Optimization of HIV vaccines for the induction of cross-reactive antibodies
用于诱导交叉反应抗体的 HIV 疫苗的优化
基本信息
- 批准号:8499205
- 负责人:
- 金额:$ 294.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-06 至 2016-10-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS VaccinesAcademiaAddressAdjuvantAdverse eventAnimal ModelAnimalsAntibodiesAntibody FormationAntibody SpecificityAntigensAreaBiodistributionBiological AssayBiological MarkersCellular ImmunityClinicalClinical ResearchClinical TrialsClinical trial protocol documentCollaborationsDNADNA FingerprintingDNA VaccinesDNA deliveryDataDevelopmentDevelopment PlansDoctor of PhilosophyDoseDrug FormulationsElectroporationEpitopesEquilibriumFundingFunding MechanismsFutureGenerationsGenesGeneticGoalsHIVHIV AntigensHIV Vaccine Trials NetworkHIV vaccineHIV-1HeadacheHumanHuman VolunteersImmune SeraImmune responseImmunizationImmunologyIndividualIndustryInfectionIntramuscularInvestigationLaboratoriesLearningLow Grade FeverMalaiseManuscriptsMassachusettsMeasurableMethodsMonitorMonkeysNational Institute of Allergy and Infectious DiseasePatientsPhasePhase I Clinical TrialsPreparationProteinsProtocols documentationPublishingQS21ReactionRecombinant ProteinsRecombinantsResearch PersonnelResistanceSafetySamplingScheduleSerumSpecific qualifier valueStagingStructureSystemT-LymphocyteTechnologyTestingTimeToll-like receptorsToxic effectToxicologyU-Series Cooperative AgreementsUniversitiesUpdateVaccinationVaccine AntigenVaccine DesignVaccine ProductionVaccinesVirusWorkbasecytokineenv Gene Productsexperiencehuman studyimmunogenicimmunogenicityimprovedinnovationmedical schoolsmeetingsmemberneutralizing antibodynext generationnonhuman primatenovelphase 1 studyplasmid DNApre-clinicalpre-clinical researchproduct developmentprogramsresearch and developmentresearch clinical testingresponsesafety studyscreeningtransmission processvaccine deliveryvaccine developmentvaccine safetyvolunteer
项目摘要
DESCRIPTION (provided by applicant):
The goal of this U19 application is to further advance the DNA prime/protein boost approach to focus on the development of broadly reactive antibody responses. This proposal is developed based on our recent phase 1 study result that, for the first time, a candidate AIDS vaccine induced both cell-mediated immunity and neutralizing antibody responses against selected primary HIV-1 isolates in the same human clinical trial. It was also the first time that DNA immunization was effective in priming high level antibody responses in human volunteers. The current proposal represents a key progress that we are able to use a highly reproducible vaccination technology platform to conduct incremental improvements on the components of actual vaccine formulations. By using the current IPCAVD program, we propose to conduct advanced vaccine optimization studies in order to address two key issues: 1) to conduct a rational selection of Env antigens in order to improve the breadth of neutralizing antibody responses, and 2) to optimize the selection of adjuvants to reduce any potential high reactogenicity in those volunteers who received the one protein boost after the high dose DNA prime in our previous clinical trial. Specifically, the following aims are proposed: Objective 1: To assemble and manage a highly productive research and development team. Objective 2: To develop the next generation polyvalent Env formulation by including Env antigens that were selected based on a well controlled rational screening system. Objective 3: To improve the safety profile by testing different adjuvants and using alternative DNA vaccine delivery method to reduce any potential reactogenicity. Objective 4: To conduct GMP manufacturing of DNA and protein vaccine components, definitive toxicology studies, and regulatory reviews of the next generation polyvalent HIV vaccine formulation. Objective 5: To plan for a Phase 1 safety and immunogenicity clinical trial and transfer GMP products to be tested in humans to NIH's HIV Vaccine Trial Network (HVTN).
