Immunogenicity and efficacy of genetically engineered gamma-herpesvirus vaccines

基因工程γ-疱疹病毒疫苗的免疫原性和功效

基本信息

批准号：
7943957
负责人：
Marcia A Blackman
金额：
$ 50万
依托单位：
TRUDEAU INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943957
关键词：
Acquired Immunodeficiency Syndrome Affect Antibodies Autologous Cell Vaccine CD4 Positive T Lymphocytes CD8B1 gene Cells Cellular Immunity Clinical Complication Cyclin D1 Development Dose Engineering Epitopes Equilibrium Genes Goals Health Herpesviridae Herpesviridae Infections Herpesvirus Vaccines Human Human Herpesvirus 4 Human Herpesvirus 8 Human Virus Immune Immune system Immunity Immunocompetent Immunocompromised Host Immunology Individual Infection Infection Control Infection prevention Joints Kaposi Sarcoma Life Longevity Lytic Lytic Phase MHC Class I Genes Malignant Neoplasms Methods Modeling Molecular Virology Mus Nucleocapsid Oncogenic Oncogenic Viruses Pathology Patients Population Role Route Safety Staging T-Lymphocyte Testing The Sun Transcription Coactivator Vaccinated Vaccination Vaccine Design Vaccines Viral Viral Antigens Virus Virus Diseases Virus Replication cancer type chemokine efficacy testing gammaherpesvirus genetically engineered virus immunogenicity immunosuppressed in vivo insight latency-associated nuclear antigen latent infection latent persistent infection lytic replication man mouse model mutant prevent protective efficacy public health relevance reactivation from latency research study ubiquitin ligase vaccination strategy vaccine candidate vaccine development viral DNA viral cyclin

项目摘要

DESCRIPTION (provided by applicant): The human gamma-herpesviruses, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus evade host immunity and establish life-long, latent infections. Latent infections are associated with the development of a variety of malignancies, particularly in immunocompromised AIDS patients. There are currently no effective vaccines for this important class of human viruses. We propose to exploit the in vivo mouse gamma- herpesvirus model to test efficacy of genetically engineered viruses as vaccines. We have shown that a latency-deficient virus fails to establish latency in 100% of recipients, and there is no in vivo reversion to wild type virus, thus fulfilling safety criteria for a genetically engineered oncogenic virus. Importantly, the vaccinated mice are protected from both latent and lytic infection following a subsequent challenge with wild type virus, thus showing protective efficacy. In the current proposal, we will further exploit the natural mouse gamma- herpesvirus infection model to test the parameters and immune correlates of protection of the latency-deficient vaccine. In addition, we will explore the vaccination efficacy of a second genetically engineered virus, which is replication-deficient. Finally, we will evaluate the impact of a further deletion of two immune evasion genes on efficacy and immune correlates of protection. Elucidation of mechanisms of protective immunity induced by "proof of concept" vaccination strategies in the experimental mouse model will provide fundamental basic insight necessary for the development of vaccines for the oncogenic human gamma-herpesviruses. PUBLIC HEALTH RELEVANCE: The gamma-herpesviruses are not cleared by the host immune system, but establish persistent latent infections. They are widely disseminated in the human population and are associated with the development of several types of cancer, especially in immunocompromised AIDS patients. An important clinical goal is to develop vaccines to prevent infection. Study of the experimental mouse model will enhance our understanding of the immune mechanisms involved in controlling infection and reveal fundamental principles that can be applied to human vaccine development. As there are currently no effective vaccines for the gamma- herpesviruses, these studies are highly significant for human health.

描述（由申请人提供）：人类γ-疱疹病毒、EB 病毒和卡波西肉瘤相关疱疹病毒逃避宿主免疫并建立终生潜伏感染。潜伏感染与多种恶性肿瘤的发生有关，尤其是免疫功能低下的艾滋病患者。目前还没有针对这一类重要人类病毒的有效疫苗。我们建议利用体内小鼠γ-疱疹病毒模型来测试基因工程病毒作为疫苗的功效。我们已经证明，潜伏期缺陷型病毒无法在 100% 的受体中建立潜伏期，并且体内不会逆转为野生型病毒，从而满足基因工程致癌病毒的安全标准。重要的是，接种疫苗的小鼠在随后受到野生型病毒攻击后可以免受潜伏感染和裂解性感染，从而显示出保护功效。在当前的提案中，我们将进一步利用天然小鼠γ-疱疹病毒感染模型来测试潜伏期缺陷疫苗的保护参数和免疫相关性。此外，我们将探索第二种复制缺陷型基因工程病毒的疫苗接种效果。最后，我们将评估进一步删除两个免疫逃避基因对保护功效和免疫相关性的影响。阐明实验小鼠模型中“概念验证”疫苗接种策略诱导的保护性免疫机制将为开发致癌性人类伽马疱疹病毒疫苗提供必要的基本见解。公共卫生相关性：γ-疱疹病毒不会被宿主免疫系统清除，但会建立持续的潜伏感染。它们在人群中广泛传播，并与多种癌症的发生有关，特别是在免疫功能低下的艾滋病患者中。一个重要的临床目标是开发疫苗来预防感染。对实验小鼠模型的研究将增强我们对控制感染的免疫机制的理解，并揭示可应用于人类疫苗开发的基本原理。由于目前尚无针对γ-疱疹病毒的有效疫苗，因此这些研究对人类健康具有非常重要的意义。