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，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类CD4的D1D2结构域遗传连接。恒河猴接种了rhFLSC，这是一种含有来自恒河猴CD4细胞的FLSC的替代版本。rhFLSC在多次低剂量R5刺激下对直肠攻击具有显著的保护作用

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.