Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials

Clinical Pharmacokinetics

Volumn 55, Issue 8, 2016, Pages 907-923

  Madelain, Vincent ^a,b   Nguyen, Thi Huyen Tram ^a,b   Olivo, Anaelle ^c   de Lamballerie, Xavier ^d,e   Guedj, Jérémie ^a,b   Taburet, Anne Marie ^c   Mentré, France ^a  

^a UNIVERSITÉ PARIS DIDEROT   (France)

^b UNIVERSITÉ PARIS DESCARTES   (France)

^c INSERM U1184   (France)

^d Aix Marseille University IRD 190 Inserm 1207   (France)

^e AIX MARSEILLE UNIVERSITY   (France)

Author keywords

[No Author keywords available]

Indexed keywords

AMINOTRANSFERASE; ANTICOAGULANT AGENT; ANTIVIRUS AGENT; AVI 7537; FAVIPIRAVIR; GALIDESIVIR; INTERFERON; RECOMBINANT NEMATODE ANTICOAGULANT PROTEIN C2; RECOMBINANT PROTEIN; TKM EBOLA; UNCLASSIFIED DRUG; URIC ACID; ZMAPP; 2-(4-AMINO-5H-PYRROLO(3,2-D)PYRIMIDIN-7-YL)-5-(HYDROXYMETHYL)PYRROLIDINE-3,4-DIOL; AMIDE; PURINE NUCLEOSIDE; PYRAZINE DERIVATIVE;

ANTIVIRAL ACTIVITY; ASTHENIA; BLEEDING; CHEST TIGHTNESS; CLINICAL EVALUATION; CLINICAL TRIAL (TOPIC); CONVALESCENCE; CYTOKINE RELEASE SYNDROME; DEPRESSION; DIARRHEA; DIZZINESS; DRUG EFFICACY; DRUG SAFETY; EBOLA HEMORRHAGIC FEVER; EBOLAVIRUS; EPIDEMIOLOGICAL DATA; FATIGUE; FEVER; GASTROINTESTINAL DISEASE; HEADACHE; HUMAN; HYPOTENSION; INFLAMMATION; IRRITABILITY; MEDICAL CARE; MEDICAL HISTORY; MEMORY DISORDER; MYALGIA; NEUROLOGIC DISEASE; NEUTROPENIA; NONHUMAN; PATIENT CARE; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PLASMA; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RASH; REVIEW; RIGOR; SIDE EFFECT; SKIN DISEASE; TACHYCARDIA; TACHYPNEA; THROMBOCYTOPENIA; THYROIDITIS; ANIMAL; ANIMAL MODEL; DISEASE OUTBREAKS; DRUG EFFECTS; HEMORRHAGIC FEVER, EBOLA; NORMAL HUMAN;

AMIDES; ANIMALS; ANTIVIRAL AGENTS; DISEASE OUTBREAKS; EBOLAVIRUS; HEALTHY VOLUNTEERS; HEMORRHAGIC FEVER, EBOLA; HUMANS; MODELS, ANIMAL; PURINE NUCLEOSIDES; PYRAZINES;

EID: 84955304814     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.1007/s40262-015-0364-1     Document Type: Review

References (94)

