Optimization of a DNA Subunit Regimen for an HIV Vaccine

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称为全长单链（FLSC）的新型免疫原，其由来自HIV-1（BaL）的gp 120组成，通过20个氨基酸的接头与人CD 4的D1 D2结构域遗传连接。用rhFLSC接种恒河猴，rhFLSC是FLSC的替代版本，含有源自恒河猴的CD 4。rhFLSC对多次低剂量R5 tropic的直肠攻击提供了显著的保护， 异源SHIV 162 P3。这些观察结果推动FLSC进入临床前开发和1期临床试验评估（由BMGF，MHRP，NIAID支持）。与RV 144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。单功能T细胞（分泌IFN-？ 或IL-2）也似乎与rhFLSC亚基产生的保护作用负相关。我们的合作者发现，pDNA和蛋白质的同时共同施用显著提高了抗体应答的效力并延长了抗体应答的寿命。在猕猴中通过电穿孔施用表达抗原和IL-12的pDNA的疫苗接种诱导多功能T细胞，已知所述多功能T细胞与也可以改善FLSC亚基提供的功效的保护相关。我们在此的目标是建立在这些观察结果的基础上，并确定pDNA/亚单位组合疫苗是否可以增强免疫应答的质量和持久性，所述免疫应答是在疫苗接种后1年后提供>70%功效所必需的。我们的第1阶段目标是根据小鼠免疫应答的质量和持久性对FLSC DNA/亚单位免疫方案进行排序。使用I期定义的最佳方案，我们将确定所选的疫苗接种方案是否提供对SHIV攻击的保护，其上级于RV 144中观察到的保护，并且通过以下II期特定目标在疫苗接种后至少一年内保持有效：基于猕猴免疫应答的质量和持久性的FLSC DNA/亚单位免疫方案的排序。2. FLSC DNA/亚单位免疫方案基于其对SHIV 162 P3攻毒的有效性排序。到本项目结束时，我们应该确定一种延长体液和细胞反应寿命的方案，以在1年后对异源SHIV 162 P3激发提供>70%的功效。如果这种优化的给药方案达到II期目标，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HIV DNA疫苗的最佳给药方案。DNA疫苗需要这种优化的递送方案来对抗HIV流行病。

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.