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Ebola Vaccines and Treatments 26/11/2014. Current Prevention and Treatment Isolation of cases Stringent infection control Contact tracing Surveillance.

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Presentation on theme: "Ebola Vaccines and Treatments 26/11/2014. Current Prevention and Treatment Isolation of cases Stringent infection control Contact tracing Surveillance."— Presentation transcript:

1 Ebola Vaccines and Treatments 26/11/2014

2 Current Prevention and Treatment Isolation of cases Stringent infection control Contact tracing Surveillance Risk communication Treatment options limited Supportive therapy centred on: – Fluid resuscitation – Correction of electrolyte abnormalities – Prevention and treatment of concomitant infections – Prevention complications of shock

3 Treatment options for Ebola virus disease At present, there is no licensed specific therapeutic drug or vaccine available for Ebola virus disease (EVD) Number of drugs and vaccines under development which have demonstrated promising results in animal models Pressure to expedite clinical trials in light of current outbreak

4 The gold standard animal model for Ebola vaccine and drug testing is the non human primate (NHP) Macaques, African green monkeys, baboons

5 WHO CONSULTATION ON POTENTIAL EBOLA THERAPIES AND VACCINE GENEVA, SWITZERLAND 4–5 SEPTEMBER 2014

6 Potential Ebola Vaccines

7 Ebola vaccines - historically Debate about requirement for vaccine previously o Rarity of disease o Lack of interest from pharmaceutical industry o Potential cost View has changed in recent years o Increasing frequency of outbreaks with high case fatality rates o Number of imported cases of viral haemorrhagic fever and laboratory exposures o Potential misuse of EVD as bioterrorism agent

8 Who to vaccinate? Valuable for: – Medical personnel – First responders – Military personnel – Researchers – Ring vaccination in outbreak

9 What’s in the pipeline? Several candidate vaccines being developed Two identified as being at the most advanced stage of development Both are recombinant vector vaccines 1.Chimpanzee adenovirus serotype 3 (cAd3-EBO) 2.Recombinant vesicular stomatitis virus (rVSV-EBO) Both are being fast-tracked but data on safety and efficacy are limited

10 1. Chimpanzee adenovirus serotype 3 (cAd3-EBO) Based on recombinant adenovirus 3 (cAd3) technology – a surface protein gene of Ebola virus is inserted into a modified chimpanzee adenovirus – resulting virus cannot replicate in humans, but is intended to induce an immune response Adenovirus causes common cold Pre-existing immunity in humans may be a problem, impairing vaccine efficacy However, cAd3 is a rare adenovirus serotype, with most humans not having pre-existing immunity

11 1. Chimpanzee adenovirus serotype 3 (cAd3-EBO) cAd3-EBO tested in 16 NHPs and found to be 100% protective (Stanley et al 2014) Phase 1 human trials began in September in US and Oxford Being developed by GlaxoSmithKline and US National Institute of Health

12 2. Recombinant vesicular stomatitis virus vaccine (rVSV-EBO) VSV causes mild flu-like illness in humans Gene for surface glycoprotein of Ebola inserted into VSV - this recombinant virus is then intended to induce an immune response in humans to Ebola virus Jones et al (2005) – 100% protective against Zaire Ebola virus (ZEBOV) in NHPs after a single vaccination

13 2. Recombinant vesicular stomatitis virus vaccine (rVSV-EBO) Feldmann et al (2007) – demonstrated varying degrees of protection post- exposure in NHPs if vaccine given up to 24 hours after exposure to a lethal dose of Ebola virus Given to lab worker exposed to ZEBOV following needle stick injury in Hamburg, 2009 – VSV viraemia but did not develop EVD – It’s not possible to know if treatment was effective or if patient was never infected

14 2. Recombinant vesicular stomatitis virus vaccine (rVSV-EBO) Phase 1 human trials began this autumn Being developed by Public Health Agency of Canada, NewLink Genetics and others

15 Potential Ebola Treatments

16 1.Antibody therapy a.Convalescent whole blood and plasma b.Monoclonal antibodies (ZMapp) 2.Antiviral therapy a.RNA-based drugs b.Brincidofovir (CMX-001) 3.Immunomodulators 4.Coagulation modulators

17 1a. Convalescent Whole Blood and Plasma Blood or plasma transfusions from Ebola survivors might prevent or treat infection in others Studies not conclusive Theoretical and anecdotal evidence Used in small number in current outbreak Well-managed blood banks critical with thorough screening to ensure – No pathogens being transmitted via transfusion – Blood types match

