoculum in human male-to-female HIV transmission, but when the SHIV inoculum was ~105x greater, protection was lost. In these NHP studies, unadjuvanted, liquid formulations of the combination of virosome-P1 + virosome-rgp41 were used. To improve immunogenicity, Mymetics embedded the toll-like receptor (TLR)7/8 adjuvant 3M-052 directly into virosome membranes and developed solid, cold-chain independent vaccine formulations that can be administered needle-free. The powdered virosome forms can be given as IN spray, sublingual (SL) tablets, or packaged into oral capsules (PO). Our overall hypothesis is that the cold-chain independent, needle-free adjuvanted solid virosome forms are significantly more immunogenic than their earlier liquid form in RMs and will induce higher mucosal fluid Ab levels after mucosal priming/mucosal boosting via different routes. Mymetics has performed pilot tests in small animals with the IN and SL forms; vaccine delivery via oral capsules needs to be optimized in RMs. The Specific Aims for Project 2 are to: 1. Optimize vaccine delivery to the ileum via enteric-coated capsules; a) monitor passage of capsules containing 99mTc or 64Cu by scans; b) attach fluorescent labels to the virosomal vaccines for detection in the near-infrared spectrum. Tissues collected at necropsy will be tested by fluorescent microscopy. 2. Test the immunogenicity of different routes of the novel adjuvanted virosomes through a prime/boost approach. We will test their relative immunogenicity via IN, SL and PO routes; boosts will be given via a different mucosal route, a novel approach. Controls will be immunized IM with the soluble virosomal vaccine. 3. Test the efficacy of the cold-chain independent, needle-free, adjuvanted virosomal vaccines against repeated low-dose intrarectal (IR) clade B SHIV (SHIV-B) challenges. The most immunogenic mucosal prime/mucosal boost regimen (see Aim 2) will be used to immunize a group of 12 RMs; control (n=12) will receive empty virosomes. All RMs will undergo ~10 weekly low-dose IR challenges with the tier 2, R5 clade B SHIVSF162P3. 4. Test whether RMs that resisted multiple SHIV-B challenges will be protected against cross-clade challenge with the tier 2 R5 clade C SHIV. Protected RMs will be used to determine correlates of protection. These innovations are highly significant for the developing world, where our novel vaccine will be a major plus to combat the AIDS epidemic.

项目2旨在测试病毒体疫苗在恒河猴(RM)/SHIV模型中的免疫原性和有效性。