Who established stringent infection control measures for Ebola virus disease

As the epidemic of Ebola virus disease (EVD) continues to worsen in West Africa, the document sets out the existing evidence on entry and exit screening in order to support decision making by EU public health authorities.

The unprecedented magnitude and geographic extent of the Ebola virus disease (EVD) outbreak in West Africa has overwhelmed the local response capacity, posing an extreme challenge for outbreak containment. 

As the number of new cases continues to rise in Guinea, Liberia and Sierra Leone [1], there is an increasing possibility that infected persons will travel to the European Union. Persons infected with EVD may arrive in the EU by direct or indirect flights from affected countries or on board freighters or passenger ships. 

Following the declaration of the Public Health Event of International Concern (PHEIC) on 8 August 2014, WHO recommended that affected countries conduct exit screening of all persons at international airports, seaports and major land crossings for unexplained febrile illness consistent with potential Ebola infection. WHO also recommended that there should be no international travel of known Ebola cases or contacts of cases, unless the travel is part of an appropriate medical evacuation. 

All affected countries have implemented exit screening, supported by the US Centers for Disease Control and Prevention (CDC). The CDC has also produced guidelines on screening at points of departure in Ebola-affected countries. Following the importation of a first case of Ebola, the US has decided to implement, in a layered approach, entry screening at five airports through which 94% of travellers from affected countries enter into the US. At the same time, and in the absence of an evaluation of the effectiveness of the implementation of exit screening in West African affected countries, a number of European countries are considering entry screening as an additional measure to reduce the likelihood of importation of cases.

This document reviews the existing evidence on entry and exit screening in order to support decision making by EU public health authorities.

1. Kuhn JH, et al. ICTV virus taxonomy profile: Filoviridae. J. Gen. Virol. 2019;100:911–912. doi: 10.1099/jgv.0.001252. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

2. Kuhn JH, et al. New filovirus disease classification and nomenclature. Nat. Rev. Microbiol. 2019;17:261–263. doi: 10.1038/s41579-019-0187-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

3. Siegert R, Shu H-L, Slenczka W, Peters D, Müller G. On the etiology of an unknown human infection originating from monkeys [German] Dtsch. Med. Wochenschr. 1967;92:2341–2343. doi: 10.1055/s-0028-1106144. [PubMed] [CrossRef] [Google Scholar]

4. Kuhn, J. H., Amarasinghe, G. & Perry, D. L. in Fields Virology: Emerging Viruses 7th edn Ch. 12 (eds Sean P. J. Whelan, Peter M. Howley, & David M. Knipe) in the press (Wolters Kluwer, 2020).

5. Formenty P, et al. Human infection due to Ebola virus, subtype Côte d’Ivoire: clinical and biologic presentation. J. Infect. Dis. 1999;179:S48–S53. doi: 10.1086/514285. [PubMed] [CrossRef] [Google Scholar]

6. Okware SI, et al. An outbreak of Ebola in Uganda. Trop. Med. Int. Health. 2002;7:1068–1075. doi: 10.1046/j.1365-3156.2002.00944.x. [PubMed] [CrossRef] [Google Scholar]

7. Kuhn JH. Filoviruses. A compendium of 40 years of epidemiological, clinical, and laboratory studies. Arch.Virol. Suppl. 2008;20:13–360. doi: 10.1007/978-3-211-69495-4_1. [PubMed] [CrossRef] [Google Scholar]

8. Martines RB, Ng DL, Greer PW, Rollin PE, Zaki SR. Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg viruses. J. Pathol. 2015;235:153–174. doi: 10.1002/path.4456. [PubMed] [CrossRef] [Google Scholar]

9. Siragam V, Wong G, Qiu X-G. Animal models for filovirus infections. Zool. Res. 2018;39:15–24. doi: 10.24272/j.issn.2095-8137.2017.053. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

10. Nakayama E, Saijo M. Animal models for Ebola and Marburg virus infections. Front. Microbiol. 2013;4:267. doi: 10.3389/fmicb.2013.00267. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

11. World Health Organization. Ebola Outbreak 2014–2016. http://www.who.int/csr/disease/ebola/en/ (2017).

12. Chippaux J-P. Outbreaks of Ebola virus disease in Africa: the beginnings of a tragic saga. J. Venom. Anim. Toxins Incl. Trop. Dis. 2014;20:44. doi: 10.1186/1678-9199-20-44. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

13. Check Hayden E. Ebola failures prompt WHO rethink. Nature. 2015;521:137. doi: 10.1038/521137a. [PubMed] [CrossRef] [Google Scholar]

14. Levett J. Disastrous events and political failures. Prehosp. Disaster Med. 2015;30:227–228. doi: 10.1017/S1049023X15004689. [PubMed] [CrossRef] [Google Scholar]

15. [No authors listed] Ebola: a failure of international collective action. Lancet384, 637 (2014). [PubMed]

16. Ippolito G, Di Caro A, Capobianchi MR. The chronology of the international response to Ebola in Western Africa: lights and shadows in a frame of conflicting position and figures. Infect. Dis. Rep. 2015;7:5957. doi: 10.4081/idr.2015.5957. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

17. Kiiza P, Adhikari NKJ, Mullin S, Teo K, Fowler RA. Principles and practices of establishing a hospital-based Ebola treatment unit. Crit. Care Clin. 2019;35:697–710. doi: 10.1016/j.ccc.2019.06.011. [PubMed] [CrossRef] [Google Scholar]

18. Janke C, et al. Beyond Ebola treatment units: severe infection temporary treatment units as an essential element of Ebola case management during an outbreak. BMC Infect. Dis. 2017;17:124. doi: 10.1186/s12879-017-2235-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

19. Lamb LE, Cox AT, Fletcher T, McCourt AL. Formulating and improving care while mitigating risk in a military Ebola virus disease treatment unit. J. R. Army Med. Corps. 2017;163:2–6. doi: 10.1136/jramc-2015-000615. [PubMed] [CrossRef] [Google Scholar]

20. Leitenberg, M., Zilinskas, R. A. & Kuhn, J. H. The Soviet Biological Weapons Program — a History (Harvard Univ. Press, 2012).

21. Radoshitzky, S. R., Bavari, S., Jahrling, P. B. & Kuhn, J. H. in Medical Aspects of Biological Warfare (Textbooks of Military Medicine) Ch. 23 (eds Bozue, J., Cote, C. K & Glass, P. J.) 569–614 (Borden Institute, US Army Medical Department Center and School, Health Readiness Center of Excellence, 2018).

22. World Health Organization. Ebola Virus Disease Democratic Republic of Congo: External Situation Report 77/2020. https://reliefweb.int/sites/reliefweb.int/files/resources/SITREP_EVD_DRC_20200128-eng.pdf (2020).

23. Maganga GD, et al. Ebola virus disease in the Democratic Republic of Congo. N. Engl. J. Med. 2014;371:2083–2091. doi: 10.1056/NEJMoa1411099. [PubMed] [CrossRef] [Google Scholar]

24. Ebola Outbreak Epidemiology Team Outbreak of Ebola virus disease in the Democratic Republic of the Congo, April-May, 2018: an epidemiological study. Lancet. 2018;392:213–221. doi: 10.1016/S0140-6736(18)31387-4. [PubMed] [CrossRef] [Google Scholar]

25. Mbala-Kingebeni P, et al. Medical countermeasures during the 2018 Ebola virus disease outbreak in the North Kivu and Ituri provinces of the Democratic Republic of the Congo: a rapid genomic assessment. Lancet Infect. Dis. 2019;19:648–657. doi: 10.1016/S1473-3099(19)30118-5. [PubMed] [CrossRef] [Google Scholar]

26. Mbala-Kingebeni P, et al. 2018 Ebola virus disease outbreak in Équateur province, Democratic Republic of the Congo: a retrospective genomic characterisation. Lancet Infect. Dis. 2019;19:641–647. doi: 10.1016/S1473-3099(19)30124-0. [PubMed] [CrossRef] [Google Scholar]

27. de La Vega M-A, et al. Ebola viral load at diagnosis associates with patient outcome and outbreak evolution. J. Clin. Invest. 2015;125:4421–4428. doi: 10.1172/JCI83162. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

28. Dodd LE, et al. A meta-analysis of clinical studies conducted during the West Africa Ebola virus disease outbreak confirms the need for randomized control groups. Sci. Transl Med. 2019;11:eaaw1049. doi: 10.1126/scitranslmed.aaw1049. [PubMed] [CrossRef] [Google Scholar]

29. Bowen ETW, et al. Viral hæmorrhagic fever in southern Sudan and northern Zaire. Preliminary studies on the aetiological agent. Lancet. 1977;309:571–573. doi: 10.1016/S0140-6736(77)92001-3. [PubMed] [CrossRef] [Google Scholar]

30. Johnson KM, Lange JV, Webb PA, Murphy FA. Isolation and partial characterisation of a new virus causing acute hæmorrhagic fever in Zaire. Lancet. 1977;309:569–571. doi: 10.1016/S0140-6736(77)92000-1. [PubMed] [CrossRef] [Google Scholar]

31. Pattyn S, van der Groen G, Jacob W, Piot P, Courteille G. Isolation of Marburg-like virus from a case of hæmorrhagic fever in Zaire. Lancet. 1977;309:573–574. doi: 10.1016/S0140-6736(77)92002-5. [PubMed] [CrossRef] [Google Scholar]

32. Pigott DM, et al. Local, national, and regional viral haemorrhagic fever pandemic potential in Africa: a multistage analysis. Lancet. 2017;390:2662–2672. doi: 10.1016/S0140-6736(17)32092-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

