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

基本信息

批准号：
10401881
负责人：
Ruth Margrit Ruprecht
金额：
$ 27.97万
依托单位：
UNIVERSITY OF LOUISIANA AT LAFAYETTE
依托单位国家：
美国
项目类别：
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/10401881
关键词：
Acquired Immunodeficiency Syndrome Adjuvant African Animal Model Animals Antibody Formation Antigens Autopsy Cells Characteristics Chinese 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 pilot test prevent programs rectal simian human immunodeficiency virus transmission process uptake vaccine delivery vaccine efficacy vaccine evaluation vaccine formulation vaccine immunogenicity vaccine platform

项目摘要

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。