CMV Vectored Herpes Simplex Vaccine

描述（由申请方提供）：本项目的长期目标是利用巨细胞病毒（CMV）载体开发针对生殖器疱疹病原体单纯疱疹病毒2型（HSV-2）的治疗性疫苗。HSV-2在人群中广泛流行，导致生殖器复发性病变，并显着增加其他性传播疾病（如艾滋病毒）的风险。尽管这种未满足的医疗需求，但没有批准的HSV-2疫苗。虽然一些疫苗方法在临床前研究中显示出希望，但它们在临床试验中未能保护个体免受新发或复发感染。考虑到T淋巴细胞在限制HSV-2再活化和相关病变发展中的已知作用，成功的HSV-2疫苗需要诱导和维持有效识别和中和感染细胞的强T细胞应答。CMV载体由于其诱导终身、高频率效应子记忆T细胞（TEM）应答的能力而独特地适合于该任务。TEM细胞群体通过持续的低水平抗原呈递来维持，从而在病原体进入的外周部位以及扩散和再活化的内部部位产生连续的免疫屏障。在非人灵长类动物模型中，CMV载体疫苗诱导的TEM显示出前所未有的针对猿猴免疫缺陷病毒的保护，包括当阴道内攻击时。事实上，受保护的动物在功能上是治愈的，这表明基于CMV的疫苗具有长期治疗效果。因此，TomegaVax的创始人目前正在开发CMV载体，用于预防和治疗HIV疫苗。在人群中，CMV是高度流行的，建立终身持续感染，无症状。与传统的病毒载体不同，CMV载体可以重复使用，即使在已经携带持续CMV感染的个体中也不会损失免疫原性或功效。重要的是，扩散缺陷型CMV载体保持与野生型载体相同的TEM刺激水平，从而即使对于免疫受损的接受者也提供安全有效的载体。为了证明使用CMV载体作为HSV-2疫苗的可行性，我们建议在完善的鼠模型中评估表达HSV-2抗原的扩散缺陷型鼠CMV载体。利用细菌人工染色体技术和创新的互补方法，我们将构建表达所选HSV抗原的野生型和传播缺陷型CMV载体。我们将详细监测和表征CMV载体对这些抗原诱导的免疫应答，并确定它们对HSV-2致死性攻击的保护能力。该I期研究将能够选择用于插入扩散缺陷型人CMV载体的保护性HSV抗原。该计划的第二阶段将集中在IND使能研究，以生产和测试HCMV载体的HSV疫苗。这项研究计划的最终产品将是一种重组治疗性疫苗，可终身预防生殖器疱疹复发。

DESCRIPTION (provided by applicant): The longterm goal of this project is to utilize cytomegalovirus (CMV) vectors in the development of a therapeutic vaccine against herpes simplex virus 2 (HSV-2), the causative agent of genital herpes. HSV-2 is widely prevalent in the population causing recurrent genital lesions and significantly increasing the risk for other sexually transmitted diseases such as HIV. Despite this unmet medical need, there is no approved vaccine for HSV-2. While some vaccine approaches have shown promise in preclinical studies, they failed to protect individuals from de novo or recurrent infection in clincal trials. Given the known role of T lymphocytes in limiting HSV-2 reactivation and the associated development of lesions, a successful HSV-2 vaccine needs to induce and maintain a strong T cell response that effectively identifies and neutralizes infected cells. CMV vectors are uniquely qualified for this task due to their ability to induce lifelong, high frequency effector memory T cll (TEM) responses. The TEM cell population is maintained by persistent, low level antigen presentation thus generating a continuous immune shield in peripheral sites of pathogen entry as well as internal sites of spreading and reactivation. In non-human primate models, TEM induced by CMV-vectored vaccines have shown unprecedented protection against simian immunodeficiency viruses, including when challenged intra- vaginally. In fact, protected animals are functionally cured, suggesting a long-term therapeutic effect of CMV- based vaccines. CMV-vectors are therefore currently being developed for prophylactic and therapeutic vaccines against HIV by the founders of TomegaVax. In the human population, CMV is highly prevalent establishing lifelong persistent infection that is asymptomatic. Unlike traditional viral vectors, CMV vectors can be used repeatedly and without any loss to immunogenicity or efficacy even in individuals already harboring persistent CMV infection. Importantly, spread-deficient CMV vectors maintain the same level of TEM stimulation as wildtype vectors thus providing safe and effective vectors even for immunocompromised recipients. To demonstrate the feasibility of using CMV vectors as HSV-2 vaccines we propose to evaluate spread-deficient murine CMV vectors expressing HSV-2 antigens in a well-established murine model. Using bacterial artificial chromosome technology and innovative complementation methods, we will construct wild- type and spread-deficient CMV vectors expressing selected HSV antigens. We will monitor and characterize in detail the immune responses induced by CMV vectors to these antigens and determine their ability to protect against lethal challenge with HSV-2. This phase I study will enable the selection of protective HSV antigens for insertion into spread-deficient human CMV vectors. Phase II of this program will then focus on IND-enabling studies to manufacture and test HCMV-vectored HSV vaccines. The ultimate product of this research program will be a recombinant therapeutic vaccine providing lifelong protection against recurring genital herpes.