RELEVANCE: Developing a further improved candidate AIDS vaccine to control HIV virus transmission in the world. An early version of this vaccine design showed promising results in its first human study.
PROJECT 1
Project Title: Optimizing the Immunogenicity of Next Generation Polyvalent HIV Vaccine
Formulations
Project Leader: Shan Lu, MD, PhD
PROJECT 1 DESCRIPTION (provided by applicant):
Project 1 will focus on the optimization of the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DNA prime/protein boost technology platform. Our first HIV vaccine formulation, DP6-001, was developed several years ago for a proof-of-concept trial to demonstrate the immunogenicity of the DNA prime/protein boost approach in human volunteers. The primary Env antigens isolated from HIV infected patients in mid-1990s were selected randomly based on their genetic clades. Rapid progress in the HIV vaccine field now provides us with a much larger selection of primary Env antigens, especially those Env proteins from clades less studied in the past and those Env proteins with more detailed information about the patients from whom the viruses were isolated. In addition, the recently developed pseudotyped neutralization assay and newly established target HIV-1 primary virus panel ("the Tiers System") provides a measurable standard to guide our selection of more relevant primary Env antigens for the development of HIV vaccines focusing on the induction of neutralizing antibody responses. By taking advantage of the above progress, we have identified a group of primary Env antigens that were able to elicit much broader neutralizing antibodies than those included in our previous formulation DP6-001. In the current Project 1 of this IPCAVD program, the following studies will be conducted: Aim 1 To finalize the selection of next generation polyvalent Env formulation to further improve the quality of neutralizing antibody activities. Aim 2 To select an immunogenic adjuvant to be used as part of the protein boost for the next generation polyvalent Env formulation. Aim 3 To test the immunogenicity of next generation polyvalent Env formulation when the DNA priming is delivered by the electroporation method. Aim 4 To examine the epitope profiles in immune sera elicited by DNA prime-protein boost approach and identify the epitope specificities of antibodies responsible for the neutralizing activities.
RELEVANCE: To optimize the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DNA prime - protein boost technology platform.
描述(由申请人提供):
