CoVPN 3008 - Multi-Center, Randomized, Efficacy Study of COVID-19 mRNA Vaccine in Regions with SARS-CoV-2 Variants of Concern

这项建议概述了新冠肺炎预防网络实施新冠肺炎疫苗效力试验的科学议程，该试验题为“新冠肺炎基因疫苗在存在SARS-CoV-2变异株地区的多中心、随机、效力研究”。随着新冠肺炎的全球流行，我们认识到对于感染SARS-CoV-2的人来说，非常需要能够改变新冠肺炎的疫苗。针对这一差距，美国国立卫生研究院(NIH)牵头迅速建立了CoVPN，与NIH支持的5个临床试验网络合作，在美国145个国家和17个国家的71个国际临床试验地点创建了一个增强的医生-科学家网络，致力于开发全球有效的SARS-CoV-2疫苗。这项第三阶段、观察者盲法、安慰剂对照、交叉接种的研究将测试新冠肺炎祖传毒株基因疫苗在预防新冠肺炎病方面的有效性，无论病情严重程度如何，并在世界上SARS-CoV-2 1.351毒株大量流行的地区，在有严重新冠肺炎风险的人中预防新冠肺炎严重疾病。这项试验的目的是在世界上当地获得有效疫苗的机会有限的地区提供尽可能快的疗效评估。受试者将按1：1的比例随机接受立即或延期接种疫苗。盲法交叉预计将在至少50个主要新冠肺炎终点宣布疫苗受益时发生，预计将在试验开始约3个月后累积。所有试验终点分析将使用合格和有效的诊断和免疫监测分析方法进行。这项研究的具体目的是证明新冠肺炎基因疫苗对病毒学确认的症状性新冠肺炎疫苗预防病毒学确认的症状性新冠肺炎的有效性，在有严重新冠肺炎风险的成年人中，在接种2剂后14天开始预防；评估新冠肺炎基因疫苗在有严重新冠肺炎风险的成年人中，在疫苗接种2剂后14天开始预防严重新冠肺炎的疫苗效力；以及评估新冠肺炎基因疫苗在有严重新冠肺炎风险的成年人中的安全性和耐受性。这项药效试验将告诉我们许多关于针对祖先武汉株SARS-CoV-2的信使核糖核酸疫苗保护暴露在不同毒株中的个人的能力，特别是在南非1.351的第一优势株。此外，它将提高我们对这些免疫反应的动态和持续时间的理解，并将在世界上替代菌株继续繁殖的部分地区合理设计和测试预防性和治疗性单抗干预措施。最后，这项试验的结果将被用于评估该疫苗产品的注册情况，以及修改计划在未来12个月内进行的未来新冠肺炎疫苗试验。

This proposal outlines the scientific agenda for the COVID-19 Prevention Network (CoVPN) for implementation of the COVID-19 vaccine efficacy trial entitled “Multi-Center, Randomized, Efficacy Study of COVID-19 mRNA Vaccine in Regions with SARS-CoV-2 Variants of Concern.” With the global COVID-19 pandemic, we recognize a significant need for vaccines that modify COVID-19 in SARS-CoV-2 infected individuals. Addressing this gap, the National Institutes of Health (NIH) led rapid constitution of the CoVPN, partnering 5 NIH supported clinical trial networks, to create an enhanced network of physician-scientists at 145 United States (US) and 71 international clinical trial sites in 17 countries dedicated to developing globally effective vaccines for SARS-CoV-2. This Phase 3, observer-blinded, placebo-controlled, crossover-vaccination study will test the efficacy of the COVID-19 ancestral strain mRNA vaccine in preventing COVID-19 disease regardless of severity, and preventing COVID-19 severe disease in people who are at risk for severe COVID-19 in areas of the world where the prevalence of the SARS-CoV-2 1.351 strain is substantial. The trial has been designed to provide as rapid assessment of efficacy as possible in regions of the world where local access to effective vaccines are limited. Subjects will be randomized in a 1:1 ratio to receive immediate or deferred vaccine. The blinded cross-over is expected to take place when vaccine benefit is declared based on at least 50 primary COVID-19 endpoints, anticipated to be accrued approximately 3 months post-trial start. All trial endpoint assays will be done using qualified and validated assays for diagnosis and immune monitoring. Specific aims of this study are to demonstrate efficacy of COVID-19 mRNA (Moderna mRNA-1273) vaccine to prevent virologically-confirmed symptomatic COVID-19 starting 14 days after dose 2 in adults who are at risk of severe COVID-19; to assess vaccine efficacy of COVID-19 mRNA vaccine to prevent severe COVID-19 starting 14 days after dose 2 in adults who are at risk of severe COVID-19; and to assess safety and tolerability of COVID-19 mRNA vaccine in adults who are at risk of severe COVID-19. This efficacy trial will tell us much about ability of an mRNA vaccine against the ancestral Wuhan strain of SARS- CoV-2 to protect individuals exposed to divergent strains, and in particular 1.351 first predominant in South Africa. In addition, it will improve our understanding of the dynamics and duration of these immune responses and will inform rational design and testing of preventive and therapeutic monoclonal antibody interventions in parts of the world where alternative strains continue to proliferate. Lastly, the results of this trial will be used to assess registration of this vaccine product as well as to modify future COVID-19 vaccine trials planned over the next 12 months.