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

原位肝移植候选者 (COLT) 中的巨细胞病毒 (CMV) 疫苗

• 批准号: 10282599
• 负责人: Ying Qing Chen
• 金额: $ 229.57万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-26 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10282599
• 关键词: Address; Allogenic; Antigens; Antiviral Agents; Antiviral Therapy; CD8-Positive T-Lymphocytes; Cells; Cellular Assay; Cellular Immunity; Clinical; Clinical Virology; Clinical assessments; Color; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Disease; Dose; Evaluation; FDA approved; Flow Cytometry; Future; Goals; Hematopoietic; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Immunosuppression; Impairment; Lead; Link; Measurement; Modified Vaccinia Virus Ankara; Morbidity - disease rate; Multi-Institutional Clinical Trial; Organ; Organ Transplantation; Outcome; Phase; Population; Prevention; Prevention strategy; Preventive; Prophylactic treatment; Protocols documentation; Risk; Safety; Solid; Standardization; Surface; T-Lymphocyte; T-Lymphocyte Subsets; Target Populations; Testing; Therapeutic; Toxic effect; Transplant Recipients; Vaccination; Vaccines; Valganciclovir; Viral Load result; Virus Diseases; antigen-specific T cells; base; clinical risk; clinically relevant; combinatorial; cost; experience; high risk; immunogenicity; improved; liver transplantation; mortality; novel; phase 2 study; prevent; primary outcome; randomized placebo controlled trial; reconstitution; seropositive; vaccine efficacy; virology

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.

项目摘要： 巨细胞病毒（CMV）由于固体器官移植受体（SOTXR）具有重大负面影响 当前的预防和治疗策略的局限 来自血清阳性供体的器官（D+）[D+R-]。 D+R-子集占所有SOTXR的约25％，但> 80％的CMV 疾病，与SOTX后的长期生存差有关。不成比例的影响 在D+r- SOTXR中，由于能力受损而产生对供体传播的主要免疫反应的能力 在免疫抑制背景下的CMV感染。引发或增强CMV特异性免疫力的策略 在SOTx之前 CMV抗病毒疗法（AVT）。我们已经开发了一种改良的疫苗Ankara病毒疫苗，Trilex， 表达免疫主导的CMV抗原PP65，IE-1和IE-2是保护性T细胞免疫的靶标。 Triplex会引起鲁棒，持久和功能性CMV特异性CD4和CD8 T细胞。 Triplex是安全的， 加速CMV保护免疫的重建，并使A显着CMV感染减少了约50％ 同种异体造血细胞TXR的2阶段研究。我们的长期目标是利用疫苗诱导的CMV- 特定的细胞免疫以减少CMV在D+R-SOTXR中的影响并定义风险的免疫相关性 （COR）和保护（COP）（即三环疫苗功效的免疫相关[VE]）。中心假设 是CMV血清神经LTX候选者的TX前三重疫苗接种引起功能CMV特异性CD4和 CD8 T细胞可改善CMV的免疫控制，并显着降低了对CMV AVT的需求 D+R-LTXR中的TX，接受预防CMV的先发制治疗（PET）。我们进一步假设那里 是针对CMV结果的特定免疫和三环疫苗COP。我们将利用我们的既定 对D+R-LTXR的目标人群的财团和初步研究（未经FDA批准） 可用的抗病毒预防选择，高度容易受到Valganciclovir毒性的影响，并且CMV- 相关的发病率，死亡率和成本）。该提案的目标是评估功效，安全性和 在第二阶段研究中，d+r-ltxr中三重的免疫原性，并使用状态 - 定义免疫COR和COP 曾经的多功能T细胞分析和新型分析方法（组合多功能性分析 抗原特异性T细胞子集[Compass]）。有效的TX CMV疫苗接种方法将转变 SOTX中的CMV预防策略。拟议的研究将定义用于临床结果的免疫COR，这 将促进对未来免疫策略的有效评估，并导致更广泛的实施 D+R-LTXR中更有效的PET CMV预防策略。