Disease Briefing: Ebola Virus Disease - Thomson Reuters

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DISEASE BRIEFING:
EBOLA VIRUS DISEASE
POWERED BY THOMSON REUTERS CORTELLIS™
IN THIS ISSUE
FACTS ABOUT EBOLA VIRUS DISEASE THE EBOLA VIRUS TRANSMISSION AND LIFE CYCLE PATHOGENESIS, MORBIDITY AND MORTALITY RISK FACTORS EPIDEMIOLOGY COST DIAGNOSIS DIFFERENTIAL DIAGNOSIS PREVENTION VACCINES TREATMENT ANTIVIRAL AGENTS MONOCLONAL ANTIBODIES SMALL INTERFERING RNAS PHOSPHORODIAMIDATE MORPHOLINO OLIGOMERS CONVALESCENT BLOOD PRODUCTS CURRENT EBOLA VIRUS DISEASE PIPELINE TARGETS FOR THERAPEUTIC INTERVENTION RELATED WEBSITES SELECTED ONLINE PUBLICATIONS EBOLA VIRUS DISEASE TREATMENT GUIDELINES BIBLIOGRAPHY 3
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Disease Briefings from Thomson Reuters are the authoritative source for
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FACTS ABOUT EBOLA VIRUS DISEASE
Ebola virus disease (also known as Ebola hemorrhagic fever) is a severe hemorrhagic illness caused
by infection with one of five Ebola viruses (Fig. 1). Ebola is an extremely virulent zoonotic pathogen
and represents a major public health threat in equatorial Africa (Choi, J.H. and Croyle, M.A., 2013;
Bausch, D.G. and Schwarz, L., 2014). Several outbreaks in humans and nonhuman primates have
been registered in the decades since the virus was first identified in the mid-1970s, most recently in
Uganda and the Democratic Republic of Congo during the summer of 2012 (Mbonye, A. et al., 2012;
Anonymous, 2012; Li, Y.H. and Chen, S.P., 2013) and in West Africa in 2014 (Baize, S. et al., 2014;
Gostin, L.O. et al., 2014).
Ebola viruses are classified as biosafety level-4 pathogens (BSL-4; risk group 4) (Rapid risk assessment:
Outbreak of Ebola virus disease in West Africa—seventh update (European Centre for Disease Prevention
and Control, October 2014)), and there is currently no treatment or vaccine available for either humans
or animals (Choi, J.H. and Croyle, M.A., 2013). Infection with Ebola virus causes profound immune
suppression and a systemic inflammatory response that culminates in potentially fatal damage to the
vascular, coagulation and immune systems (Feldmann, H. and Geisbert, T.W., 2011). The average case
fatality rate of the disease is 65% (Lefebvre, A. et al., 2014) but can be as high as 90%, leading to
concern that Ebola virus could be used as an agent of biological warfare (Madrid, P.B. et al., 2013).
Figure 1. Created by CDC
microbiologist Frederick
A. Murphy, this colorized
transmission electron
micrograph (TEM) reveals
some of the ultrastructural
morphology displayed
by an Ebola virus virion.
Photo courtesy of Centers
for Disease Control and
Prevention, Public Health
Image Library.
THOMSON REUTERS CORTELLIS™ | DISEASE BRIEFING: EBOLA VIRUS DISEASE
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THE EBOLA VIRUS
Viral hemorrhagic fevers are a diverse group of life-threatening animal and human diseases caused by
RNA viruses belonging to four discrete families: Arenaviridae, Filoviridae, Bunyaviridae and Flaviviridae
(Ippolito, G. et al., 2012).
The Ebola viruses and the related Marburg virus (Lake Victoria Marburgvirus) belong to the Filoviridae
family, order Mononegavirales. Like other filoviruses, Ebola is an enveloped, non-segmented, singlestranded, negative-sense RNA virus (Fig. 2). Ebolavirus (EBOV) particles are filamentous with a
uniform diameter (80 nm) but vary in length, reaching up to 14,000 nm (Feldmann, H. and Geisbert,
T.W., 2011; Leroy, E.M. et al., 2011).
Figure 2. Ebola virus:
structure.
The 18.9-kb viral genome consists of eight major subgenomic mRNAs encoding for seven structural
proteins organized in the following fashion: 3’ leader – nucleoprotein (NP) – virion protein (VP) 35 –
VP40 – glycoprotein (GP) – VP30 – VP24 – RNA-dependent RNA polymerase (L)-5’ trailer, and one
nonstructural protein (sGP) (Feldmann, H. and Geisbert, T.W., 2011; Leroy, E.M. et al., 2011). The
ribonucleoprotein complex, which is involved in viral transcription and replication, is composed of a
genomic RNA molecule encapsulated by NP linked to VP30 and VP35 and the RNA-dependent RNA
polymerase (Leroy, E.M. et al., 2011). The trimeric glycoprotein GP forms surface spikes on the virion
envelope that mediate cellular attachment and entry; GP acts as a shield, impeding antiviral immunity,
and is believed to be a major determinant of pathogenicity (Reynard, O. et al., 2009). VP40, the
most abundant protein, is associated with the inner surface and drives the process of viral budding
(Harty, R.N., 2009; Silva, L.P. et al., 2012). VP24, VP35 and NP are required for the formation of the
nucleocapsid (Beniac, D.R. et al., 2012) and are important determinants of pathogenicity (de Wit, E. et
al., 2011). VP35 acts as a type I interferon antagonist, while VP24 interferes with interferon signaling
(Feldmann, H. and Geisbert, T.W., 2011). More recently, VP35 has also been shown to bind to and mask
the viral RNA, preventing the host immune system from attacking it (Leung, D.W. et al., 2010). The
three-dimensional structure and organization of EBOV have been determined using cryo-electron
microscopy and cryo-electron tomography (Beniac, D.R. et al., 2012).
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Five distinct Ebola viruses have been described (Bausch, D.G. and Schwarz, L., 2014). Four of these
are native to Africa and are pathogenic to humans as well as nonhuman primates: Sudan Ebola
virus (SEBOV, discovered in 1976), Zaire Ebola virus (ZEBOV, discovered in 1976), Taï Forest (formerly
Côte d’Ivoire Ebola virus [CIEBOV], discovered in 1994) (Feldmann, H. and Geisbert, T.W., 2011) and
Bundibugyo Ebola virus (BEBOV, discovered in 2007) (MacNeil, A. et al., 2010; Wamala, J.F. et al.,
2010). A fifth virus, Reston Ebola virus (REBOV, discovered in 1989), is found only in the Philippines
and to date appears to cause disease only in nonhuman primates and domestic pigs (Miranda, M.E.
and Miranda, N.L., 2011), and is associated with asymptomatic infection in humans (Feldmann, H.,
2014). Virulence differs among the different virus strains, ZEBOV being associated with the highest
case-fatality rate (Feldmann, H. and Geisbert, T.W., 2011; Feldmann, H., 2014). In addition to their
pathogenicity in humans, Ebola viruses are also a significant cause of morbidity and mortality in great
apes (Leroy, E.M. et al., 2011) (Table I).
TABLE I. IMPORTANT RNA VIRUSES AND THE DISEASES THEY PRODUCE IN HUMANS
Family/Characteristics
Viruses
Diseases
Orthomyxoviruses
(Orthomyxoviridae) Singlestranded RNA, enveloped
(No DNA step in replication;
negative-sense genome;
segmented genome)
Influenza A and B virus
Upper respiratory infection, croup
Paramyxoviruses
(Paramyxoviridae) Singlestranded RNA, enveloped
nonsegmented genome)
Parainfluenza 1-3 virus
Respiratory syncytial virus
Measles virus
Measles
Mumps
Aseptic meningitis
Coronaviruses (Coronaviridae)
Single-stranded RNA,
enveloped (No DNA step in
replication; positive-sense
genome)
Human coronaviruses
Upper respiratory infection
Rhabdoviruses (Rhabdoviridae)
replication; negative-sense
genome; nonsegmented
genome)
Rabies virus
Rabies
Picornaviruses (Picornaviridae)
nonenveloped
Rhinoviruses
Common cold
Hepatitis A virus
Hepatitis
Enteroviruses:
• Polioviruses
• Coxsackie A24 viruses
• Coxsackie B viruses
• Coxsackie B1-5 viruses
• Coxsackie A9 viruses
• Echoviruses
Paralysis
Acute hemorrhagic conjunctivitis
Myocarditis, pericarditis
Aseptic meningitis
Aseptic meningitis
Aseptic meningitis, encephalitis
Caliciviruses(Calciviridae)
nonenveloped
Norwalk virus
Gastroenteritis
Hepatitis E virus
Hepatitis
Togaviruses (Togaviridae)
genome)
Alphaviruses (Group A
arboviruses)
Encephalitis, hemorrhagic fever
Rubivirus
Rubella
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TABLE I. IMPORTANT RNA VIRUSES AND THE DISEASES THEY PRODUCE IN HUMANS
Family/Characteristics
Viruses
Diseases
Flaviviruses (Flaviviridae)
genome)
Group B arboviruses
Encephalitis, hemorrhagic fever
Hepatitis C virus
Hepatitis
Dengue virus
Dengue fever
Bunyaviruses (Bunyaviridae)
genome; segmented genome)
Some arboviruses
Encephalitis, hemorrhagic fevers
Hantavirus
Fever, renal involvement
Reoviruses (Reoviridae) Double- Human rotaviruses
stranded RNA, nonenveloped
Gastroenteritis
Arenaviruses (Arenaviridae)
genome;segmented genome)
Lymphocytic
Meningitis
choriomeningitis (LCM virus)
Lassa virus
Hemorrhagic fever
Retroviruses (Retroviridae)
enveloped (DNA step in
replication)
HTLV-I, HTLV-II
T cell leukemia, lymphoma, paresis
HIV-1, HIV-2
AIDS
Filoviruses (Filoviridae) Singlestranded RNA, enveloped
nonsegmented genome)
Marburg virus
Marburg disease
Ebola virus
Ebola hemorrhagic fever
TRANSMISSION AND LIFE CYCLE
Filoviruses are zoonotic, and fruit bats are widely considered to be reservoir species and primary source
of infection. Bats of the Pteropodidae family appear to be a natural reservoir for Zaire Ebola virus
(Ebola virus disease. WHO Fact Sheet no. 103 (World Health Organization, updated September 2014)),
and naturally infected fruit bats have been identified throughout the endemic region, although they do
not appear to suffer illness or death (O’Shea, T.J. et al., 2014). Other potential reservoirs and vectors
may also exist (Feldmann, H. and Geisbert, T.W., 2011; de Wit, E. et al., 2011). In the case of REBOV,
swine have been identified as a natural host species (Barrette, R.W. et al., 2009), and Rousettus
amplexicaudatus fruit bats may be a natural reservoir species (Taniguchi, S. et al., 2011).
