Immunogenicity and efficacy of genetically engineered gamma-herpesvirus vaccines

描述（由申请方提供）：人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身潜伏感染。潜伏性感染与多种恶性肿瘤的发生有关，特别是在免疫功能低下的艾滋病患者中。目前还没有针对这类重要的人类病毒的有效疫苗。我们建议利用在体内小鼠γ-疱疹病毒模型来测试基因工程病毒作为疫苗的效力。我们已经表明，潜伏缺陷型病毒未能在100%的受体中建立潜伏期，并且没有体内回复野生型病毒，因此满足遗传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用野生型病毒攻击后被保护免受潜伏性和裂解性感染，因此显示出保护功效。在本提案中，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缺陷疫苗的保护的参数和免疫相关性。此外，我们将探索第二种基因工程病毒的疫苗接种效果，这种病毒是复制缺陷的。最后，我们将评估进一步删除两个免疫逃避基因对保护效力和免疫相关性的影响。在实验小鼠模型中阐明“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人类γ-疱疹病毒疫苗提供必要的基本见解。 公共卫生相关性：γ-疱疹病毒不能被宿主免疫系统清除，而是建立持续的潜伏感染。它们在人群中广泛传播，并与几种癌症的发展有关，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预防感染的疫苗。对实验小鼠模型的研究将增强我们对控制感染所涉及的免疫机制的理解，并揭示可应用于人类疫苗开发的基本原则。由于目前没有针对γ-疱疹病毒的有效疫苗，这些研究对人类健康具有高度意义。

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.