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

该提案概述了COVID-19预防网络（CoVPN）实施COVID-19疫苗有效性试验的科学议程，该试验名为“多中心、随机、COVID-19 mRNA疫苗在SARS-CoV-2变异体地区的有效性研究”。随着COVID-19全球大流行，我们认识到对SARS-CoV-2感染个体的COVID-19修饰疫苗的巨大需求。为了解决这一差距，美国国立卫生研究院（NIH）领导了CoVPN的快速构建，与5个NIH支持的临床试验网络合作，在145个美国（US）和17个国家的71个国际临床试验中心建立了一个增强的医生-科学家网络，致力于开发全球有效的SARS-CoV-2疫苗。这项III期、双盲、安慰剂对照、交叉疫苗接种研究将测试COVID-19祖先株mRNA疫苗在预防COVID-19疾病（无论严重程度如何）以及在SARS-CoV-2 1.351株流行率较高的世界各地有严重COVID-19风险的人群中预防COVID-19严重疾病的有效性。该试验旨在为世界上当地获得有效疫苗有限的地区提供尽可能快速的疗效评估。受试者将以1：1的比例随机接受立即或延迟疫苗接种。当基于至少50个主要COVID-19终点（预计在试验开始后约3个月累积）宣布疫苗获益时，预计将进行盲态交叉。所有试验终点测定均将使用经鉴定和验证的诊断和免疫监测测定进行。本研究的具体目的是证明COVID-19 mRNA的有效性（Moderna mRNA-1273）疫苗，用于预防病毒学证实的症状性COVID-19，在有严重COVID-19风险的成年人中接种第2剂后14天开始;评估COVID-19 mRNA疫苗在有严重COVID-19风险的成年人中从第2剂接种后14天开始预防严重COVID-19的疫苗效力-十九岁;并评估COVID-19 mRNA疫苗在有严重COVID-19风险的成年人中的安全性和耐受性。这项有效性试验将告诉我们很多关于针对SARS-CoV-2的祖先武汉毒株的mRNA疫苗保护暴露于不同毒株的个体的能力，特别是1.351首先在南非占主导地位。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，并将为世界上替代菌株继续扩散的部分地区的预防性和治疗性单克隆抗体干预措施的合理设计和测试提供信息。最后，该试验的结果将用于评估该疫苗产品的注册情况，以及修改未来12个月计划进行的COVID-19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.