Vaccination with self-launching RhCMV/SIV DNA vaccine vectors
使用自启动 RhCMV/SIV DNA 疫苗载体进行疫苗接种
基本信息
- 批准号:10037603
- 负责人:
- 金额:$ 23.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-10 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAnimalsAreaAttenuated VaccinesAutopsyBacterial Artificial ChromosomesBacterial GenomeBloodClinical TrialsCold ChainsComplexCytomegalovirusDNADNA VaccinesDNA deliveryDataDevelopmentDigestionDiseaseDoseEffectivenessElectroporationEnterobacteria phage P1 Cre recombinaseExcisionGeneticGenetic RecombinationGenomeGenomic DNAGlycoproteinsGoalsHIVHIV vaccineHealthHumanImmune responseImmunityIn VitroIncidenceInfectionIntravenousLaboratoriesMacacaMacaca mulattaMalariaMediatingMethodsModelingNatureNucleic AcidsOutcomePathogenicityPatientsPreparationReplication OriginRhesusSIVSIV VaccinesSalivaSerial PassageSignal TransductionSiteTestingTissuesTransfectionTuberculosisUncertaintyVaccinatedVaccinationVaccinesVertebral columnViralViral GenomeViral VectorVirionVirusWorkbasecost effectiveexperimental studyglobal healthimmunogenicityin vivointerestmutantnonhuman primatenovelnovel vaccinesparticleprophylacticrecombinaseresponserestriction enzymeterminasetissue culturevaccine deliveryvaccine developmentvectorvector genomevector vaccinevector-based vaccinevirus envelope
项目摘要
PROJECT SUMMARY/ABSRACT
A prophylactic HIV vaccine would be of tremendous benefit for global health by helping to reduce the
number of infected people. Similarly, new vaccine approaches are needed with the potential to
reduce incidence of tuberculosis and malaria. RhCMV-vectored SIV vaccines have demonstrated
tremendous potential for eliciting immune responses that can control SIV infection, but the unstable
CMV genome and the relatively large proportion of non-infectious virions in vaccine stocks present
major practical challenges, which have already delayed tests of CMV-vectored vaccines in human
patients. Additionally, the need for a cold chain that is likely infeasible in some HIV-endemic areas is
problematic. Here we describe and propose to test a vaccine platform based on delivery of the CMV-
based vaccine vector genome in nucleic-acid form. We have shown that the delivered genomes are
capable of initiating self-sustaining replication in vivo, and that this vector replication engenders
immune responses that appear at least equal if not superior to those stimulated by (conventional)
vaccination with encapsidated vaccine-vector particles. Successful completion of this R21 project
will thus accelerate CMV-based vaccine development for HIV and potentially other diseases as
well. Indeed, we believe that an advance such as this is required before CMV-vectored vaccines can
have the positive impact on human health that is so hoped for by the field. The goal of this work is to
provide a practical, cost-effective platform for cytomegalovirus-based vaccine delivery in vivo. Our
hypothesis is that RhCMVdIL10-SIVgag and -SIVenv vaccines delivered as replication-competent,
self-excising BAC DNA can elicit immune responses that have the unique character associated with
RhCMV-vectored vaccination and that are protective against SIV. This hypothesis will be addressed
in two specific aims using the rhesus macaque non-human primate model. Aim 1 will determine the
optimal in vivo delivery method for replication and dissemination of, as well as host immune
responses to, a novel, self-launching RhCMVdIL10-SIV vaccine. Three different methods of in vivo
BAC DNA delivery will be tested for immunogenicity. Cellular and humoral immune responses,
including the development of Mamu-E-restricted responses, will be assessed in addition to replication
and dissemination of the vector. Aim 2 will test if RhCMVdIL10-SIVgag and -SIVenv vaccines are
protective against SIV disease when delivered as self-launching BACs. We will determine the extent
of protection achieved against low-dose, pathogenic SIV challenge following vaccination of macaques
using the optimal delivery method identified in Aim 1. The novel vaccine vectors that are described in
this proposal will solve many of the hurdles that are limiting the development of current CMV-based
viral vectors and have broad applicability for other diseases that impact human health.
