Immune responses to VSV/HIV/SIV Hybrids in Macaques

猕猴对 VSV/HIV/SIV 杂交种的免疫反应

• 批准号: 7626325
• 负责人: John K. Rose
• 金额: $ 71.04万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626325
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Address; Animals; Antibodies; Antibody Formation; Antigens; Attenuated; CD8B1 gene; Cellular Immunity; Clinical Trials; Complement; Control Animal; Development; Effectiveness; Epidemic; Gagging; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; HIV vaccine; Human; Humoral Immunities; Hybrids; Immune; Immune response; Immunity; Infection; Infection prevention; Intramuscular; Life; Macaca; Macaca mulatta; Memory Loss; Modeling; Mus; Nose; Oral; Pathogenesis; Pathogenicity; Phase; Population; Proteins; Replication-Associated Process; Replicon; Route; SIV; Safety; Semliki forest virus; System; T memory cell; T-Lymphocyte; Testing; Vaccinated; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral Load result; Virus; base; cytokine; env Gene Products; env Genes; gag Gene Products; killings; memory recall; neutralizing antibody; nonhuman primate; novel; particle; public health relevance; response; vector; vector vaccine; vector-based vaccine; vesicular stomatitis virus G protein

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.

描述（由申请人提供）：测试新的有效和安全的疫苗载体对HIV疫苗的开发非常重要。基于减毒水泡性口炎病毒（VSV）的疫苗载体是细胞和体液免疫的有效诱导剂。尽管VSV载体在超过100种非人灵长类动物中通过鼻、口或肌内途径给药时没有显示出致病性，但由于担心任何减毒活病毒载体的潜在致病性，临床试验的批准是困难的。为了解决这些安全性问题，并产生更容易获得批准的载体，已经开发了基于VSV的新的单循环载体以及混合VSV-塞姆利基森林病毒（SFV）繁殖复制子，并在小鼠中进行了测试，结果非常好。这些媒介还具有显著的优势，即在人群中不存在对它们的预先存在的免疫力。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。对中和抗体诱导的分析需要我们使用一个致病性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，将制备和表征表达SIVsmE 660 Env和Gag蛋白（有和没有细胞因子GM-CSF）的单循环、基于VSV的引发载体。在VSV载体引发期间表达GM-CSF增强小鼠的记忆T细胞回忆。此外，将制备表达相同Env和Gag蛋白的VSV-SFV杂合复制子颗粒作为加强载体。在第二个目标中，将在恒河猴中评价这些载体。将在初免和加强后详细研究SIV中和抗体应答和SIV特异性T细胞应答。我们假设新的载体在诱导细胞免疫应答方面将是高度有效的，并且当适当的Env抗原表达时，可能能够诱导或至少引发SIV中和抗体。将用高致病性SIVsmE 660毒株攻毒接种猕猴和对照，攻毒后将进行详细的病毒学和免疫学分析。使用SIVsmE 660攻击模型的优点在于，在恒河猴感染期间产生针对攻击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引发，则有可能推进AIDS的SIV模型，其中除了细胞介导的免疫之外，中和抗体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的，但非致病性的，病毒衍生的载体，在人群中没有预先存在的免疫力。将主要评价载体在诱导SIV中和抗体和细胞介导的免疫方面的有效性，以及它们在严格的非人灵长类动物攻击模型中预防AIDS的能力。这些载体以后可以作为HIV疫苗进入临床试验，使用能够诱导对HIV的广泛反应性细胞和体液免疫的抗原。