Immune responses to VSV/HIV/SIV Hybrids in Macaques

描述（由申请人提供）：测试新的有效和安全的疫苗载体对开发艾滋病毒疫苗很重要。基于减毒水疱性口炎病毒（VSV）的疫苗载体是细胞免疫和体液免疫的有效诱导剂。尽管经鼻、口或肌肉注射途径给药的VSV载体在100多种非人灵长类动物中没有表现出致病性，但由于担心任何减毒活病毒载体的潜在发病机制，批准临床试验是困难的。为了解决这些安全问题，并产生更容易获得批准的载体，基于VSV和VSV-塞姆利基森林病毒（SFV）杂交繁殖复制子的新的单循环载体已经开发出来，并在小鼠身上进行了测试，取得了良好的结果。这些病媒还具有显著的优势，即人群中对它们没有预先存在的免疫力。该项目的主要目标是测试这些新载体在非人灵长类动物中诱导细胞和体液免疫的有效性。中和抗体的诱导分析需要使用一种能够产生中和抗体的致病性SIV模型。在该项目的第一个目标中，将制备和表征单周期、基于vsv的表达SIVsmE660 Env和Gag蛋白的带和不带细胞因子GM-CSF的引物载体。在VSV载体启动过程中表达GM-CSF可增强小鼠记忆t细胞的回忆。此外，还将制备表达相同Env和Gag蛋白的VSV-SFV杂交复制子颗粒作为增强载体。在第二个目标中，这些载体将在恒河猴中进行评估。SIV中和抗体反应和SIV特异性t细胞反应将在启动和增强后详细研究。我们假设新的载体在诱导细胞免疫应答方面将是非常有效的，并且当适当的Env抗原表达时，可能能够诱导或至少先导SIV中和抗体。接种疫苗的猕猴和对照将受到高致病性SIVsmE660毒株的攻击，攻击后将进行详细的病毒学和免疫学分析。使用SIVsmE660攻毒模型的优点是，在恒河猴感染期间可产生针对攻毒病毒的显著中和抗体。如果这些抗体可以在疫苗接种期间产生或启动，那么就有可能推进艾滋病SIV模型，其中中和抗体除了细胞介导的免疫外，可能能够预防感染或至少有助于控制感染后的病毒载量。公共卫生相关性：艾滋病流行始于25年前，已造成2 700多万人死亡，其中包括2006年的290万人，但尚未研制出有效的艾滋病疫苗。该项目的目标是测试人群中没有预先免疫的强效但非致病性的病毒衍生载体。这些载体将主要评估其在诱导SIV中和抗体和细胞介导免疫方面的有效性，以及在严格的非人灵长类动物挑战模型中对艾滋病的保护能力。这些载体后来可以作为艾滋病毒疫苗进入临床试验，使用能够诱导对艾滋病毒产生广泛反应性细胞和体液免疫的抗原。

DESCRIPTION (provided by applicant): Testing of new potent and safe vaccine vectors is important to development of an HIV vaccine. Vaccine vectors based on attenuated vesicular stomatitis virus (VSV) are potent inducers of both cellular and humoral immunity. Although VSV vectors have shown no pathogenicity in more than 100 non-human primates when given by nasal, oral, or intramuscular routes, approval for clinical trials was difficult because of concerns about potential pathogenesis of any live-attenuated virus vectors. To address such safety concerns, and generate vectors that would be approved more easily, new single-cycle vectors based on VSV and also a hybrid VSV-Semliki Forest Virus (SFV) propagating replicon, have been developed and tested in mice with excellent results. These vectors also have the significant advantage that there is no pre-existing immunity to them in the human population. The major goal this project is to test the effectiveness of these new vectors in non-human primates for induction of both cellular and humoral immunity. The analysis of induction of neutralizing antibody requires that we use a pathogenic SIV model in which neutralizing antibody can be generated. In the first aim of the project, single-cycle, VSV-based priming vectors expressing SIVsmE660 Env and Gag proteins with and without the cytokine GM-CSF will be prepared and characterized. Expression GM-CSF during priming by VSV vectors enhances memory T-cell recall in mice. In addition, VSV-SFV hybrid replicon particles expressing the same Env and Gag proteins will be prepared as boosting vectors. In the second aim, these vectors will be evaluated in rhesus macaques. SIV neutralizing antibody responses and SIV-specific T-cell responses will be studied in detail following prime and boost. We hypothesize that the new vectors will be highly effective at inducing cellular immune responses, and may be able to induce or at least prime for SIV neutralizing antibody when the appropriate Env antigen is expressed. Vaccinated macaques and controls will be challenged with the highly pathogenic SIVsmE660 strain and detailed virological and immunological analyses will be performed following challenge. Use of the SIVsmE660 challenge model has the advantage that significant neutralizing antibodies to the challenge virus are generated during infection of rhesus macaques. If these antibodies can be generated or primed for during vaccination, there is the potential to advance an SIV model of AIDS in which neutralizing antibody in addition to cell mediated immunity, may be able to prevent infection or at least contribute to controlling viral load following infection. PUBLIC HEALTH RELEVANCE: The AIDS epidemic began more than twenty-five years ago and has killed more than 27 million people including 2.9 million in 2006, yet no effective AIDS vaccine has been developed. The goal this project is to test potent, but non-pathogenic, virus-derived vectors for which there is no pre-existing immunity in the human population. The vectors will be evaluated primarily for their effectiveness at inducing SIV neutralizing antibody and cell mediated immunity, but also for their ability to protect against AIDS in a stringent, non-human primate challenge model. These vectors could later be moved into clinical trials as HIV vaccines using antigens capable of inducing broadly reactive cellular and humoral immunity to HIV.