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）：我们计划探索非常成功的减毒黄热病 (YF-17D) 疫苗、通过电穿孔传递的 rDNA 以及 IL-12 和 rAd35 是否可以用作载体，在初免/加强中表达 SIV 蛋白艾滋病病毒疫苗接种方案。在一系列高度集成的实验中，我们将首先确定疫苗的最佳病毒靶点。然后，我们将把结果汇总到最终的功效实验中，以测试这些载体，如果成功，可以避免数百万人遭受痛苦。 世界各地的人们。我们的应用程序旨在解决 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目标。这将使我们能够设计一种编码成功免疫反应的关键目标的疫苗。其次，我们将开发三种全新的疫苗载体。如果我们在这一努力中取得成功，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：这些研究的完成应该会产生新的疫苗设计方法。此外，如果我们的三种载体中的任何一种能够在非人类灵长类动物中有效诱导有效的艾滋病病毒特异性免疫反应，我们就可以将这些载体推进到人体临床试验中。 ****************************************************** ****************************************************** ************** 项目一：保护性免疫 项目负责人：大卫·沃特金斯 （申请人提供的描述）我们假设重组黄热病疫苗 (rYF) 或 rDNA（通过电穿孔与 IL-12 一起递送；EP+IL-12）初免，随后重组腺病毒血清型 35 (rAd35) 加强可以控制同源或异源艾滋病病毒攻击后的病毒复制。我们计划通过对高致病性 SIV 分离株 SIVmac251 和 SIVsmE660 进行严格挑战，在猕猴中检验这一假设。在之前的一项研究中，我们发现，在八只接种疫苗的印度恒河猴中，有六只受到致病性 SIVsmE660 粘膜攻击后，先进行 rDNA 初免，然后再进行 rAd5 加强（编码除 Env 之外的所有 SIVmac239 蛋白），可减少急性期和慢性期复制。事实上，六名疫苗接种者在攻击后一年内没有检测到病毒复制。在使用致病性 SIV 攻击的疫苗实验中，这种积极结果极为罕见。我们还发现疫苗诱导的针对 Gag 和 Vif 的 T 细胞反应与这一良好结果相关。我们假设 SIV 蛋白质组中有额外的靶标可以诱导有效的 T 细胞反应。最近，我们在 lAVI 的同事表明，用 EP 编码所有 SIV 蛋白（包括 Env）的 rDNA 质粒以及编码 IL-12 的质粒进行疫苗接种，然后进行 rAd5 加强，可减少高致病性 SIVmac239 攻击病毒的病毒复制。八只猕猴中的七只。事实上，这些疫苗结果以及 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类灵长类疫苗结果。我们现在的目的是进行疫苗研究，以确定哪些 SIV 蛋白作为我们第一个具体目标中控制病毒复制的靶标是重要的。为了改进这最后两个实验，我们还将在疫苗中加入新发现的神秘开放阅读框（cORF）。我们的第二个具体目标是确定 rYF 或 rDNA (EP+IL-12) 引发以及随后的 rAd35 加强是否可以在同源或异源艾滋病病毒攻击后控制病毒复制。