33. Roels TH, et al. Ebola hemorrhagic fever, Kikwit, Democratic Republic of the Congo, 1995: risk factors for patients without a reported exposure. J. Infect. Dis. 1999;179:S92–S97. doi: 10.1086/514286. [PubMed] [CrossRef] [Google Scholar]

34. Dowell SF, et al. Transmission of Ebola hemorrhagic fever: a study of risk factors in family members, Kikwit, Democratic Republic of the Congo, 1995. Commission de Lutte contre les Epidemies a Kikwit. J. Infect. Dis. 1999;179:S87–S91. doi: 10.1086/514284. [PubMed] [CrossRef] [Google Scholar]

35. Galas A. The determinants of spread of Ebola virus disease - an evidence from the past outbreak experiences. Folia Med. Cracov. 2014;54:17–25. [PubMed] [Google Scholar]

36. Bausch DG, et al. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J. Infect. Dis. 2007;196:S142–S147. doi: 10.1086/520545. [PubMed] [CrossRef] [Google Scholar]

37. Deen GF, et al. Ebola RNA persistence in semen of Ebola virus disease survivors - final report. N. Engl. J. Med. 2017;377:1428–1437. doi: 10.1056/NEJMoa1511410. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

38. Kreuels B, Addo MM, Schmiedel S. Severe Ebola virus infection complicated by gram-negative septicemia. N. Engl. J. Med. 2015;372:1377. doi: 10.1056/NEJMc1414481. [PubMed] [CrossRef] [Google Scholar]

39. Moreau M, et al. Lactating mothers infected with Ebola virus: EBOV RT-PCR of blood only may be insufficient. Euro Surveill. 2015;20:21017. doi: 10.2807/1560-7917.ES2015.20.3.21017. [PubMed] [CrossRef] [Google Scholar]

40. Vetter P, et al. Ebola virus shedding and transmission: review of current evidence. J. Infect. Dis. 2016;214:S177–S184. doi: 10.1093/infdis/jiw254. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

41. Mate SE, et al. Molecular evidence of sexual transmission of Ebola virus. N. Engl. J. Med. 2015;373:2448–2454. doi: 10.1056/NEJMoa1509773. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

42. Dean NE, Halloran ME, Yang Y, Longini IM. Transmissibility and pathogenicity of Ebola virus: a systematic review and meta-analysis of household secondary attack rate and asymptomatic infection. Clin. Infect. Dis. 2016;62:1277–1286. doi: 10.1093/cid/ciw114. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

43. Chowell G, Hengartner NW, Castillo-Chavez C, Fenimore PW, Hyman JM. The basic reproductive number of Ebola and the effects of public health measures: the cases of Congo and Uganda. J. Theor. Biol. 2004;229:119–126. doi: 10.1016/j.jtbi.2004.03.006. [PubMed] [CrossRef] [Google Scholar]

44. Smit MA, Michelow IC, Glavis-Bloom J, Wolfman V, Levine AC. Characteristics and outcomes of pediatric patients with Ebola virus disease admitted to treatment units in Liberia and Sierra Leone: a retrospective cohort study. Clin. Infect. Dis. 2017;64:243–249. doi: 10.1093/cid/ciw725. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

45. Aylward B, et al. Ebola virus disease in West Africa - the first 9 months of the epidemic and forward projections. N. Engl. J. Med. 2014;371:1481–1495. doi: 10.1056/NEJMoa1411100. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

46. Dowell SF. Ebola hemorrhagic fever: why were children spared? Pediatr. Infect. Dis. J. 1996;15:189–191. doi: 10.1097/00006454-199603000-00002. [PubMed] [CrossRef] [Google Scholar]

47. Glynn JR. Age-specific incidence of Ebola virus disease. Lancet. 2015;386:432. doi: 10.1016/S0140-6736(15)61446-5. [PubMed] [CrossRef] [Google Scholar]

48. Agua-Agum J, et al. Ebola virus disease among children in West Africa. N. Engl. J. Med. 2015;372:1274–1277. doi: 10.1056/NEJMc1415318. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

49. Chérif MS, et al. Ebola virus disease in children during the 2014-2015 epidemic in Guinea: a nationwide cohort study. Eur. J. Pediatr. 2017;176:791–796. doi: 10.1007/s00431-017-2914-z. [PubMed] [CrossRef] [Google Scholar]

50. Bower H, et al. Exposure-specific and age-specific attack rates for Ebola virus disease in Ebola-affected households, Sierra Leone. Emerg. Infect. Dis. 2016;22:1403–1411. doi: 10.3201/eid2208.160163. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

51. Schwartz, D. A., Anoko, J. N. & Abramowitz, S. A. (eds) Pregnant in the Time of Ebola: Women and Their Children in the 2013–2015 West African Epidemic (Springer, 2019).

52. Okoror L, Kamara A, Kargbo B, Bangura J, Lebby M. Transplacental transmission: a rare case of Ebola virus transmission. Infect. Dis. Rep. 2018;10:7725. doi: 10.4081/idr.2018.7725. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

53. Fallah MP, et al. Pregnancy outcomes in Liberian women who conceived after recovery from Ebola virus disease. Lancet. Glob. Health. 2016;4:e678–e679. [PubMed] [Google Scholar]

54. Haddad LB, Horton J, Ribner BS, Jamieson DJ. Ebola infection in pregnancy: a global perspective and lessons learned. Clin. Obstet. Gynecol. 2018;61:186–196. doi: 10.1097/GRF.0000000000000332. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

55. Baggi FM, et al. Management of pregnant women infected with Ebola virus in a treatment centre in Guinea, June 2014. Euro Surveill. 2014;19:20983. doi: 10.2807/1560-7917.ES2014.19.49.20983. [PubMed] [CrossRef] [Google Scholar]

56. Oduyebo T, et al. A pregnant patient with Ebola virus disease. Obstet. Gynecol. 2015;126:1273–1275. doi: 10.1097/AOG.0000000000001092. [PubMed] [CrossRef] [Google Scholar]

57. Nordenstedt H, et al. Ebola virus in breast milk in an Ebola virus-positive mother with twin babies, Guinea, 2015. Emerg. Infect. Dis. 2016;22:759–760. doi: 10.3201/eid2204.151880. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

58. Arias A, et al. Rapid outbreak sequencing of Ebola virus in Sierra Leone identifies transmission chains linked to sporadic cases. Virus Evol. 2016;2:vew016. doi: 10.1093/ve/vew016. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

59. Wauquier N, Padilla C, Becquart P, Leroy E, Vieillard V. Association of KIR2DS1 and KIR2DS3 with fatal outcome in Ebola virus infection. Immunogenetics. 2010;62:767–771. doi: 10.1007/s00251-010-0480-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

60. World Health Organization. Technical Guidelines for Integrated Disease Surveillance and Response in the African Region. https://www.afro.who.int/publications/technical-guidelines-integrated-disease-surveillance-and-response-african-region-0 (2010).

61. Huizenga E, et al. A modified case definition to facilitate essential hospital care during Ebola outbreaks. Clin. Infect. Dis. 2019;68:1763–1768. doi: 10.1093/cid/ciy798. [PubMed] [CrossRef] [Google Scholar]

62. Gire SK, et al. Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. Science. 2014;345:1369–1372. doi: 10.1126/science.1259657. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

63. Dudas G, et al. Virus genomes reveal factors that spread and sustained the Ebola epidemic. Nature. 2017;544:309–315. doi: 10.1038/nature22040. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

64. Carroll MW, et al. Temporal and spatial analysis of the 2014–2015 Ebola virus outbreak in West Africa. Nature. 2015;524:97–101. doi: 10.1038/nature14594. [PubMed] [CrossRef] [Google Scholar]

65. Tong Y-G, et al. Genetic diversity and evolutionary dynamics of Ebola virus in Sierra Leone. Nature. 2015;524:93–96. doi: 10.1038/nature14490. [PubMed] [CrossRef] [Google Scholar]

66. Diallo B, et al. Resurgence of Ebola virus disease in Guinea linked to a survivor with virus persistence in seminal fluid for more than 500 days. Clin. Infect. Dis. 2016;63:1353–1356. doi: 10.1093/cid/ciw601. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

67. Schindell BG, Webb AL, Kindrachuk J. Persistence and sexual transmission of filoviruses. Viruses. 2018;10:683. doi: 10.3390/v10120683. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

68. Den Boon S, et al. Ebola virus infection associated with transmission from survivors. Emerg. Infect. Dis. 2019;25:249–255. doi: 10.3201/eid2502.181011. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

69. Whitmer SLM, et al. Active Ebola virus replication and heterogeneous evolutionary rates in EVD survivors. Cell Rep. 2018;22:1159–1168. doi: 10.1016/j.celrep.2018.01.008. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

70. Azarian T, et al. Impact of spatial dispersion, evolution, and selection on Ebola Zaire virus epidemic waves. Sci. Rep. 2015;5:10170. doi: 10.1038/srep10170. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

71. Bray M, Davis K, Geisbert T, Schmaljohn C, Huggins J. A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. J. Infect. Dis. 1999;179:S248–S258. doi: 10.1086/514292. [PubMed] [CrossRef] [Google Scholar]

72. Bente D, Gren J, Strong JE, Feldmann H. Disease modeling for Ebola and Marburg viruses. Dis. Model. Mech. 2009;2:12–17. doi: 10.1242/dmm.000471. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

73. Osterholm MT, et al. Transmission of Ebola viruses: what we know and what we do not know. MBio. 2015;6:e00137. [PMC free article] [PubMed] [Google Scholar]

74. Geisbert TW, Strong JE, Feldmann H. Considerations in the use of nonhuman primate models of Ebola virus and Marburg virus infection. J. Infect. Dis. 2015;212:S91–S97. doi: 10.1093/infdis/jiv284. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

