Long-term ocular sequelae and biological determinants of post-acute Ebola virus disease - PROJECT SUMMARY/ABSTRACT. Ocular post-acute sequelae of Ebola virus disease (EVD) (PASE) can be defined according to symptoms or signs attributed to EVD which persist or manifest after EVD in up to 34% of survivors. Uveitis, retinal scars, and decreased intraocular pressure are among the findings associated with ocular PASE over the 5-year post-EVD period (termed “early PASE”). After 5 years, there is evidence of ongoing and incident ocular PASE (termed “late PASE”), but the trajectory is unknown. In addition to uveitis and other known PASE, EVD survivors can develop other ocular PASE—some of which are vision-threatening and preventable with medical therapy (e.g., cystoid macular edema), or surgically reversible (e.g., cataracts). Acute EVD can cause viral persistence, inflammation, and autoimmunity, 3 inter-related biological mechanisms that may play a role in early PASE pathogenesis. Viral persistence has been found in the eyes, spinal cord, and testes (often concurrently) for as long as 2 years post-EVD and may also contribute to subsequent autoimmunity and inflammation. In 2014, the NIH-funded Partnership for Research on Vaccines and Infectious Diseases in Liberia (PREVAIL) launched the largest longitudinal cohort study (P3) (2015-21) to date of EVD survivors (n=966) and uninfected comparators (n=2,784) to investigate PASE for up to 5 years after acute EVD. The P3 cohort offers a unique and large sampling frame with detailed characterizations of PASE and access to a biorepository of blood and semen samples. The overaching objective of this R01 proposal is to assess the prevalence and biological determinants of ocular PASE. Central hypothesis: Viral persistence, inflammation, and autoimmunity are part of a biological cascade that causes early ocular PASE, and following viral control, late ocular PASE can occur either due to post-viral mechanisms (e.g., autoimmunity) or as complications of early ocular PASE. We will test this with 2 Specific Aims: Aim 1. To estimate excess prevalence of late ocular PASE at 9-13 years post- EVD; Aim 2: To assess the biological determinants of ocular PASE. Leveraging the P3 cohort and existing research infrastructure, we will launch a new 4-year follow-up period, re-sampling the eye (ocular) cohort, many of whom donated semen for viral RNA testing. Using prospectively collected and previously banked samples and existing P3 data, we will investigate biological mechanisms of ocular PASE. The study team has a strong history of successful collaboration with ophthalmologic expertise in natural history studies and post- acute sequelae of EVD, methodological expertise in epidemiology, detailed knowledge of the P3 dataset and analytical approach, and understanding of Liberian culture. This R01 will yield insights into biologic targets for interventions while identifying late ocular PASE that could be preventable or reversible.