Although ebolaviruses are known to infect great apes, the high case fatality rates recorded in these
animals, together with their declining populations and limited geographical range, indicate they are
likely to be dead-end hosts for the virus rather than reservoir species (Pigott, D.M. et al., 2014).
Ebola virus is often transmitted to humans from the carcasses of infected animals. In the endemic
region of Africa, chimpanzees and other primates are often used as food. Once the virus has infected
one human it can be transmitted to others, usually through mucosal surfaces or breaks in the skin,
when an individual comes into direct contact with body fluids (blood, saliva, urine, feces, sweat, genital
secretions), tissues or organs from a symptomatic patient or cadaver. Person-to-person transmission of
EBOV is relatively inefficient, as seen by a secondary attack rate of approximately 10% (Feldmann, H.
and Klenk, H.D., 1996). The disease is contagious only when a patient is manifesting acute symptoms,
and risk of transmission is greatest during the late stages of disease or immediately after death (Rapid
risk assessment: Outbreak of Ebola virus disease in West Africa—seventh update (European Centre for
Disease Prevention and Control, October 2014)). The virus has been detected in semen of convalescing
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men for 40–100 days after disease onset. Most guidelines recommend preventive measures for up to 61
days, although the United States Army Medical Research Institute of Infectious Diseases recommends
that survivors avoid sexual contact for a period of three months (MacKay, I.M. and Arden, K.E., 2014).
Transmission is common in the healthcare setting, where nurses and doctors are in close contact with
patients and their body secretions at the most infectious stages. It can also occur laboratory setting
if samples are not handled with strict care. During the seminal outbreaks in Sudan and Zaire in 1976,
reuse of contaminated needles contributed significantly to the spread of the disease (Feldmann, H.
and Geisbert, T.W., 2011). Transmission from infected mothers to infants via breast milk has been
hypothesized but not confirmed (Feldmann, H. and Geisbert, T.W., 2011). Aerosol/airborne transmission
has not been observed in the natural or laboratory setting (Alimonti, J. et al., 2014; Fauci, A.S., 2014).
PATHOGENESIS, MORBIDITY AND MORTALITY
The virus is trophic for a range of cell types, but infects and replicates preferentially in monocytes,
macrophages and dendritic cells. These cells also play an important role in the subsequent
dissemination of the virus throughout the body via the lymphatic system and blood (Feldmann, H. and
Geisbert, T.W., 2011; Leroy, E.M. et al., 2011). Viral replication is intense, mostly occurring in secondary
lymphoid organs and the liver. The virus subsequently spreads to hepatocytes, endothelial cells,
fibroblasts and epithelial cells. In spite of the intensity and extent of viral replication in organs such
as the liver, the resulting damage does not appear to be sufficient to result in death or other severe
manifestations of Ebola hemorrhagic fever, suggesting that the host response must also contribute
to pathogenesis. The exaggerated release of cytokines and other inflammatory mediators results in
a cytokine storm with detrimental consequences ranging from vascular leakage to T-cell apoptosis
(Leroy, E.M. et al., 2011). An early, robust and balanced immune response, characterized by IgM
response within two days of symptom onset and IgG response within 5-8 days of symptom onset, is
associated with a more favorable outcome (Hoenen, T. et al., 2012).
Following an incubation period ranging anywhere from 2-21 days, Ebola virus disease emerges abruptly
and is characterized by nonspecific early symptoms of fever, chills, malaise and myalgia. These may
be followed by multisystem involvement manifesting as prostration, anorexia, nausea/vomiting,
abdominal pain, diarrhea, chest pain, cough, shortness of breath, headache, confusion, coma, edema
or postural hypotension. Hemorrhagic symptoms manifest at the peak of illness and include petechiae,
ecchymoses, uncontrolled bleeding or oozing from venopuncture sites and mucosal hemorrhage; these
may be severe, although fewer than half of all patients have hemorrhagic manifestations. Massive blood
loss, if it does occur, usually affects the gastrointestinal tract. Late-stage symptoms include shock,
convulsions, profound metabolic disturbances, diffuse coagulopathy and multiorgan failure, manifesting
as a syndrome that is similar in some ways to septic shock. Symptoms manifest earlier and disease
progresses more rapidly in patients with fatal disease, with death occurring 6-10 days after onset of
symptoms (Feldmann, H. and Geisbert, T.W., 2011; de Wit, E. et al., 2011; Hoenen, T. et al., 2012).
The route of infection may influence both the course of disease and outcome. The incubation period
following transmission via contact exposure is reported to be longer than for parenteral infection
(mean 9.5 vs. 6.3 days) (Feldmann, H. and Geisbert, T.W., 2011). Viral load is linked to outcome, with
data in humans and nonhuman primates showing improved likelihood of survival when viremia is
lower than 1x10(4.5) pfu/mL of blood (Feldmann, H. and Geisbert, T.W., 2011). Outcome is also closely
associated to the infecting strain. The case-fatality rate ranges from 60-90% for Zaire Ebola virus
species to 40–60% for Sudan Ebola (Feldmann, H. and Geisbert, T.W., 2011; Leroy, E.M. et al., 2011) and
approximately 40% for Bundibugyo Ebola (MacNeil, A. et al., 2010). Only one person has been infected
with the Taï Forest strain and survived the illness (de Wit, E. et al., 2011; Leroy, E.M. et al., 2011). In a
meta-analysis of WHO data from 20 outbreaks involving Zaire, Sudan and Bundibugyo Ebola species,
including the 2014 outbreak, the average case fatality rate was estimated to be 65.4% (Lefebvre, A.
et al., 2014). No human cases of illness caused by Reston Ebola virus infection have been reported.
In February 2009, WHO reported that four people working with infected pigs in the Philippines had
tested positive for REBOV antibodies, but did not show symptomatic disease (Anonymous, 2009;
Ebola Reston in pigs and humans in the Philippines (World Health Organization, February 3, 2009)).
Although the REBOV strain appears at this time to be less pathogenic to humans, it should be noted
that all subjects analyzed were healthy adult males. There are no data available at this time for
potentially more vulnerable groups such as children, pregnant women or immunosuppressed patients
(Ebola virus disease. WHO Fact Sheet no. 103 (World Health Organization, updated September 2014)).
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Among survivors, sequelae may persist long after recovery from acute illness and include myelitis,
recurrent hepatitis, psychosis, uveitis (Feldmann, H. and Geisbert, T.W., 2011) and prolonged poor
health, as well as psychosocial sequelae such as fear and rejection (Macneil, A. and Rollin, P.E., 2012).
High antibody titers may be detected for years after infection (Leroy, E.M. et al., 2011).
RISK FACTORS
With the exception of periodic outbreaks, EBOV does not typically persist in the human population.
Thus the introduction of EBOV from the reservoir species to humans appears to involve one or more
stochastic events: typically transmission of the virus from the reservoir species (bats) to the incidental
nonhuman host species (chimpanzees, gorillas), followed by human contact with the infected animal,
primarily during the hunting and preparation of bush meat (Macneil, A. and Rollin, P.E., 2012),
although direct transmission from bats to humans is also possible (Hoenen, T. et al., 2012). The
observation of REBOV infection in domestic pigs in the Philippines and the subsequent demonstration
in laboratory studies that ZEBOV can also be transmitted among swine (Kobinger, G.P. et al., 2011) has
led to concern that humans could theoretically become infected through the consumption of food and
other products obtained from infected pigs (Hoenen, T. et al., 2012), although no cases of this type of
animal-to-human transmission have been observed in the field.