18 1b. Monoclonal Antibodies - ZMapp Cocktail of 3 monoclonal antibodies – c13C6 and c2G4 and c4G7 Manufactured in tobacco plants Targets Ebola virus glycoprotein Attaches to the virus and block its infective potential

19 1b. ZMAPP: What’s the Evidence? Qiu et al (2014) – Study of 21 rhesus macaques – ZMAPP able to rescue 100% of macaques infected with lethal dose of EBOV when treatment initiated up to 5 days post lethal Ebola challenge – Some NHPs with advanced disease fully recovered

20 1b. Monoclonal Antibodies - ZMapp Not yet tested in human trials Small number of cases from current outbreak given drug on compassionate basis with variable results Current supplies of drug exhausted Efforts being made to scale up production, task difficult due to its complex production processes Phase 1 clinical trials planned

21 2a. RNA-based drugs Interfere with translation of Ebola virus mRNA to protein Prevent virus from replicating

22 2a. RNA-based drugs Favipiravir (T-705) Orally available Approved for influenza treatment in Japan Efficacy against Ebola in mice (Oestereich et al 2014) However, in study of monkeys only 1 out of 6 survived (Wong et al 2014) Higher dose regimens (2-5 influenza dosing) being evaluated in NHP models Potential benefit in current outbreak, supplies should be readily available as already in late stage trials in US for influenza

23 2a. RNA-based drugs TKM-Ebola Intravenously available It is a small interfering RNA (siRNA), affecting 3 of Ebola’s 7 proteins Limited safety and efficacy data are available Clinical hold on phase 1 trials in early 2014, because of increased cytokine levels in healthy individuals FDA has approved the emergency use of TKM-Ebola during the current outbreak Risk versus benefit should be estimated when deciding whether to use this agent

24 2a. RNA-based drugs AVI-7537 Intravenously available In early stage development for treatment of Ebola virus It is an antisense phosphorodiamidate morpholino oligimers (PMO) that inhibits VP24 protein of Ebola virus Efficacious in NHP studies (Geisbert et al 2010; Iversen et al 2012) Studies ongoing in NHPs and humans to further evaluate safety, efficacy and dosing

25 2b. Brincidofovir (CMX-001) Orally available It is early and late clinical trails for a variety of DNA viruses (e.g. adenovirus, cytomegalovirus, smallpox as a biodefence agent) Brincidofovir is a prodrug of cidofovir but fewer renal side-effects than cidofovir In vitro tests have shown its potential for treatment of EVD, paradoxical as Ebola not a DNA virus 6 October 2014, received FDA approval for emergency use in this outbreak and used in treatment of cases in Dallas, Nebraska and New York 16 October 2014, received FDA approval to commence phase 2 clinical trials to assess safety, efficacy and tolerability in patients with Ebola Brincidofovir to be evaluated in a clinical study in patients with confirmed Ebola in West Africa

26 3. Immunomodulators Interferons Commercially available Efficacy in rodents Delayed time to death but no overall increased survival in NHPs (Smith et al 2013)

27 4. Coagulation Modulators Severe coagulation disorder occurs in EVD Disseminated intravascular coagulation (DIC) picture

28 5. Coagulation Modulators Recombinant Activated Protein C – Inhibits clotting factors – Levels of protein C low in EVD Recombinant Nematode Anticoagulant Protein – Inhibits clotting factors (tissue factor pathway) Limited success with both in NHP studies (Hensley et al 2007; Geisbert et al 2003)

29 Ethical Questions How much emphasis should be placed on experimental interventions in response to this outbreak? If experimental drugs and vaccines become available, what are the ethical considerations relating to their use?

30

31 Take Home Messages Ebola outbreak in West Africa continues to escalate Mounting pressure to expedite clinical research WHO meeting in Switzerland Sept 2014 Promising results in NHPs but limited data on safety and efficacy in humans Two potential recombinant vaccines CAd3 – based VSV – based

32 Take Home Messages Potential Treatments —Convalescent whole blood and plasma —Monoclonal antibodies (ZMapp) —Antiviral drugs (Brincidofovir and TKM-Ebola have FDA emergency use approval) —Immunomodulators —Coagulation modulators Use of experimental interventions raises ethical questions Should not distract from public health measures needed to curb outbreak

