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几个月内演变成全球人道主义危机，感染了28，600多人，造成11，300多人死亡-使之前所有疫情的总和黯然失色。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次疫情。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中检测到埃博拉病毒，清楚地表明这种病原体是持久性的，并将成为西非和中非各地不同规模反复爆发的原因。虽然西非疫情已经结束，但EVD幸存者的临床问题仍然存在，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和衰弱的躯体主诉的潜在机制。本提案的主要目的是在最大的EVD幸存者队列中严格描述EVD幸存者免疫应答的保护和病理作用。具体而言： · 目的通过测定抗体水平和中和能力（保护作用的关键相关因素）来描述EBOV感染的体液免疫应答，并评估急性感染后1 - 10年血清阴性EVD存活者的记忆免疫应答 · AIM II将研究自身免疫激活作为埃博拉后并发症的潜在机制 我们将与西非的医疗保健领导人和埃博拉幸存者代表建立密切而牢固的工作关系，并在利比里亚和塞拉利昂建立了完善的临床研究基础设施，我们在那里招募，登记，纵向跟踪和采样了700多名EVD幸存者和1,000多名家庭接触者。所提出的工作将提供体液免疫应答的急需的纵向表征、对EBOV感染的记忆免疫应答的评价以及作为存活EVD的长期并发症的潜在机制的自身免疫激活的研究。自西非疫情爆发以来的6年里，发生了7次疫情，包括有史以来第二大的埃博拉疫情，问题不是是否会发生另一次大规模疫情，而是何时发生。这项研究将确保世界更好地为下一次流行病做好准备，通过提高对感染体液免疫反应持久性的认识，提高对EVD临床并发症的认识，并通过在以下领域实施临床研究平台： 很可能会复发EVD

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.