Ebola

Vaccines and
Treatments

26/11/2014
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
 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
45 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
Whats 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
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 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
Its 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. 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
 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: Whats 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
Ebolas 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
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:
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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
 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.
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Jones SM, Feldmann M, Stroher U, Geisbert JB, Fernando L, Grolla A et al. Live attenuated recombinant vaccine
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Oestereich L, Ludtke A, Wurr S, Rieger T, Munoz-Fontela C, Gunther S. Successful treatment of advanced
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Smith LM, Hensley LE, Geisbert TW, et al. Interferon-beta therapy prolongs survival in rhesus macaque
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 References
Statement on the WHO Consultation on potential Ebola therapies and vaccines.
http://www.who.int/mediacentre/news/statements/2014/ebola-therapies-consulta
tion/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
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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,
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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]