1. Report of an International Commission. Ebola haemorrhagic fever in Zaire, 1976. Bull World Health Organ. 1978;56:271–93.
2. World Health Organization. Ebola Situation Report, 23 September 2015. Ebola [Internet]. http://apps.who.int/iris/bitstream/10665/185279/1/ebolasitrep_23Sept2015_eng.pdf?ua=1. Cited 28 Sep 2015.
3. Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377:849–62.
4. Bukreyev AA, Chandran K, Dolnik O, Dye JM, Ebihara H, Leroy EM, et al. Discussions and decisions of the 2012–2014 International Committee on Taxonomy of Viruses (ICTV) Filoviridae Study Group, January 2012–June 2013. Arch Virol. 2014;159:821–30.
5. Kuhn JH, Becker S, Ebihara H, Geisbert TW, Johnson KM, Kawaoka Y, et al. Proposal for a revised taxonomy of the family Filoviridae: classification, names of taxa and viruses, and virus abbreviations. Arch Virol. 2010;155:2083–103.
6. Ansari AA. Clinical features and pathobiology of Ebolavirus infection. J Autoimmun. 2014;55:1–9.
7. Choi JH, Croyle MA. Emerging targets and novel approaches to Ebola virus prophylaxis and treatment. BioDrugs Clin Immunother Biopharm Gene Ther. 2013;27:565–83.
8. Dudas G, Rambaut A. Phylogenetic analysis of Guinea 2014 EBOV Ebolavirus outbreak. PLoS Curr Outbreaks. 2014;6. doi:10.1371/currents.outbreaks.84eefe5ce43ec9dc0bf0670f7b8b417d.
9. Beeching NJ, Fenech M, Houlihan CF. Ebola virus disease. BMJ. 2014;349:g7348.
10. Moyen N, Thirion L, Emmerich P, Dzia-Lepfoundzou A, Richet H, Boehmann Y, et al. Risk factors associated with Ebola and Marburg viruses seroprevalence in blood donors in the Republic of Congo. PLoS Negl Trop Dis. 2015;9:e0003833.
11. Leroy EM, Baize S, Volchkov VE, Fisher-Hoch SP, Georges-Courbot MC, Lansoud-Soukate J, et al. Human asymptomatic Ebola infection and strong inflammatory response. Lancet Lond Engl. 2000;355:2210–5.
12. Schieffelin JS, Shaffer JG, Goba A, Gbakie M, Gire SK, Colubri A, et al. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N Engl J Med. 2014;371:2092–100.
13. Yazdanpanah Y, Arribas JR, Malvy D. Treatment of Ebola virus disease. Intensive Care Med. 2015;41:115–7.
14. Fowler RA, Fletcher T, Fischer WA, Lamontagne F, Jacob S, Brett-Major D, et al. Caring for critically ill patients with Ebola virus disease: perspectives from West Africa. Am J Respir Crit Care Med. 2014;190:733–7.
15. van Griensven J, De Weiggheleire A, Delamou A, Smith PG, Edwards T, Vandekerckhove P, 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(1):69–74.
16. World Health Organization. Categorization and prioritization of drugs for consideration for testing or use in patients infected with Ebola. In: Ebola treatments and interventions. 3 July 2015 [Internet]. http://www.who.int/medicines/ebola-treatment/2015_0703TablesofEbolaDrugs.pdf?ua=1. Cited 7 Sep 2015.
17. Li TCM, Chan MCW, Lee N. Clinical implications of antiviral resistance in influenza. Viruses. 2015;7:4929–44.
18. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antivir Res. 2013;100:446–54.
19. Arias A, Thorne L, Goodfellow I. Favipiravir elicits antiviral mutagenesis during virus replication in vivo. eLife. 2014;3:e03679.
20. Toyama Chemicals. Summary of product characteristics of Avigan (unpublished reference).
21. Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antivir Res. 2014;105:17–21.
22. Smither SJ, Eastaugh LS, Steward JA, Nelson M, Lenk RP, Lever MS. Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model. Antivir Res. 2014;104:153–5.
23. Madelain V, Oestereich L, Graw F, Nguyen THT, de Lamballerie X, Mentré F, et al. Ebola virus dynamics in mice treated with favipiravir. Antivir Res. 2015;123:70–7.
24. Sissoko D, Laouenan C, Folkessons E, M’Lebing AB, Beavogui AH, Baize S et al. Favipiravir for treatment of Ebola virus disease (the JIKI Trial): a historically-controlled, single arm proof-of-concept trial in Guinea. PLOS Medicine. 2016. (In press)
25. Mentré F, Taburet A-M, Guedj J, Anglaret X, Keïta S, de Lamballerie X, et al. Dose regimen of favipiravir for Ebola virus disease. Lancet Infect Dis. 2015;15:150–1.
26. Bouazza N, Treluyer J-M, Foissac F, Mentré F, Taburet A-M, Guedj J, et al. Favipiravir for children with Ebola. Lancet. 2015;385:603–4.
27. Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, Van Tongeren SA, et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature. 2014;508:402–5.
