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:10624800
- 负责人:
- 金额:$ 127.72万
- 依托单位:
- 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 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAdjuvantAfricanAnimal ModelAnimalsAntibody FormationAntigensAutopsyCellsCharacteristicsChineseCold ChainsControl GroupsDetectionDeveloping CountriesDoseEnteralEpidemicFemaleFollow-Up StudiesFormulationGenerationsHIVHIV-1ImmunizationImmunizeIntramuscularIsotopesLabelLeadLiquid substanceMacaca mulattaMembraneMicroscopyModelingMonitorMorbidity - disease rateMucous MembraneNeedlesOralPeptidesPlant ResinsPowder dose formRadioactive TracersRecombinantsRectumRefrigerationRegimenRouteSIVScanningSmall IntestinesSolidStomachSurfaceSystemic infectionTLR7 geneTabletsTestingTissuesTracerVaccinationVaccinesVirosome VaccinesVirosomesVirusVirus-like particleWomanWorkcapsulecombatdesignefficacy studyefficacy testingexperimental studyhuman maleileumimmunogenicimmunogenicityimprovedinfluenzavirusinnovationliquid formulationmanmortalitynovelnovel strategiesnovel vaccinesparenteral administrationparticlepilot testpreventprogramsrectalsimian human immunodeficiency virustransmission processuptakevaccine deliveryvaccine efficacyvaccine evaluationvaccine formulationvaccine immunogenicityvaccine 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 gp 41肽(病毒体-P1)或重组截短的HIV gp 41(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
大了~ 105倍,保护就失去了。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-rgp 41的组合。为了提高免疫原性,Mymetics嵌入了
Toll样受体(TLR)7/8佐剂3 M-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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ruth Margrit Ruprecht其他文献
Ruth Margrit Ruprecht的其他文献
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{{ truncateString('Ruth Margrit Ruprecht', 18)}}的其他基金
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 - 财政年份:2019
- 资助金额:
$ 127.72万 - 项目类别:
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:
10401881 - 财政年份:2019
- 资助金额:
$ 127.72万 - 项目类别:
Functional cure and virus eradication by early HAART plus vaccination with live attenuated rubella virus vectors in macaque infants and neonates
通过早期HAART加疫苗接种减毒风疹病毒载体对猕猴婴儿和新生儿进行功能性治愈和病毒根除
- 批准号:
8924693 - 财政年份:2015
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Functional cure and virus eradication by early HAART plus vaccination with live attenuated rubella virus vectors in macaque infants and neonates
通过早期HAART加疫苗接种减毒风疹病毒载体对猕猴婴儿和新生儿进行功能性治愈和病毒根除
- 批准号:
9139875 - 财政年份:2015
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$ 127.72万 - 项目类别:
Optimized Adaptation of Simian-tropic R5 HIV Clade C to Pig-tailed Macaques
猿猴嗜R5 HIV Cclade C对猪尾猕猴的优化适应
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8714894 - 财政年份:2013
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Do Early Maternal Antibodies Facilitate Oral Transmission of HIV in Infants?
早期母体抗体是否会促进艾滋病毒在婴儿中的经口传播?
- 批准号:
8513307 - 财政年份:2012
- 资助金额:
$ 127.72万 - 项目类别:
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