75. Alfson KJ, et al. Particle-to-PFU ratio of Ebola virus influences disease course and survival in cynomolgus macaques. J. Virol. 2015;89:6773–6781. doi: 10.1128/JVI.00649-15. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

76. Urbanowicz RA, et al. Human adaptation of Ebola virus during the West African outbreak. Cell. 2016;167:1079–1087.e5. doi: 10.1016/j.cell.2016.10.013. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

77. Dietzel E, Schudt G, Krähling V, Matrosovich M, Becker S. Functional characterization of adaptive mutations during the West African Ebola virus outbreak. J. Virol. 2017;91:e01913–e01916. doi: 10.1128/JVI.01913-16. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

78. Diehl WE, et al. Ebola virus glycoprotein with increased infectivity dominated the 2013–2016 epidemic. Cell. 2016;167:1088–1098.e6. doi: 10.1016/j.cell.2016.10.014. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

79. Wang MK, Lim S-Y, Lee SM, Cunningham JM. Biochemical basis for increased activity of Ebola glycoprotein in the 2013–16 epidemic. Cell Host Microbe. 2017;21:367–375. doi: 10.1016/j.chom.2017.02.002. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

80. Marzi A, et al. Recently identified mutations in the Ebola virus-Makona genome do not alter pathogenicity in animal models. Cell Rep. 2018;23:1806–1816. doi: 10.1016/j.celrep.2018.04.027. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

81. Kyle JE, et al. Plasma lipidome reveals critical illness and recovery from human Ebola virus disease. Proc. Natl Acad. Sci. USA. 2019;116:3919–3928. doi: 10.1073/pnas.1815356116. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

82. Eisfeld AJ, et al. Multi-platform’omics analysis of human Ebola virus disease pathogenesis. Cell Host Microbe. 2017;22:817–829.e8. doi: 10.1016/j.chom.2017.10.011. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

83. Carette JE, et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011;477:340–343. doi: 10.1038/nature10348. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

84. Côté M, et al. Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature. 2011;477:344–348. doi: 10.1038/nature10380. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

85. Takada A, et al. A system for functional analysis of Ebola virus glycoprotein. Proc. Natl Acad. Sci. USA. 1997;94:14764–14769. doi: 10.1073/pnas.94.26.14764. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

86. Schnittler H-J, Feldmann H. Marburg and Ebola hemorrhagic fevers: does the primary course of infection depend on the accessibility of organ-specific macrophages? Clin. Infect. Dis. 1998;27:404–406. doi: 10.1086/517704. [PubMed] [CrossRef] [Google Scholar]

87. Ryabchikova, E. I. & Price, B. B. S. Ebola and Marburg Viruses: a View of Infection Using Electron Microscopy. (Battelle, 2004).

88. Geisbert TW, et al. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am. J. Pathol. 2003;163:2347–2370. doi: 10.1016/S0002-9440(10)63591-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

89. Zaki, S. R. & Peters, C. J. in Pathology of infectious diseases (ed. Connor D. H.) 347–364 (Appleton & Lange, 1997).

90. Geisbert TW, Jahrling PB, Hanes MA, Zack PM. Association of Ebola-related Reston virus particles and antigen with tissue lesions of monkeys imported to the United States. J. Comp. Pathol. 1992;106:137–152. doi: 10.1016/0021-9975(92)90043-T. [PubMed] [CrossRef] [Google Scholar]

91. Bray M, Geisbert TW. Ebola virus: the role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever. Int. J. Biochem. Cell Biol. 2005;37:1560–1566. doi: 10.1016/j.biocel.2005.02.018. [PubMed] [CrossRef] [Google Scholar]

92. Wahl-Jensen V, et al. Role of Ebola virus secreted glycoproteins and virus-like particles in activation of human macrophages. J. Virol. 2005;79:2413–2419. doi: 10.1128/JVI.79.4.2413-2419.2005. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

93. Wahl-Jensen V, et al. Ebola virion attachment and entry into human macrophages profoundly effects early cellular gene expression. PLoS Negl. Trop. Dis. 2011;5:e1359. doi: 10.1371/journal.pntd.0001359. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

94. Gupta M, Mahanty S, Ahmed R, Rollin PE. Monocyte-derived human macrophages and peripheral blood mononuclear cells infected with Ebola virus secrete MIP-1α and TNF-α and inhibit poly-IC-induced IFN-α in vitro. Virology. 2001;284:20–25. doi: 10.1006/viro.2001.0836. [PubMed] [CrossRef] [Google Scholar]

95. Ströher U, et al. Infection and activation of monocytes by Marburg and Ebola viruses. J. Virol. 2001;75:11025–11033. doi: 10.1128/JVI.75.22.11025-11033.2001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

96. Bosio CM, et al. Ebola and Marburg viruses replicate in monocyte-derived dendritic cells without inducing the production of cytokines and full maturation. J. Infect. Dis. 2003;188:1630–1638. doi: 10.1086/379199. [PubMed] [CrossRef] [Google Scholar]

97. Geisbert TW, et al. Mechanisms underlying coagulation abnormalities in Ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J. Infect. Dis. 2003;188:1618–1629. doi: 10.1086/379724. [PubMed] [CrossRef] [Google Scholar]

98. Mahanty S, et al. Impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses. J. Immunol. 2003;170:2797–2801. doi: 10.4049/jimmunol.170.6.2797. [PubMed] [CrossRef] [Google Scholar]

99. Bosio CM, et al. Ebola and Marburg virus-like particles activate human myeloid dendritic cells. Virology. 2004;326:280–287. doi: 10.1016/j.virol.2004.05.025. [PubMed] [CrossRef] [Google Scholar]

100. Hensley LE, Young HA, Jahrling PB, Geisbert TW. Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily. Immunol. Lett. 2002;80:169–179. doi: 10.1016/S0165-2478(01)00327-3. [PubMed] [CrossRef] [Google Scholar]

101. Younan P, et al. Ebola virus-mediated T-lymphocyte depletion is the result of an abortive infection. PLoS Pathog. 2019;15:e1008068. doi: 10.1371/journal.ppat.1008068. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

102. Geisbert TW, et al. Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses. Lab. Invest. 2000;80:171–186. doi: 10.1038/labinvest.3780021. [PubMed] [CrossRef] [Google Scholar]

103. Baize S, et al. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Nat. Med. 1999;5:423–426. doi: 10.1038/7422. [PubMed] [CrossRef] [Google Scholar]

104. Ryabchikova EI, Kolesnikova LV, Luchko SV. An analysis of features of pathogenesis in two animal models of Ebola virus infection. J. Infect. Dis. 1999;179:S199–S202. doi: 10.1086/514293. [PubMed] [CrossRef] [Google Scholar]

105. Harcourt BH, Sanchez A, Offermann MK. Ebola virus inhibits induction of genes by double-stranded RNA in endothelial cells. Virology. 1998;252:179–188. doi: 10.1006/viro.1998.9446. [PubMed] [CrossRef] [Google Scholar]

106. Harcourt BH, Sanchez A, Offermann MK. Ebola virus selectively inhibits responses to interferons, but not to interleukin-1β, in endothelial cells. J. Virol. 1999;73:3491–3496. doi: 10.1128/JVI.73.4.3491-3496.1999. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

107. Basler CF, et al. The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3. J. Virol. 2003;77:7945–7956. doi: 10.1128/JVI.77.14.7945-7956.2003. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

108. Basler CF, et al. The Ebola virus VP35 protein functions as a type I IFN antagonist. Proc. Natl Acad. Sci. USA. 2000;97:12289–12294. doi: 10.1073/pnas.220398297. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

109. Cárdenas WB, et al. Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling. J. Virol. 2006;80:5168–5178. doi: 10.1128/JVI.02199-05. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

110. Feng Z, Cerveny M, Yan Z, He B. The VP35 protein of Ebola virus inhibits the antiviral effect mediated by double-stranded RNA-dependent protein kinase PKR. J. Virol. 2007;81:182–192. doi: 10.1128/JVI.01006-06. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

111. Leung DW, et al. Structure of the Ebola VP35 interferon inhibitory domain. Proc. Natl Acad. Sci. USA. 2009;106:411–416. doi: 10.1073/pnas.0807854106. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

112. Leung DW, et al. Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35. Nat. Struct. Mol. Biol. 2010;17:165–172. doi: 10.1038/nsmb.1765. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

113. Luthra P, et al. Mutual antagonism between the Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome. Cell Host Microbe. 2013;14:74–84. doi: 10.1016/j.chom.2013.06.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

114. Prins KC, Cárdenas WB, Basler CF. Ebola virus protein VP35 impairs the function of interferon regulatory factor-activating kinases IKKε and TBK-1. J. Virol. 2009;83:3069–3077. doi: 10.1128/JVI.01875-08. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

115. Woolsey C, et al. A VP35 mutant Ebola virus lacks virulence but can elicit protective immunity to wild-type virus challenge. Cell Rep. 2019;28:3032–3046.e6. doi: 10.1016/j.celrep.2019.08.047. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

116. Zhu Y, et al. Characterization of the RNA silencing suppression activity of the Ebola virus VP35 protein in plants and mammalian cells. J. Virol. 2012;86:3038–3049. doi: 10.1128/JVI.05741-11. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

117. Kaletsky RL, Francica JR, Agrawal-Gamse C, Bates P. Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein. Proc. Natl Acad. Sci. USA. 2009;106:2886–2891. doi: 10.1073/pnas.0811014106. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