28. Stonehouse J, Staab T, Bennett R. 26th Annual Piper Jaffray Healthcare Conference. New York, USA; 2014.
29. Stonehouse J, Sheridan B, Staab T, Bennett R. Citi 10th Annual Biotech Conference. Boston, USA; 2015.
30. BioCryst Pharmaceuticals Inc. BioCryst announces study results for BCX4430 in a non-human primate model of Ebola virus infection. In: Press Release. 23 Dec 2014 [Internet]. http://investor.shareholder.com/biocryst/releasedetail.cfm?ReleaseID=888802. Cited 7 Sep 2015.
31. Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB, et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014;514:47–53.
32. Murin CD, Fusco ML, Bornholdt ZA, Qiu X, Olinger GG, Zeitlin L, et al. Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Proc Natl Acad Sci. 2014;111:17182–7.
33. Zeitlin L, Pettitt J, Scully C, Bohorova N, Kim D, Pauly M, et al. Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant. Proc Natl Acad Sci. 2011;108:20690–4.
34. National Institute of Allergy and Infectious Diseases. Safety and Pharmacokinetics of a Single ZMappTM Administration in Healthy Adult Volunteers [Internet]. https://clinicaltrials.gov/ct2/show/NCT02389192?term=zmapp+ebola&rank=2. Cited 7 Sep 2015.
35. European Medicines Agency. Medicinal products under development for the treatment of Ebola. In: Interim assessment report, 22 Jan 2015 [Internet]. http://www.ema.europa.eu/docs/en_GB/document_library/Report/2014/12/WC500179062.pdf. Cited 7 Sep 2015.
36. Pettitt J, Zeitlin L, Kim DH, Working C, Johnson JC, Bohorov O, et al. Therapeutic intervention of ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail. Sci Transl Med. 2013;5:199ra113.
37. Olinger GG, Pettitt J, Kim D, Working C, Bohorov O, Bratcher B, et al. Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. Proc Natl Acad Sci. 2012;109:18030–5.
38. Qiu X, Audet J, Wong G, Fernando L, Bello A, Pillet S, et al. Sustained protection against Ebola virus infection following treatment of infected nonhuman primates with ZMAb. Sci Rep. 2013;3:3365.
39. Qiu X, Wong G, Fernando L, Audet J, Bello A, Strong J, et al. mAbs and Ad-vectored IFN-α therapy rescue Ebola-infected nonhuman primates when administered after the detection of viremia and symptoms. Sci Transl Med. 2013;5:207ra143.
40. National Institute of Allergy and Infectious Diseases. Putative investigational therapeutics in the treatment of patients with known ebola infection—full text view—ClinicalTrials.gov [Internet]. https://clinicaltrials.gov/ct2/show/NCT02363322?term=zmapp+ebola&rank=1. Cited 7 Sep 2015.
41. George PM, Badiger R, Alazawi W, Foster GR, Mitchell JA. Pharmacology and therapeutic potential of interferons. Pharmacol Ther. 2012;135:44–53.
42. Bekisz J, Schmeisser H, Hernandez J, Goldman ND, Zoon KC. Human interferons alpha, beta and omega. Growth Factors. 2004;22:243–51.
43. Lin F, Young HA. Interferons: success in anti-viral immunotherapy. Cytokine Growth Factor Rev. 2014;25:369–76.
44. Basler CF, Amarasinghe GK. Evasion of interferon responses by Ebola and Marburg viruses. J Interferon Cytokine Res. 2009;29:511–20.
45. Wong G, Kobinger GP, Qiu X. Characterization of host immune responses in Ebola virus infections. Expert Rev Clin Immunol. 2014;10:781–90.
46. Geisbert TW, Hensley LE, Gibb TR, Steele KE, Jaax NK, Jahrling PB. Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses. Lab Invest. 2000;80:171–86.
47. Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist. 2001;6:34–55.
48. Radwanski E, Perentesis G, Jacobs S, Oden E, Affrime M, Symchowicz S, et al. Pharmacokinetics of Interferon α-2b in Healthy Volunteers. J Clin Pharmacol. 1987;27:432–5.
49. Vidal 2015 dictionary [Internet]. https://www.vidal.fr/. Cited 7 Sep 2015.
50. Rogge MC, Liu Y, Galluppi GR. Interferon beta assessment in non-Chinese and Chinese subjects: pharmacokinetics and pharmacodynamic activity of an endogenous cytokine are not race dependent. J Clin Pharmacol. 2014;54:1153–61.
51. Subramanian GM, Moore PA, Gowen BB, Olsen AL, Barnard DL, Paragas J, et al. Potent in vitro activity of the albumin fusion type 1 interferons (albumin-interferon-alpha and albumin-interferon-beta) against RNA viral agents of bioterrorism and the severe acute respiratory syndrome (SARS) virus. Chemotherapy. 2008;54:176–80.
