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
• 负责人: Timothy R Fouts
• 金额: $ 100万
• 依托单位: PROFECTUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658372
• 关键词: Adjuvant; Amino Acids; Animals; Antibodies; Antibody Formation; Antigens; Avidity; B-Lymphocytes; Characteristics; Clinical Trials; Combined Vaccines; Control Groups; DNA; DNA Vaccines; DNA delivery; Data; Development; Dose; Drops; Electroporation; Epidemic; Evaluation; Exercise; Gagging; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Human; Immune; Immune response; Immunization; Interferons; Interleukin-12; Interleukin-2; Length; Link; Longevity; Macaca; Macaca mulatta; Mus; National Institute of Allergy and Infectious Disease; Phase; Phase I Clinical Trials; Plasmids; Population; Proteins; Regimen; SIV; Small Business Innovation Research Grant; T-Lymphocyte; Vaccination; Vaccines; Virus; base; combat; efficacy testing; improved; innovation; meetings; novel; pre-clinical; prophylactic; rectal; research study; response; simian human immunodeficiency virus; success

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.

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，该免疫原由源自 HIV-1(BaL) 的 gp120 组成，通过 20 个氨基酸接头与人类 CD4 的 D1D2 结构域进行遗传连接。恒河猴接种了 rhFLSC，这是 FLSC 的替代版本，含有源自恒河猴的 CD4。 rhFLSC 通过多次、低剂量的 R5tropic 提供了针对直肠挑战的显着保护，并且 异源SHIV162P3。这些观察结果推动 FLSC 进入临床前开发并在 1 期临床试验中进行评估（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。存在大量单功能 T 细胞（分泌 IFN-？ 或 IL-2）似乎也与 rhFLSC 亚基产生的保护呈负相关。我们的合作者发现，pDNA 和蛋白质的同时共同施用可显着提高抗体反应的效力并延长其寿命。在猕猴中通过电穿孔接种表达抗原的 pDNA 和 IL-12 会诱导多功能 T 细胞，已知这些 T 细胞与保护作用相关，也可以提高 FLSC 亚基提供的功效。我们的目标是基于这些观察结果，确定 pDNA/亚基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 1 年后提供 > 70% 的功效。我们第一阶段的目标是根据小鼠免疫反应的质量和持久性对 FLSC DNA/亚基免疫方案进行排序。使用第一阶段定义的顶级方案，我们将确定所选疫苗接种方案是否能提供优于 RV144 中观察到的 SHIV 攻击保护，并通过以下第二阶段具体目标在疫苗接种后至少一年内保持有效： 1. 根据猕猴免疫反应的质量和持久性对 FLSC DNA/亚基免疫方案进行排序。 2.根据FLSC DNA/亚单位免疫方案对抗SHIV162P3攻击的功效对它们进行排序。到该项目结束时，我们应该确定一种能够延长体液和细胞反应寿命的治疗方案，以在 1 年后对异源 SHIV162P3 攻击提供 > 70% 的疗效。如果这种优化的给药方案能够实现 II 期目标，它将快速进入人体临床试验。