Optimization of a DNA Subunit Regimen for an HIV Vaccine

HIV 疫苗 DNA 亚基方案的优化

基本信息

  • 批准号:
    8410231
  • 负责人:
  • 金额:
    $ 22.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-07-01 至 2013-05-04
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Our primary approach to develop an effective prophylactic vaccine against HIV utilizes a novel immunogen called the Full Length Single Chain (FLSC) that consists of gp120 derived from HIV-1(BaL) genetically linked via a 20 amino acid linker to the D1D2 domains of human CD4. Rhesus macaques were inoculated with rhFLSC, a surrogate version of FLSC that contains CD4 derived from rhesus macaques. The rhFLSC provided significant protection against rectal challenge with multiple, low doses of R5 tropic, and heterologous SHIV162P3. These observations propelled FLSC into preclinical development and evaluation in a phase 1 clinical trial (supported by BMGF, MHRP, NIAID). Consistent with the observations made in the RV144 clinical trial, the protection we observed waned as the antibody titers dropped. The presence of significant populations of single function T cells (secreting IFN-? or IL-2) also appeared to inversely correlate with the protection generated by rhFLSC subunit. Our collaborators found that the simultaneous coadministration of pDNA and protein dramatically heightens the potency and extends the lifespan of the antibody response. Vaccination with pDNA expressing antigen and IL-12 administered by electroporation in macaques induces multifunctional T cells that are known to correlate with protection that could also improve the efficacy provided by FLSC subunit. Our goal here is to build upon these observations and determine if a pDNA/subunit combination vaccine can enhance the quality and durability of the immune response necessary to provide >70% efficacy after 1 year post vaccination. Our phase 1 objective is to rank order FLSC DNA/subunit immunization regimens based on the quality and durability of the immune response in mice. Using the top regimens defined in Phase I, we will determine if the selected vaccination regimen provides protection from SHIV challenge that is superior to that observed in RV144 and remains effective out to at least one year post vaccination through the following phase II specific aims: 1. Rank order FLSC DNA/subunit immunization regimens based on the quality and durability of the immune response in macaques. 2. Rank order FLSC DNA/subunit immunization regimens based on their efficacy against SHIV162P3 challenge. By the end of this project, we should identify a regimen that extends the longevity of humoral and cellular responses to provide >70% efficacy upon heterologous SHIV162P3 challenge after 1 year. Should this optimized delivery regimen fulfill the phase II goals, it will be fast-tracked into human clinical trials. PUBLIC HEALTH RELEVANCE: The objective of this project is to identify optimal an optimal delivery regimen for an HIV DNA vaccine. Such an optimized delivery regimen is needed for DNA vaccines to combat the HIV epidemic.
描述(由申请人提供):我们开发有效的HIV预防性疫苗的主要方法是利用一种名为全长单链(FLSC)的新型免疫原,该免疫原由来自HIV-1(BAL)的gp120组成,通过20个氨基酸的连接物与人CD4的D1D2结构域进行遗传连接。研究人员给恒河猴接种了rhFLSC,这是一种代用的FLSC,含有来自恒河猴的CD4。重组人胎肝干细胞通过多次、低剂量的R5受体拮抗剂提供了显著的直肠保护作用,并且 异源SHIV162P3。这些观察结果推动了FLSC在1期临床试验中进行临床前开发和评估(由BMGF、MHRP、NIAID支持)。与RV144临床试验中的观察结果一致,我们观察到的保护作用随着抗体滴度的下降而减弱。存在大量的单一功能T细胞(分泌干扰素? 或IL-2)与rhFLSC亚单位产生的保护作用呈负相关。我们的合作者发现,同时联合注射pDNA和蛋白质可以显著提高抗体反应的效力并延长抗体反应的寿命。用表达PDNA的抗原和IL-12电穿孔免疫猕猴,可以诱导出多功能T细胞,这种T细胞具有保护作用,也可以提高FlsC亚单位提供的效力。我们的目标是建立在这些观察的基础上,并确定PDNA/亚单位组合疫苗是否可以提高免疫反应的质量和持久性,从而在疫苗接种后一年提供70%的疗效。我们的第一阶段目标是根据小鼠免疫反应的质量和持久性对FLSC DNA/亚单位免疫方案进行排序。使用第一阶段定义的顶级方案,我们将确定所选择的疫苗方案是否提供了比RV144中观察到的更好的抗SIV攻击的保护,并通过以下第二阶段的特定目标在接种后至少一年仍然有效:1.根据猕猴免疫反应的质量和持久性对FLSC DNA/亚单位免疫方案进行排序。2.根据对SHIV162P3攻击的有效性,对FLSC DNA/亚单位免疫方案进行排序。到这个项目结束时,我们应该确定一种方案,延长体液和细胞反应的寿命,在一年后对异种SHIV162P3攻击提供70%的疗效。如果这种优化的给药方案实现了第二阶段的目标,它将快速进入人体临床试验。 公共卫生相关性:该项目的目标是确定艾滋病毒DNA疫苗的最佳投放方案。DNA疫苗需要这样一种优化的递送方案来抗击艾滋病毒流行。

