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。基于减毒水泡性口炎病毒(VSV)的疫苗载体是一种有效的细胞和体液免疫诱导剂。虽然VSV载体通过鼻腔、口腔或肌肉注射途径在100多个非人类灵长类动物中没有显示出致病性，但由于担心任何活的减毒病毒载体的潜在致病作用，临床试验很难批准。为了解决这些安全问题，并产生更容易批准的载体，基于VSV和混合VSV-Semliki森林病毒(SFV)复制子的新的单循环载体已经被开发出来，并在小鼠身上进行了测试，获得了良好的结果。这些媒介也有一个显著的优势，那就是在人类人口中不存在对它们的预先存在的免疫力。这个项目的主要目标是测试这些新载体在非人类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要求我们使用一个致病的SIV模型，在该模型中可以产生中和抗体。在该项目的第一个目标中，将制备和鉴定表达SIVsmE660 Env和Gag蛋白的单循环、基于VSV的启动载体，该载体带有和不带有细胞因子GM-CSF。VSV载体启动过程中GM-CSF的表达增强小鼠记忆T细胞回忆。此外，还将制备表达相同Env和Gag蛋白的VSV-SFV杂合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身上进行评估。SIV中和抗体反应和SIV特异性T细胞反应将在PRIME和BOOST之后详细研究。我们推测，新载体在诱导细胞免疫反应方面将是高效的，并且当适当的环境抗原被表达时，可能能够诱导或至少激发SIV中和抗体。接种疫苗的猕猴和对照组将接受高致病性SIVsmE660毒株的挑战，并将在挑战后进行详细的病毒学和免疫学分析。使用SIVsmE660挑战模型的优点是，在感染恒河猴期间会产生针对挑战病毒的显著中和抗体。如果在疫苗接种期间能够产生或准备这些抗体，就有可能推进艾滋病的SIV模型，在该模型中，除了细胞免疫外，中和抗体可能能够预防感染，或者至少有助于控制感染后的病毒载量。公共卫生意义：艾滋病流行始于25年多前，已导致2700多万人死亡，其中包括2006年的290万人，但尚未开发出有效的艾滋病疫苗。该项目的目标是测试有效但非致病性的病毒衍生载体，这些载体在人类群体中没有预先存在的免疫力。这些载体将主要根据它们在诱导SIV中和抗体和细胞免疫方面的有效性进行评估，还将评估它们在严格的非人类灵长类动物挑战模型中预防艾滋病的能力。这些载体稍后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的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.