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
• 负责人: Timothy R Fouts
• 金额: $ 70.02万
• 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/8642864
• 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）：我们开发有效的预防性疫苗针对HIV的主要方法利用了一种称为全长单链（FLSC）的新型免疫原，该免疫原是由源自HIV-1（BAL）的GP120组成的，该GP120通过20氨基酸链接到遗传链接到人类CD4的D1D2域。 RHFLSC接种了恒河猕猴，Rhflsc是FLSC的替代版本，其中包含源自恒河猕猴的CD4。 RHFLSC在多种剂量的R5热带地区为直肠挑战提供了重大保护，并且 异源SHIV162P3。这些观察结果将FLSC推向了1期临床试验中的临床前发展和评估（BMGF，MHRP，NIAID支持）。与RV144临床试验中的观察结果一致，随着抗体滴度下降，我们观察到的保护减弱。单个功能T细胞的重要种群的存在（分泌IFN-？ 或IL-2）似乎也与RHFLSC亚基产生的保护成反比。我们的合作者发现，pDNA和蛋白质的同时共同给药可显着提高效力，并延长抗体反应的寿命。通过猕猴中电穿孔进行抗原和IL-12的pDNA疫苗接种会诱导多功能的T细胞，这些T细胞已知与保护相关，这也可以提高FLSC亚基提供的疗效。我们的目标是基于这些观察结果，并确定PDNA/亚基组合疫苗是否可以提高疫苗后1年后提供> 70％疗效所需的免疫反应的质量和耐用性。我们的第1阶段目标是根据小鼠免疫反应的质量和耐用性来对FLSC DNA/亚基免疫方案进行对。使用第一阶段定义的最高方案，我们将确定所选的疫苗接种方案是否提供了避免SHIV挑战的保护，该方案是否优于RV144中观察到的挑战，并且在接种后至少一年内通过以下II阶段特定目的有效：1。等级订单FLSC DNA/亚基免疫，基于MACABYENMABEES INMACEES的质量和耐受性。 2。基于对SHIV162P3挑战的功效，等级顺序FLSC DNA/亚基免疫方案。到该项目结束时，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年后在异源SHIV162P3挑战中提供> 70％的功效。如果这种优化的交付方案实现了II期目标，则将快速进入人类的临床试验。