Risk factors for human-to-human transmission of EBOV include close contact with sick individuals,
primarily in the family or health care setting, and contact with dead bodies during preparation and
burial. Health care workers in low-resource settings are at very high risk of infection (Macneil, A. and
Rollin, P.E., 2012).
EPIDEMIOLOGY
The first cases of Ebola hemorrhagic fever were reported in 1976, when two nearly simultaneous
outbreaks occurred in northern Zaire (now the Democratic Republic of Congo) and southern Sudan.
The causative agents of the outbreaks were identified as two different species of a novel filovirus, which
was named “Ebola” after a river in northern Zaire.
Confirmed cases of Ebola virus disease have been reported in the Congo, Côte d’Ivoire, Democratic
Republic of Congo, Gabon, Sudan and Uganda (Geographic distribution of Ebola hemorrhagic fever
outbreaks and fruit bats of Pteropodidae family (World Health Organization, 2009)), as shown in Table
II. The largest outbreak prior to 2014 took place in Uganda between October 2000 and February 2001,
during which time 425 people developed clinical illness and 224 (53%) died (Okware, S.I. et al., 2002).
In July 2012, a new index case of Ebola virus disease was confirmed by the World Health Organization
in Uganda. A total of 24 probable and confirmed cases of Ebola hemorrhagic fever were reported to
WHO in Uganda, including 16 deaths, by the time that the outbreak was declared “under control” in
August (Ebola in Uganda—update (World Health Organization, August 17, 2012)). However, also in
August 2012, 15 suspected new cases of Ebola and 10 deaths were reported in the Democratic Republic
of Congo. By September 15, 2012, the number of laboratory-confirmed and probable cases of Ebola
hemorrhagic fever in the Congo had reached 46, of which 19 were fatal (Ebola outbreak in Democratic
Republic of Congo, update (World Health Organization, September 18, 2012)). All told, three separate
outbreaks of Ebola were recorded in 2012 (Table II).
In March 2014, WHO announced that a new outbreak of Ebola virus disease had been detected in
Guinea (Baize, S. et al., 2014), and later spread to Liberia and Sierra Leone. It was later determined
that the first infection occurred in a remote region of Guinea in December 2013 (Briand, S. et al., 2014).
This was the first time that the disease had been detected in West Africa, according to WHO, and is the
largest, most complex and severe outbreak ever seen in the history of the disease. As of January 12,
2015, WHO and CDC had been advised of a total of 21,206 probable, suspected and confirmed cases
worldwide, including 8,386 reported deaths worldwide. Of these, 21,171 cases and 8,371 deaths have
been reported in three countries with most widespread and intense transmission: Guinea, Sierra Leone
and Liberia (see WHO Global Alert and Response: Ebola virus disease (EVD) and Ebola hemorrhagic
fever—2014 Ebola outbreak in West Africa (Centers for Disease Control and Prevention) for up-to-date
information).
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According to WHO, at least 15 other countries are at high risk during this outbreak: Mali, Ivory Coast,
Senegal and Guinea-Bissau (the four countries bordering the three affected countries), as well as
Benin, Cameroon, the Central African Republic, the Democratic Republic of Congo, Ghana, South
Sudan, Nigeria, Mauritania, Togo and Burkina Faso (Gulland, A., 2014). The first case of Ebola was
reported in Mali, which shares a border with Guinea, on October 23, 2014.
The magnitude of the outbreak—albeit unprecedented—was considered to be vastly underestimated
due to underreporting (Meltzer, M.I. et al., 2014). Using a modeling tool called EbolaResponse and
estimating an underreporting factor of 2.5, CDC epidemiologists estimated that without scale-up of
effective interventions, Sierra Leone and Liberia would have a total of approximately 8,000 Ebola cases
(21,000 total cases when corrected for underreporting) by September 30, 2014 (Meltzer, M.I. et al.,
2014). With a basic reproductive number (R0) of 1.51 in Liberia and 1.38 in Sierra Leone (Anonymous,
2014), the number of cases was growing exponentially in those countries of most intense transmission.
Case numbers were doubling every 24 days in Liberia and every 30 days in Sierra Leone (Anonymous,
2014). According to CDC’s projection model, if these trends were extrapolated, and without additional
interventions or changes in community behavior (e.g., notable reductions in unsafe burial practices),
Liberia and Sierra Leone would have approximately 550,000 Ebola cases (1.4 million when corrected
for underreporting) by January 20, 2015 (Meltzer, M.I. et al., 2014). However, Yale University
investigators and collaborators later published results of a new analysis which takes into account
clustering as an important factor affecting transmission dynamics. They estimated that the R0 in Sierra
Leone is 1.4, and that the estimated number of secondary infections is 1.35. They also asserted that
underreporting is not as widespread as initially feared, and that approximately 17% (maximum 70%) of
cases in Sierra Leone are unreported (Scarpino, S.V. et al., 2014).
The case fatality rate for this outbreak has been estimated at 51%, but ranges from 42% at some
geographic sites to 66% at others. However, this rate is also probably underestimated, as it does not
take into account the delay between onset of symptoms and disease outcome. Researchers from the
London School of Hygiene Tropical Medicine estimated that the case fatality rate was actually closer
to 70% (Kucharski, A.J. and Edmunds, W.J., 2014). The basic reproductive rate (R0) also varies across
the affected region. Although previously reported to be closer to 1.5, a transmission modeling study
conducted by NIH researchers and applied to data from Monserrado County, Liberia, shows that the R0
in that area is 2.49 (Lewnard, J.A. et al., 2014).
On August 8, 2014, the Director-General of WHO Margaret Chan declared the Ebola outbreak in West
Africa a Public Health Emergency of International Concern (Gostin, L.O. et al., 2014). On September 18,
United Nations Secretary-General Ban Ki-moon announced that the UN would deploy an emergency
health mission to combat the outbreak (UN announces mission to combat Ebola, declares outbreak
‘threat to peace and security’ (United Nations News Release, September 18, 2014)).
On September 30, CDC confirmed the first case of imported Ebola virus disease diagnosed in the U.S.
The patient, a Liberian, was asymptomatic at the time of travel to the U.S. and developed symptoms
approximately five days after arriving in the United States (First imported case of Ebola diagnosed in
the United States (Centers for Disease Control and Prevention, September 30, 2014)). In October 2014,
the first case of Ebola virus infection contracted outside the African continent was reported in Madrid,
Spain. The patient was an assistant nurse who treated a Spanish missionary who had been repatriated
to the country for treatment in September (Diagnosticado un caso secundario de contagio por virus
Ébola (Spanish Ministry of Health, Social Services and Equality press release, October 6, 2014)). Two
healthcare workers in the U.S. who had provided care for a patient in that country with imported EBV
were also diagnosed with Ebola in October.
Gene sequencing studies indicate that the West Africa outbreak is caused by a divergent lineage of the
Zaire ebolavirus. The virus, which mutates at a rate of about 7 × 10–4 substitutions per site per year, likely
spread from Central Africa into Guinea and West Africa over recent decades. The West Africa outbreak
does not appear to involve the emergence of a divergent and endemic virus (Dudas, G. and Rambaut, A.,
2014). However, Harvard University researchers reported in August that the virus is mutating quickly and
in ways that could affect current diagnostics and future vaccines and treatments (Gire, S.K. et al., 2014).
A concurrent outbreak of Ebola virus disease, unrelated to the outbreak in West Africa, was laboratoryconfirmed on August 26, 2014 by WHO in the Democratic Republic of Congo (DRC) (WHO Global Alert
and Response: Ebola virus disease (EVD)). On October 9, WHO reported that 68 cases and 49 deaths
had been registered in that country (WHO Global Alert and Response: Ebola virus disease (EVD)).
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TABLE II. CHRONOLOGY OF MAJOR EBOLA HEMORRHAGIC FEVER OUTBREAKS
(AS OF MARCH 2014)
Year
Country
Virus subtype
Cases
Deaths
Case fatality
2012
Democratic Republic
of Congo
BEBOV
57
29
51%
2012
Uganda
SEBOV
7
4
57%
2012
Uganda
SEBOV
24
17
71%
2011
Uganda
SEBOV
1
1
100%
2008
Democratic Republic
of Congo
ZEBOV
32
14
44%
2007
Uganda
BEBOV
149
37
25%
2007
Democratic Republic
of Congo
ZEBOV
264
187
71%
2005
Congo
ZEBOV
12
10
83%
2004
Sudan
SEBOV
17
7
41%
2003
(Nov–Dec)
Congo
ZEBOV
35
29
83%
2003
(Jan–Apr)
Congo
ZEBOV
143
128
90%
2001–2002
Congo
ZEBOV
59
44
75%
2001–2002
Gabon
ZEBOV
65
53
82%
2000
Uganda
SEBOV
425
224
53%
1996
South Africa (ex
Gabon)
ZEBOV
1
1
100%
1996 (Jul–Dec)
Gabon
ZEBOV
60
45
75%
1996 (Jan–Apr) Gabon
ZEBOV
31
21
68%
1995
Democratic Republic
of Congo
ZEBOV
315
254
81%
1994
Côte d'Ivoire
CIEBOV
1
0
0%
1994
Gabon
ZEBOV
52
31
60%
1979
Sudan
SEBOV
34
22
65%
1977
Democratic Republic
of Congo
ZEBOV
1
1
100%
1976
Sudan
SEBOV
284
151
53%
1976
Democratic Repubic
of Congo
ZEBOV
318
280
88%
Abbreviations used:
SEBOV, Sudan Ebola virus;
ZEBOV, Zaire Ebola virus;
BEBOV, Bundibugyo Ebola
virus; CIEBOV, Côte d’Ivoire
Ebola virus.
