The Protective and Pathologic Features of the EVD Survivor Immune System

自发现埃博拉病毒(EBOV)以来的40多年里，埃博拉疫情爆发的频率、规模和持续时间都有所增加。2014-2016年肆虐西非的疫情在短短几个月内演变为一场全球人道主义危机，感染人数超过2.86万人，死亡人数超过11300人--超过以往所有疫情的总和。此外，在西非埃博拉疫情结束后的六年里，几内亚和刚果民主共和国又爆发了七起疫情。埃博拉病毒在几内亚和刚果民主共和国的复发，以及在利比里亚蝙蝠体内检测到埃博拉病毒，清楚地表明这种病原体是持续存在的，并将成为西非和中非不同规模反复爆发的原因。虽然西非的疫情已经结束，但埃博拉病毒幸存者的临床关切依然存在，包括针对重复感染的免疫保护的持久性，以及绝大多数人报告的持续性和衰弱的躯体症状背后的机制。这项建议的主要目标是严格描述最大的埃博拉幸存者队列之一的埃博拉幸存者免疫反应的保护性和病理学效应。具体地说，就是： ·AIM I将通过测量抗体水平和中和能力来表征对EBOV感染的体液免疫反应，这是保护的关键相关因素，并评估血清阴性EVD幸存者在急性感染后1至10年的记忆免疫反应 ·AIM II将研究自身免疫激活作为埃博拉后并发症的机制 我们将在与西非医疗保健领导人和埃博拉幸存者代表密切而牢固的工作关系以及我们在利比里亚和塞拉利昂建立的完善的临床研究基础设施的背景下开展这项工作，我们在利比里亚和塞拉利昂招募、招募并纵向跟踪和采样了700多名埃博拉幸存者和1000多名家庭接触者。这项拟议的工作将提供亟需的体液免疫反应的纵向表征，对EBOV感染的记忆免疫反应的评估，以及对自身免疫激活作为EVD存活期长期并发症的机制的研究。自西非疫情爆发以来的6年里，共爆发了7起疫情，其中包括有史以来第二大的埃博拉疫情，问题不是是否会再次爆发大规模疫情，而是何时爆发。这项研究将通过更好地了解体液免疫反应对感染的持久性，更好地了解埃博拉病毒病的临床并发症，并通过在以下领域实施临床研究平台，确保世界为下一次疫情做好准备 很可能会再次出现埃博拉病毒病。

In the more than 40 years since the discovery of the Ebola virus (EBOV) there has been an increase in both the frequency, size, and duration of Ebola outbreaks. The 2014-2016 outbreak that devastated West Africa evolved within the span of months into a global humanitarian crisis, infecting over 28,600 people and killing more than 11,300 - eclipsing all previous outbreaks combined. Moreover, in the six years since the end of the West African Ebola epidemic, there have been seven additional outbreaks in Guinea and the Democratic Republic of Congo (DRC). The recurrence of Ebola in Guinea and the DRC and the detection of the Ebola virus in a bat in Liberia, make it clear that this pathogen is persistent and will be the cause of recurrent outbreaks of varying scales across West and Central Africa. While the West African epidemic has ended, the clinical concerns of EVD survivors persist including the longevity of immune protection against repeat infection and the mechanisms underlying the persistent and debilitating somatic complaints reported by an overwhelming majority. The primary objective of this proposal is a rigorous characterization of the protective and pathologic effects of the EVD survivor immune response in one of the largest EVD survivor cohorts. Specifically: • AIM I will characterize the humoral immune response to EBOV infection by measuring antibody levels and neutralizing capacity - a key correlate of protection, and assessing the memory immune response in seronegative EVD survivors from 1 to 10 years following acute infection • AIM II will investigate autoimmune activation as a mechanism underlying post-Ebola complications We will conduct this work in the context of close and strong working relationships with healthcare leaders and Ebola survivor representatives in West Africa, and well-developed infrastructure for clinical research that we have established in Liberia and Sierra Leone where we have recruited, enrolled, and longitudinally followed and sampled more than 700 EVD survivors and over 1,000 household contacts. The proposed work will provide a much-needed longitudinal characterization of the humoral immune response, evaluation of the memory immune response to EBOV infection, and investigation of autoimmune activation as a mechanism underlying the long- term complications of surviving EVD. With seven outbreaks, including the second largest Ebola outbreak ever, occurring in the 6 years since the West African epidemic, the question is not if another large outbreak will occur but when. This study will ensure that the world is better prepared for the next epidemic through an improved understanding of the durability of the humoral immune response to infection, an improved understanding of the clinical complications of EVD, and through the implementation of clinical research platforms in areas that are likely to see a recurrence of EVD.