Ebola vaccines and treatment - Health Protection Surveillance Centre

Report
Ebola
Vaccines and Treatments
26/11/2014
Current Prevention and Treatment
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Isolation of cases
Stringent infection control
Contact tracing
Surveillance
Risk communication
Treatment options limited
Supportive therapy centred on:
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Fluid resuscitation
Correction of electrolyte abnormalities
Prevention and treatment of concomitant infections
Prevention complications of shock
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
• The gold standard animal
model for Ebola vaccine
and drug testing is the non
human primate (NHP)
• Macaques, African green
monkeys, baboons
WHO CONSULTATION ON
POTENTIAL EBOLA
THERAPIES AND VACCINE
GENEVA, SWITZERLAND
4–5 SEPTEMBER 2014
Potential Ebola Vaccines
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
Who to vaccinate?
• Valuable for:
– Medical personnel
– First responders
– Military personnel
– Researchers
– Ring vaccination in outbreak
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.
2.
Chimpanzee adenovirus serotype 3 (cAd3-EBO)
Recombinant vesicular stomatitis virus (rVSV-EBO)
• Both are being fast-tracked but data on safety and
efficacy are limited
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
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
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
2. Recombinant vesicular stomatitis
virus vaccine (rVSV-EBO)
• Feldmann et al (2007)
– demonstrated varying degrees of protection postexposure 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
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
Potential Ebola Treatments
Potential Ebola Treatments
1. Antibody therapy
a.
b.
Convalescent whole blood and
plasma
Monoclonal antibodies (ZMapp)
2. Antiviral therapy
a.
b.
RNA-based drugs
Brincidofovir (CMX-001)
3. Immunomodulators
4. Coagulation modulators
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
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
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
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
2a. RNA-based drugs
• Interfere with translation of
Ebola virus mRNA to protein
• Prevent virus from replicating
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
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
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
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
3. Immunomodulators
Interferons
• Commercially available
• Efficacy in rodents
• Delayed time to death but no overall
increased survival in NHPs (Smith et al 2013)
4. Coagulation Modulators
• Severe coagulation
disorder occurs in EVD
• Disseminated
intravascular coagulation
(DIC) picture
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)
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?
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
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
References
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Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377(9768):849-62
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Feldmann H, Jones SM, Daddario DiCaprio KM et al. Effective post-exposure treatment of Ebola
infection. Plos Pathog. 2007;3:e2
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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
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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;375:18961905
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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
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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
References
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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.
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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
References
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Statement on the WHO Consultation on potential Ebola therapies and vaccines.
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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