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.

我们假设重组黄热病疫苗(RYF)或rDNA(通过电穿孔沿着 用IL-12；EP+IL-12)启动，然后用重组腺病毒血清35型(RAd35)Boost可以控制 在同源或异源艾滋病病毒挑战后病毒复制。我们计划对此进行测试 对高致病性SIV分离株SIVmac251和SIVmac251进行严格挑战的猕猴假说 SIVsmE660。在之前的一项研究中，我们发现rDNA素数后面跟着rAd5 Boost(编码所有 除Env外的SIVmac239蛋白)减少了致病后的急性和慢性期复制 SIVsmE660黏膜攻击在8只接种疫苗的印度猕猴中的6只。事实上，其中六个 在挑战后一年，接种疫苗的人没有检测到病毒复制。这一积极的结果是 在疫苗实验中使用致病性SIV挑战的情况非常罕见。我们还发现，疫苗诱导的 T细胞对GAG和VIF的反应与这一良好结果相关。我们假设有 SIV蛋白质组中可以诱导有效T细胞反应的其他靶点。最近，我们的 Lavi的同事们已经证明，用编码所有SIV蛋白的rDNA质粒接种疫苗 (包括Env)通过EP和编码IL-12的质粒一起，随后rAd5 Boost减少病毒复制 在8只猕猴中有7只感染了高致病性SIVmac239挑战病毒。事实上，这些疫苗 结果，与Louis Picker使用重组恒河猴巨细胞病毒(RhCMV)的最新发现一样 媒介是迄今为止最令人鼓舞的非人类灵长类疫苗结果。我们现在的意图是 进行疫苗研究，以确定哪些SIV蛋白是控制病毒的重要靶点 在我们的第一个特定目标中复制。为了改进这最后两个实验，我们还将 在疫苗中包括新发现的神秘开放阅读框架(CORF)。我们的第二个具体目标是 确定ryf或rDNA(EP+IL-12)启动后rAd35增强是否可以控制病毒复制 在同源或异种艾滋病病毒挑战之后。