Vaccination responses in lung transplant recipients

项目摘要/摘要 肺移植(LT)受者患有危及生命的肺部感染，可引发急性 拒绝和死亡。尽管接种疫苗是预防感染的最有效方法，但疫苗的效力 仅限于免疫功能低下的实体器官移植受者。JAMA最近的两项研究表明，大多数 移植受者未能对SARS-CoV-2mRNA疫苗产生抗体反应；抗代谢物 免疫抑制剂进一步抑制了这种反应。为了促进更有效的疫苗接种策略， 了解免疫抑制的LT受者的疫苗反应是一个迫切的、尚未得到满足的需要。 采用系统疫苗学方法，这笔赠款描述了复杂的疫苗引发的免疫反应。 解决肝移植受者疫苗免疫原性不足的问题。随着新冠肺炎大流行 高度关注LT接受者的脆弱性，创建面向疫苗的生物库，以促进 系统生物学分析可以加强新成立的NIH LT联盟。 在这项提案中，我们联合来自斯坦福大学、伊诺瓦-费尔法克斯和休斯顿卫理公会的医生/科学家建立一个 面向疫苗接种的生物库作为临床中心(CC)的重点。应对RFA的探索 对于特定于中心的假设，我们的CC寻求一个紧迫问题的答案：接受LT的人对 接种疫苗吗？赠款假设是，面向疫苗接种的生物库将促进全面的 异地受者流感疫苗免疫应答分析 而且使用抗代谢物免疫抑制剂可以预测天然保护性降低 以及这些患者的适应性反应。在目标1中，来自接种疫苗的患者的生物检疫 针对新冠肺炎，水痘带状疱疹，肺炎球菌和流感将被前瞻性地收集并储存到 生成生物资源库。为了解决假设驱动的问题，可以用有限的预算实现，目标2 使用系统疫苗学工具评估流感疫苗，这是最常见的疫苗接种 给肝移植患者。目标2a以体液免疫和先天免疫为特征，目标2b侧重于细胞免疫，以及 Aim 2c利用生物信息学工具建立了疫苗反应网络。目标2还将评估是否使用 一种作为免疫抑制的抗代谢物降低流感疫苗的免疫原性。聚焦的基本原理 新冠肺炎上关于流感的一点是，当这个项目开始时，大多数患者都将接种针对后者的疫苗。 然而，当未来的倡议可用时，我们的CC有很好的设备来测试其他类型的疫苗。在……里面 除了促进LT联盟内部的互动和共享资源外， 斯坦福大学CC将通过以下方式改进高危LT患者的疫苗设计、佐剂和给药方案 提高了对免疫反应的理解。在这里收集的信息可以提供信息并改进疫苗接种 为所有免疫抑制患者所做的努力。

PROJECT SUMMARY / ABSTRACT Lung transplantation (LT) recipients suffer from life-threatening pulmonary infections that can trigger acute rejection and death. Although vaccination is the most effective way for preventing infections, vaccine efficacy is limited in immunocompromised solid organ transplant recipients. Two recent JAMA studies suggest that most transplant recipients fail to mount antibody responses to SARS-CoV-2 mRNA vaccines; anti-metabolite immunosuppressants further dampened this response. To facilitate more effective vaccination strategies, there is an urgent unmet need to understand vaccine responses in immunosuppressed LT recipients. Adopting a system vaccinology approach, this grant characterizes complex vaccine-elicited immune responses to address the problem of deficient vaccine immunogenicity in LT recipients. As the COVID-19 pandemic heightens focus on the vulnerability of LT recipients, the creation of a vaccine-oriented biobank to facilitate system biology analyses can strengthen the newly-formed NIH LT Consortium. In this proposal, we unite physicians/scientists from Stanford, Inova-Fairfax, and Houston Methodist to build a vaccination-oriented biorepository as the focus of a clinical center (CC). Responding to the RFA to explore center-specific hypotheses, our CC seeks an answer to the pressing question: ‘how do LT recipients respond to vaccinations?’ The grant hypothesis is that a vaccination-oriented biorepository will facilitate the holistic analysis of influenza vaccine-induced immune responses in LT recipients from geographically distant regions and that the use of an anti-metabolite immunosuppressant predicts reduced protective innate and adaptive responses in these patients. In Aim 1, biospecimens from patients immunized by vaccines against COVID-19, varicella-zoster, pneumococcus, and influenza will be prospectively collected and banked to generate the biorepository. To address hypothesis-driven questions achievable with a modest budget, Aim 2 uses system vaccinology tools to evaluate the influenza vaccines, the most common vaccinations administered to LT patients. Aim 2a characterizes humoral and innate immunity, Aim 2b focuses on cellular immunity, and Aim 2c builds a vaccine response network with bioinformatics tools. Aim 2 will also assess whether the use of an anti-metabolite as immunosuppression reduces influenza vaccine immunogenicity. The rationale for focusing on influenza over COVID-19 is that most patients will be vaccinated against the latter when this project begins. However, our CC is well-equipped to test other types of vaccinations when future initiatives are available. In addition to fostering interactions and shared resources within the LT Consortium, the main purpose of the Stanford CC is to improve vaccine designs, adjuvants, and administration protocols in at-risk LT patients through an improved understanding of immune responses. Information gleaned here can inform and improve vaccination efforts for all immunosuppressed patients.