Protective Immunity

保护性免疫

• 批准号: 8307106
• 负责人: David I Watkins
• 金额: $ 51.45万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307106
• 关键词: AIDS vaccine development; Acute; Adenoviruses; Animals; Chronic Phase; Cytomegalovirus; Electroporation; Flavivirus; Gagging; Genes; HIV; HIV vaccine; Human; Immune response; Immunity; Institutes; Instruction; Intention; Interleukin-12; Life; Macaca; Macaca mulatta; Monkeys; Open Reading Frames; Outcome; Plasmids; Proteins; Proteome; Recombinant DNA; Recombinants; SIV; Serotyping; T cell response; Testing; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Virus; Yellow Fever; Yellow Fever Vaccine; design; improved; nonhuman primate; novel vaccines; prevent; research study; vector

We hypothesize that a recombinant yellow fever vaccine (rYF) or rDNA (delivered by electroporation along with IL-12; EP+IL-12) prime followed by a recombinant adenovirus serotype 35 (rAd35) boost can control viral replication after either a homologous or heterologous AIDS virus challenge. We plan to test this hypothesis in macaques using rigorous challenges with the highly pathogenic SIV isolates, SIVmac251 and SIVsmE660. In a previous study, we found that a rDNA prime followed by a rAd5 boost (encoding all of the SIVmac239 proteins except for Env) reduced acute and chronic phase replication after a pathogenic SIVsmE660 mucosal challenge in six of eight vaccinated Indian rhesus macaques. Indeed, six of the vaccinees have no detectable viral replication at one year post challenge. This positive outcome is exceedingly rare in vaccine experiments using a pathogenic SIV challenge. We also discovered that vaccineinduced T cell responses against Gag and Vif correlated with this good outcome. We postulate that there are additional targets in the SIV proteome that can induce efficacious T cell responses. More recently our colleagues at lAVI have shown that vaccination with rDNA plasmids encoding all of the SIV proteins (including Env) by EP along with a plasmid encoding IL-12, followed by a rAd5 boost reduced viral replication of the highly pathogenic SIVmac239 challenge virus in seven of eight macaques. Indeed these vaccine results, along with the recent findings of Louis Picker using recombinant rhesus cytomegalovirus (rhCMV) vectors are the most encouraging non-human primate vaccine results to date. Our intention now is to perform a vaccine study to determine which of the SIV proteins are important targets for the control of viral replication in our first specific aim. In an attempt to improve upon these last two experiments we will also include newly discovered cryptic open reading frames (cORFs) in the vaccine. Our second specific aim is to determine whether a rYF or rDNA (EP+IL-12) prime followed by a rAd35 boost can control viral replication after either a homologous or heterologous AIDS virus challenge.

我们假设一种重组黄热病疫苗（RYF）或rDNA（通过沿电穿孔传递 与IL-12； EP+IL-12）Prime随后是重组腺病毒血清型35（RAD35）升压可以控制 同源或异源艾滋病病毒挑战后的病毒复制。我们计划测试这个 在高度致病的SIV分离株SIVMAC251和 SIVSME660。在先前的研究中，我们发现rDNA Prime随后是RAD5增强（编码所有 SIVMAC239蛋白除ENV降低了致病性后的急性和慢性相复制 SIVSME666粘膜挑战赛中的六个疫苗接种了印度恒河猕猴。确实，六个 挑战后一年，疫苗在一年中没有可检测的病毒复制。这种积极的结果是 在疫苗实验中使用致病性SIV挑战极为罕见。我们还发现疫苗诱导 T细胞反应对GAG和VIF的反应与这种良好结果相关。我们假设有 SIV蛋白质组中的其他靶标可以诱导有效的T细胞反应。最近我们 Lavi的同事表明，用编码所有SIV蛋白的rDNA质粒疫苗接种 （包括ENV）EP以及编码IL-12的质粒，然后降低了Rad5的病毒复制 在八个猕猴中的七个中，高度致病性的SIVMAC239挑战病毒中。确实是这些疫苗 结果，以及使用重组恒星病毒（RHCMV）的Louis Picker的最新发现。 载体是迄今为止最令人鼓舞的非人类灵长类动物疫苗结果。我们现在的意图是 进行疫苗研究以确定哪种SIV蛋白是控制病毒的重要靶标 在我们的第一个特定目标中复制。为了改善这两个实验，我们也将 在疫苗中包括新发现的神秘开放式阅读框（CRFS）。我们的第二个具体目标是 确定RYF还是RDNA（EP+IL-12）Prime，然后是Rad35 Boost可以控制病毒复制 在同源或异源艾滋病病毒挑战之后。