这项U19应用的目标是进一步推进DNA初始/蛋白质增强方法,以专注于开发广泛反应的抗体反应。这一建议是基于我们最近的第一阶段研究结果,即在同一人类临床试验中,候选艾滋病疫苗首次同时诱导了对选定的HIV-1初级分离株的细胞免疫和中和抗体反应。这也是DNA免疫首次有效地在人类志愿者中引发高水平的抗体反应。目前的提案代表着一项关键进展,即我们能够使用高度可重复性的疫苗接种技术平台对实际疫苗配方的成分进行渐进改进。通过使用当前的IPCAVD计划,我们建议进行高级疫苗优化研究,以解决两个关键问题:1)合理选择Env抗原,以提高中和抗体反应的广度;2)优化佐剂选择,以减少在我们先前的临床试验中,在大剂量DNA启动后接受一次蛋白质强化治疗的志愿者的任何潜在的高反应性。具体地说,提出了以下目标:目标1:组建和管理一支高生产率的研发团队。目的:通过良好控制的合理筛选系统筛选出新一代多价环状病毒(Env)抗原,开发新一代多价环状病毒制剂。目的:通过测试不同的佐剂和使用替代的DNA疫苗接种方法来减少任何潜在的反应性,以改善安全性。目标4:进行DNA和蛋白质疫苗成分的GMP制造,明确的毒理学研究,以及对下一代多价HIV疫苗配方的监管审查。目的:计划一期安全性和免疫原性的临床试验,并将GMP产品在人体上测试转移到NIH的HIV疫苗试验网络(HVTN)。
相关性:开发一种进一步改进的候选艾滋病疫苗,以控制艾滋病毒在世界上的传播。这种疫苗设计的早期版本在其第一次人体研究中显示了令人振奋的结果。
项目1
项目名称:优化新一代多价HIV疫苗的免疫原性
配方
项目负责人:陆山,医学博士,博士
项目1描述(申请人提供):
项目1将侧重于利用多基因、多价DNA主/蛋白质增强技术平台优化下一代多价环境艾滋病毒疫苗配方。我们的第一个HIV疫苗配方DP6-001是几年前开发的,用于概念验证试验,以证明DNA Prime/Protein Boost方法在人类志愿者中的免疫原性。从90年代中期的HIV感染者中分离出主要的Env抗原,根据其基因分支随机选择。HIV疫苗领域的快速发展现在为我们提供了更多的主要Env抗原选择,特别是那些过去研究较少的分支的Env蛋白,以及那些具有更详细的病毒分离患者信息的Env蛋白。此外,最近开发的伪型中和试验和新建立的靶向HIV-1初级病毒小组(“TIERS系统”)提供了一个可测量的标准,以指导我们选择更相关的初级环境抗原来开发专注于诱导中和抗体应答的HIV疫苗。通过利用上述进展,我们已经确定了一组主要的Env抗原,它们能够产生比我们以前的配方DP6-001中包含的中和抗体更广泛的中和抗体。在本次IPCAVD计划的项目1中,将进行以下研究:目的1最终确定下一代多价环境蛋白制剂的选择,以进一步提高中和抗体活性的质量。目的2选择一种免疫原佐剂作为下一代多价环境蛋白制剂中蛋白质增强的一部分。目的3检测新一代多价环状病毒制剂在DNA电穿孔引爆时的免疫原性。目的4检测DNA质蛋白Boost法诱导的免疫血清中的表位分布,鉴定中和活性抗体的表位特异性。
相关性:利用多基因、多价DNA主蛋白Boost技术平台优化下一代多价环境艾滋病毒疫苗配方。
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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Shan Lu其他文献
Shan Lu的其他文献
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{{ truncateString('Shan Lu', 18)}}的其他基金
Optimizing the immunogenicity of next generation polyvalent HIV vaccine formulati
优化下一代多价 HIV 疫苗配方的免疫原性
- 批准号:
8499206 - 财政年份:2013
- 资助金额:
$ 294.72万 - 项目类别:
Optimization of HIV vaccines for the induction of cross-reactive antibodies
用于诱导交叉反应抗体的 HIV 疫苗的优化
- 批准号:
7883581 - 财政年份:2009
- 资助金额:
$ 294.72万 - 项目类别:
Optimization of HIV vaccines for the induction of cross-reactive antibodies
用于诱导交叉反应抗体的 HIV 疫苗的优化
- 批准号:
8303374 - 财政年份:2009
- 资助金额:
$ 294.72万 - 项目类别:
Induction of neutralizing antibodies targeting CD4 binding region of HIV-1 Env
诱导针对 HIV-1 Env 的 CD4 结合区的中和抗体
- 批准号:
8118542 - 财政年份:2009
- 资助金额:
$ 294.72万 - 项目类别:
Optimizing the immunogenicity of next generation polyvalent HIV vaccine formulati
优化下一代多价 HIV 疫苗配方的免疫原性
- 批准号:
7701147 - 财政年份:2009
- 资助金额:
$ 294.72万 - 项目类别:
Optimization of HIV vaccines for the induction of cross-reactive antibodies
用于诱导交叉反应抗体的 HIV 疫苗的优化
- 批准号:
7665598 - 财政年份:2009
- 资助金额:
$ 294.72万 - 项目类别:
Induction of neutralizing antibodies targeting CD4 binding region of HIV-1 Env
诱导针对 HIV-1 Env 的 CD4 结合区的中和抗体
- 批准号:
8513885 - 财政年份:2009
- 资助金额:
$ 294.72万 - 项目类别:
Induction of neutralizing antibodies targeting CD4 binding region of HIV-1 Env
诱导针对 HIV-1 Env 的 CD4 结合区的中和抗体
- 批准号:
7645923 - 财政年份:2009
- 资助金额:
$ 294.72万 - 项目类别:
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