CoVPN 3008 A Phase 3, Multi-Center, Randomized, Efficacy Study of COVID-19 mRNA Vaccine in Regions with SARS-CoV-2 Variants of Concern

摘要：随着COVID-19全球大流行，我们认识到对SARS-CoV-2感染者的COVID-19修饰疫苗的迫切需求。为了弥补这一差距，美国国立卫生研究院（NIH）牵头快速组建了CoVPN，与NIH支持的5个临床试验网络合作，在美国145个站点和17个国家的71个国际临床试验点建立了一个加强的医师科学家网络，致力于开发全球有效的SARS-CoV-2疫苗。鉴于其在过去20年中实施全球艾滋病毒疫苗试验的丰富经验，艾滋病毒疫苗试验网络LOC被选为CoVPN疫苗试验的LOC。这项3期、观察者盲法、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）以及在世界上SARS-CoV-2 1.351株流行率较高的地区有严重COVID-19风险的人群中预防COVID-19严重疾病的功效。该试验的目的是在当地获得有效疫苗的机会有限的地区尽可能快速地评估疫苗的效力。受试者将按1:1的比例随机接受立即或延迟接种疫苗。盲法交叉试验预计将在根据至少50个COVID-19主要终点宣布疫苗获益时进行，预计将在试验开始后约3个月累积。所有试验终点分析将使用合格和有效的分析方法进行诊断和免疫监测。本研究的具体目的是证明COVID-19 mRNA （Moderna mRNA-1273）疫苗在有严重COVID-19风险的成人接种第2剂后14天开始预防病毒学证实的症状性COVID-19的有效性；评估COVID-19 mRNA疫苗在有严重COVID-19风险的成人接种2剂后14天开始预防严重COVID-19的疫苗效果；评估COVID-19 mRNA疫苗在有严重COVID-19风险的成人中的安全性和耐受性。这项疗效试验将告诉我们很多关于mRNA疫苗对抗SARS-CoV-2祖先武汉株的能力，以保护暴露于不同菌株的个体，特别是首先在南非盛行的1.351。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，并将为在世界上替代菌株继续增殖的部分地区进行预防性和治疗性单克隆抗体干预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，并修改计划在未来12个月内进行的未来COVID-19疫苗试验。

Abstract: 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. Due to its extensive experience implementing global HIV vaccine trials over the last 20 years, the HIV Vaccine Trials Network (HVTN) LOC was selected as the LOC for CoVPN vaccine trials. 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.