52. Jahrling PB, Geisbert TW, Geisbert JB, Swearengen JR, Bray M, Jaax NK, et al. Evaluation of immune globulin and recombinant interferon-alpha2b for treatment of experimental Ebola virus infections. J Infect Dis. 1999;179(Suppl 1):S224–34.
53. Smith LM, Hensley LE, Geisbert TW, Johnson J, Stossel A, Honko A, et al. Interferon-β therapy prolongs survival in rhesus macaque models of Ebola and Marburg hemorrhagic fever. J Infect Dis. 2013;208:310–8.
54. Qiu X, Audet J, Wong G, Pillet S, Bello A, Cabral T, et al. Successful treatment of Ebola virus-infected cynomolgus macaques with monoclonal antibodies. Sci Transl Med. 2012;4:138ra81–138ra81.
55. Thi EP, Mire CE, Lee ACH, Geisbert JB, Zhou JZ, Agans KN, et al. Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates. Nature. 2015;521:362–5.
56. Castanotto D, Rossi JJ. The promises and pitfalls of RNA-interference-based therapeutics. Nature. 2009;457:426–33.
57. Tekmira Pharmaceuticals Corporation. Safety, tolerability and pharmacokinetic first in human (FIH) study for intravenous (IV) TKM-100802—ClinicalTrials.gov [Internet]. https://clinicaltrials.gov/ct2/show/NCT02041715?term=tkm+ebola&rank=2. Cited 7 Sep 2015.
58. Kraft CS, Hewlett AL, Koepsell S, Winkler AM, Kratochvil CJ, Larson L, 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.
59. Geisbert TW, Lee ACH, Robbins M, Geisbert JB, Honko AN, Sood V, et al. Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet. 2010;375:1896–905.
60. US Securities and Exchange Commission. Tekmira provides update on TKM-Ebola-Guinea [Internet]. 2015. http://www.sec.gov/Archives/edgar/data/1447028/000117184315003522/newsrelease.htm. Cited 30 Sep 2015.
61. Heald AE, Iversen PL, Saoud JB, Sazani P, Charleston JS, Axtelle T, et al. Safety and pharmacokinetic profiles of phosphorodiamidate morpholino oligomers with activity against Ebola virus and marburg virus: results of two single-ascending-dose studies. Antimicrob Agents Chemother. 2014;58:6639–47.
62. Iversen PL, Warren TK, Wells JB, Garza NL, Mourich DV, Welch LS, et al. Discovery and early development of AVI-7537 and AVI-7288 for the treatment of Ebola virus and Marburg virus infections. Viruses. 2012;4:2806–30.
63. Warren TK, Warfield KL, Wells J, Swenson DL, Donner KS, Van Tongeren SA, et al. Advanced antisense therapies for postexposure protection against lethal filovirus infections. Nat Med. 2010;16:991–4.
64. Warren TK, Whitehouse CA, Wells J, Welch L, Heald AE, Charleston JS, et al. A single phosphorodiamidate morpholino oligomer targeting VP24 protects rhesus monkeys against lethal ebola virus infection. mBio. 2015;6:e02344–14.
65. Stassens P, Bergum PW, Gansemans Y, Jespers L, Laroche Y, Huang S, et al. Anticoagulant repertoire of the hookworm Ancylostoma caninum. Proc Natl Acad Sci. 1996;93:2149–54.
66. Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E, Hensley LE. Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J Infect Dis. 2003;188:1618–29.
67. de Pont ACJM, Moons AHM, de Jonge E, Meijers JCM, Vlasuk GP, Rote WE, et al. Recombinant nematode anticoagulant protein c2, an inhibitor of tissue factor/factor VIIa, attenuates coagulation and the interleukin-10 response in human endotoxemia. J Thromb Haemost. 2004;2:65–70.
68. Vlasuk GP, Bradbury A, Lopez-Kinninger L, Colón S, Bergum PW, Maki S, et al. Pharmacokinetics and anticoagulant properties of the factor VIIa-tissue factor inhibitor recombinant Nematode anticoagulant protein c2 following subcutaneous administration in man. Dependence on the stoichiometric binding to circulating factor X. Thromb Haemost. 2003;90:803–12.
69. Giugliano RP, Wiviott SD, Stone PH, Simon DI, Schweiger MJ, Bouchard A, et al. Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial. J Am Coll Cardiol. 2007;49:2398–407.
70. Lee A, Agnelli G, Büller H, Ginsberg J, Heit J, Rote W, et al. Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation. 2001;104:74–8.
71. Moons AHM, Bijsterveld NR, Koch KT, Meijers JCM, Tijssen JGP, van der Poll T, et al. Inhibition of the tissue factor pathway of coagulation by recombinant nematode anticoagulant protein c2 during elective coronary stent implantation. Neth Heart J. 2004;12:48–54.
72. Geisbert TW, Hensley LE, Jahrling PB, Larsen T, Geisbert JB, Paragas J, et al. Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet. 2003;362:1953–8.