Source: Ebola haemorrhagic
fever. Fact sheet No.103
(World Health Organization,
updated March 2014).
Available at http://www.who.
int/mediacentre/factsheets/
fs103/en/index.html.
For more epidemiology information, consult the Incidence and Prevalence Database (IPD):
IPD: Ebola virus.
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COST
Under normal conditions, Ebola virus disease is rare and as such incurs a relatively low direct cost
to society. Nonethless, the long-term, indirect cost to an affected community can be significant. For
example, in a community serviced by few health care workers, the illness or death of a nurse or doctor
may temporarily leave residents without any medical care at all. Furthermore, when a health center with
limited resources must care for a patient with Ebola, standard medical care and attention for patients
with other diseases may not be available (Macneil, A. and Rollin, P.E., 2012; Hoenen, T. et al., 2012).
The economic impact of the 2014 Ebola outbreak (now called an epidemic by CDC), like the size of the
outbreak itself, is unprecedented. According to projections by the World Bank, the two-year regional
financial impact of the outbreak in the three hardest hit countries (Guinea, Sierra Leone and Liberia)
could reach USD 32.6 billion (Ebola: New World Bank group study forecasts billions in economic loss if
epidemic lasts longer, spreads in West Africa (World Bank press release, October 8, 2014))
DIAGNOSIS
Ebola virus infections can only be diagnosed definitively in the laboratory. A number of different tests
have been used to identify the virus, including:
• enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G and M
(Nakayama, E. et al., 2010);
• antigen detection tests;
• serum neutralization test;
• reverse transcriptase polymerase chain reaction (RT-PCR) assay (Wang, Y.P. et al., 2011);
• electron microscopy of clinical specimens (Wang, Y.P. et al., 2011);
• virus isolation by cell culture (Wang, Y.P. et al., 2011).
In August 2014, during the west Africa outbreak of Ebola virus disease, the FDA issed an Emergency
Use Authorization for use by the Department of Defense (DoD) of a new in vitro diagnostic assay
for the detection of Ebola. The Ebola Zaire (Target 1) Real-Time PCR (TaqMan) (EZ1 rRT-PCR) assay
is authorized to test for the presumptive presence of Ebola Zaire virus (detected in the West Africa
outbreak in 2014) in Trizol-inactivated whole blood and Trizol-inactivated plasma specimens from
individuals in affected areas with signs and symptoms of Ebola virus infection or who are at risk for
exposure or may have been exposed to the Ebola Zaire virus (detected in the West Africa outbreak in
2014) in conjunction with epidemiological risk factors. This authorization is limited to the use of the
authorized EZ1 rRT-PCR Assay on specified instruments by laboratories designated by DoD.
Clinical specimens should be handled according to WHO guidelines (see Interim infection control
recommendations for care of patients with suspected or confirmed filovirus (Ebola, Marburg)
hemorrhagic fever (World Health Organization, March 2008)) and analyzed in a biosafety level 4 (BSL4) laboratory (Leroy, E.M. et al., 2011).
DIFFERENTIAL DIAGNOSIS
Particularly in the early stages of an outbreak, the diagnosis of Ebola virus disease may be hindered
by the similarity of its symptoms to those of other diseases that are frequently encountered in
the affected region. These diseases—which should be considered in the differential diagnosis of
Ebola—include Marburg virus and other viral hemorrhagic fevers, malaria, typhoid fever, shigellosis,
cholera, rickettsiosis, meningococcal septicemia, plague, leptospirosis, anthrax, typhus, yellow fever,
Chikungunya fever and fulminant viral hepatitis (Feldmann, H. and Geisbert, T.W., 2011; Ebola virus
disease. WHO Fact Sheet no. 103 (World Health Organization, updated September 2014)).
11
PREVENTION
Especially during outbreaks, proper preventive measures should be taken to reduce the risk of
disease transmission. These include educational public health messages regarding proper handling
of potentially infected animals, reducing contact with infected patients, and proper burial measures
for people suspected to have died from Ebola. Health care workers, who are at risk of contracting
the illness through close contact with patients, should wear gloves and other appropriate personal
protective equipment (Del Rio, C. et al., 2014). Laboratory workers handling samples obtained from
suspected Ebola victims should take the proper precautions.
Although the virus can survive in liquid or dried material for several days, readily available hygiene
measures such as soap and water, alcohol-based hand sanitizers and bleach are all effective for
disrupting the viral envelope (Frieden, T.R. et al., 2014). Ebola viruses are also inactivated by heating to
60°C for 60 minutes, or boiling for 5 minutes (Rapid risk assessment: Outbreak of Ebola virus disease
in West Africa—seventh update (European Centre for Disease Prevention and Control, October 2014)).
During the current outbreak in West Africa, travel restrictions have been proposed as a method of
avoiding further spread of the disease. Although WHO is not recommending any travel or trade
restrictions (Travel and transport risk assessment: Interim guidance for public health authorities and
the transport sector (World Health Organization, September 2014)), as of October 2014, thirty EU/EEA
countries had recommended this option for their citizens. Twenty-six recommended that non-essential
travel should be avoided or postponed, and four advised against all travel in the affected areas (Rapid
risk assessment: Outbreak of Ebola virus disease in West Africa—seventh update (European Centre
for Disease Prevention and Control, October 2014)). Affected countries implemented exit screening
at airports, and several European countries as well as the U.S. began entry screening of individuals
arriving from the affected zone (Rapid risk assessment: Outbreak of Ebola virus disease in West Africa—
seventh update (European Centre for Disease Prevention and Control, October 2014)).
VACCINES
Because Ebola virus disease is relatively rare and primarily affects underdeveloped countries, the
development of a vaccine has traditionally been given low priority. However recent factors have
changed this outlook, namely the potential for use of the virus as a weapon of bioterrorism (Geisbert,
T.W. et al., 2010) and the unprecedented outbreak in West Africa in 2014. As a result, various preand postexposure vaccines have been developed and evaluated (Table III). Conventional inactivated
viral vaccines were the first vaccines studied, but were not effective in nonhuman primate models
(Richardson, J.S. et al., 2010). Greater efficacy has been reported for postexposure vaccines based on
vesicular stomatitis virus (VSV), as well as preexposure vaccines based on recombinant adenovirus type
5, human parainfluenza virus type 3 (Falzarano, D. et al., 2011; Richardson, J.S. et al., 2010) and viruslike particle vaccines (Warfield, K.L. et al., 2007; Warfield, K.L. and Aman, M.J., 2011). A DNA vaccine
expressing envelope glycoproteins (GP) from the Zaire and Sudan species as well as the nucleoprotein
(NP) was tested in a phase I clinical study in healthy adult volunteers (Martin, J.E. et al., 2006).
The first success was achieved using a recombinant VSV-based Ebola vaccine. In addition to promising
results obtained in guinea pigs, mice and rhesus macaques (Feldmann, H. et al., 2007), the vaccine
was also successfully administered to an individual who suffered an accidental laboratory exposure.
The subject, who was given the vaccine 48 hours after the accident, developed a fever but had no other
signs of disease, and the virus remained undetectable in serum and peripheral blood during a threeweek observation period (Guenther, S. et al., 2011). Although this incident appears to demonstrate
efficacy, it was never confirmed that the individual had actually been infected with EBOV (Falzarano,
D. et al., 2011). Nonetheless, in the absence of any effective treatment for Ebola hemorrhagic fever, a
postexposure vaccine is considered the best alternative to protect laboratory and health care personnel
working with the virus (Falzarano, D. et al., 2011).
