Vaccine-Induced Immunity to CMV

造血细胞移植（HCT）受者的CMV感染是一个持续存在的问题，其影响了造血干细胞移植（HCT）的预后。 这是一个非常成功的治疗方法。以更昔洛韦/膦甲酸抗病毒治疗为主 预防移植后CMV疾病（Tx）的策略。尽管在配方和 抗病毒药物的使用使Tx后恢复期和CMV风险复杂化并延长 疾病考虑到这些警告，我们正在寻求一种新的治疗策略，重点是启动或 增强健康志愿者和HCT供体中CMV特异性T细胞免疫。在研制这种疫苗时 策略，假设目标人群将具有免疫能力，并判断疫苗接种 如果自限性CMV个体对疫苗的免疫应答等同，则成功 感染，这在第一个近似代表一种保护性反应。为此，在具体目标 (SA1)将构建表达四种CMV抗原的减毒痘病毒（MVA）（CMV-MVA） 包括UL 32、UL 44、UL 83和UL 123-外显子4，用于刺激对CMV的细胞免疫。MVA有 几个优点，包括无毒力，低炎症反应和人类致病性，和 包含多种CMV抗原将确保美国广泛的疫苗覆盖率。缺乏病毒装配 在哺乳动物中，以及在严重免疫抑制的猕猴、啮齿动物和 在HIV-AIDS患者中的应用是其用于HCT接受者的候选资格的证据。SA 1中构建的CMV-MVA 将被鉴定为具有免疫功能，随后转移到经过认证的cGMP 临床生产的制造商。为了确保rMVA对Tx受体的安全性，在SA 2中进行了一项安全性研究， 将在健康CMV阳性和阴性志愿者中进行。免疫方案将模拟 在不延迟Tx的情况下向Tx供体提供两剂疫苗所需的时间框架。一项II期试验 在SA 3中建议使用140名疫苗接种者和未接种对照的随机平衡队列， 确定在Tx之前用CMV-MVA免疫供体是否会导致病程改变 和Tx接受者中CMV病毒血症的程度。这项试验将有足够的把握度， 作为疫苗成功的衡量标准，病毒血症的发生率将具有统计学意义。成功限制 通过这种方法治疗急性CMV感染为解决晚期CMV的重要问题奠定了基础 在一些实施方案中，本发明提供了通过用相同或改进形式的CMV-MVA免疫Tx受体来治疗疾病的方法。

CMV infection of hematopoietic cell transplant (HCT) recipients is a continuing problem that impacts the outcome of this very successful therapy. Anti-viral treatment with ganciclovir/foscarnet is the main treatment strategy to prevent CMV disease post-transplant (Tx). Despite significant advances in formulation and delivery of anti-virals, their use complicates and extends the post-Tx recovery period and risk for CMV disease. Considering these caveats, we are pursuing a novel therapeutic strategy that focuses on priming or enhancing CMV-specific T cell immunity in healthy volunteers and HCT donors. In developing this vaccine strategy, it is assumed that the target population will be immunocompetent, and vaccination judged successful if immunity to CMV in response to the vaccine is equivalent in individuals with self-limited CMV infection, which at first approximation represents a protective response. Towards this end in Specific Aim (SA1) attenuated poxviruses (MVA) will be constructed that express four CMV antigens (CMV-MVA) including UL32, UL44, UL83, and UL123-exon4 for stimulation of cellular immunity to CMV. MVA has several advantages including avirulence, low inflammatory response and pathogenicity in humans, and inclusion of multiple CMV antigens will ensure broad vaccine coverage for the USA. Lack of viral assembly in mammals, together with studies showing its safety in heavily immunosuppressed macaques, rodents, and in HIV-AIDS patients is evidence of its candidacy for use in HCT recipients. CMV-MVA constructed in SA1 will be qualified as immunologically functional, and subsequently transferred to a certified cGMP manufacturer for clinical production. To ensure safety of the rMVA for Tx recipients, a safety study in SA2 will be conducted in healthy CMV positive and negative volunteers. The immunization regimen will model the time frame required for providing two doses of vaccine to Tx donors without delaying Tx. A Phase II trial using a randomized balanced cohort of 140 vaccinees and unvaccinated controls is proposed in SA3 to establish whether immunization of a donor with CMV-MVA prior to Tx will result in modification of the course and magnitude of CMV-viremia in a Tx recipient. This trial will be sufficiently powered that a 62% reduction in viremia will be statistically meaningful as a measure of the success of the vaccine. Successful limitation of acute CMV infection by this approach lays the foundation for addressing the important problem of late CMV disease by immunizing Tx recipients with the same or an improved version of CMV-MVA.