Summary of key studies evidencing sites of EBOV persistence
| Study | Experimental design | Key finding | Site |
|---|---|---|---|
| Human clinical studies | |||
| Varkey et al. [18] (2015) | US doctor—recrudescence case study | 1st case of ocular-related recrudescence. | Eye |
| Jacobs et al. [10] (2016) & Bosworth et al. [19] (2021) | Scottish nurse—recrudescence case study | 1st case of severe EBOV recrudescence—meningitis. | Brain |
| Bower et al. [20] (2016) | Case study of pregnancy | Delivery of EBOV-positive stillborn. | Placenta |
| Sissoko et al. [21] (2017) | Longitudinal 26 male survivors | 50% clear semen RNA by day 115, 90% clear by day 394. | Semen |
| Deen et al. [22] (2017) | Cohort convenience sample study 220 male survivors | 27% positive for EBOV RNA at any given timepoint, 11% positive at 10–12 months. | Semen |
| Barnes et al. [23] (2017) | Case study of male survivor | Detection of viable EBOV in semen. | Semen |
| Fischer et al. [24] (2017) | Longitudinal 149 male survivors | 8% men EBOV RNA semen positive > 2 years after initial infection. | Semen |
| Sissoko et al. [25] (2017) | Case study of infant death | Detection of EBOV in breast milk likely causing vertical transmission. | Breast milk |
| Whitmer et al. [26] (2018) | Sequencing of clinical isolates from survivors | Ongoing EBOV replication and heterogeneous evolutionary rates in persistence. | Eye; Semen |
| Sneller et al. [27] (2019) | PREVAIL III: longitudinal study 966 survivors—sequelae | 26% uveitis. EBOV RNA shedding in semen is intermittent. Max 40-month semen persistence. | Semen |
| Liu et al. [28] (2019) | Longitudinal case study of female survivor | EBOV RNA in vaginal fluid 36 days after EVD. | Vaginal secretions |
| Keita et al. [29] (2019) | PostEboGui: 40-month longitudinal study of survivors | 2/168 breast milk positive for EBOV RNA—210 and 500 days after EVD discharge. | Semen; breast milk |
| Luo et al. [30] (2019) | Modelling EBOV transmission dynamics | Sexual transmission important contribution to outbreaks. | Semen |
| Khurana et al. [31] (2020) | Longitudinal clinical antibody measurements | Immunological evidence persistence may still occur even if not detected in semen. | Semen |
| Kofman et al. [32] (2021) | Longitudinal study of 131 male survivors | Semen sample EBOV RNA positive 988 days following EVD hospital discharge. | Semen |
| Medina-Rivera et al. [33] (2021) | Systematic review of clinical studies | Detection of EBOV in breast milk likely resulting in transmission. | Breast milk |
| Thorson et al. [34] (2021) | Longitudinal 220 male survivors | Max duration 696 days. Risk factors: older age, increased EVD severity. | Semen |
| Dyal et al. [35] (2023) | Longitudinal 131 male survivors | Risk factors: older age, decreased EVD severity, high IgG3. | Semen |
| Fallah et al. [36] (2023) | Observational cohort study pregnant women | Largest pregnancy study of EVD survivors. 2/354 breastmilk samples positive. | Breast milk; vaginal secretions; placenta |
| Mukadi-Bamuleka et al. [11] (2024) | Case report of 2 fatal meningoencephalitis | 2nd evidence of brain recrudescence in humans. Persistent EBOV very slow mutation rate. | Brain |
| Animal studies | |||
| Zeng et al. [37] (2017) | NHP model—112 | 1st animal model studying EBOV persistence in IPNs. | Testes; eye; brain |
| Coffin et al. [38] (2018) | MARV NHP model—73 | Sertoli cells as reservoir, breakdown of blood-testes barrier leads to infiltration of immunosuppressive Tregs. | Testes |
| Cooper et al. [39] (2018) | EBOV guinea pig model | Identifies many tropisms in EVD previously overlooked. | Female repro tract |
| Watson et al. [40] (2021) | Ferret model | EBOV RNA in eye with polymerase stop codon mutations. | Eye |
| Johnson et al. [41] (2021) | NHP model | Rare in vivo identification of low levels of defective interfering genomes (DIGs) in testes. | Testes |
| Worwa et al. [42] (2022) | NHP case study | Association between persistent intraocular EBOV RNA with severe uveitis. | Eye |
| Liu et al. [43] (2022) | NHP model—24 | Discovery of new tropisms in male & female repro tracts and fluid. | Male & female repro tracts |
| Liu et al. [44] (2022) | NHP model—36 | 7/36 persistence within the brain, of which 2/7 associated with recrudescence. | Brain |
| Gao et al. [45] (2023) | In vitro & rat model | EBOV stimulated vascular endothelial growth factor production by pericytes leading to blood-brain barrier breakdown. | Brain |
| Clancy et al. [46] (2023) | Mouse-adapted EBOV sexual transmission model | 1st animal model of EBOV sexual transmission. Epididymal epithelium as EBOV reservoir. | Semen |
EBOV: Ebola virus; EVD: EBOV disease; IPN: immune privileged niche; MARV: Marburg virus; NHP: non-human primate