73. Hites M, Dell’Anna AM, Scolletta S, Taccone FS. The challenges of multiple organ dysfunction syndrome and extra-corporeal circuits for drug delivery in critically ill patients. Adv Drug Deliv Rev. 2014;77:12–21.
74. Roberts DJ, Hall RI. Drug absorption, distribution, metabolism and excretion considerations in critically ill adults. Expert Opin Drug Metab Toxicol. 2013;9:1067–84.
75. Shurtleff AC, Warren TK, Bavari S. Nonhuman primates as models for the discovery and development of ebolavirus therapeutics. Expert Opin Drug Discov. 2011;6:233–50.
76. Chimerix. An Open-Label, Multicenter study of the safety and anti viral activity of brincidofovir (BCV, CMX001) for Ebola virus disease—full text view—ClinicalTrials.gov [Internet]. https://clinicaltrials.gov/ct2/show/NCT02271347?term=brincidofovir+ebola&rank=1. Cited 25 Sep 2015.
77. Warren T, Jordan R, Lo M, Soloveva V, Ray A, Bannister R, et al. Nucleotide prodrug GS-5734 is a broad-spectrum filovirus inhibitor that provides complete therapeutic protection against the development of Ebola virus disease (EVD) in infected non-human primates. 2015;IDweek 2015:LB-2. https://idsa.confex.com/idsa/2015/webprogram/Paper54208.html. Accessed 1 Dec 2015.
78. Gilead Sciences. Gilead provides update on investigational compound, GS-5734, for the treatment of Ebola virus disease, Gilead [Internet]. http://www.gilead.com/news/press-releases/2015/10/gilead-provides-update-on-investigational-compound-gs5734-for-the-treatment-of-ebola-virus-disease. Cited 1 Dec 2015.
79. Shoemaker CJ, Schornberg KL, Delos SE, Scully C, Pajouhesh H, Olinger GG, et al. Multiple cationic amphiphiles induce a Niemann-Pick C phenotype and inhibit Ebola virus entry and infection. PLoS One. 2013;8:e56265.
80. Gehring G, Rohrmann K, Atenchong N, Mittler E, Becker S, Dahlmann F, et al. The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry. J Antimicrob Chemother. 2014;69:2123–31.
81. Neveu G, Barouch-Bentov R, Ziv-Av A, Gerber D, Jacob Y, Einav S. Identification and targeting of an interaction between a tyrosine motif within hepatitis C virus core protein and AP2M1 essential for viral assembly. PLoS Pathog. 2012;8:e1002845.
82. Basu A, Li B, Mills DM, Panchal RG, Cardinale SC, Butler MM, et al. Identification of a small-molecule entry inhibitor for filoviruses. J Virol. 2011;85:3106–19.
83. Wolf MC, Freiberg AN, Zhang T, Akyol-Ataman Z, Grock A, Hong PW, et al. A broad-spectrum antiviral targeting entry of enveloped viruses. Proc Natl Acad Sci. 2010;107:3157–62.
84. Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, et al. Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature. 2011;477:344–8.
85. Warren TK, Warfield KL, Wells J, Enterlein S, Smith M, Ruthel G, et al. Antiviral activity of a small-molecule inhibitor of filovirus infection. Antimicrob Agents Chemother. 2010;54:2152–9.
86. Kinch MS, Yunus AS, Lear C, Mao H, Chen H, Fesseha Z, et al. FGI-104: a broad-spectrum small molecule inhibitor of viral infection. Am J Transl Res. 2009;1:87–98.
87. Aman MJ, Kinch MS, Warfield K, Warren T, Yunus A, Enterlein S, et al. Development of a broad-spectrum antiviral with activity against Ebola virus. Antivir Res. 2009;83:245–51.
88. Nguyen T, Guedj J. HCV kinetic models and their implications in drug development. CPT Pharmacomet Syst Pharmacol. 2015;4:231–42.
89. Canini L, Perelson AS. Viral kinetic modeling: state of the art. J Pharmacokinet Pharmacodyn. 2014;41:431–43.
90. Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, Sanchez A, et al. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J Infect Dis. 2007;196:S142–7.
91. Varkey JB, Shantha JG, Crozier I, Kraft CS, Lyon GM, Mehta AK, et al. Persistence of Ebola virus in ocular fluid during convalescence. N Engl J Med. 2015;372:2423–7.
92. Tully CM, Lambe T, Gilbert SC, Hill AVS. Emergency Ebola response: a new approach to the rapid design and development of vaccines against emerging diseases. Lancet Infect Dis. 2015;15:356–9.
93. Martínez MJ, Salim AM, Hurtado JC, Kilgore PE. Ebola virus infection: overview and update on prevention and treatment. Infect Dis Ther. 2015;4(4):365–90.
94. Henao-Restrepo AM, Longini IM, Egger M, Dean NE, Edmunds WJ, Camacho A, 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;386:857–66.