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: 10624800
• 负责人: Ruth Margrit Ruprecht
• 金额: $ 127.72万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624800
• 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-1; 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; Rectum; Refrigeration; Regimen; Route; SIV; Scanning; Small Intestines; Solid; Stomach; Surface; Systemic infection; TLR7 gene; Tablets; Testing; Tissues; Tracer; Vaccination; Vaccines; Virosome 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

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旨在测试恒河猴（RM）/SHIV模型中的病毒体疫苗免疫原性和功效。 Mymetics改善了由空的流感病毒样颗粒建立的病毒体疫苗，这些颗粒显示 其表面上的伸长HIV GP41肽（Virosome-P1）或重组截短的HIV GP41（病毒体 - RGP41）。早些时候，中国RMS给出了两个肌内（IM）素数，然后是两个鼻内（IN）增强 100％免受持续性全身感染的保护，低剂量腔内后没有血清转换为SIV GAG Shiv挑战。印度RMS的后续研究显示，只要SHIV剂量为78％至87％ 〜7x104倍人类男性艾滋病毒传播中的艾滋病毒中值艾滋病毒接种物，但是当SHIV接种物 大约105倍，丢失了保护。在这些NHP研究中 使用了病毒体-P1 + Virosome-RGP41的组合。为了提高免疫原性，Mymetics嵌入了 Toll样受体（TLR）7/8辅助3M-052直接进入病毒体膜，并发展出固体，冷链 独立的疫苗配方，可以无针。粉末状的垂体体形式可以是 如喷雾剂，舌下（SL）片剂或包装到口腔胶囊（PO）中。我们的总体假设是 冷链独立的无针佐剂固体染色体形式的免疫原性明显更高 比其较早的RMS液体形式，粘膜启动/粘膜后会诱导更高的粘膜液AB水平 通过不同的路线提升。 Mymetics在IN和SL形式的小动物中进行了试点测试。 通过口服胶囊输送疫苗需要在RMS中进行优化。项目2的具体目标是： 1。通过肠涂层胶囊优化疫苗输送到回肠； a）胶囊的监视通过 通过扫描包含99mtc或64cu； b）将荧光标签连接到病原体疫苗上以检测 近红外光谱。在尸检时收集的组织将通过荧光显微镜进行测试。 2。测试新型佐剂病毒体的不同途径的免疫原性， 方法。我们将通过IN，SL和PO路线测试其相对免疫原性。提升将通过 不同的粘膜路线，一种新颖的方法。控制物将通过可溶性病毒体疫苗免疫IM。 3。测试冷链独立，无针，佐剂的病毒体疫苗的功效 低剂量的直肠内（IR）进化枝B SHIV（SHIV-B）挑战。最免疫原性的粘膜素/粘膜 提升方案（见目标2）将用于免疫12 RMS；控制（n = 12）将被空 病毒体。所有RMS将在第2层B SHIVSF162P3中遇到约10个每周的低剂量IR挑战。 4.测试是否会保护抵抗多个SHIV-B挑战的RMS免受交叉挑战 带有2层R5进化枝C S SHIV。受保护的RMS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，我们的新型疫苗将是主要优势 打击艾滋病流行。