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旨在检测恒河猴（RM）/SHIV模型中病毒体疫苗的免疫原性和有效性。 Mymetics已经改进了由空流感病毒样颗粒构建的病毒体疫苗， 在其表面上的延长的HIV gp41肽（病毒体-P1）或重组截短的HIV gp41（病毒体-P1）， rgp41）。早些时候，中国RM给予两次肌内（IM）初免，随后两次鼻内（IN）加强， 100%防止持续性全身感染，并且在低剂量阴道内给药后未血清转化为SIV Gag SIV挑战。在印度RM中的一项随访研究显示，只要SHIV剂量为 约为人类男性对女性艾滋病毒传播中HIV接种中位数的7 × 104倍，但当SHIV接种 大约是105倍，失去了保护。在这些NHP研究中，使用了本发明的无佐剂液体制剂。 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，并形成固体冷链 独立的疫苗制剂，可以无针给药。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 不依赖于冷链的无针佐剂化的固体病毒体形式显著地更具免疫原性 在RM中的早期液体形式，并且在粘膜引发/粘膜后将诱导更高的粘膜液Ab水平。 通过不同的路线进行提升。Mymetics已经在小动物中进行了IN和SL形式的试点试验; 需要在RM中优化通过口服胶囊的疫苗递送。项目2的具体目标是： 1.优化通过肠溶胶囊向回肠的疫苗递送; a）监测胶囊的通过 B）将荧光标记物连接到病毒体疫苗上，用于在 近红外光谱尸检时采集的组织将通过荧光显微镜进行检测。 2.通过初免/加强免疫测试新型佐剂病毒体的不同途径的免疫原性 approach.我们将通过IN、SL和PO途径测试其相对免疫原性;将通过免疫增强剂给予加强。 不同的粘膜途径，一种新的方法。对照组将用可溶性病毒体疫苗IM免疫。 3.测试不依赖冷链的、无针的、含佐剂的病毒体疫苗对重复感染的有效性。 低剂量直肠内（IR）进化枝B SHIV（SHIV-B）攻击。免疫原性最强的粘膜初免/粘膜 将使用加强方案（参见目标2）免疫一组12只RM;对照组（n = 12）将接受空 病毒体。所有RM将接受约10次每周一次的低剂量IR激发，使用2级R5进化枝B SHIVSF 162 P3。 4.测试抵抗多次SHIV-B攻击的RM是否会受到交叉进化枝攻击的保护 二级R5进化枝C SIV受保护的RM将用于确定保护的相关性。 这些创新对发展中国家意义重大，我们的新型疫苗将成为发展中国家的一大优势。 来对抗艾滋病的流行。