In September 2014, the U.S. National Institutes of Health (NIH) announced that an investigational
Ebola vaccine codeveloped by the National Institute of Allergy and Infectious Diseases (NIAID) and
GlaxoSmithKline (GSK) was poised to begin initial phase I testing. The investigational vaccine was
designed at the NIAID’s Vaccine Research Center in collaboration with the U.S. Army Medical Research
Institute of Infectious Diseases and the GSK subsidiary Okairos. The vaccine candidate is based on
12
chimp adenovirus type 3 (ChAd3), which is used as a vector to deliver segments of genetic material
derived from two Ebola virus species: Zaire Ebola and Sudan Ebola. The experimental NIAID/GSK
vaccine performed well in protecting nonhuman primates from Ebola infection (Stanley, D.A. et al.,
2014). The U.S. phase I trial (VRC 207) enrolled 20 healthy adults aged 18-50 years. One group of
10 subjects received an intramuscular injection of the NIAID/GSK experimental vaccine, while the
second group received a single injection of the same vaccine but at a higher dose. Participants will be
evaluated nine times over a 48-week period. The trial will evaluate the experimental vaccine’s safety
and ability to generate an immune system response in these healthy adults. Four-week results were
published in November and indicated that the bivalent vaccine is safe and immunogenic with a single
dose in healthy volunteers. According to a preliminary report, the vaccine was found safe and induced
glycoprotein-specific antibodies in all 20 individuals, with the higher dose level eliciting a substantially
greater response (Ledgerwood, J.E. et al., 2014). A monovalent version of the NIAID/GSK vaccine that
contains genetic material from only the Zaire Ebola species has also been tested in a phase I safety
study in 60 healthy adults in the U.K. The vaccine was shown immunogenic at the doses tested, and
no safety issues were reported (Rampling, T. et al., 2015). The rChAd3 vaccine has also been evaluated
successfully in volunteer studies in Mali and Switzerland (Mohammadi, D., 2015), and was progressed
to phase II/III testing in Liberia in early 2015.
In October 2014, phase I trials began at the Walter Reed Army Institute of Research to evaluate VSVEBOV, an Ebola vaccine developed by scientists at the Public Health Agency of Canada’s National
Microbiology Laboratory. Development of VSV-EBOV was initially funded by the Canadian government
and is now the subject of a collaboration between NewLink Genetics and Merck & Co. The vaccine was
tested favorably in volunteers to assess its safety, determine the appropriate dosage and identify any
side effects (Mohammadi, D., 2015). This vaccine is also being evaluated in phase II/III trials in Liberia.
In order to provide optimum protection against all strains of Ebola as well as the related Marburg
virus, an eventual vaccine would ideally need to contain at least three components (Feldmann, H. and
Geisbert, T.W., 2011). Furthermore, given the remoteness of the endemic region, a single-dose vaccine
is most desirable (Geisbert, T.W. et al., 2010; Hoenen, T. et al., 2012). Finally, the route of vaccine
administration is an important consideration. Although intramuscular injection is the most widely
used route of administration for current vaccines, a product that must be administered with a needle
presents significant safety risks in an outbreak situation. Thus mucosal immunization (e.g., intranasal
or oral) has been proposed as an attractive alternative, and needle-free delivery systems are being
pursued (Richardson, J.S. et al., 2010). In general, a postexposure prophylactic vaccine that could be
routinely administered to health care professionals in the endemic zone, with mass vaccination of the
regional population in the event of an outbreak (i.e., ring vaccination), is conceivably the most practical
approach (Macneil, A. and Rollin, P.E., 2012; Hoenen, T. et al., 2012).
In October 2014, WHO convened a meeting of scientists, pharmaceutical companies, international
agencies, NGOs and development banks in order to establish a plan for accelerating the development
and deployment of experimental Ebola vaccines. The agency predicted that hundreds of thousands of
vaccine doses would be ready for use in mid-2015. Furthermore, vaccine development should continue
at the current pace, regardless of the outcome of the West African outbreak, with the objective of
mitigating the risk of failure, assessing the need for boosters, and of stockpiling vaccines for future use
(WHO high-level meeting on Ebola vaccines access and financing—Summary report (World Health
Organization, October 23, 2014)). In a January 2015 meeting led by WHO, plans were announced
to progress Ebola vaccines to phase III in the three most affected countries “within a month”
(Mohammadi, D., 2015).
13
TABLE III. EBOLA VACCINES UNDER ACTIVE DEVELOPMENT
Drug Name
Organization
Description
Status
rChAdC3 Ebola
(Zaire)
GlaxoSmithKline/
National Institute
Allergy Infect Dis
Ebola vaccine consisting of
recombinant chimpanzee adenovirus
serotype 3 (rChAd3) expressing
glycoprotein (GP) derived from Zaire
Ebola (ZEBOV) virus
Phase II/III
rVSV-EBOV
Public Health
Agency of
Canada/NewLink
Genetics
Phase II/III
recombinant Vesicular Stomatitis virus
(rVSV) with the VSV-G envelope protein
removed, expressing Ebola virus Kikwit
strain (Zaire 1995) glycoproteins GP1
and GP2
Ad26.ZEBOV
Crucell
Ebola vaccine consisting of an E1/
E3-deleted recombinant adenovirus
serotype 26 expressing Zaire
Ebolavirus (ZEBOV) glycoprotein (GP)
under the control of cytomegalovirus
(CMV) promoter and the simian virus
40 (SV40) polyadenylation sequence
Phase I
Ad5-EBOV
Tianjin CanSino
Biotechnology
Recombinant Adenovirus 5 vectored
vaccine against Ebolavirus Zaire 2014
strain
Phase I
EBOV GP
Novavax
Ebola vaccine consisting in
nanoparticles made of Guinea EBOV
[H.sapiens-wt/SLE/2014/ManoRiver
G3798, cluster 3] glycoprotein (GP)
Phase I
MVA-BN Filo
Bavarian Nordic
Filovirus vaccine consisting of an
attenuated version of the Modified
Vaccinia Ankara (MVA-BN) virus
encoding Ebola and Marburg virus
antigens
Phase I
cAd3-EBO
GlaxoSmithKline/
National Institute
Allergy Infect Dis
recombinant chimpanzee adenovirus
serotype 3 (rChAd3) comprising nucleic
acids encoding antigenic glycoproteins
from Sudan and Zaire Ebola virus
species
Phase I
BNSP-333-GP
US Department of Bivalent vaccine consisting of
Health & Human
recombinant rabies BNSP333 virus
Services
carrying the Zaire ebola virus (ZEBOV)
Mayinga strain glycoprotein (GP)
Preclinical
GOVX-E301
GeoVax Labs
Monovalent ebola vaccine consisiting
on virus-like particles (VLP) based
on modified vaccinia ankara (MVA)
vector encoding for Zaire Ebola strain
glycoprotein
Preclinical
GOVX-E302
GeoVax Labs
Trivalent ebola vaccine consisting
vector encoding for Zaire, Sudan and
Bunibugyo Ebola strains glycoproteins
Preclinical
14
TABLE III. EBOLA VACCINES UNDER ACTIVE DEVELOPMENT
Drug Name
Organization
Description
Status
NoBola
Pentamer
Pharmaceuticals
Ebola vaccine consisting of genetically Preclinical
engineered chimeric virus-like particle
proteins containing key Ebola epitopes;
produced using NodaVax technology
rVSV-Ebola
Profectus
BioSciences
Recombinant attenuated vesicular
stomatitis virus (rVSV) expressing
surface glycoproteins from Ebola virus,
using Vesiculovax delivery system
821158
Inovio
Pharmaceuticals/
GeneOne Life
Science
Synthetic polyvalent-filovirus vaccine
Preclinical
consisting of three DNA plasmids
(pVAX1) encoding genetically optimized
full-length envelope glycoprotein
derived from Zaire ebolavirus (ZEBOV),
Sudan Ebolavirus (SUDV) and Marburg
marburg virus (MARV) 2005 Angola
outbreak strain consensus sequences,
respectively
866988
Profectus
BioSciences
Trivalent Ebola vaccine constisting on
three attenuated vesicular stomatitis
virus, rVSVN4CT1, expressing the G
proteins of Sudan ebolavirus variant
Gulu (S-EboV), Zaire ebolavirus variant
Kikwit (Z-EboV), and Marburgvirus
variant Angola (MarV); using
VesiculoVax technology platform
Preclinical
Preclinical
TREATMENT
At this time there are no safe and effective vaccines, nor are there any effective disease-specific postexposure treatments for Ebola virus disease (Choi, J.H. and Croyle, M.A., 2013). Supportive therapy—
which is directed toward maintenance of blood volume and electrolyte balance, pain management
and control of secondary infections—is the only available option (Feldmann, H. and Klenk, H.D., 1996;
Richardson, J.S. et al., 2010; Feldmann, H., 2014). Patients should be isolated and all contacts traced,
and medical personnel should follow proper procedures including use of adequate barrier techniques
and HEPA-filtered respirators (Feldmann, H. and Klenk, H.D., 1996; Bausch, D.G. et al., 2008).
Various experimental treatment approaches have been proposed and evaluated in rodents and/or
nonhuman primates including passively acquired antibodies such as those obtained in whole blood
or plasma of convalescent patients (Burnouf, T. et al., 2014), surface glycoprotein (GP)-specific
monoclonal antibodies (Qiu, X. et al., 2012; Qiu, X. et al., 2012; Takada, A. et al., 2007), antisense
oligonucleotides (Warren, T.K. et al., 2010), small interfering RNAs (siRNAs) (Geisbert, T.W. et al.,
2010), modulators of the coagulation cascade (Hensley, L.E. et al., 2007; Garamszegi, S. et al., 2014)
and inflammatory modulators such as type I interferon (Feldmann, H. and Geisbert, T.W., 2011). Earlierstage studies have suggested potential for inhibitors of the endo/lysosomal cholesterol transporter
protein Niemann-Pick C1 (NPC1), which interacts with the virus glycoprotein GP and is essential for viral
entry (Cote, M. et al., 2011; Carette, J.E. et al., 2011; Choi, J.H. and Croyle, M.A., 2013), as well as for
microtubule inhibitors and estrogen receptor modulators, which may inhibit viral entry and/or fusion
(Johansen, L.M. et al., 2013; Kouznetsova, J. et al., 2014).
