1. EBOLA 2014 OUTBREAK, EXPERIMENTAL TREATMENTS AND RISK MANAGEMENT 1

2. Presentation plan  Virus and disease  West African outbreak in 2014  Cases outside West Africa and experimental treatments  Risk management  Other treatments and vaccines 2

3. Virus and disease 3

4. Ebola virus = EBOV  Family : Filoviridae, RNA virus, 5 species, specie now: Zaire Ebola Virus : ZEBOV  Ebola virus disease (EVD): fatal hemorrhagic fever in humans and other mammals  Ebola was discovered in 1976 in two outbreaks: one in Sudan and the other near the Ebola river in the Democratic Republic of Congo  Scientists believe that bats are the natural reservoir for the virus 4 http://www.who.int/mediacentre/factsheets/fs103/en/

5. Transmission 5 Rupa Kanapathipillai et al., N England J Med 2014 ; 371

6. Symptoms  Ebola can only be spread to others after symptoms begin.  Symptoms can appear from 2 to 21 days after exposure. Fever fatigue Muscle pain Headache Sore throat Followed by : Diarrhea Vomiting Rash Symptoms of impaired kidney and liver function In some cases : internal and external bleeding 6 cdc.gov

7. After diagnosis  Quarantine  Symptoms of Ebola are treated as they appear  Providing IV fluids balancing electrolytes (body salts)  Maintaining oxygen status and blood pressure  Treating other infections if they occur  Experimental vaccines and treatments for Ebola are under development  Recovery from Ebola depends on good supportive care and the patient’s immune response  Countries affected do not have the capacity to manage an outbreak of this size 7 cdc.gov

8. Historic of outbreaks 8

9. West African outbreak in 2014 9

10. Seems to have started in a village near Guéckédou, Guinea, where bat hunting is common. 10

11. West African outbreak in 2014 11

12. West African outbreak in 2014 12

13. West African outbreak in 2014 13

14. West African outbreak in 2014 14

15. West African outbreak in 2014 15

16. West African outbreak in 2014 CDC : last update October 25, 2014 16

17. Cases of Ebola outside West Africa and experimental treatments 17

18. Cases of Ebola outside West Africa 18

19. August, 2 2 aid workers (Dr Brantly), from Liberia, treated by Z-mapp, both recovered 19

20. Z-mapp  3 humanized monoclonal antibodies  Manufactured in tobacco plant Nicotiana benthamiana  Under development as treatment for Ebola virus disease  Tested in primates  Not been subjected to a randomized clinical trial to prove its safety or its efficacy  Tested in humans during the 2014 West Africa Ebola virus outbreak  9 persons treated: 5 recovered and 4 died  Out of stock  In trials : Z-mabs (Mapp) : similar to Z- mapp Mapp Biopharmaceutical, Kentucky BioProcessing subsidiary of Reynolds American, USA Experimental biopharmaceutical drug 20

21. August, 2 2 aid workers (Dr Brantly), from Liberia, treated by Z-mapp, both recovered September 5, Dr Sacra, American, from Liberia Treated with TKM- Ebola and Brantly’s blood 21

22. TKM- EBOLA (TKM 100- 802)  3 small interfering RNA (siRNA) cause the destruction of 3 proteins in Ebola virus  Effectiveness in non human primates against Zaire Ebola virus (Geisbert et al., Lancet 2010 ; 375 : 1896)  Clinical trials:  Phase I: in January 2014 : safety, tolerability and PK, healthy subjects, single ascending dose tested  Consortium TKM with WHO to provide a clinical trial in West Africa Tekmira Pharmaceuticals, Vancouver with the department of USA defense 22

23. Blood- therapy  Transfusion of serum of recovered infected patient  Contains antibodies against Ebola virus  Dr Brantly’s blood who recovered from the disease was used on compatible patients 23

24. August, 2 2 aid workers (Dr Brantly), from Liberia, treated by Z-mapp, both recovered 7, Missionary Parajes from Liberia to Spain, treated by Z-mapp, died September 5, Dr Sacra, American, from Liberia Treated with TKM- Ebola and Brantly’s blood 22, missionary Garcia from Sierra Leone to Spain, treated by ? Died 24

25. August, 2 2 aid workers (Dr Brantly), from Liberia, treated by Z-mapp, both recovered 7, Missionary Parajes from Liberia to Spain, treated by Z-mapp, died September 5, Dr Sacra, American, from Liberia Treated with TKM- Ebola and Brantly’s blood 9 : French nurse from Liberia, treated (?), recovered - Favipiravir - Z-mapp - TKM-Ebola 22, missionary Garcia from Sierra Leone to Spain, treated by ? Died 25

