Vaccination responses in lung transplant recipients

项目概要/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。虽然接种疫苗是预防感染的最有效方法，但疫苗的效力是 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， 移植受体未能对SARS-CoV-2 mRNA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战略， 迫切需要了解免疫抑制LT接受者的疫苗应答。 采用系统疫苗学的方法，这项赠款的特点是复杂的疫苗引起的免疫反应 以解决LT接受者中疫苗免疫原性缺陷的问题。随着COVID-19疫情 加强对LT接受者脆弱性的关注，建立一个以疫苗为导向的生物库， 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-费尔法克斯大学和休斯顿卫理公会的医生/科学家， 作为临床中心（CC）重点的疫苗接种导向生物储存库。响应RFA，探索 中心特定的假设，我们的CC寻求一个紧迫的问题的答案：“LT接受者如何应对 疫苗？”格兰特假设是，一个以接种疫苗为导向的生物储存库将促进整体的 流感疫苗在地理上遥远的LT受者中诱导的免疫应答的分析 区域，使用抗代谢免疫抑制剂预测先天性保护性降低 和适应性反应。在目标1中，来自疫苗免疫患者的生物标本 针对COVID-19，水痘-带状疱疹，肺炎球菌和流感将前瞻性地收集和储存， 生成生物储藏库。为了解决假设驱动的问题，目标2 使用系统疫苗学工具来评估流感疫苗，这是最常见的疫苗接种 LT患者。目标2a描述了体液免疫和先天免疫，目标2b侧重于细胞免疫， Aim 2c利用生物信息学工具建立疫苗反应网络。目标2还将评估是否使用 作为免疫抑制剂的抗代谢物降低流感疫苗的免疫原性。重点的理由 在新冠肺炎的流行性感冒方面，最重要的一点是，当该项目开始时，大多数患者将接种新冠肺炎疫苗。 然而，我们的CC已准备就绪，在未来的举措可用时测试其他类型的疫苗接种。在 除了促进LT联盟内部的互动和共享资源外， 斯坦福大学CC将通过以下措施改善高危LT患者的疫苗设计、佐剂和给药方案： 提高对免疫反应的理解。这里收集的信息可以告知和改善疫苗接种 所有免疫抑制患者的努力。

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.