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

项目概要： 巨细胞病毒（CMV）在实体器官移植受者（SOTxR）中具有主要的负面影响， 目前的预防和治疗策略的局限性，特别是在CMV血清阴性受体（R-） 来自血清阳性供体的器官（D+）[D+R-]。D+R-亚群占所有SOTxR的约25%，但占CMV的>80% 并且与SOTx后更差的长期生存独立相关。的不成比例的影响 在D+R中，SOTxR是由于对供体传播的 免疫抑制背景下的CMV感染。引发或增强CMV特异性免疫的策略 在SOTx之前，可以在SOTx之后更有效地预防/控制CMV，最大限度地减少对毒性药物的需求。 CMV抗病毒治疗（AVT）。我们已经开发了一种改良的安卡拉牛痘病毒疫苗，Triplex， 表达免疫显性CMV抗原pp 65、IE-1和IE-2，它们是保护性T细胞免疫的靶标。 三重激发稳健、持久和功能性CMV特异性CD 4和CD 8 T细胞。Triplex很安全 加速CMV保护性免疫的重建，并将显著的CMV感染减少约50%。 同种异体造血细胞TxR的2期研究。我们的长期目标是利用疫苗诱导的CMV- 特异性细胞免疫，以减少CMV对D+R- SOTxR的影响，并确定风险的免疫相关性 (CoR)和用于保护（CoP）（即三联疫苗效力的免疫相关性[VE]）。核心假设 CMV血清阴性LTx候选物的Tx前三重疫苗接种激发了功能性CMV特异性CD 4， CD 8 T细胞，导致CMV的免疫控制改善，并显着降低对CMV AVT后的需要。 D+R- LTxR中接受抢先治疗（PET）以预防CMV的Tx。我们进一步假设， 是CMV结局的特异性免疫CoR和三联疫苗的CoP。我们将利用现有的 在具有高度未满足需求的D+R- LTxR目标人群中进行的联合研究和初步研究（未经FDA批准 可用的抗病毒预防选择，对缬更昔洛韦毒性高度敏感，和显著的CMV- 相关的发病率、死亡率和成本）。本提案的目的是评估疗效、安全性和 在II期研究中，确定D+ R-LTxR中三链体的免疫原性，并使用状态- 最先进的多功能T细胞测定和新的分析方法（组合多功能性分析 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中的CMV预防策略。拟议的研究将为临床结局定义免疫CoR， 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 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.