118. Reid SP, et al. Ebola virus VP24 binds karyopherin α1 and blocks STAT1 nuclear accumulation. J. Virol. 2006;80:5156–5167. doi: 10.1128/JVI.02349-05. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

119. Reid SP, Valmas C, Martinez O, Sanchez FM, Basler CF. Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin α proteins with activated STAT1. J. Virol. 2007;81:13469–13477. doi: 10.1128/JVI.01097-07. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

120. Pleet ML, DeMarino C, Lepene B, Aman MJ, Kashanchi F. The role of exosomal VP40 in Ebola virus disease. DNA Cell Biol. 2017;36:243–248. doi: 10.1089/dna.2017.3639. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

121. Pleet ML, et al. Ebola VP40 in exosomes can cause immune cell dysfunction. Front. Microbiol. 2016;7:1765. doi: 10.3389/fmicb.2016.01765. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

122. Mandl JN, Feinberg MB. Robust and sustained immune activation in human Ebola virus infection. Proc. Natl Acad. Sci. USA. 2015;112:4518–4519. doi: 10.1073/pnas.1503864112. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

123. McElroy AK, et al. Human Ebola virus infection results in substantial immune activation. Proc. Natl Acad. Sci. USA. 2015;112:4719–4724. doi: 10.1073/pnas.1502619112. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

124. Henao-Restrepo AM, et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!) Lancet. 2017;389:505–518. doi: 10.1016/S0140-6736(16)32621-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

125. Henao-Restrepo AM, et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet. 2015;386:857–866. doi: 10.1016/S0140-6736(15)61117-5. [PubMed] [CrossRef] [Google Scholar]

126. Mulangu S, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N. Engl. J. Med. 2019;381:2293–2303. doi: 10.1056/NEJMoa1910993. [PubMed] [CrossRef] [Google Scholar]

127. McElroy AK, et al. Kinetic analysis of biomarkers in a cohort of US patients with Ebola virus disease. Clin. Infect. Dis. 2016;63:460–467. doi: 10.1093/cid/ciw334. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

128. Muñoz-Fontela C, McElroy AK. Ebola virus disease in humans: pathophysiology and immunity. Curr. Top. Microbiol. Immunol. 2017;411:141–169. [PMC free article] [PubMed] [Google Scholar]

129. Ruibal P, et al. Unique human immune signature of Ebola virus disease in Guinea. Nature. 2016;533:100–104. doi: 10.1038/nature17949. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

130. Davis CW, et al. Longitudinal analysis of the human B cell response to Ebola virus infection. Cell. 2019;177:1566–1582.e7. doi: 10.1016/j.cell.2019.04.036. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

131. Sow MS, et al. New evidence of long-lasting persistence of Ebola virus genetic material in semen of survivors. J. Infect. Dis. 2016;214:1475–1476. doi: 10.1093/infdis/jiw078. [PubMed] [CrossRef] [Google Scholar]

132. Abbate JL, Murall CL, Richner H, Althaus CL. Potential impact of sexual transmission on Ebola virus epidemiology: Sierra Leone as a case study. PLoS Negl. Trop. Dis. 2016;10:e0004676. doi: 10.1371/journal.pntd.0004676. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

133. Chancellor JR, et al. Uveitis and systemic inflammatory markers in convalescent phase of Ebola virus disease. Emerg. Infect. Dis. 2016;22:295–297. doi: 10.3201/eid2202.151416. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

134. Chughtai AA, Barnes M, Macintyre CR. Persistence of Ebola virus in various body fluids during convalescence: evidence and implications for disease transmission and control. Epidemiol. Infect. 2016;144:1652–1660. doi: 10.1017/S0950268816000054. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

135. Velásquez GE, et al. Time from infection to disease and infectiousness for Ebola virus disease, a systematic review. Clin. Infect. Dis. 2015;61:1135–1140. doi: 10.1093/cid/civ531. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

136. Richardson ET, et al. Minimally symptomatic infection in an Ebola ‘hotspot’: a cross-sectional serosurvey. PLoS Negl. Trop. Dis. 2016;10:e0005087. doi: 10.1371/journal.pntd.0005087. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

137. Timothy JWS, et al. Early transmission and case fatality of Ebola virus at the index site of the 2013–16 west African Ebola outbreak: a cross-sectional seroprevalence survey. Lancet. Infect. Dis. 2019;19:429–438. doi: 10.1016/S1473-3099(18)30791-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

138. Glynn JR, et al. Asymptomatic infection and unrecognised Ebola virus disease in Ebola-affected households in Sierra Leone: a cross-sectional study using a new non-invasive assay for antibodies to Ebola virus. Lancet. Infect. Dis. 2017;17:645–653. doi: 10.1016/S1473-3099(17)30111-1. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

139. Xu Z, et al. Epidemiologic characteristics, clinical manifestations, and risk factors of 139 patients with Ebola virus disease in western Sierra Leone. Am. J. Infect. Control. 2016;44:1285–1290. doi: 10.1016/j.ajic.2016.04.216. [PubMed] [CrossRef] [Google Scholar]

140. Fowler RA, et al. Caring for critically ill patients with Ebola virus disease. Perspectives from West Africa. Am. J. Respir. Crit. Care Med. 2014;190:733–737. doi: 10.1164/rccm.201408-1514CP. [PubMed] [CrossRef] [Google Scholar]

141. Barry M, et al. Clinical predictors of mortality in patients with Ebola virus disease. Clin. Infect. Dis. 2015;60:1821–1824. doi: 10.1093/cid/civ202. [PubMed] [CrossRef] [Google Scholar]

142. Qin E, et al. Clinical features of patients with Ebola virus disease in Sierra Leone. Clin. Infect. Dis. 2015;61:491–495. doi: 10.1093/cid/civ319. [PubMed] [CrossRef] [Google Scholar]

143. Chertow DS, et al. Ebola virus disease in West Africa - clinical manifestations and management. N. Engl. J. Med. 2014;371:2054–2057. doi: 10.1056/NEJMp1413084. [PubMed] [CrossRef] [Google Scholar]

144. Dietz PM, Jambai A, Paweska JT, Yoti Z, Ksiazek TG. Epidemiology and risk factors for Ebola virus disease in Sierra Leone-23 May 2014 to 31 January 2015. Clin. Infect. Dis. 2015;61:1648–1654. [PubMed] [Google Scholar]

145. Cournac JM, et al. Rhabdomyolysis in Ebola virus disease. Results of an observational study in a treatment center in Guinea. Clin. Infect. Dis. 2016;62:19–23. doi: 10.1093/cid/civ779. [PubMed] [CrossRef] [Google Scholar]

146. Lado M, et al. Clinical features of patients isolated for suspected Ebola virus disease at Connaught Hospital, Freetown, Sierra Leone: a retrospective cohort study. Lancet Infect. Dis. 2015;15:1024–1033. doi: 10.1016/S1473-3099(15)00137-1. [PubMed] [CrossRef] [Google Scholar]

147. Rojek A, Horby P, Dunning J. Insights from clinical research completed during the west Africa Ebola virus disease epidemic. Lancet Infect. Dis. 2017;17:e280–e292. doi: 10.1016/S1473-3099(17)30234-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

148. Wilson AJ, et al. Thromboelastography in the management of coagulopathy associated with Ebola virus disease. Clin. Infect. Dis. 2016;62:610–612. doi: 10.1093/cid/civ977. [PubMed] [CrossRef] [Google Scholar]

149. Sagui E, et al. Severe Ebola virus infection with encephalopathy: evidence for direct virus involvement. Clin. Infect. Dis. 2015;61:1627–1628. doi: 10.1093/cid/civ606. [PubMed] [CrossRef] [Google Scholar]

150. de Greslan T, et al. Ebola virus-related encephalitis. Clin. Infect. Dis. 2016;63:1076–1078. doi: 10.1093/cid/ciw469. [PubMed] [CrossRef] [Google Scholar]

151. Fitzpatrick G, et al. The contribution of Ebola viral load at admission and other patient characteristics to mortality in a Médecins Sans Frontières Ebola case management centre, Kailahun, Sierra Leone, June–October 2014. J. Infect. Dis. 2015;212:1752–1758. doi: 10.1093/infdis/jiv304. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

152. Schieffelin JS, et al. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N. Engl. J. Med. 2014;371:2092–2100. doi: 10.1056/NEJMoa1411680. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

153. Rollin PE, Bausch DG, Sanchez A. Blood chemistry measurements and D-dimer levels associated with fatal and nonfatal outcomes in humans infected with Sudan Ebola virus. J. Infect. Dis. 2007;196:S364–S371. doi: 10.1086/520613. [PubMed] [CrossRef] [Google Scholar]

154. Bah EI, et al. Clinical presentation of patients with Ebola virus disease in Conakry, Guinea. N. Engl. J. Med. 2015;372:40–47. doi: 10.1056/NEJMoa1411249. [PubMed] [CrossRef] [Google Scholar]

155. Waxman M, Aluisio AR, Rege S, Levine AC. Characteristics and survival of patients with Ebola virus infection, malaria, or both in Sierra Leone: a retrospective cohort study. Lancet Infect. Dis. 2017;17:654–660. doi: 10.1016/S1473-3099(17)30112-3. [PubMed] [CrossRef] [Google Scholar]

156. Vernet M-A, et al. Clinical, virological, and biological parameters associated with outcomes of Ebola virus infection in Macenta, Guinea. JCI Insight. 2017;2:e88864. doi: 10.1172/jci.insight.88864. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

157. Carroll MW, et al. Deep sequencing of RNA from blood and oral swab samples reveals the presence of nucleic acid from a number of pathogens in patients with acute Ebola virus disease and is consistent with bacterial translocation across the gut. mSphere. 2017;2:e00325-17. doi: 10.1128/mSphereDirect.00325-17. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

158. Dhillon RS, Srikrishna D, Garry RF, Chowell G. Ebola control: rapid diagnostic testing. Lancet Infect. Dis. 2015;15:147–148. doi: 10.1016/S1473-3099(14)71035-7. [PubMed] [CrossRef] [Google Scholar]

159. World Health Organization. Urgently Needed: Rapid, Sensitive, Safe and Simple Ebola Diagnostic Tests. http://www.who.int/mediacentre/news/ebola/18-november-2014-diagnostics/en (2014).

