Human-to-human transmission and adaptation of Ebola virus

Available online at www.sciencedirect.com
ScienceDirect
Human transmission of Ebola vi
rus
Philip Lawrence1,2, Nicolas Danet1, Olivier Reynard1,
Valentina Volchkova1 and Viktor Volchkov1
Ever since the first recognised outbreak of Ebolavirus in 1976,
retrospective epidemiological analyses and extensive studies
with animal models have given us insight into the nature of the
pathology and transmission mechanisms of this virus. In this
review focusing on Ebolavirus, we present an outline of our
current understanding of filovirus human-to-human
transmission and of our knowledge concerning the molecular
basis of viral transmission and potential for adaptation, with
particular focus on what we have learnt from the 2014 outbreak
in West Africa. We identify knowledge gaps relating to
transmission and pathogenicity mechanisms, molecular
adaptation and filovirus ecology.
Addresses

1 Molecular Basis of Viral Pathogenicity, International Centre
for
Research in Infectiology (CIRI), INSERM U1111 – CNRS
UMR5308,
Université Lyon 1, Ecole Normale Supérieure de Lyon, Lyon
69007,
France
2 Université de Lyon, UMRS 449, Laboratoire de Biologie
Générale,
Université Catholique de Lyon – EPHE, Lyon 69288, France
Corresponding author: Volchkov, Viktor ([email protected])
Current Opinion in Virology 2017, 22:51–58
This review comes from a themed issue on Emerging viruses:
intraspecies transmission
Edited by Ron A.M Fouchier and Lin-Fa Wang
For a complete overview see the Issue and the Editorial
Available online 22nd December 2016
http://dx.doi.org/10.1016/j.coviro.2016.11.013
1879-6257/# 2016 Published by Elsevier B.V.
Introduction
Filoviruses are enveloped, non-segmented, negative-
strand RNA viruses, composed of three genera: Ebola-

virus, Marburgvirus and Cuevavirus (Figure 1) [1–3]. Ebo-
lavirus and Marburgvirus are together the causative agents
of severe disease in human and non-human primates
(NHPs) displaying fatality rates reaching 90% [1]
(Table 1). There are currently five known, genetically
distinct species of Ebolavirus — Zaire ebolavirus (EBOV),
Sudan ebolavirus (SUDV), Taı̈ Forest ebolavirus (TAFV),
Bundibugyo ebolavirus (BDBV) and the Asian filovirus;
Reston ebolavirus (RESTV) [2]. Almost all human cases
are due to the emergence or re-emergence of EBOV in
Gabon, Republic of the Congo, Democratic Republic of
www.sciencedirect.com
Congo (DRC), and most recently in West Africa [4], and
of SUDV in Sudan and Uganda [5] (Table 1).
The increase in the number of outbreaks of Ebola virus
disease (EVD) in Africa since 2000 (Table 1) has been
postulated to result from increased contact between wild-
life and humans [6]. The ever increasing encroachment of
mankind into previously uninhabited areas will continue
to bring not only humans but also potentially susceptible,
domesticated animals into contact with unknown patho-
gens and their reservoir species [7]. Deforestation and

climate change can also be expected to cause certain
species to modify their geographic and ecological distri-
bution and potentially into greater proximity to human
agricultural exploits or settlements. It appears thus urgent
to better understand both filovirus ecology and the mech-
anisms involved in viral transmission from their natural
hosts and between humans.
Retrospective analysis of human outbreaks since the first
EBOV epidemic in 1976 and intensive studies performed
on animal models have helped to understand both the
nature of EBOV pathology and its transmission. However,
the 2014 outbreak has again shown that a complete
knowledge of EBOV human-to-human transmission
mechanisms is still lacking and is in many cases based
only on retrospective observations rather than empirical
data. Here, focusing on EBOV, we present an overview of
our current understanding of filovirus transmission in
humans. We also summarise our current knowledge con-

