Yellow Fever, rDNA (EP+IL-12) and rAd35 as Vectors for AIDS Vaccine Development

黄热病、rDNA (EP IL-12) 和 rAd35 作为艾滋病疫苗开发的载体

• 批准号: 8301117
• 负责人: David I Watkins
• 金额: $ 215.84万
• 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/8301117
• 关键词: Yellow; Fever; rDNA; EP+IL; 12

DESCRIPTION (provided by applicant): We plan to explore whether the highly successful attenuated yellow fever (YF-17D) vaccine, rDNA delivered by electroporation along with IL-12 and rAd35 can be used as vectors to express SIV proteins in a prime/boost regimen for vaccination against the AIDS virus. In a highly integrated series of experiments, we will first define the best viral targets for a vaccine. We will then bring the results together in a final efficacy experiment to test the vectors that, if successful, could prevent suffering by millions of people worldwide. Our application seeks to address four of the ten research areas outlined in the HIVRAD program announcement. Our project has the potential to impact HIV vaccine development on two fronts. First, we will define the targets of a successful vaccine in a challenge experiment. This will allow us to design a vaccine encoding the critical targets of a successful immune response. Second, we will develop three entirely novel vaccine vectors. If we are successful in this endeavor, our results will have a profound effect on HIV vaccine design. PUBLIC HEALTH RELEVANCE: Completion of these studies should yield new methods of vaccine design. Furthermore, if any of our three vectors can effectively induce efficacious AIDS virus-specific immune responses in non-human primates, we could advance these vectors into human clinical trials. ******************************************************************************************************************** Project 1: Protective Immunity Project Leader: David Watkins (Description as provided by applicant) 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 vaccine-induced 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 as targets for the control of viral replication in our firs 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.

描述（由申请人提供）：我们计划探索高度成功的减毒黄热病（YF-17 D）疫苗（通过电穿孔沿着IL-12和rAd 35递送的rDNA）是否可用作载体，以在针对AIDS病毒的疫苗接种的初免/加强方案中表达SIV蛋白。在一系列高度整合的实验中，我们将首先确定疫苗的最佳病毒靶点。然后，我们将把结果汇总在一起，进行最终的功效实验，以测试这些载体，如果成功的话，可以防止数百万人遭受痛苦。 世界各地的人们。我们的申请旨在解决HIVRAD计划公告中概述的十个研究领域中的四个。我们的项目有可能在两个方面影响艾滋病毒疫苗的开发。首先，我们将在挑战实验中确定成功疫苗的靶点。这将使我们能够设计一种疫苗，编码成功免疫反应的关键目标。其次，我们将开发三种全新的疫苗载体。如果我们在这奋进取得成功，我们的结果将对艾滋病毒疫苗的设计产生深远的影响。 公共卫生相关性：这些研究的完成将产生疫苗设计的新方法。此外，如果我们的三种载体中的任何一种能够有效地在非人灵长类动物中诱导有效的艾滋病病毒特异性免疫应答，我们就可以将这些载体推进人体临床试验。 ******************************************************************************************************************** 项目1：保护性抗扰度 项目负责人：大卫沃特金斯 我们假设重组黄热病疫苗（rYF）或rDNA（通过电穿孔沿着IL-12递送; EP+IL-12）初免，随后是重组腺病毒血清型35（rAd 35）加强，可以在同源或异源AIDS病毒攻击后控制病毒复制。我们计划在猕猴中使用高致病性SIV分离株SIVmac 251和SIVsmE 660进行严格的挑战来验证这一假设。在以前的研究中，我们发现，rDNA引物，然后是rAd 5加强（编码所有的SIVmac 239蛋白质，除了Env）减少急性和慢性期复制后，致病性SIVsmE 660粘膜攻击在8个接种疫苗的印度恒河猴中的6个。事实上，6名疫苗接种者在攻毒后一年内没有检测到病毒复制。这种阳性结果在使用致病性SIV攻击的疫苗实验中是极其罕见的。我们还发现，疫苗诱导的T细胞对Gag和Vif的反应与这种良好的结果相关。我们假设SIV蛋白质组中有其他靶点可以诱导有效的T细胞应答。最近，我们在IAVI的同事已经表明，通过EP用编码所有SIV蛋白（包括Env）的rDNA质粒连同编码IL-12的质粒一起沿着接种，随后用rAd 5加强，减少了八只猕猴中的七只中的高致病性SIVmac 239攻击病毒的病毒复制。事实上，这些疫苗结果，沿着Louis Picker最近使用重组恒河猴巨细胞病毒（rhCMV）载体的发现，是迄今为止最令人鼓舞的非人灵长类动物疫苗结果。我们现在的目的是进行疫苗研究，以确定哪些SIV蛋白质作为我们第一个特定目标中控制病毒复制的靶点是重要的。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隐蔽开放阅读框架（cORF）。我们的第二个具体目标是确定rYF或rDNA（EP+IL-12）引发后再用rAd 35加强是否可以在同源或异源AIDS病毒攻击后控制病毒复制。