The study of investigational agents is hindered by the need to manipulate EBOV in high-level biosafety
labs as well as by ethical constraints, which make the testing of drugs in traditional controlled
clinical trials unfeasible. Some researchers have proposed evaluating investigational agents in the
field, under outbreak conditions, while recognizing the myriad political, scientific, financial, logistic,
ethical and legal challenges that this presents (Bausch, D.G. et al., 2008; Adebamowo, C. et al.,
15
2014). In September 2014, during the West Africa outbreak of EBV, a fast-track initiative for evaluating
investigational therapies was launched. Debate about the appropriate context for administering
and evaluating therapies in an outbreak setting continues, although most agree that the traditional
randomized, controlled trial model is neither ethical nor practical (Adebamowo, C. et al., 2014).
ANTIVIRAL AGENTS
No conventional or licensed antiviral agents have been found effective against EBOV (Bausch, D.G.
et al., 2008; Kondratowicz, A.S. and Maury, W.J., 2012). Viral load has been linked to survival, with
a 2-3 log difference in viral load sometimes accounting for the difference between survival and
death. Research efforts are thus being directed to the discovery of new antiviral agents that are
capable of reducing viral load, albeit transiently, as well as other agents that directly inhibit the virus
(Kondratowicz, A.S. and Maury, W.J., 2012) or viral entry (Choi, J.H. and Croyle, M.A., 2013).
The nucleoside analogue BCX-4430, a viral RNA polymerase inhbitor, has shown promising activity
in rodent and nonhuman primate models of Ebola virus infection. Administered post-viral exposure to
rodents, intramuscular BCX-4430 was shown to protect against Ebola virus as well as Marburg virus
disease. More significantly, BCX-4430 completely protected cynomolgus macaques from Marburg virus
infection when administered as late as 48 hours post-infection. This represents the first time that a smallmolecule antiviral drug has been found effective in treating filovirus disease (Warren, T.K. et al., 2014).
In early October 2014, Chimerix’s brincidofovir was provided for potential use in patients with Ebola virus
disease after emergency INDs were granted by the FDA. An NDA was filed in November for a clinical trial
to assess the safety, tolerability and efficacy of the product in patients who are confirmed to have Ebola
virus infection. In vitro tests previously confirmed the activity of brincidofovir against the Ebola virus.
Brincidofovir is an oral nucleotide analogue that has shown broad-spectrum in vitro antiviral activity
against all five families of DNA viruses that affect humans. An open-label phase II study evaluating
brincidofovir in up to 140 patients with confirmed Ebola Virus Disease was initiated on January 2, 2015 at
Médecins Sans Frontières (MSF)’s ELWA 3 Ebola Management Centre in Monrovia, Liberia.
Also in October 2014, Fujifilm announced that its subsidiary, Toyama Chemical, would increase
production of the viral RNA polymerase inhibitor favipiravir, which has been approved in Japan for
the treatment of influenza, in preparation for large-scale clinical use against Ebola virus infection.
The French and Guinean governments are planning to initiate clinical trials of favipiravir in patients
with EBV infection in mid-November. The drug has been administered as an emergency treatment in
European hospitals to several patients who contracted Ebola virus infection in West Africa. Fujifilm has
sufficient 200-mg tablets for 20,000 courses of treatment and a further stock of active pharmaceutical
ingredient sufficient for 300,000 courses. The company will start additional production in midNovember in anticipation of positive results from the clinical trials and in preparation for expansion of
the Ebola virus outbreak. The Japanese government is willing to fund the provision of pharmaceuticals
developed by Japanese companies in order to prevent the spread of Ebola virus.
Antiviral agents are most likely to be effective during the earlier (incubation and precoagulopathy)
stages of disease progression (Ippolito, G. et al., 2012).
MONOCLONAL ANTIBODIES
Neutralizing monoclonal antibodies (MAbs) are also being explored as a way of reducing viral load
and slowing or halting the progression of Ebola virus disease, either in the context of prevention or of
postexposure prophylaxis. This approach has been used with some success in nonhuman primates
(Olinger, G.G., Jr. et al., 2012; Pettitt, J. et al., 2013).
In a study in rhesus monkeys, MB-003—a cocktail of MAbs to three human constant regions that is
manufactured in Nicotiana benthamiana—demonstrated 100% efficacy in preventing EBOV infection
when administered 1 hour to 2 days following EBOV inoculation. MB-003 can be produced in a relatively
rapid time-frame in a cost-effective manner. The MAb (50 mg/kg) administered 3 times to macaques
that displayed positive indications of an active EBOV infection, such as a positive PCR result and fever,
prevented the deaths of 3 out of 7 animals compared to mock-treated controls, none of which survived
(P = 0.029). Two survivors did not show disease symptoms, while the other developed a moderate
16
rash and moderate prostration. Survivors had reduced viremia at the time of dosing compared to
nonsurvivors. Distinct differences in blood chemistry between the two groups were also apparent.
All animals showed decreased platelet and red blood cell counts, but treated nonsurvivors also
demonstrated significant elevations in liver enzymes, blood urea nitrogen and substantial progressive
morbidity. There were no adverse events related to treatment in the survivors (Pettitt, J. et al., 2013).
In August 2014, two American healthcare workers who were infected with EBOV in the West Africa
outbreak were treated with an experimental MAb therapy known as ZMappTM, developed by Mapp
Biopharmaceutical in collaboration with Defyrus and the U.S. and Canadian governments. ZMapp is
composed of three humanized monoclonal antibodies manufactured in Nicotiana. It is an optimized
cocktail combining the best components of MB-003 and another early MAb cocktail known as ZMAb
(Lyon, G.M. et al., 2014).
ZMapp was submitted to further testing in nonhuman primates in order to determine the optimum
dosing regimen and therapeutic window. Following intramuscular administration of a lethal dose of
Ebola virus-Kikwit strain (EBOV-K), 3 groups of 6 rhesus monkeys each were administered three doses
of ZMapp (50 mg/kg per dose) at varying intervals: on days 3, 6 and 9; days 4, 7 and 10; or days 5, 8
and 11. A control group was administered MAb 4E10 or saline on days 4, 7 and 10. Fever, which emerged
within 3-7 days of EBOV challenge, resolved in all treated animals regardless of dosing regimen. Live
virus was detected in blood by day 3 in 17 of 18 NHPs; all showed undetectable viral loads by day 21. All
18 ZMapp-treated animals survived the challenge, including those with the longest treatment delay. In
contrast, all 3 control NHPs died 4-8 days after viral challenge. EBOV-K was used in the study because
the Guinean strain (EBOV-G) now circulating in West Africa was unavailable at the time; however ZMapp
was subsequently shown to inhibit EBOV-G in vitro. Given its prolonged therapeutic window and potent
anti-EBOV activity, these study results support the promise of ZMapp as the first agent for use in the
setting of treatment (as opposed to immediate post-exposure prophylaxis) of patients with Ebola virus
disease (Qiu, X. et al., 2014).
Table IV presents monoclonal antibodies under active development for the treatment of Ebola
virus disease.
TABLE IV. MONOCLONAL ANTIBODIES UNDER DEVELOPMENT FOR TREATMENT OF
EBOLA VIRUS DISEASE
Drug Name
Organization
Description
Status
ZMapp
Public Health Agency
of Canada/Mapp
Biopharmaceutical/
US Army Med Res Inst
Infectious Diseases/
Defyrus
Optimized cocktail combination
of three humanized monoclonal
antibodies targeting epitopes of Ebola
virus (EBOV), comprising the best
components of MB-003 and ZMAb
antibodies; produced in Nicotiana
plants
Clinical
H3
OncoSynergy
Humanized monoclonal IgG kappa
antibody targeting human beta1
integrin (ITGB1)
Preclinical
MB-003
US Army Med Res
Inst Infectious
Diseases/Mapp
Biopharmaceutical/
Kentucky BioProcessing
(KBP)
Preclinical
Mixture of deimmunized mousehuman chimeric monoclonal antibodies
(h-13F6, c13C6 and c6D8) targeting
non-overlapping glycoprotein (GP)
epitopes of Ebola virus (EBOV);
produced via Nicotiana benthamiana
(deltaXTFT)-based rapid antibody
manufacturing platform (RAMP)
ZMAb
of Canada
Combination of three neutralizing
Preclinical
monoclonal antibodies, 1H3, 2G4 and
4G7, targeting the soluble glycoprotein
(sGP) portion (amino acids 1 to 295),
the GP2 and epitopes in the C-terminal
portion of GP1of the Ebola virus (EBOV)
envelope glycoprotein, respectively
17
SMALL INTERFERING RNAS
Inhibition of viral gene expression using small interfering RNAs (siRNAs) is a growing area of antiviral
research (Arbuthnot, P., 2010) and is one of the few promising approaches to the treatment of Ebola at
this time.