cerning the molecular basis of viral transmission and
potential adaptation including that gained from the recent
outbreak, together with our opinions on knowledge gaps
and future directions for research.
Transmission routes
In humans, EBOV has been evidenced either directly or
via detection of viral RNA in a range of bodily fluids
including blood, stool, semen, breast milk and saliva as
well as sweat and tears [8,9]. It is generally accepted that
contact with such fluids/fomites from an infected and
symptomatic, or deceased person is the most likely route
of transmission of EBOV. Other than direct or close
contact with these fluids, transmission routes proposed
for EBOV involve the presence of infectious virus in
fomites, droplets and aerosols [10
��
]. Experiments using
NHPs have shown that EBOV is both highly infectious
and contagious [11–13].Evidence from NHP studies
has confirmed viral infection associated with a variety

of administration routes including oral, conjunctival,
52 Emerging viruses: intraspecies transmission
Figure 1
RAVV
EBOV
RESTV
SUDVBDBV
TAFV
LLOV
MARV
Ebolavirus
Cuevavirus
Marburgvirus
0.1
Filoviridae
Current Opinion in Virology
Phylogenetic relationship for the viral famiy Filoviridae. The
family

Filoviridae are enveloped, non-segmented, negative-strand RNA
viruses of the order Mononegavirales, composed of three major
genera: Ebolavirus, Marburgvirus and Cuevavirus. There are
currently
five known, genetically distinct species of Ebolavirus — Zaire
ebolavirus (EBOV), Sudan ebolavirus (SUDV), Taı̈ Forest
ebolavirus
(TAFV), Bundibugyo ebolavirus (BDBV) and Reston ebolavirus
(RESTV).
The genus Marburgvirus comprises one viral species; Marburg
marburgvirus with two current viral members Marburg virus
(MARV)
and Ravn virus (RAVV). The genus Cuevavirus currently has
one
species member Lloviu cuevavirus (LLOV). 29 filovirus L
protein
sequences for the illustrated virus species were obtained from
the
ViPR database and aligned using the muscle algorithm. The
aligned
sequences served to generate the phylogenetic tree using the
distance method in the Seaview software [80]. The scale bar

indicates
evolutionary distance between each node.
submucosal and respiratory routes amongst others. Based
on detailed analysis of available data [10
��
,14] the trans-
mission routes for EBOV can be summarised as follows.
Direct contact
As stated above, evidence from outbreaks, epidemiologi-
cal data and NHP models have all confirmed direct
contact of an individual with contaminated bodily fluids
from a symptomatic patient or from a disease victim as the
most likely interhuman transmission route. It is interest-
ing to note that recent data from an NHP study using the
West African outbreak EBOV Makona variant suggest
that more natural routes of infection via oral or conjunc-
tiva mucosa may require higher doses of EBOV to pro-
duce disease [13], although further studies are required in
comparison to other EBOV variants to confirm such

observations. Since the recent epidemic however it has
also become clear that sexual transmission of EBOV
presents a certain risk even with patients that are no
longer symptomatic for EVD and this many months after
remission [15,16
��
,17,18]. Indeed, infectious EBOV can
be detected in semen of survivors at least up to around
500 days [19,20] and sexual transmission has already been
linked to the start of new chains of transmission [21,22].
Droplet transmission
By common definition [23] droplet transmission is
thought to occur up to a metre from an infected individual
depending on the stability of the virus in question and
specific environmental conditions. Cases of droplet trans-
mission are suspected from epidemiological data for
patients where no direct contact was reported [24]. In
the case of EBOV, the presence of virus in droplets might
arise from a range of infected fluids, including blood,

vomit, saliva or diarrhoea or be produced by coughing or
during medical intervention.
Fomites
Transmission from fomites involves viral deposition on
surfaces that have been in contact with contaminated
secretions including disposed medical waste or corpses
[10
��
,14]. Indeed, contamination from disease victims
appears common and has been linked to many cases of
transmission, highlighting funerals and burial practices as
key transmission events [25
�
]. Viable virus has been
detected on solid surfaces and liquids several days to
several weeks after contamination and infectious virus has
been retrieved from EBOV infected monkeys seven days
after death and RNA detected up to 10 weeks [26]. Data
is however often lacking concerning the stability of virus

on surfaces and in secretions not typically associated with
transmission of enveloped RNA viruses, including vomit
and diarrhoea.
Aerosols
Experimental data from NHPs have shown that mechan-
ical aerosolisation of virus particles can cause disease with
even low infectious doses [27] but the relevance of such
findings in a natural setting is unclear [10
��
]. Stability
studies would also suggest that aerosolised particles pro-
duced in this way are relatively unstable (loss of 99% of
particles after 100 min at room temperature and humidi-
ty) [28]. As stated above, the majority of transmission
cases arise from direct contact and in outbreak settings
containment is possible without strict precautions against
airborne transmission [10
��
,14].