160. Nouvellet P, et al. The role of rapid diagnostics in managing Ebola epidemics. Nature. 2015;528:S109–S116. doi: 10.1038/nature16041. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

161. Diallo MSK, et al. Prevalence of infection among asymptomatic and paucisymptomatic contact persons exposed to Ebola virus in Guinea: a retrospective, cross-sectional observational study. Lancet Infect. Dis. 2019;19:308–316. doi: 10.1016/S1473-3099(18)30649-2. [PubMed] [CrossRef] [Google Scholar]

162. Erickson BR, et al. Ebola virus disease diagnostics, Sierra Leone: analysis of real-time reverse transcription-polymerase chain reaction values for clinical blood and oral swab specimens. J. Infect. Dis. 2016;214:S258–S262. doi: 10.1093/infdis/jiw296. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

163. Wannier SR, et al. Estimating the impact of violent events on transmission in Ebola virus disease outbreak, Democratic Republic of the Congo, 2018–2019. Epidemics. 2019;28:100353. doi: 10.1016/j.epidem.2019.100353. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

164. Kucharski AJ, et al. Measuring the impact of Ebola control measures in Sierra Leone. Proc. Natl Acad. Sci. USA. 2015;112:14366–14371. doi: 10.1073/pnas.1508814112. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

165. World Health Organization. Clinical management of patients with viral haemorrhagic fever: a pocket guide for front-line health workers. http://apps.who.int/iris/bitstream/10665/205570/1/9789241549608_eng.pdf?ua=1 (2016).

166. Bevilacqua N, et al. Criteria for discharge of patients with Ebola virus diseases in high-income countries. Lancet Glob. Health. 2015;3:e739–e740. doi: 10.1016/S2214-109X(15)00205-3. [PubMed] [CrossRef] [Google Scholar]

167. World Health Organization. Interim advice on the sexual transmission of the Ebola virus disease. http://www.who.int/reproductivehealth/topics/rtis/ebola-virus-semen/en/ (2016).

168. Henao Restrepo, A. M. Update on candidate Ebola vaccines: available data on immunogenicity, efficacy and safety. http://www.who.int/immunization/sage/meetings/2018/october/SAGE_october_2018_ebola_Henaorestrepo.pdf (WHO, 2018).

169. European Commission. Vaccine against Ebola: Commission grants first-ever market authorisation. https://ec.europa.eu/commission/presscorner/detail/en/IP_19_6246 (2019). Market authorization in Europe for Ebola virus vaccine.

170. World Health Organization. Preliminary results on the efficacy of rVSV-ZEBOV-GP Ebola vaccine using the ring vaccination strategy in the control of an Ebola outbreak in the Democratic Republic of the Congo: an example of integration of research into epidemic response. https://www.who.int/csr/resources/publications/ebola/ebola-ring-vaccination-results-12-april-2019.pdf?ua=1 (2019).

171. Wells CR, et al. Ebola vaccination in the Democratic Republic of the Congo. Proc. Natl Acad. Sci. USA. 2019;116:10178–10183. doi: 10.1073/pnas.1817329116. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

172. London School of Hygiene & Tropical Medicine. Uganda starts Ebola vaccine trial among healthcare and frontline workers. https://www.lshtm.ac.uk/newsevents/news/2019/uganda-starts-ebola-vaccine-trial-among-healthcare-and-frontline-workers (2019).

173. Huttner A, et al. The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial. Lancet Infect. Dis. 2015;15:1156–1166. doi: 10.1016/S1473-3099(15)00154-1. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

174. US Food and Drug Administration. First FDA-approved vaccine for the prevention of Ebola virus disease, marking a critical milestone in public health preparedness and response. https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-ebola-virus-disease-marking-critical-milestone-public-health (2019).

175. Wolf T, et al. Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care. Lancet. 2015;385:1428–1435. doi: 10.1016/S0140-6736(14)62384-9. [PubMed] [CrossRef] [Google Scholar]

176. World Health Organization. Essential medicines and health products. Table of drug clinical trials. https://www.who.int/medicines/ebola-treatment/ebola_drug_clinicaltrials/en/ (2019).

177. Sissoko D, et al. Experimental treatment with favipiravir for Ebola virus disease (the JIKI trial): a historically controlled, single-arm proof-of-concept trial in Guinea. PLoS Med. 2016;13:e1001967. doi: 10.1371/journal.pmed.1001967. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

178. Dunning J, et al. Experimental treatment of Ebola virus disease with TKM-130803: a single-arm phase 2 clinical trial. PLoS Med. 2016;13:e1001997. doi: 10.1371/journal.pmed.1001997. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

179. The PREVAIL II Writing Group, et al. A randomized, controlled trial of ZMapp for Ebola virus infection. N. Engl. J. Med. 2016;375:1448–1456. doi: 10.1056/NEJMoa1604330. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

180. World Health Organization. Notes for the record: consultation on Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI) for Ebola virus disease (EVD). http://www.who.int/ebola/drc-2018/notes-for-the-record-meuri-ebola.pdf (2018).

181. Qiu X, et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014;514:47–53. doi: 10.1038/nature13777. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

182. Davey RT, Jr., Nordwall J, Proschan MA. Trial of ZMapp for Ebola virus infection. N. Engl. J. Med. 2017;376:700–701. doi: 10.1056/NEJMc1614625. [PubMed] [CrossRef] [Google Scholar]

183. Gaudinski MR, et al. Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study. Lancet. 2019;393:889–898. doi: 10.1016/S0140-6736(19)30036-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

184. Corti D, et al. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science. 2016;351:1339–1342. doi: 10.1126/science.aad5224. [PubMed] [CrossRef] [Google Scholar]

185. Sivapalasingam S, et al. Safety, pharmacokinetics, and immunogenicity of a co-formulated cocktail of three human monoclonal antibodies targeting Ebola virus glycoprotein in healthy adults: a randomised, first-in-human phase 1 study. Lancet Infect. Dis. 2018;18:884–893. doi: 10.1016/S1473-3099(18)30397-9. [PubMed] [CrossRef] [Google Scholar]

186. Pascal KE, et al. Development of clinical-stage human monoclonal antibodies that treat advanced Ebola virus disease in nonhuman primates. J. Infect. Dis. 2018;218:S612–S626. doi: 10.1093/infdis/jiy285. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

187. Warren TK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531:381–385. doi: 10.1038/nature17180. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

188. National Instite of Allergy and Infectious Diseases. Independent Monitoring Board recommends early termination of Ebola therapeutics trial in DRC because of favorable results with two of four candidates. https://www.niaid.nih.gov/news-events/independent-monitoring-board-recommends-early-termination-ebola-therapeutics-trial-drc (2019).

189. van Griensven J, et al. The use of Ebola convalescent plasma to treat Ebola virus disease in resource-constrained settings: a perspective from the field. Clin. Infect. Dis. 2016;62:69–74. doi: 10.1093/cid/civ680. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

190. van Griensven J, et al. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N. Engl. J. Med. 2016;374:33–42. doi: 10.1056/NEJMoa1511812. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

191. van Griensven J, Edwards T, Baize S. Efficacy of convalescent plasma in relation to dose of Ebola virus antibodies. N. Engl. J. Med. 2016;375:2307–2309. doi: 10.1056/NEJMc1609116. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

192. Mora-Rillo M, et al. Acute respiratory distress syndrome after convalescent plasma use: treatment of a patient with Ebola virus disease contracted in Madrid, Spain. Lancet Respir. Med. 2015;3:554–562. doi: 10.1016/S2213-2600(15)00180-0. [PubMed] [CrossRef] [Google Scholar]

193. Lamontagne F, et al. Evidence-based guidelines for supportive care of patients with Ebola virus disease. Lancet. 2018;391:700–708. doi: 10.1016/S0140-6736(17)31795-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

194. Cotte J, et al. Fluid resuscitation in Ebola virus disease: a comparison of peripheral and central venous accesses. Anaesth. Crit. Care Pain. Med. 2015;34:317–320. doi: 10.1016/j.accpm.2015.06.010. [PubMed] [CrossRef] [Google Scholar]

195. Kraft CS, et al. The use of TKM-100802 and convalescent plasma in 2 patients with Ebola virus disease in the United States. Clin. Infect. Dis. 2015;61:496–502. doi: 10.1093/cid/civ334. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

196. Chertow DS, Uyeki TM, DuPont HL. Loperamide therapy for voluminous diarrhea in Ebola virus disease. J. Infect. Dis. 2015;211:1036–1037. doi: 10.1093/infdis/jiv001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

197. Billioux BJ, Smith B, Nath A. Neurological complications of Ebola virus infection. Neurotherapeutics. 2016;13:461–470. doi: 10.1007/s13311-016-0457-z. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

198. Chertow DS, et al. Severe meningoencephalitis in a case of ebola virus disease: a case report. Ann. Intern. Med. 2016;165:301–304. doi: 10.7326/M15-3066. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

199. Uyeki TM, et al. Clinical management of Ebola virus disease in the United States and Europe. N. Engl. J. Med. 2016;374:636–646. doi: 10.1056/NEJMoa1504874. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