项目概要/摘要
预防性艾滋病毒疫苗将有助于减少艾滋病毒感染,
感染人数。同样,需要新的疫苗方法,
减少肺结核和疟疾的发病率。RhCMV载体的SIV疫苗已经证明
巨大的潜力,引发免疫反应,可以控制SIV感染,但不稳定
CMV基因组和疫苗储备中相对较大比例的非感染性病毒体
主要的实际挑战,已经推迟了CMV载体疫苗在人类中的试验
患者此外,对冷链的需求在一些艾滋病毒流行地区可能是不可行的,
有问题在这里,我们描述并提出测试基于CMV-1的递送的疫苗平台。
基于核酸形式的疫苗载体基因组。我们已经证明,交付的基因组是
能够在体内启动自我维持复制,并且这种载体复制产生
与(常规)免疫刺激相比,至少表现出相等(如果不是上级的话)的免疫反应
用包被的疫苗载体颗粒接种。成功完成R21项目
因此,将加速基于CMV的艾滋病毒和其他潜在疾病疫苗的开发,
好.事实上,我们认为,在CMV载体疫苗能够
对人类健康产生积极影响,这是该领域所希望的。这项工作的目标是
为基于巨细胞病毒的疫苗体内递送提供了一个实用的、具有成本效益的平台。我们
假设RhCMVdIL 10-SIVgag和-SIVenv疫苗以复制能力递送,
自我切除的BAC DNA可以引发免疫反应,这种免疫反应具有与以下特征相关的独特特征:
RhCMV载体疫苗接种,并对SIV具有保护作用。这一假设将得到解决
在两个特定的目标使用恒河猴非人类灵长类动物模型。目标1将决定
用于复制和传播以及宿主免疫的最佳体内递送方法
一种新型的自启动RhCMVdIL 10-SIV疫苗。三种不同的体内方法
将检测BAC DNA递送的免疫原性。细胞和体液免疫反应,
包括Mamu-E限制性反应的发展,除了复制外,
传播媒介。目标2将测试RhCMVdIL 10-SIVgag和-SIVenv疫苗是否
当作为自我启动的BAC提供时,可以预防SIV疾病。我们将确定
猕猴接种疫苗后,
使用目标1中确定的最佳交付方法。描述于以下文献中的新型疫苗载体:
这一建议将解决许多限制当前基于CMV的
病毒载体,并且对于影响人类健康的其它疾病具有广泛的适用性。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('DENNIS J. HARTIGAN-O'CONNOR', 18)}}的其他基金
Genetic adjuvants to elicit neutralizing antibodies against HIV
基因佐剂可引发抗艾滋病毒中和抗体
- 批准号:
10491642 - 财政年份:2023
- 资助金额:
$ 23.34万 - 项目类别:
Nonhuman Primate Testing Center for Evaluation of Somatic Cell Genome Editing Tools: Antibodies Supplement
非人类灵长类动物体细胞基因组编辑工具评估测试中心:抗体补充剂
- 批准号:
10827650 - 财政年份:2023
- 资助金额:
$ 23.34万 - 项目类别:
Multi-omic understanding of the transformed host T-cell response to HIV following therapeutic vaccination
治疗性疫苗接种后转化宿主 T 细胞对 HIV 反应的多组学理解
- 批准号:
10731710 - 财政年份:2023
- 资助金额:
$ 23.34万 - 项目类别:
Center for Somatic Cell Genome Editing in Nonhuman Primates
非人类灵长类体细胞基因组编辑中心
- 批准号:
10773947 - 财政年份:2023
- 资助金额:
$ 23.34万 - 项目类别:
CCR5 immunotoxins as components of HIV cure regimens
CCR5 免疫毒素作为 HIV 治疗方案的组成部分
- 批准号:
10664839 - 财政年份:2022
- 资助金额:
$ 23.34万 - 项目类别:
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