EBOV transmission and molecular potential
for virus adaptation/evolution
Pathogens such as EBOV would appear already intrin-
sically able to break the interspecies barrier and both
the intrahuman and interhuman barriers, allowing the
virus to propagate within the human population. How-
ever, as the specific natural host of Ebolavirus is yet to
be discovered it is difficult to clearly assess whether
EBOV needs any adaptation to successfully infect
humans or other species. Nevertheless, evidence of
EBOV infection has been reported in various wild
species including primates, bats, duikers or domestic
pigs [29–32], and thus far, similarly to Marburgvirus, bats
are thought to be the most likely natural reservoir for
this virus [33
�
].
Human transmission of Ebola virus Lawrence et al. 53
Table 1
List of Ebolavirus outbreaks (1976–present day)

Year(s) Country Ebola subtype Reported number
of human cases
Reported
number of
fatalities
Case
fatality
rate
August–November 2014 Democratic Republic of the Congo
Ebola virus 66 49 74
March 2014–Present Guinea, Sierra Leone, Liberia and others*
Ebola virus 28 616* 11 310* �70**
November 2012–January 2013 Uganda Sudan virus 6 3 50
June–November 2012 Democratic Republic of the Congo
Bundibugyo virus 36 13 36
June–October 2012 Uganda Sudan virus 11 4 36
May 2011 Uganda Sudan virus 1 1 100
December 2008–February 2009 Democratic Republic of the
Congo Ebola virus 32 15 47
November 2008 Philippines Reston virus 6 (asymptomatic) 0 0

December 2007–January 2008 Uganda Bundibugyo virus 149 37
25
2007 Democratic Republic of the Congo Ebola virus 264 187 71
2005 Republic of the Congo Ebola virus 12 10 83
2004 Sudan (South Sudan) Sudan virus 17 7 41
November–December 2003 Republic of the Congo Ebola virus
35 29 83
December 2002–April 2003 Republic of the Congo Ebola virus
143 128 89
October 2001–March 2002 Republic of the Congo Ebola virus
57 43 75
October 2001–March 2002 Gabon Ebola virus 65 53 82
2000–2001 Gulu, Uganda Sudan virus 425 224 53
1996 South Africa Ebola virus 2 1 50
1996–1997 (July–January) Gabon Ebola virus 60 45 74
1996 (January–April) Gabon Ebola virus 37 21 57
1994 Côte d’Ivoire (Ivory Coast) Taı̈ Forest virus 1 0 0
1994 Gabon Ebola virus 52 31 60
1989–1990 Philippines Reston virus 3 (asymptomatic) 0 0

1990 USA Reston virus 4 (asymptomatic) 0 0
1977 Ebola Ebola virus 1 1 100
Adapted from [5,79]
* Includes cases from Guinea, Sierra Leone and Liberia only.
** Estimated.
In terms of susceptibility to infection and species tropism,
filoviruses have one surface glycoprotein (GP) (Figure 2)
that drives binding and entry of the virus through inter-
action with multiple cellular surface molecules [34,35].
The cellular endosomal receptor Niemann-Pick C1
(NPC1) has been identified as playing a key role in the
fusion process through binding the proteolytically-primed
GP. Mapping of the key positions on NPC-1 and EBOV
GP responsible for EBOV tropism shows that these
residues are shared between both susceptible bat and
human cell lines [36
�

,37]. Such data suggest that EBOV
would not require specific adaptation for successful entry
into human cells. Likewise, molecular studies performed
on human macrophages and a Marburgvirus bat isolate
suggest that no further adaptation is necessary for spill-
over from bats to the human population [38]. In rodent
models however, Ebolavirus infection with wild-type
EBOV virus results in an asymptomatic illness [39–41].
Importantly, sequential passaging of wild-type virus in
these small animal models can lead to the generation of
highly pathogenic variants of the virus that display muta-
tions in three viral genes: polymerase (L), nucleoprotein
(NP) and viral protein VP24, when compared to the
initial, wild-type viral sequence [40,42,43]. By generating
recombinant viruses containing different combinations of
these mutations, it was subsequently shown that a single
mutation in VP24 was sufficient for the virus to acquire
virulence in Guinea pigs [40,42]. Similarly, an adapted
EBOV strain containing mutations in VP24 and NP genes
is lethal in immunocompetent mice and hamsters [39,40].