The efficacy of TKM-Ebola (also known as Ebola SNALP, TKM-100201), a stable nucleic acid lipid
particles (SNALP)-targeted siRNA directed against the Ebola virus was assessed in a nonhuman
primate model of uniformly lethal Zaire Ebola virus (ZEBOV) hemorrhagic fever in a proof-of-concept
study in rhesus macaques. TKM-Ebola, consisting of three pooled SNALP-formulated anti-ZEBOV
siRNA molecules targeting ZEBOV protein L, matrix protein VP40 and polymerase cofactor VP35, was
administered at 2 mg/kg/dose by bolus i.v. infusion to three macaques at 30 minutes and on days 1,
3 and 5 following a ZEBOV challenge. Another group of four macaques received the treatment at 30
minutes and on days 1–6 following the challenge with ZEBOV. Four and seven treatments with TKMEbola after ZEBOV exposure correlated with 66 and 100% protection against lethal ZEBOV infection,
respectively. The treatment was well tolerated, with only minor changes in liver enzymes possibly
related to viral infection reported (Geisbert, T.W. et al., 2010).
The genomic sequence of Ebola-Guinea, the virus responsible for the outbreak in West Africa, was
determined from several viral isolates and published in the New England Journal of Medicine. With
this information, Tekmira developed a modified RNAi therapeutic, based on TKM-Ebola, to specifically
target Ebola-Guinea. The company has commenced limited GMP manufacture of TKM-Ebola-Guinea
and supply of this product will be available in December 2014.
TKM-Ebola is being developed under a contract with the U.S. government’s Transformational Medical
Technologies Program. The product is being developed under the FDA’s Animal Efficacy Rule for
therapeutics that cannot meet the requirements for traditional approval because human efficacy
studies are not feasible.
PHOSPHORODIAMIDATE MORPHOLINO OLIGOMERS
Antisense drugs work at the genetic level to interrupt the process by which disease-causing proteins
are produced. Antisense drugs are complementary strands of small segments of mRNA. To create
antisense drugs, nucleotides are linked together in short chains called oligonucleotides. Each antisense
drug is designed to bind to a specific sequence of nucleotides in its mRNA target to inhibit production
of the protein encoded by the target mRNA. By acting at this earlier stage in the disease-causing
process, antisense drugs have the potential to provide greater therapeutic benefit than traditional
drugs, which do not act until the disease-causing protein has already been produced.
Phosphorodiamidate morpholino oligomers (PMOs) are a class of synthetic, nonionic antisense
oligonucleotide analogues designed to interfere with translational processes by forming base-pair
duplexes with specific RNA sequences (Warren, T.K. et al., 2012). Positively charged PMOs, also
known as PMOplus, have been found effective for the postexposure protection of Ebola and Marburg
hemorrhagic fever in nonhuman primates (Warfield, K.L. et al., 2006; Warren, T.K. et al., 2012).
In an early prophylactic proof-of-principal trial in rhesus monkeys, administration of a combination
of PMOs, VP35/VP24/L PMOs, from day 2 prior to EBOV infection through day 9 of infection showed
substantial efficacy (75% protection), with two monkeys surviving the EBOV challenge with few clinical
signs, one monkey showing complete clearance of the EBOV infection and one monkey succumbing to
infection on day 10. All 3 vehicle-treated animals died from infection on days 7, 9 and 10, and treatment
with VP35 alone did not confer protection in this nonhuman primate model. PMOs also protected 75%
of rhesus macaques from lethal EBOV infection (Warfield, K.L. et al., 2006).
AVI-7573, a 19-mer PMO targeting a specific VP24 Ebola virus gene translational start site, has been
selected for development as a potential treatment for Ebola virus disease (Iversen, P.L. et al., 2012). The
PMO has fast-track development status in the U.S., where phase I testing was initiated in 2012.
18
CONVALESCENT BLOOD PRODUCTS
Transfusion of blood and blood products obtained from survivors of an infection was first proposed
as a method of treating infections in the early 20th century, prior to the availability of drugs and
vaccines. The practice is based on the theory that protective antibodies are present in the blood from
convalecent donors who have survived the disease, and that transfusion of blood products obtained
from this source may spur a specific immune response in infected and ailing recipients (Burnouf,
T. and Seghatchian, J., 2014). Originally used in 1901 to treat diphtheria and tetanus (First trials of
blood-based Ebola therapy kick off (Nature News, December 15, 2014)), passive immunotherapy using
convalescent blood products has also been used over the years to treat hepatitis A, poliomyelitis,
SARS, Argentine hemorrhagic fever, and swine and avian flu (Burnouf, T. and Seghatchian, J., 2014).
In December 2014, a trial evaluating this potential treatment was initiated in Liberian patients with
Ebola virus disease. The 70-patient study is funded by the Bill & Melinda Gates Foundation and
organized by ClinicalRM in coordination with national health authorities and WHO. It will assess the
efficacy of Ebola convalescent plasma (ECP) to reduce viral load and improve survival in patients
with Ebola virus disease. The ECP is obtained from donors using plasmapheresis (Haemonetics PCS2
plasma collection system) and is subjected to a pathogen inactivation technology (Cerus INTERCEPT
pathogen inactivation blood system) in order to reduce the risk of transfusion-transmitted infections.
Another transfusion study is slated to begin in Guinea in late December, and will enroll 200-300
patients (First trials of blood-based Ebola therapy kick off (Nature News, December 15, 2014)).
CURRENT EBOLA VIRUS DISEASE PIPELINE
Consult Table V for an overview of all products mentioned in this review, including drugs, biologics and
diagnostic agents that have been marketed or are under active development for this indication. The
table may also include drugs not covered in the preceding sections because their mechanism of action
is unknown or not well characterized.
TABLE V. DRUGS AND BIOLOGICS UNDER ACTIVE INVESTIGATION FOR THE PREVENTION AND
TREATMENT OF EBOLA VIRUS DISEASE
Drug Name
Organization
Description
Status
rChAdC3
Ebola (Zaire)
GlaxoSmithKline/
National Institute
Allergy Infect Dis
Ebola vaccine consisting of recombinant
chimpanzee adenovirus serotype 3
(rChAd3) expressing glycoprotein (GP)
derived from Zaire Ebola (ZEBOV) virus
Phase II/III
rVSV-EBOV
of Canada/NewLink
Genetics
Vesicular Stomatitis virus (rVSV) with
the VSV-G envelope protein removed,
expressing Ebola virus Kikwit strain (Zaire
1995) glycoproteins GP1 and GP2
Phase II/III
AVI-7537
Sarepta Therapeutics
19-Mer phosphorodiamidate morpholino
Phase I
antisense oligomer (PMO) whose sequence
is: 5'-GCCATGGTTTTTTCTCAGG-3'
Ad26.ZEBOV
Crucell
Ebola vaccine consisting of an E1/E3deleted recombinant adenovirus serotype
26 expressing Zaire Ebolavirus (ZEBOV)
glycoprotein (GP) under the control of
cytomegalovirus (CMV) promoter and the
simian virus 40 (SV40) polyadenylation
sequence
Phase I
Ad5-EBOV
Tianjin CanSino
Biotechnology
Recombinant Adenovirus 5 vectored
vaccine against Ebolavirus Zaire 2014
strain
Phase I
19
Drug Name
Organization
Description
Status
EBOV GP
Novavax
Ebola vaccine consisting in nanoparticles
made of Guinea EBOV [H.sapiens-wt/
SLE/2014/ManoRiver G3798, cluster 3]
glycoprotein (GP)
Phase I
Ebola SNALP Tekmira
Combination of small interfering RNAs
with 2'-O-methyl versions of guanines and
uridines (EK-1 mod, VP24-1160 mod and
VP35-855 mod) respectively targeting the
Zaire Ebola virus L, VP and VP35 genes
formulated in stable nucleic acid lipid
particles (SNALPs)
Phase I
MVA-BN Filo
Bavarian Nordic
Filovirus vaccine consisting of an
attenuated version of the Modified
Vaccinia Ankara (MVA-BN) virus encoding
Ebola and Marburg virus antigens
Phase I
cAd3-EBO
GlaxoSmithKline/
National Institute
Allergy Infect Dis
chimpanzee adenovirus serotype 3
(rChAd3) comprising nucleic acids
encoding antigenic glycoproteins from
Sudan and Zaire Ebola virus species
Phase I
Favipiravir
Toyama
6-Fluoro-3-hydroxypyrazine-2carboxamide
Clinical
ZMapp
of Canada/Mapp
Biopharmaceutical/
US Army Med Res Inst
Infectious Diseases/
Defyrus
Optimized cocktail combination of three
humanized monoclonal antibodies
targeting epitopes of Ebola virus (EBOV),
comprising the best components of MB003 and ZMAb antibodies; produced in