200. Sueblinvong V, et al. Critical care for multiple organ failure secondary to Ebola virus disease in the United States. Crit. Care Med. 2015;43:2066–2075. doi: 10.1097/CCM.0000000000001197. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

201. Johnson DW, et al. Lessons learned: critical care management of patients with Ebola in the United States. Crit. Care Med. 2015;43:1157–1164. doi: 10.1097/CCM.0000000000000935. [PubMed] [CrossRef] [Google Scholar]

202. Auffermann WF, Kraft CS, Vanairsdale S, Lyon GM, III, Tridandapani S. Radiographic imaging for patients with contagious infectious diseases: how to acquire chest radiographs of patients infected with the Ebola virus. AJR Am. J. Roentgenol. 2015;204:44–48. doi: 10.2214/AJR.14.14041. [PubMed] [CrossRef] [Google Scholar]

203. Langer M, et al. Intensive care support and clinical outcomes of patients with Ebola virus disease (EVD) in West Africa. Intensive Care Med. 2018;44:1266–1275. doi: 10.1007/s00134-018-5308-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

204. Connor MJ, Jr., et al. Successful delivery of RRT in Ebola virus disease. J. Am. Soc. Nephrol. 2015;26:31–37. doi: 10.1681/ASN.2014111057. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

205. Centers for Disease Control and Prevention. Recommendations for safety performing acute hemodialysis in patients with Ebola virus disease (EVD) in U.S. hospitals. http://www.cdc.gov/vhf/ebola/healthcare-us/hospitals/acute-hemodialysis.html (2015).

206. Torabi-Parizi P, Davey RT, Jr., Suffredini AF, Chertow DS. Ethical and practical considerations in providing critical care to patients with Ebola virus disease. Chest. 2015;147:1460–1466. doi: 10.1378/chest.15-0278. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

207. Murthy S. Ebola and provision of critical care. Lancet. 2015;385:1392–1393. doi: 10.1016/S0140-6736(15)60712-7. [PubMed] [CrossRef] [Google Scholar]

208. Halpern SD, Emanuel EJ. Use of life-sustaining therapies for patients with Ebola virus disease. Ann. Intern. Med. 2015;163:70. doi: 10.7326/L15-5106-2. [PubMed] [CrossRef] [Google Scholar]

209. Garske T, et al. Heterogeneities in the case fatality ratio in the West African Ebola outbreak 2013–2016. Philos. Trans. R Soc. Lond. B Biol. Sci. 2017;372:20160308. doi: 10.1098/rstb.2016.0308. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

210. World Health Organization. Optimized supportive care for Ebola virus disease. Clinical management standard operating procedures. https://www.who.int/csr/resources/publications/optimized-supportive-care/en/ (2019). Field manual focusing on delivery of optimized supportive care in the 2018-present EVD outbreak in the Democratic Republic of the Congo.

211. Lyon GM, et al. Clinical care of two patients with Ebola virus disease in the United States. N. Engl. J. Med. 2014;371:2402–2409. doi: 10.1056/NEJMoa1409838. [PubMed] [CrossRef] [Google Scholar]

212. Hunt L, et al. Clinical presentation, biochemical, and haematological parameters and their association with outcome in patients with Ebola virus disease: an observational cohort study. Lancet Infect. Dis. 2015;15:1292–1299. doi: 10.1016/S1473-3099(15)00144-9. [PubMed] [CrossRef] [Google Scholar]

213. Iwen PC, et al. Safety considerations in the laboratory testing of specimens suspected or known to contain Ebola virus. Am. J. Clin. Pathol. 2015;143:4–5. doi: 10.1309/AJCP26MIFUIETBPL. [PubMed] [CrossRef] [Google Scholar]

214. de La Vega M-A, Bello A, Chaillet P, Kobinger GP. Diagnosis and management of Ebola samples in the laboratory. Expert. Rev. Anti Infect. Ther. 2016;14:557–567. doi: 10.1080/14787210.2016.1176912. [PubMed] [CrossRef] [Google Scholar]

215. Gignoux E, et al. Effect of artesunate-amodiaquine on mortality related to Ebola virus disease. N. Engl. J. Med. 2016;374:23–32. doi: 10.1056/NEJMoa1504605. [PubMed] [CrossRef] [Google Scholar]

216. O'Shea MK, et al. Diagnosis of febrile illnesses other than Ebola virus disease at an Ebola Treatment Unit in Sierra Leone. Clin. Infect. Dis. 2015;61:795–798. doi: 10.1093/cid/civ399. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

217. Kangbai JB, Heumann C, Hoelscher M, Sahr F, Froeschl G. Epidemiological characteristics, clinical manifestations, and treatment outcome of 139 paediatric Ebola patients treated at a Sierra Leone Ebola treatment center. BMC Infect. Dis. 2019;19:81. doi: 10.1186/s12879-019-3727-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

218. Damkjær M, Rudolf F, Mishra S, Young A, Storgaard M. Clinical features and outcome of Ebola virus disease in pediatric patients: a retrospective case series. J. Pediatr. 2017;182:378–381.e1. doi: 10.1016/j.jpeds.2016.11.034. [PubMed] [CrossRef] [Google Scholar]

219. Shah T, et al. Inpatient signs and symptoms and factors associated with death in children aged 5 years and younger admitted to two Ebola management centres in Sierra Leone, 2014: a retrospective cohort study. Lancet Glob. Health. 2016;4:e495–e501. doi: 10.1016/S2214-109X(16)30097-3. [PubMed] [CrossRef] [Google Scholar]

220. Trehan I, Kelly T, Marsh RH, George PM, Callahan CW. Moving towards a more aggressive and comprehensive model of care for children with Ebola. J. Pediat. 2016;170:28–33.e1-7. doi: 10.1016/j.jpeds.2015.11.054. [PubMed] [CrossRef] [Google Scholar]

221. Caluwaerts S, et al. Dilemmas in managing pregnant women with Ebola: 2 case reports. Clin. Infect. Dis. 2016;62:903–905. doi: 10.1093/cid/civ1024. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

222. Nelson JM, Griese SE, Goodman AB, Peacock G. Live neonates born to mothers with Ebola virus disease: a review of the literature. J. Perinatol. 2016;36:411–414. doi: 10.1038/jp.2015.189. [PubMed] [CrossRef] [Google Scholar]

223. Bebell LM, Oduyebo T, Riley LE. Ebola virus disease and pregnancy: a review of the current knowledge of Ebola virus pathogenesis, maternal, and neonatal outcomes. Birth Defects Res. 2017;109:353–362. doi: 10.1002/bdra.23558. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

224. Haddad LB, Jamieson DJ, Rasmussen SA. Pregnant women and the Ebola crisis. N. Engl. J. Med. 2018;379:2492–2493. doi: 10.1056/NEJMp1814020. [PubMed] [CrossRef] [Google Scholar]

225. Mupapa K, et al. Ebola hemorrhagic fever and pregnancy. J. Infect. Dis. 1999;179:S11–S12. doi: 10.1086/514289. [PubMed] [CrossRef] [Google Scholar]

226. Dörnemann J, et al. First newborn baby to receive experimental therapies survives Ebola virus disease. J. Infect. Dis. 2017;215:171–174. [PMC free article] [PubMed] [Google Scholar]

227. Centers for Disease Control and Prevention. Care of a neonate born to a mother who is confirmed to have Ebola, is a person under investigation, or has been exposed to Ebola. Interim Guidance for U.S. Hospitals on the Care of a Neonate Born to a Mother who is Confirmed to have Ebola, is a Person under Investigation (PUI), or has been Exposed to Ebola. http://www.cdc.gov/vhf/ebola/healthcare-us/hospitals/neonatal-care.html (2016).

228. Bwaka MA, et al. Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients. J. Infect. Dis. 1999;179:S1–S7. doi: 10.1086/514308. [PubMed] [CrossRef] [Google Scholar]

229. Rowe AK, et al. Clinical, virologic, and immunologic follow-up of convalescent Ebola hemorrhagic fever patients and their household contacts, Kikwit, Democratic Republic of the Congo. J. Infect. Dis. 1999;179:S28–S35. doi: 10.1086/514318. [PubMed] [CrossRef] [Google Scholar]

230. Sneller MC, et al. A longitudinal study of Ebola sequelae in Liberia. N. Engl. J. Med. 2019;380:924–934. doi: 10.1056/NEJMoa1805435. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

231. World Health Organization. Caring for Ebola survivors: Supporting survivors to recover their lives and livelihoods. http://www.who.int/csr/disease/ebola/survivors/caring-for-survivors/en/ (2016).