The recent epidemic is the first time that such an out-
break has been described in terms of the genetic evolu-
tion of the viral genome over the course of an epidemic.
Systematic deep sequencing of EBOV positive patients
has thus provided new insights into viral spread and
transmission chains [4,44–48,49
�
]. The extent of the
2014 West Africa outbreak lead to numerous concerns
about the ability of the EBOV Makona variant to evolve
in terms of pathogenicity and/or transmissibility in the
human population [44,50]. The emergence of variants
with a lower pathogenicity was also feared; as such viruses
can potentially establish a long-term endemic presence of
the virus in afflicted countries [51]. Initially thought to be
Figure 2

NP VP35 VP40 sGP/GP VP30 VP24 L3′
Leader
5′
Trailer
Current Opinion in Virology
Schematic representation of Ebola virus genome. The 19 kb
negative-sense RNA genome of EBOV and its seven genes give
rise to the individual
viral structural and non-structural proteins. The central core of
the virion is formed by the genomic RNA molecule
encapsulated by nucleoprotein
(NP) and linked to viral inner capsid proteins 30 (VP30) and 35
(VP35) and the RNA-dependent RNA polymerase (L), together
with VP24 forming
the viral ribonucleoprotein complex (RNP) that is essential for
viral transcription, replication and encapsidation. The two
remaining viral proteins,
surface glycoprotein (GP) and VP40 are membrane-associated;
VP40 is displayed at the inner surface of the lipid bilayer of the
viral envelope and
is linked to the RNP. Through transcriptional RNA editing,
three GP gene specific mRNA products are expressed from the
GP gene of EBOV,
coding for full-length transmembrane surface GP and the
soluble, non-structural proteins sGP and ssGP. Star indicates
the position of the GP

gene editing site.
able to evolve more rapidly [44], the whole genome
mutation rate for EBOV Makona now appears to be
comparable with that observed during other EBOV
outbreaks, with a substitution rate estimated at
�1.3 � 10�3 nucleotides/site/year [45–48]. Indeed, the
molecular data, as well as the epidemiological analysis
allowing estimation of parameters such as the basic re-
production number R0, so far obtained cannot discrimi-
nate EBOV Makona from previous outbreak variants
[25
�
,44,52–55]. In general, EBOV Makona would appear
however to have a longer incubation time than most
previous EBOV outbreaks, potentially allowing a longer
period of dissemination from infected persons between
different regions, facilitating propagation of the virus
[25
�
,44,52].
Although both synonymous and non-synonymous muta-

tions are detected in all viral genes, the most frequent
gene mutations observed during the outbreak were locat-
ed in GP, NP, and L [44,45,47,48,49
�
,56], and interest-
ingly this tendency appears conserved between previous
outbreaks when such data is available [49
�
,57,58
�
]. Anal-
ysis of the EBOV Makona GP mucin-like domain
has shown it to be more subject to positive selection in
several studies, with an acquisition of mutations in B and
T cell epitopes [50,54,57,58
�
]. Additionally for GP, a non-
synonymous mutation at amino acid 82 (A82V) appeared
to be selected in a region containing the receptor-binding
domain [47,49
�
]. Indeed, recent analyses of this A82V
mutation in pseudovirus or reverse genetics systems have

