Cytomegalovirus (CMV) Vaccine in Orthotopic Liver Transplant candidates (COLT)

项目总结： 巨细胞病毒(CMV)对实体器官移植受者(SOTxR)的主要负面影响是 目前预防和治疗策略的局限性，特别是在CMV血清阴性受者(R-)中 来自血清阳性捐赠者的器官(D+)[D+R-]。D+R-子集占所有SOTxR的~25%，但占CMV的80% 疾病，与SOTx后较差的长期存活率独立相关。不成比例的影响 在D+R-SOTxR中，SOTxR是由于对供者传播的初级免疫反应的能力受损所致 巨细胞病毒感染在免疫抑制的背景下。诱导或增强CMV特异性免疫的策略 SOTx之前可以更有效地预防/控制SOTx之后的CMV，最大限度地减少对有毒物质的需求 巨细胞病毒抗病毒治疗(AVT)。我们已经开发出一种改良的安卡拉牛痘病毒疫苗，三联疫苗， 表达免疫优势的CMV抗原pp65、IE-1和IE-2，这些抗原是保护性T细胞免疫的靶标。 Triplex可诱导强大、持久且功能正常的CMV特异性的CD4和CD8T细胞。三联是安全的， 加速了CMV保护性免疫的重建，并使CMV感染显著减少了约50% 异基因造血细胞TxR的2期研究。我们的长期目标是利用疫苗引发的CMV- 特异性细胞免疫以减少巨细胞病毒对D+R-SOTxR的影响并确定风险的免疫相关因素 (COR)和保护(COP)(即三联疫苗效力的免疫相关性[VE])。中心假说 TX前对CMV血清阴性的LTX候选疫苗进行三联免疫可诱导功能性CMV特异性CD4和 CD8T细胞，增强了对CMV的免疫控制，显著降低了术后对CMV AVT的需求 接受预防性治疗(PET)以预防CMV的D+R-LTxR中的Tx。我们进一步假设在那里 是CMV转归和三联疫苗COP的特异性免疫核心。我们将利用我们已建立的 有高度未满足需求的D+R-LTxR目标人群的联盟和初步研究(未经FDA批准 可用的抗病毒预防选择，对伐更昔洛韦毒性高度敏感，以及显著的CMV- 相关的发病率、死亡率和成本)。这项建议的目标是评估疗效、安全性和 二期研究中D+R-LTxR三联体的免疫原性，并用状态- 最先进的多功能T细胞分析和新的分析方法(组合多功能分析 抗原特异性T细胞亚群[COMPASS])。一种有效的TX前CMV疫苗接种方法将改变 SOTx中CMV的防治策略。拟议的研究将定义免疫心脏病对临床结果的影响， 将促进对未来基于免疫的战略的有效评估，并导致更广泛地实施 在D+R-LTxR中更有效的PET CMV预防策略。

PROJECT SUMMARY : Cytomegalovirus (CMV) has a major negative impact in solid organ transplant recipients (SOTxR) due to limitations in current preventive and therapeutic strategies, especially in CMV seronegative recipients (R-) of organs from seropositive donors (D+) [D+R-]. The D+R- subset comprises ~25% of all SOTxR but >80% of CMV disease and is independently associated with worse long-term survival after SOTx. The disproportionate impact in D+R- SOTxR results from an impaired ability to develop a primary immune response to donor-transmitted CMV infection in the context of immunosuppression. Strategies that elicit or enhance CMV-specific immunity prior to SOTx could lead to more effective prevention/control of CMV after SOTx, minimizing the need for toxic CMV antiviral therapy (AVT). We have developed a modified vaccinia Ankara virus vaccine, Triplex, that expresses immunodominant CMV antigens pp65, IE-1, and IE-2 that are targets of protective T cell immunity. Triplex elicits robust, long-lasting, and functional CMV-specific CD4 and CD8 T cells. Triplex was safe, accelerated reconstitution of CMV protective immunity, and reduced significant CMV infection by ~50% in a phase 2 study of allogeneic hematopoietic cell TxR. Our long-term goals are to harness vaccine-induced CMV- specific cellular immunity to reduce the impact of CMV in D+R- SOTxR and to define immune correlates of risk (CoR) and for protection (CoP) (i.e. immune correlates of Triplex vaccine efficacy [VE]). The central hypothesis is that pre-Tx Triplex vaccination of CMV seronegative LTx candidates elicits functional CMV-specific CD4 and CD8 T cells, leading to improved immune control of CMV and significantly decreases the need for CMV AVT post- Tx in D+R- LTxR who receive preemptive therapy (PET) for CMV prevention. We further hypothesize that there are specific immune CoR for CMV outcomes and CoP of Triplex vaccine. We will leverage our established consortium and preliminary studies in a target population of D+R- LTxR with high unmet need (no FDA-approved available antiviral prophylaxis options, highly susceptible to valganciclovir toxicity, and significant CMV- associated morbidity, mortality, and cost). The objectives of this proposal are to assess the efficacy, safety and immunogenicity of Triplex in D+R- LTxR in a phase 2 study and to define the immune CoR and CoP using state- of-the-art polyfunctional T cell assays and novel analytic approaches (COMbinatorial Polyfunctionality analysis of Antigen-Specific T cell Subsets [COMPASS]). An effective pre-Tx CMV vaccination approach would transform CMV prevention strategies in SOTx. The proposed studies will define immune CoR for clinical outcomes, which will facilitate efficient evaluation of future immune-based strategies, and lead to broader implementation of the more effective PET CMV prevention strategy in D+R- LTxR.