232. Yeh S, Shantha JG, Hayek B, Crozier I, Smith JR. Clinical manifestations and pathogenesis of uveitis in Ebola virus disease survivors. Ocul. Immunol. Inflamm. 2018;26:1128–1134. doi: 10.1080/09273948.2018.1484493. [PubMed] [CrossRef] [Google Scholar]

233. Qureshi AI, et al. Study of Ebola virus disease survivors in Guinea. Clin. Infect. Dis. 2015;61:1035–1042. doi: 10.1093/cid/civ453. [PubMed] [CrossRef] [Google Scholar]

234. Tiffany A, et al. Ebola virus disease complications as experienced by survivors in Sierra Leone. Clin. Infect. Dis. 2016;62:1360–1366. doi: 10.1093/cid/ciw158. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

235. Howlett P, et al. Ebola virus disease complicated by late-onset encephalitis and polyarthritis, Sierra Leone. Emerg. Infect. Dis. 2016;22:150–152. doi: 10.3201/eid2201.151212. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

236. Clark DV, et al. Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. Lancet Infect. Dis. 2015;15:905–912. doi: 10.1016/S1473-3099(15)70152-0. [PubMed] [CrossRef] [Google Scholar]

237. Epstein L, Wong KK, Kallen AJ, Uyeki TM. Post-Ebola signs and symptoms in U.S. survivors. N. Engl. J. Med. 2015;373:2484–2486. doi: 10.1056/NEJMc1506576. [PubMed] [CrossRef] [Google Scholar]

238. Kibadi K, et al. Late ophthalmologic manifestations in survivors of the 1995 Ebola virus epidemic in Kikwit, Democratic Republic of the Congo. J. Infect. Dis. 1999;179:S13–S14. doi: 10.1086/514288. [PubMed] [CrossRef] [Google Scholar]

239. Mattia JG, et al. Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study. Lancet Infect. Dis. 2016;16:331–338. doi: 10.1016/S1473-3099(15)00489-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

240. Nanyonga M, Saidu J, Ramsay A, Shindo N, Bausch DG. Sequelae of Ebola virus disease, Kenema District, Sierra Leone. Clin. Infect. Dis. 2016;62:125–126. doi: 10.1093/cid/civ795. [PubMed] [CrossRef] [Google Scholar]

241. Scott JT, et al. Post-Ebola syndrome, Sierra Leone. Emerg. Infect. Dis. 2016;22:641–646. doi: 10.3201/eid2204.151302. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

242. Shantha JG, Crozier I, Yeh S. An update on ocular complications of Ebola virus disease. Curr. Opin. Ophthalmol. 2017;28:600–606. doi: 10.1097/ICU.0000000000000426. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

243. Shantha JG, et al. Long-term management of panuveitis and iris heterochromia in an Ebola survivor. Ophthalmology. 2016;123:2626–2628.e2. doi: 10.1016/j.ophtha.2016.07.013. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

244. Hugo M, et al. Post-traumatic stress reactions in Ebola virus disease survivors in Sierra Leone. Emerg. Med. 2015;5:285. doi: 10.4172/2165-7548.1000285. [CrossRef] [Google Scholar]

245. Mohammed A, et al. An evaluation of psychological distress and social support of survivors and contacts of Ebola virus disease infection and their relatives in Lagos, Nigeria: a cross sectional study–2014. BMC Public Health. 2015;15:824. doi: 10.1186/s12889-015-2167-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

246. Reardon S. Ebola’s mental-health wounds linger in Africa. Nature. 2015;519:13–14. doi: 10.1038/519013a. [PubMed] [CrossRef] [Google Scholar]

247. Evans DK, Popova A. West African Ebola crisis and orphans. Lancet. 2015;385:945–946. doi: 10.1016/S0140-6736(15)60179-9. [PubMed] [CrossRef] [Google Scholar]

248. Save the Children Foundation. Ebola crisis: facts, FAQs, and how to help. http://www.savethechildren.org/site/c.8rKLIXMGIpI4E/b.9208421/k.244F/Ebola_Response_in_West_Africa.htm?msource=weklpebo1014 (2015).

249. Gatiso TT, et al. The impact of the Ebola virus disease (EVD) epidemic on agricultural production and livelihoods in Liberia. PLoS Negl. Trop. Dis. 2018;12:e0006580. doi: 10.1371/journal.pntd.0006580. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

250. Chow A, et al. Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor. J. Infect. Dis. 2011;203:149–157. doi: 10.1093/infdis/jiq042. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

251. Hoarau J-J, et al. Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response. J. Immunol. 2010;184:5914–5927. doi: 10.4049/jimmunol.0900255. [PubMed] [CrossRef] [Google Scholar]

252. Roques P, Gras G. Chikungunya fever: focus on peripheral markers of pathogenesis. J. Infect. Dis. 2011;203:141–143. doi: 10.1093/infdis/jiq026. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

253. Jacobs M, et al. Late Ebola virus relapse causing meningoencephalitis: a case report. Lancet. 2016;388:498–503. doi: 10.1016/S0140-6736(16)30386-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

254. Varkey JB, et al. Persistence of Ebola virus in ocular fluid during convalescence. N. Engl. J. Med. 2015;372:2423–2427. doi: 10.1056/NEJMoa1500306. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

255. Christie A, et al. Possible sexual transmission of Ebola virus - Liberia, 2015. Morb. Mortal. Wkly. Rep. 2015;64:479–481. [PMC free article] [PubMed] [Google Scholar]

256. Fischer WA, II, Wohl DA. Confronting Ebola as a sexually transmitted infection. Clin. Infect. 2016;62:1272–1276. doi: 10.1093/cid/ciw123. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

257. Martini GA, Schmidt HA. Spermatogenic transmission of the “Marburg virus”. (Causes of “Marburg simian disease”) [German] Klin. Wochenschr. 1968;46:398–400. doi: 10.1007/BF01734141. [PubMed] [CrossRef] [Google Scholar]

258. Dokubo EK, et al. Persistence of Ebola virus after the end of widespread transmission in Liberia: an outbreak report. Lancet Infect. Dis. 2018;18:1015–1024. doi: 10.1016/S1473-3099(18)30417-1. [PubMed] [CrossRef] [Google Scholar]

259. Subissi L, et al. Ebola virus transmission caused by persistently infected survivors of the 2014–2016 outbreak in West Africa. J. Infect. Dis. 2018;218:S287–S291. doi: 10.1093/infdis/jiy280. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

260. Liu WJ, et al. Comprehensive clinical and laboratory follow-up of a female patient with Ebola virus disease: Sierra Leone Ebola virus persistence study. Open Forum Infect. Dis. 2019;6:ofz068. [PMC free article] [PubMed] [Google Scholar]

261. Rodriguez LL, et al. Persistence and genetic stability of Ebola virus during the outbreak in Kikwit, Democratic Republic of the Congo, 1995. J. Infect. Dis. 1999;179:S170–S176. doi: 10.1086/514291. [PubMed] [CrossRef] [Google Scholar]

262. Bower H, et al. Delivery of an Ebola virus-positive stillborn infant in a rural community health center, Sierra Leone, 2015. Am. J. Trop. Med. Hyg. 2016;94:417–419. doi: 10.4269/ajtmh.15-0619. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

263. Sissoko D, et al. Ebola virus persistence in breast milk after no reported illness: a likely source of virus transmission from mother to child. Clin. Infect. Dis. 2017;64:513–516. [PMC free article] [PubMed] [Google Scholar]

264. Zeng X, et al. Identification and pathological characterization of persistent asymptomatic Ebola virus infection in rhesus monkeys. Nat. Microbiol. 2017;2:17113. doi: 10.1038/nmicrobiol.2017.113. [PubMed] [CrossRef] [Google Scholar]

265. Fischer WA, II, et al. Shifting the paradigm - applying universal standards of care to Ebola virus disease. N. Engl. J. Med. 2019;380:1389–1391. doi: 10.1056/NEJMp1817070. [PubMed] [CrossRef] [Google Scholar]

266. Epelboin, A. & Formenty, P. in Les Maladies Infectieuses Émergentes: État de la Situation et Perspectives (eds Leport, C. & Guégan, J. F.) 111–113 (Haut Conseil de la Santé Publique, 2011).

267. Hewlett, B. S. & Hewlett, B. L. Ebola, Culture and Politics: the Anthropology of an Emerging Disease (Thomson Wadsworth, 2008).

268. Prinz A. Contributions to visual anthropology - ethnomedical background of the Ebola epidemic 2004 in Yambio, South Sudan. Vienn. Ethnomed. Newsl. 2005;7:16–19. [Google Scholar]

269. Chandler C, et al. Ebola: limitations of correcting misinformation. Lancet. 2015;385:1275–1277. doi: 10.1016/S0140-6736(14)62382-5. [PubMed] [CrossRef] [Google Scholar]

270. Richards P, et al. Social pathways for Ebola virus disease in rural Sierra Leone, and some implications for containment. PLoS Negl. Trop. Dis. 2015;9:e0003567. doi: 10.1371/journal.pntd.0003567. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

271. Sams K, Desclaux A, Sow S. ‘They’ll inject you and you’ll die’: from medication non-compliance to acceptance in Guinea’s Ebola treatment units. Anthropol. Med. 2019 doi: 10.1080/13648470.2019.1615749. [PubMed] [CrossRef] [Google Scholar]

272. Thys S, Boelaert M. The origin of Ebola: biomedical approach versus popular interpretations in Macenta, Guinea [French] Santé Publique. 2017;29:497–507. doi: 10.3917/spub.174.0497. [PubMed] [CrossRef] [Google Scholar]

273. Desclaux A, Anoko J. Anthropology engaged against Ebola (2014–2016): approaches, contributions and new questions [French] Santé Publique. 2017;29:477–485. doi: 10.3917/spub.174.0477. [PubMed] [CrossRef] [Google Scholar]

274. Kasereka MC, Hawkes MT. ‘The cat that kills people:’ community beliefs about Ebola origins and implications for disease control in Eastern Democratic Republic of the Congo. Pathog. Glob. Health. 2019;113:149–157. doi: 10.1080/20477724.2019.1650227. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

275. World Health Organization. Case definition recommendations for Ebola or Marburg virus diseases. https://www.who.int/csr/resources/publications/ebola/case-definition/en/ (2014).

276. Centers for Disease Control and Prevention. Case definition for Ebola virus disease (EVD). https://www.cdc.gov/vhf/ebola/clinicians/evaluating-patients/case-definition.html (2014).

277. Centers for Disease Control and Prevention. Ebola (Ebola Virus Disease). Transmission. https://www.cdc.gov/vhf/ebola/transmission/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fvhf%2Febola%2Fexposure%2Frisk-factors-when-evaluating-person-for-exposure.html (2019).

