Identification of a unique humoral immune signature of Sudan ebolavirus persistence in human survivors

Since finding that long-term persistence of ebolavirus RNA exists in a subset of human survivors for up to 5 years post infection in several organs, viral reactivation has been implicated in recurrence of acute disease among ebolavirus disease survivors and linked to small disease outbreaks. Thus, identifying correlates of ebolavirus persistence are critical to the long-term care of survivors and outbreak management. We analyzed the humoral immune response using a comprehensive systems serology approach in 86 the 87 survivors (98.8%) of the 2022-2023 Sudan ebolavirus (SUDV) outbreak in Uganda. Across the survivors, 55% of eligible survivors (20 of 36 survivors) were found to have persistence of viral RNA in either semen or breastmilk for up to 6 months following initial infection, whereas the remaining 45% tested negative (16 of 36 survivors). We found an elevated, unique, and sustained humoral immune signature associated with persistence of viral RNA in SUDV survivors and specifically have identified 4 humoral immune features that together predicted persistence: glycoprotein-specific antibody dependent cellular phagocytosis [ADCP], nucleoprotein-specific IgG2, nucleoprotein-specific IgA1, and VP40-specific IgM. Moreover, analysis of the 4 features in the remaining 50 SUDV survivors who were ineligible for semen or breastmilk sampling, predicted an additional 17 survivors with humoral immune responses consistent with viral RNA persistence survivors. We also find that antibodies against the VP40 (matrix protein), were associated with faster clearance of persistent viral RNA. Thus, a subset of humoral immune responses could be important for monitoring and clearing viral persistence in ebolavirus disease survivors.