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功效。 Mymetics 改进了由空的流感病毒样颗粒制成的病毒体疫苗，这些颗粒显示出 表面延长的 HIV gp41 肽（病毒体-P1）或重组截短的 HIV gp41（病毒体- rgp41）。早些时候，中国的 RM 给予两次肌内 (IM) 初免，然后进行两次鼻内 (IN) 加强。 100% 免受持续性全身感染，并且在低剂量阴道内注射后没有血清转化为 SIV Gag SHIV 挑战。对印度 RM 进行的一项后续研究表明，只要 SHIV 剂量为 人类男性到女性 HIV 传播中 HIV 接种量中位数的约 7x104 倍，但是当 SHIV 接种量 约大 105 倍，失去保护。在这些 NHP 研究中，未添加佐剂的液体制剂 使用病毒体-P1 + 病毒体-rgp41 的组合。为了提高免疫原性，Mymetics 嵌入了 Toll 样受体 (TLR)7/8 佐剂 3M-052 直接进入病毒体膜并开发固体冷链 可以无针注射的独立疫苗配方。粉末状病毒体形式可以是 以 IN 喷雾剂、舌下 (SL) 片剂或包装成口服胶囊 (PO) 的形式给药。我们的总体假设是 不依赖冷链、无针辅助的固体病毒体形式具有明显更高的免疫原性 与 RM 中早期的液体形式相比，在粘膜启动/粘膜后会诱导更高的粘膜液抗体水平 通过不同的途径提升。 Mymetics 已对 IN 和 SL 形式的小动物进行了初步测试； 在 RM 中，通过口服胶囊输送疫苗需要进行优化。项目 2 的具体目标是： 1. 通过肠溶胶囊优化疫苗向回肠的输送； a) 监测胶囊的通过 扫描结果含有 99mTc 或 64Cu； b) 将荧光标记附加到病毒体疫苗上以便在 近红外光谱。尸检时收集的组织将通过荧光显微镜进行测试。 2.通过初免/加强测试新型佐剂病毒颗粒不同途径的免疫原性 方法。我们将通过IN、SL和PO途径测试它们的相对免疫原性；提升将通过 不同的粘膜途径，新颖的方法。对照将用可溶性病毒体疫苗进行肌肉注射免疫。 3. 测试不依赖冷链、无针、佐剂病毒体疫苗对反复感染的功效 低剂量直肠内 (IR) 分支 B SHIV (SHIV-B) 挑战。最具免疫原性的粘膜初免/粘膜 加强方案（参见目标 2）将用于对 12 个 RM 组进行免疫；控制（n=12）将接收空 病毒体。所有 RM 将接受约 10 周的 2 级 R5 进化枝 B SHIVSF162P3 低剂量 IR 挑战。 4. 测试抵抗多次 SHIV-B 挑战的 RM 是否会受到保护以免受跨进化枝挑战 与 2 级 R5 进化枝 C SHIV 一起。受保护的 RM 将用于确定保护的相关性。 这些创新对于发展中国家来说非常重要，我们的新型疫苗将成为发展中国家的一大优势 抗击艾滋病流行。