26. Favipiravir =T-705  = Avigan ®  Oral anti-viral against RNA viruses  Approved against seasonal influenza  Inhibits replication of Zaire Ebola Virus in cell culture  In mouse model : effective even if initiated at day 6 post infection  November: trials in Guinea  Production to treat 20 000 potential patients Developed by FujiFilm subsidiary Toyama Chemicals Co., Japan 26

27. August, 2 2 aid workers (Dr Brantly), from Liberia, treated by Z-mapp, both recovered 7, Missionary Parajes from Liberia to Spain, treated by Z-mapp, died September 5, Dr Sacra, American, from Liberia Treated with TKM- Ebola and Brantly’s blood 9 : French nurse from Liberia, treated (?), recovered - Favipiravir - Z-mapp - TKM-Ebola 22, missionary Garcia from Sierra Leone to Spain, treated by ? Died 30 : Mr Duncan, Liberian man, tested positive in Dallas, treated with brincidofovir 27

28. Brincidofovi r (CMX001)  Oral anti-viral drug active against DNA viruses  In phase III for adenovirus and cytomegalovirus  Potential treatment of Ebola virus disease shown in preliminary in vitro tests (RNA virus)  Patient in US (Mr Duncan) received it but was very ill and died  Approval by FDA in October 16 to start Phase II trials for Ebola (emergency investigational new drug applications) Chimerix (USA) 28

29. August, 2 2 aid workers (Dr Brantly), from Liberia, treated by Z-mapp, both recovered 7, Missionary Parajes from Liberia to Spain, treated by Z-mapp, died September 5, Dr Sacra, American, from Liberia Treated with TKM- Ebola and Brantly’s blood 9 : French nurse from Liberia, treated (?), recovered - Favipiravir - Z-mapp - TKM-Ebola 22, missionary Garcia from Sierra Leone to Spain, treated by ? Died 30 : Mr Duncan, Liberian man, tested positive in Dallas, treated with brincidofovir October 8, Mr Duncan died October: Contamination of 2 nurses Vinson and Pham, recovered October: Contamination of spanish nurse Romero, treated with Z-mapp, recovered 29

30. Risk management 30

31. Outbreak control  Prevention :  Reduce the risk of wildlife-to-human transmission  Contact with infected fruits, animals  Animal products should be cooked  Reduce the risk of human-to-human transmission  Direct contact with people with Ebola symptoms  Gloves, personal protective equipment  Outbreak containment measures  Prompt and safe burial of the dead  Identifying people in contact and monitoring 31 Who.int

32. Health-care settings  Health-care workers have frequently been infected while treating patients  Precautions:  Basic hand hygiene  Personal protective equipment  Safe injection practices  Safe burial practices  Guidelines from CDC (USA), eCDC (Europe), Ministery of health (France) …  procedure for personal protective equipment  caring for suspect or confirmed patients  environmental infection control in hospitals  safe handling of human remains …… 32 Who.int

33. 33 cdc.org

34. Other treatments 34

35. AVI-6002  Antisense drug  Combinaison AVI-7537 and AVI-7539 against viral matrix proteins VP 24 and VP 35  Effectiveness in non human primates against Zaire Ebolavirus  Phase I: favorable safety Developped by Sarepta Therapeutics, Cambridge,USA 35

36. cAd3- ZEBOV Vaccine  Adenovirus carrying two genes of the Ebola virus  Animal testing: production of proteins that stimulate the immune system to produce antibodies  Fast tracked in human studies in August  First Phase I in USA, UK and Mali  Results by the end of 2014  If successful: vaccination of healthcare workers in Sierra Leone, Guinea and Liberia GSK (UK) 36

37. VSV- ZEBOV Vaccine  Vesicular stomatitis virus and Ebola gp  provoke an immune response  Protective efficacy against Ebola in animals (80-100 %)  Phase I allows in USA, Canada results previous December 2014  October: 800-1000 vials sent to WHO: 3 shipments for precautions, (-80°), tested previous with volunteers from Germany, Switzerland, Gabon, Kenya Developped by the Canadian National Microbiology Laboratory, collaboration with NewLink Genetics 37

38. Conclusion 38

39. Conclusion  Important Ebola outbreak  Experimental treatments and vaccines  USA, UK, France, Germany, Italy : discussion for organization : aid workers and resources 39

40. 40 Thanks for your attention Any questions ?