项目成果

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Timothy R Fouts其他文献

Timothy R Fouts的其他文献

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{{ truncateString('Timothy R Fouts', 18)}}的其他基金

Optimization of a DNA Subunit Regimen for an HIV Vaccine
HIV 疫苗 DNA 亚基方案的优化
  • 批准号:
    8810334
  • 财政年份:
    2014
  • 资助金额:
    $ 22.4万
  • 项目类别:
Optimization of a DNA Subunit Regimen for an HIV Vaccine
HIV 疫苗 DNA 亚基方案的优化
  • 批准号:
    8658372
  • 财政年份:
    2012
  • 资助金额:
    $ 22.4万
  • 项目类别:
Development of sG as a human vaccine against Nipah/Hendra
开发 sG 作为针对尼帕/亨德拉的人类疫苗
  • 批准号:
    9055627
  • 财政年份:
    2012
  • 资助金额:
    $ 22.4万
  • 项目类别:
Optimization of a DNA Subunit Regimen for an HIV Vaccine
HIV 疫苗 DNA 亚基方案的优化
  • 批准号:
    8642864
  • 财政年份:
    2012
  • 资助金额:
    $ 22.4万
  • 项目类别:
Preclinical Development of Full Length Single Chain
全长单链的临床前开发
  • 批准号:
    8306726
  • 财政年份:
    2010
  • 资助金额:
    $ 22.4万
  • 项目类别:
Preclinical Development of Full Length Single Chain
全长单链的临床前开发
  • 批准号:
    8296938
  • 财政年份:
    2010
  • 资助金额:
    $ 22.4万
  • 项目类别:
Preclinical Development of Full Length Single Chain
全长单链的临床前开发
  • 批准号:
    8013359
  • 财政年份:
    2010
  • 资助金额:
    $ 22.4万
  • 项目类别:
Enhancing DNA vaccines using modified Cholera Toxin A1 Subunit as an adjuvant
使用改良霍乱毒素 A1 亚基作为佐剂增强 DNA 疫苗
  • 批准号:
    7337874
  • 财政年份:
    2007
  • 资助金额:
    $ 22.4万
  • 项目类别:
Enhancing DNA vaccines using modified Bacterial Toxin A1 Subunits as adjuvants
使用改良细菌毒素 A1 亚基作为佐剂增强 DNA 疫苗
  • 批准号:
    7844676
  • 财政年份:
    2007
  • 资助金额:
    $ 22.4万
  • 项目类别:
Enhancing DNA vaccines using modified Bacterial Toxin A1 Subunits as adjuvants
使用改良细菌毒素 A1 亚基作为佐剂增强 DNA 疫苗
  • 批准号:
    8244560
  • 财政年份:
    2007
  • 资助金额:
    $ 22.4万
  • 项目类别:

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