The Protective and Pathologic Features of the EVD Survivor Immune System

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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.