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: 7802317
• 负责人: John K. Rose
• 金额: $ 70.65万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802317
• 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; Memory Loss; Modeling; Mus; Nose; Oral; Pathogenesis; Pathogenicity; Phase; Population; Proteins; Replication-Associated Process; Replicon; Route; SIV; Safety; Semliki forest virus; System; T cell response; 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）：新的有效且安全的疫苗载体的测试对于艾滋病毒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 载体通过鼻腔、口腔或肌肉注射途径对 100 多种非人类灵长类动物没有显示出致病性，但由于担心任何减毒活病毒载体的潜在发病机制，临床试验的批准很困难。为了解决此类安全问题，并生成更容易获得批准的载体，基于 VSV 以及混合 VSV-Semliki 森林病毒 (SFV) 繁殖复制子的新型单周期载体已被开发出来，并在小鼠中进行了测试，并取得了优异的结果。这些载体还具有显着的优势，即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类灵长类动物中诱导细胞和体液免疫的有效性。中和抗体诱导的分析需要我们使用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 的引发载体，该载体表达 SIVsmE660 Env 和 Gag 蛋白，有或没有细胞因子 GM-CSF。 VSV 载体启动期间表达 GM-CSF 可增强小鼠的记忆 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，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 细胞反应将在初免和加强后进行详细研究。我们假设新载体将非常有效地诱导细胞免疫反应，并且当表达适当的 Env 抗原时，可能能够诱导或至少引发 SIV 中和抗体。接种疫苗的猕猴和对照将受到高致病性 SIVsmE660 菌株的攻击，攻击后将进行详细的病毒学和免疫学分析。使用SIVsmE660攻击模型的优点是在恒河猴感染期间产生针对攻击病毒的显着中和抗体。如果这些抗体可以在疫苗接种过程中产生或引发，就有可能推进艾滋病的 SIV 模型，其中中和抗体除了细胞介导的免疫之外，还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：艾滋病流行已超过 25 年前，已导致超过 2700 万人死亡，其中 2006 年死亡人数为 290 万人，但目前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，这些载体在人群中没有预先存在的免疫力。将主要评估这些载体在诱导 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类灵长类动物攻击模型中预防艾滋病的能力。这些载体随后可以作为艾滋病毒疫苗进入临床试验，使用能够诱导针对艾滋病毒的广泛反应性细胞和体液免疫的抗原。

项目成果

A single-cycle vaccine vector based on vesicular stomatitis virus can induce immune responses comparable to those generated by a replication-competent vector.

基于水泡性口炎病毒的单周期疫苗载体可以诱导与具有复制能力的载体产生的免疫反应相当的免疫反应。

• 发表时间: 2005-11
• 作者: Publicover, Jean;Ramsburg, Elizabeth;Rose, John K
• 通讯作者: Rose, John K

Requirement for CD4 T cell help in maintenance of memory CD8 T cell responses is epitope dependent.

CD4 T 细胞帮助维持记忆 CD8 T 细胞反应的需要是表位依赖性的。

• 发表时间: 2007-05-15
• 作者: Ramsburg, Elizabeth A;Publicover, Jean M;Coppock, Dagan;Rose, John K
• 通讯作者: Rose, John K

Virus-Like Vesicle-Based Therapeutic Vaccine Vectors for Chronic Hepatitis B Virus Infection.

用于慢性乙型肝炎病毒感染的病毒样囊泡治疗疫苗载体。

• 发表时间: 2015-10
• 作者: Reynolds, Tracy D;Buonocore, Linda;Rose, Nina F;Rose, John K;Robek, Michael D
• 通讯作者: Robek, Michael D

Rapid quantification of SIV-specific CD8 T cell responses with recombinant vaccinia virus ELISPOT or cytokine flow cytometry.

使用重组痘苗病毒 ELISPOT 或细胞因子流式细胞术快速定量 SIV 特异性 CD8 T 细胞反应。

• 发表时间: 2000-11-10
• 作者: Moretto, W J;Drohan, L A;Nixon, D F
• 通讯作者: Nixon, D F

In vitro evolution of high-titer, virus-like vesicles containing a single structural protein.

含有单一结构蛋白的高滴度病毒样囊泡的体外进化。

• 发表时间: 2014-11-25
• 影响因子: 11.1
• 作者: Rose, Nina F;Buonocore, Linda;Schell, John B;Chattopadhyay, Anasuya;Bahl, Kapil;Liu, Xinran;Rose, John K
• 通讯作者: Rose, John K