33 References Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377(9768):849-62 Feldmann H, Jones SM, Daddario DiCaprio KM et al. Effective post-exposure treatment of Ebola infection. Plos Pathog. 2007;3:e2 Geisbert TW, Hensley LE, Jahrling PB, Larsen T, Geisbert JB, Paragas J, Young HA, Fredking TM, Rote WE, Vlasuk GP. Treatment of Ebola virus infection with a recombinant inhibitor of VIIa/tissue factor: a study in rhesus monkeys. Lancet. 2003;362:1953-58 Geisbert TW, Lee AC, Robbins M, Geisbert JB, Honko AN, Sood V, Johnson JC, de Jong S, Tavakoli I, Judge A, Hensley LE, MacLachlan I. Post exposure protection of non human primates against a lethal Ebola challenge with RNA interference: a proof of concept study. Lancet. 2010;375:1896- 1905 Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E, Hensley LE. Mechanisms underlying coagulation abnormalities in Ebola haemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J Infect Dis. 2003;188(11):1618-1629 Hensley LE, Stevens EL, Yan SB, Geisbert JB, Macias WL, Larsen T, Daddario-DiCaprio KM, Cassell GH, Jahrling PB, Geisbert TW. Recombinant human activated protein C for the postexposure treatment of Ebola haemorrhagic fever. J Infect Dis. 2007; 196(suppl 2):S390-S399

34 References Iversen PL, Warren TK, Wells JB, Garza NL, Mourich DV, Welch LS, Panchal RG, Bavari S. Discovery and early development of AVI-7537 and AVI-7288 for the treatment of Enola virus and Marburg virus infections. Viruses. 2012;4:2806-2830 Jones SM, Feldmann M, Stroher U, Geisbert JB, Fernando L, Grolla A et al. Live attenuated recombinant vaccine protects non human primates against Ebola and Marburg viruses. Nature medicine. 2005;11(7):786-90 Marzi A, Feldmann H. Ebola virus vaccines: an overview of current approaches. Expert Rev Vaccines. 2014;13(4):521-531 Mupapa K, Massamba M, Kibadi K, et al. Treatment of Ebola haemorrhagic fever with blood transfusions from convalescent patients. International Scientific and Technical Committee. J Infect Dis. 1999;179(suppl 1):S18-S23 Oestereich L, Ludtke A, Wurr S, Rieger T, Munoz-Fontela C, Gunther S. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res. 2014;105:17-21 Smith LM, Hensley LE, Geisbert TW, et al. Interferon-beta therapy prolongs survival in rhesus macaque models of Ebola and Marburg. J Infect Dis. 2013;208:210-8 Stanley DA, Honko AN, Asiedu C, Trefry JC, Lau-Kilby AW, Johnson JC, Hensley L, Ammendola V, Abbate A, Grazioli F, Foulds KE, Cheng C, Wang L, Donaldson MM, Colloca S, Folgori A, Roederer M, Nabel GJ, Mascola J, Cortese R, Koup RA, Sullivan NJ. Chimpanzee adenovirus vaccine generates acute and durable immunity against ebolavirus challenge. Nat Med. 2014;20(10):1126-9

35 References Statement on the WHO Consultation on potential Ebola therapies and vaccines. http://www.who.int/mediacentre/news/statements/2014/ebola-therapies-consultation/en/ http://www.who.int/mediacentre/news/statements/2014/ebola-therapies-consultation/en/ Sullivan NJ, Geisbert TW,Geisbert et al. Accelerated vaccination for Ebola virus haemorrhagic fever in non human primates. Nature. 2003;424:681-4 Tuffs A. Experimental vaccine may have saved Hamburg scientist from Ebola fever. BMJ. 2009;338:b1223 Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB, Fausther-Bovendo H, Wei H, Aviles J, Hiatt E, Johnson A, Morton J, Swope K, Bohorov O, Bohorova N, Goodman C, Kim D, Pauly MH, Velasco J, Pettitt J, Olinger GG, Whaley K, Xu B, Strong JE, Zeitlin L, Kobinger GP. Reversion of advanced Ebola virus disease in non human primates with ZMAPP. Nature. 2014;514(7520):47-53 Wong G, Qiu X, Olinger GG, Kobinger GP. Post-exposure therapy of filovirus infections. Trends Microbiol. 2014;22(8):456-63 Recent review Bishop B. Potential and emerging treatment options for Ebola virus disease. Annals of Pharmacotherapy. 2014; Nov 20. pii: 1060028014561227. [Epub ahead of print]


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