Defining long-term sequelae and humoral immunity in Sudan ebolavirus survivors

PROJECT SUMMARY Uganda has experienced seven outbreaks of the highly pathogenic orthoebolavirus, Sudan virus (SUDV) since 2000. SUDV has reemerged in Uganda twice since September 2022 - first with an outbreak with 142 confirmed cases and 55 known deaths between September-December 2022, and again in January 2025, with 9 confirmed cases and 1 death as of mid-February 2025. Beyond the high mortality associated with orthoebolavirus infection, survival from infection is marked by long-term health problems in a subset of survivors including persistence of viral RNA in immune-privileged sites for months to years after recovery, and development of long- term disease sequelae symptoms that can be debilitating. These long-term impacts on survivors have been primarily studied in the context of Ebola virus (EBOV), and thus data are lacking for SUDV. We have begun to fill in those gaps through the analysis of SUDV survivors of the 2022 outbreak in Uganda together with the Ugandan Ministry of Health and researchers from the Uganda Virus Research Institute and Makerere University. Shortly after the end of the outbreak, we enrolled 86 of the 87 SUDV survivors into a study to enable long-term analysis of viral persistence, sequelae, and host immunity. We have found that 20 individuals of the 42 individuals who were eligible testing of viral RNA in secretions from immune-privileged sites (e.g. semen and breastmilk) had evidence of viral persistence beyond acute infection into convalescence. In addition, we have found that over half of the survivors report post-SUDV sequelae symptoms at 3 months after infection, with 39% of survivors still reporting symptoms 24 months after infection. As viral persistence and sequelae in the context of EBOV have been shown in survivors past 5 years, here we aim to leverage our approved research protocol and existing cohort of the survivors of the 2022 SUDV outbreak in Uganda to maintain serial sampling through 5 years post-infection. To date, we have already collected samples and sequelae data at 7 timepoints starting from 3 months post-infection through 2 years post- infection. We propose to continue sample and data collection every 6 months on these survivors through 5 years- post infection to capture clinical sequelae data, viral persistence, and immune dynamics for a total of 5 years after acute infection. The samples and data collected through this proposal will be used in subsequent studies to investigate the relationship between humoral immune responses, virus persistence, and development of chronic sequelae in SUDV. If successful, the samples and clinical data collected will represent among the most complete, continuous, and comprehensive analysis of sequelae and viral persistence of any human Ebolavirus infection to date.