Nicotiana plants
Clinical
LB-1148
Leading Biosciences
Solution containing tranexamic acid, an
osmotic agent and balanced electrolytes
and energy support
IND Filed
BCX-4430
BioCryst
(2S, 3S, 4R, 5R)-2-(4-Amino-5H-pyrrolo[3,
2-d]pyrimidin-7-yl)-5-(hydroxymethyl)
pyrrolidine-3, 4-diol
Preclinical
Bivalent vaccine consisting of recombinant
rabies BNSP333 virus carrying the Zaire
ebola virus (ZEBOV) Mayinga strain
glycoprotein (GP)
Preclinical
BNSP-333-GP US Department of
Health & Human
Services
CB-008
Canopus BioPharma
Preclinical
GBV-006
Globavir Biosciences
Preclinical
GOVX-E301
GeoVax Labs
Monovalent ebola vaccine consisiting
vector encoding for Zaire Ebola strain
glycoprotein
GOVX-E302
GeoVax Labs
Trivalent ebola vaccine consisting on virus- Preclinical
like particles (VLP) based on modified
vaccinia ankara (MVA) vector encoding for
Zaire, Sudan and Bunibugyo Ebola strains
glycoproteins
Preclinical
20
Drug Name
Organization
Description
Status
H3
OncoSynergy
Humanized monoclonal IgG kappa
antibody targeting human beta1 integrin
(ITGB1)
Preclinical
JK-05
Academy of Military
Medical Sciences/
Sihuan Pharmaceutical
Preclinical
MB-003
US Army Med Res
Inst Infectious
Diseases/Mapp
Biopharmaceutical/
Kentucky BioProcessing
(KBP)
Preclinical
Mixture of deimmunized mouse-human
chimeric monoclonal antibodies (h-13F6,
c13C6 and c6D8) targeting nonoverlapping glycoprotein (GP) epitopes of
Ebola virus (EBOV); produced via Nicotiana
benthamiana (deltaXTFT)-based rapid
antibody manufacturing platform (RAMP)
NoBola
Pentamer
Pharmaceuticals
Ebola vaccine consisting of genetically
engineered chimeric virus-like particle
proteins containing key Ebola epitopes;
produced using NodaVax technology
Preclinical
Rintatolimod
HemispheRx
Poly(I):poly(C12U)
Preclinical
TKM-EbolaGuinea
Tekmira
Modified RNAi therapeutic, based on TKM- Preclinical
Ebola small interference RNA, targeting
the Guinea Ebola virus L polymerase,
VP24 and VP35 genes formulated in stable
nucleic acid lipid particles (SNALPs)
ZMAb
of Canada
Combination of three neutralizing
monoclonal antibodies, 1H3, 2G4 and 4G7,
targeting the soluble glycoprotein (sGP)
portion (amino acids 1 to 295), the GP2
and epitopes in the C-terminal portion of
GP1of the Ebola virus (EBOV) envelope
glycoprotein, respectively
Preclinical
rVSV-Ebola
Profectus BioSciences
Recombinant attenuated vesicular
stomatitis virus (rVSV) expressing surface
glycoproteins from Ebola virus, using
Vesiculovax delivery system
Preclinical
866326
Vaxart
Ebola vaccine consisting of a nonPreclinical
replicating adenovirus type 5 vector coexpressing an Ebola virus glycoprotein and
the gene for a TLR3 ligand that will act as
an adjuvant
866988
Profectus BioSciences
Trivalent Ebola vaccine constisting on
Preclinical
three attenuated vesicular stomatitis virus,
rVSVN4CT1, expressing the G proteins of
Sudan ebolavirus variant Gulu (S-EboV),
Zaire ebolavirus variant Kikwit (Z-EboV),
and Marburgvirus variant Angola (MarV);
using VesiculoVax technology platform
821158
Inovio
Pharmaceuticals/
GeneOne Life Science
Synthetic polyvalent-filovirus vaccine
consisting of three DNA plasmids (pVAX1)
encoding genetically optimized full-length
envelope glycoprotein derived from Zaire
ebolavirus (ZEBOV), Sudan Ebolavirus
(SUDV) and Marburg marburg virus
(MARV) 2005 Angola outbreak strain
consensus sequences, respectively
Preclinical
21
TARGETS FOR THERAPEUTIC INTERVENTION
For an overview of validated therapeutic targets for this indication, see Figure 3. The targetscape shows
an overall cellular and molecular landscape or comprehensive network of connections among the
current therapeutic targets for the treatment of the condition and their biological actions. An arrow
indicates a positive effect; a dash indicates a negative effect. Gray or lighter symbols are targets that
are not validated. For in-depth information on a specific target or mechanism of action, see the
corresponding section in this report.
Figure 3. Ebola virus disease
targetscape.
RELATED WEBSITES
Centers for Disease Control and Prevention, Special Pathogens Branch Ebola Hemorrhagic Fever
http://www.cdc.gov/vhf/ebola/
European Centre for Disease Prevention and Control Ebola and Marburg Fevers
http://ecdc.europa.eu/en/healthtopics/ebola_marburg_fevers/Pages/index.aspx
National Institute of Allergy and Infectious Diseases—Health and research topics: Ebola/Marburg
http://www.niaid.nih.gov/topics/ebolamarburg/pages/default.aspx
World Health Organization Viral Hemorrhagic Fevers website
http://www.who.int/topics/haemorrhagic_fevers_viral/en/
22
SELECTED ONLINE PUBLICATIONS
Ebola outbreak (collection of articles and other resources from the New England Journal of Medicine)
http://www.nejm.org/page/ebola-outbreak
Ebola resource center—Open access articles from BioMed Central
http://www.springer.com/biomed/virology/spotlight+on+ebola?SGWID=0-1771314-0-0-0
Ebola resource centre (collection of articles and other resources from The Lancet)
http://ebola.thelancet.com/
Nature special: Ebola outbreak in West Africa (collection of articles and other resources from the
Nature family of journals) http://www.nature.com/news/ebola-1.15750?WT.ec_id=NEWS-20140826
Arbuthnot, P. Harnessing RNA interference for the treatment of viral infections. Drug News Perspect
2010, 23(6): 341
EBOLA VIRUS DISEASE TREATMENT GUIDELINES
Interim guidance for preparing Ebola assessment hospitals (Centers for Disease Control and
Prevention, December 2014)
http://www.cdc.gov/vhf/ebola/hcp/preparing-ebola-assessment-hospitals.html
Interim guidance for preparing Ebola treatment centers (Centers for Disease Control and Prevention,
December 2014) http://www.cdc.gov/vhf/ebola/hcp/preparing-ebola-treatment-centers.html
Interim guidance for U.S. hospital preparedness for patients with possible or confirmed Ebola virus
disease: A framework for a tiered approach (Centers for Disease Control and Prevention, December
2014) http://www.cdc.gov/vhf/ebola/hcp/us-hospital-preparedness.html
Ebola virus disease—What ophthalmologists need to know (American Academy of Ophthalmology,
November 2014)
http://one.aao.org/clinical-statement/ebola-virus-disease--what-ophthalmologists-need-to
Interim U.S. guidance for monitoring and movement of persons with potential Ebola virus exposure
(Centers for Disease Control and Prevention, October 2014)
http://www.cdc.gov/vhf/ebola/pdf/monitoring-and-movement.pdf
Rapid risk assessment: Outbreak of Ebola virus disease in West Africa—seventh update (European
Centre for Disease Prevention and Control, October 2014)
http://ec.europa.eu/health/preparedness_response/docs/ebola_riskassessment_en.pdf
Ebola response roadmap (World Health Organization, August 2014)
http://apps.who.int/iris/bitstream/10665/131596/1/EbolaResponseRoadmap.pdf
Ebola virus disease: clinical management and guidance (Public Health England, August 2014)
https://www.gov.uk/government/collections/ebola-virus-disease-clinical-management-and-guidance
Guidelines for evaluation of US patients suspected of having Ebola virus disease (Centers for Disease
Control and Prevention, August 2014) http://emergency.cdc.gov/han/han00364.asp
Interim infection prevention and control guidance for care of patients with suspected or confirmed
filovirus haemorrhagic fever in health-care settings, with focus on Ebola (World Health Organization,
August 2014) http://www.who.int/csr/resources/who-ipc-guidance-ebolafinal-09082014.pdf?ua=1
Infection prevention and control recommendations for hospitalized patients with known or suspected
Ebola hemorrhagic fever in U.S. hospitals (Centers for Disease Control and Prevention, August 2014)
http://www.cdc.gov/vhf/ebola/hcp/infection-prevention-and-control-recommendations.html
23
Technical guidelines for integrated disease surveillance and response in the African region, 2nd edition
(World Health Organization/Centers for Disease Control and Prevention, 2010)
http://www.afro.who.int/en/downloads/doc_download/6057-technical-guidelines-for-integrateddisease-surveillance-and-response-in-the-african-region-2010.html
Interim infection control recommendations for care of patients with suspected or confirmed filovirus
(Ebola, Marburg) hemorrhagic fever (World Health Organization, March 2008)
http://www.who.int/entity/csr/bioriskreduction/interim_recommendations_filovirus.pdf
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Disease Briefing: Ebola Virus Disease - Thomson Reuters

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