278. Levine AC, et al. Derivation and internal validation of the Ebola prediction score for risk stratification of patients with suspected Ebola virus disease. Ann. Emerg. Med. 2015;66:285–293.e1. doi: 10.1016/j.annemergmed.2015.03.011. [PubMed] [CrossRef] [Google Scholar]

279. Wahl-Jensen, V. et al. in Viral Hemorrhagic Fevers Ch. 7 (eds Singh, S. K. & Ruzek, D.) 99–127 (CRC Press, 2013).

280. Judson SD, Fischer R, Judson A, Munster VJ. Ecological contexts of index cases and spillover events of different ebolaviruses. PLoS Pathog. 2016;12:e1005780. doi: 10.1371/journal.ppat.1005780. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

281. Emanuel J, Marzi A, Feldmann H. Filoviruses: ecology, molecular biology, and evolution. Adv. Virus Res. 2018;100:189–221. doi: 10.1016/bs.aivir.2017.12.002. [PubMed] [CrossRef] [Google Scholar]

282. Kuhn, J. H. in Harrison’s principles of internal medicine Vol. 2 Ch. 205 (eds J. Larry Jameson et al.) (McGraw-Hill Education, 2018).

283. White JM, Schornberg KL. A new player in the puzzle of filovirus entry. Nat. Rev. Microbiol. 2012;10:317–322. doi: 10.1038/nrmicro2764. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

284. Ploquin A, Zhou Y, Sullivan NJ. Ebola immunity: gaining a winning position in lightning chess. J. Immunol. 2018;201:833–842. doi: 10.4049/jimmunol.1700827. [PubMed] [CrossRef] [Google Scholar]

285. Etard J-F, et al. Multidisciplinary assessment of post-Ebola sequelae in Guinea (Postebogui): an observational cohort study. Lancet Infect. Dis. 2017;17:545–552. doi: 10.1016/S1473-3099(16)30516-3. [PubMed] [CrossRef] [Google Scholar]

286. Shantha JG, et al. Ophthalmic manifestations and causes of vision impairment in Ebola virus disease survivors in Monrovia, Liberia. Ophthalmology. 2017;124:170–177. doi: 10.1016/j.ophtha.2016.10.011. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

287. Hereth-Hebert E, et al. Ocular complications in survivors of the Ebola outbreak in Guinea. Am. J. Ophthalmol. 2017;175:114–121. doi: 10.1016/j.ajo.2016.12.005. [PubMed] [CrossRef] [Google Scholar]

288. Cnops L, et al. Where are the Ebola diagnostics from last time? Nature. 2019;565:419–421. doi: 10.1038/d41586-019-00212-y. [PubMed] [CrossRef] [Google Scholar]

289. Dahlke C, et al. Dose-dependent T-cell dynamics and cytokine cascade following rVSV-ZEBOV immunization. EBioMedicine. 2017;19:107–118. doi: 10.1016/j.ebiom.2017.03.045. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

290. Milligan ID, et al. Safety and immunogenicity of novel adenovirus type 26- and modified vaccinia Ankara-vectored Ebola vaccines: a randomized clinical trial. JAMA. 2016;315:1610–1623. doi: 10.1001/jama.2016.4218. [PubMed] [CrossRef] [Google Scholar]

291. Huttner A, et al. Determinants of antibody persistence across doses and continents after single-dose rVSV-ZEBOV vaccination for Ebola virus disease: an observational cohort study. Lancet Infect. Dis. 2018;18:738–748. doi: 10.1016/S1473-3099(18)30165-8. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

292. Kennedy SB, et al. Phase 2 placebo-controlled trial of two vaccines to prevent Ebola in Liberia. N. Engl. J. Med. 2017;377:1438–1447. doi: 10.1056/NEJMoa1614067. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

293. Samai M, et al. The Sierra Leone trial to introduce a vaccine against Ebola: an evaluation of rVSVG-ZEBOV-GP vaccine tolerability and safety during the West Africa Ebola outbreak. J. Infect. Dis. 2018;217:S6–S15. doi: 10.1093/infdis/jiy020. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

294. McWilliams IL, et al. Pseudovirus rVSVΔG-ZEBOV-GP infects neurons in retina and CNS, causing apoptosis and neurodegeneration in neonatal mice. Cell Rep. 2019;26:1718–1726.e4. doi: 10.1016/j.celrep.2019.01.069. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

295. van den Pol AN, Mao G, Chattopadhyay A, Rose JK, Davis JN. Chikungunya, influenza, Nipah, and Semliki Forest chimeric viruses with vesicular stomatitis virus: actions in the brain. J. Virol. 2017;91:e02154-16. doi: 10.1128/JVI.02154-16. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

296. Halperin SA, et al. Immunogenicity, lot consistency, and extended safety of rVSVDeltaG-ZEBOV-GP vaccine: a phase 3 randomized, double-blind, placebo-controlled study in healthy adults. J. Infect. Dis. 2019;220:1127–1135. doi: 10.1093/infdis/jiz241. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

297. Winslow RL, et al. Immune responses to novel adenovirus type 26 and modified vaccinia virus Ankara-vectored Ebola vaccines at 1 year. JAMA. 2017;317:1075–1077. doi: 10.1001/jama.2016.20644. [PubMed] [CrossRef] [Google Scholar]


Page 2

EBOV detection tests used in the field

Test (manufacturer)Test typeTargetSamplesSensitivitySpecificityViruses detected
Rapid viral antigen detection tests
Dual Path Platform (DPP) Ebola antigen system (Chembio)aImmunochromatographic lateral flow assayVP40Venous whole blood (EDTA), venous plasma (EDTA) and capillary fingerstick whole bloodQualitative; less sensitive than PCR; requires confirmatory testingFrom limited data, does not cross-react with other ebolavirusesEBOV
OraQuick Ebola rapid antigen test (OraSure Technologies)b,cImmunochromatographic lateral flow assayVP40Oral fluid and whole blood97.1% (from oral fluid from deceased individuals); LLOD: 53 ng per ml for whole blood samples and 106 ng per ml for oral fluid98–100% from venous whole blood samples; 99.1–100% from oral fluid from deceased individualsBDBV, EBOV and SUDV; does not differentiate between ebolaviruses
SD Q Line Ebola Zaire Ag test (SD Biosensor)bImmunoprecipitation lateral flow assayGP1,2, NP and VP40Plasma, serum and whole blood84.9% for whole blood and plasma99.7% for whole blood and plasmaEBOV
PCR-based tests
Ebola real-time RT-PCR kit (Liferiver Bio-tech)bFluorescent real-time RT-PCRNucleic acids from ebolavirusesSerum, body fluid and urineLLOD: 23.9 copies of viral genome per reactionNot availableEbolaviruses
EZ1 test (DOD)aReal-time TaqMan RT-PCR with fluorescent reporter dye detected at each PCR cycleEBOV nucleic acidsWhole blood and plasmaQualitative; LLOD: 100–1,000 pfu per ml depending on live or inactivated EBOV isolate and cycler used100%; no cross-reactivity with other ebolaviruses or marburgvirusesEBOV
FilmArray NGDS BT-E (BioFire)aFluorescent nested multiplex RT-PCREBOV nucleic acidsWhole blood, plasma and serumLLOD: 1,000 pfu per ml or 4.36 × 103 genome equivalentsd per ml for live virusEBOV; no cross-reactivity with other ebolaviruses or marburgvirusesEBOV
FilmArray Biothreat-E (BioFire)aFluorescent nested multiplex RT-PCREBOV nucleic acidsWhole blood and urine95% detection rate confirms LOD; LOD: 6 × 105 pfu per ml using γ-irradiated EBOV89–100% using whole blood samples, depending on the study population (Sierra Leone and UK)EBOV
Idylla Ebola virus triage test (Biocartis)aQualitative real-time RT-PCR with fluorescent reporter dyes generated upon amplification of cDNAEBOV and SUDV nucleic acidsWhole blood and urine97% positive agreement compared with a non-reference standard; LLOD: 465 pfu per ml or 178 copies per ml100% for EBOVEBOV and SUDV
LightMix Ebola Zaire TIB MolBio with Lightcycler (Roche)aQualitative real-time RT-PCR with fluorescent reporter dye detected at each PCR cycleEBOV nucleic acidsWhole blood95% positive agreement compared with a non-reference standard; LLOD: 4,781 pfu per ml100% for EBOVEBOV
Ebola virus NP real-time RT-PCR (ThermoFisher (CDC))aQualitative real-time RT-PCR with fluorescent reporter dye detected at each PCR cycleEBOV NP RNAWhole blood, serum, plasma and urinee99.80%; LLOD: 600–700 TCID50 copies per ml100% for EBOVEBOV
RealStar Ebolavirus RT-PCR kit (Altona Diagnostics)a,bReal-time RT-PCR with fluorescent dye-labelled probes to detect PCR ampliconsNucleic acids from ebolavirusesPlasma82%; LLOD: 1 pfu per ml100% for EBOVEbolaviruses
EBOV VP40 real-time RT-PCR (CDC)aReal-time RT-PCR with fluorescent dye-labelled probes to detect PCR ampliconsEBOV VP40 RNAWhole blood, serum, plasma and urineeLLOD: 400–600 TCID50 per ml from whole blood; 250–600 TCID50 per ml, depending on body fluid sample and extraction method used100% for EBOVEBOV
Gene Xpert Ebola (Cepheid)a,bReal-time RT-PCR with fluorescent signal from probes for quality controlEBOV NP and GP nucleic acidsWhole blood and oral fluids100%; LLOD: 232.4 genomic copies per ml99.5% from whole blood; 100% from oral fluidEBOV