highlighted the role of this mutation in adaptation to a
human host through a certain refining of receptor binding
affinity and associated increase in viral fitness in human
cells [59
��
,60,61]. Whilst GP mutations probably reflect
the arms race between the immune system and the virus
or differences in receptor binding affinity [57,59
��
,60–62],
mutations in NP, VP30, VP35 and L, the four proteins
forming the viral ribonucleoprotein replication complex,
might play a role in viral adaptation in the human popu-
lation in the processes of viral transcription, replication or
encapsidation or in facilitating the interaction of cellular
factors with viral proteins and RNA in a new host envi-
ronment, as already shown for Influenza [63]. For EBOV,
mutations in L have already been speculated to play a role
in both GP editing and viral replication rates [64], al-

though experimental evidence for this is currently lack-
ing. Several recent studies based on the genetic analysis
of Makona variants arising during the recent outbreak
have shown that mutations in VP30 and in L [65] or in NP
and L [59
��
] can have implications for virus adaptation
and fitness.
As single mutations often occur at the cost of viral fitness,
which need to be compensated by other co-mutations, it
appears essential to continue to analyse co-occurring
mutations to fully understand viral evolution and adapta-
tion [59
��
,65–67]. EBOV co-mutation network analysis
shows strong evidence of selection for GP, NP, L and
VP40, especially for EBOV Makona, with mutations
occurring more frequently in protein interaction domains
[58
�
]. This study suggests that a still understudied coop-

eration between viral proteins exists and could play a role
in viral adaptation to humans. In addition, several studies
reported serial T>C substitutions in viral genomes, sug-
gested to be due to specific cellular Adenosine Deami-
nase Acting on RNA (ADAR) enzymes [45,46,68]. The
role of these substitutions is currently unknown but
ADAR modifications have been shown to be involved
in replication and pathogenesis for several other viruses
including influenza and measles virus and therefore merit
further investigation [69].
Another major discovery of sequence analyses was the low
percentage (�1%) of viral GP gene specific mRNA
encoding for the full-length, transmembrane, surface
GP [44]. In fact Ebolavirus is somewhat unique in this
respect in that synthesis of its surface GP is dependent on
transcriptional RNA editing at a site constituting seven
consecutive U residues (editing site) present within the
GP gene (Figure 2). Direct expression of the GP gene
however results in synthesis of a nonstructural secreted

glycoprotein termed sGP [70], which has been proposed
to participate in the immune evasion of EBOV by cap-
turing certain antibodies directed against GP [71]. Early
reports based on cell culture experiments had indicated a
figure of around 1:4 for the ratio of surface GP versus sGP
transcripts [70,72]. Discovery of a much lower percentage
in patients during the outbreak corroborates recent find-
ings indicating that the editing site is also a transcription
termination signal and highlights the necessity for a
productive viral cycle to minimize surface GP expression,
as recently demonstrated [73,74]. Interestingly, these
observations resemble those seen in experimental animal
models of adaptation in which it was demonstrated that
control over surface GP expression is also exerted at the
GP editing site at the genomic level [75,76]. On the other
hand, the maintenance of the wild-type editing site may

indicate that a well-balanced, rationally minimal expres-
sion of surface GP vs. synthesis of secreted sGP offers a
selective advantage and that this feature is an essential
element in the replication and spread of EBOV, playing a
role in viral pathogenicity and in counteracting the im-
mune system [71,73,77]. In keeping with this idea,
another mutation hotspot that was identified during the
2014 outbreak is near the GP tumour necrosis factor-alpha
converting enzyme (TACE) cleavage site (Q638R/L)
[49
�
]. This cleavage site is responsible for an additional
decrease in expressed membrane-bound GP via its re-
moval from the cell surface as a shed form that is proposed
to play a role in virus dissemination and pathogenesis
[77,78]. However, the biological significance of this mu-
tation remains to be tested.
Conclusions and areas for future study
Coupled with data from animal models, the outbreak in
West Africa has again highlighted the importance of

contact with bodily fluids for a successful transmission.
However, further characterisation of which fluids are most
likely to lead to infection needs to be performed in terms
of virus loads and survival rates. In the same vein there is
currently very little experimental data on how the virus
physically penetrates into the body. Likewise the relative
impact and risk associated with the potential of sexual
transmission of EBOV should be thoroughly investigated.
Based on everything that we have learnt concerning the
genomics of the latest outbreak it will be vital to continue
to perform molecular studies to assess the importance of
the various mutations and polymorphisms consistently
detected from epidemiological data in terms of their
impact on virus immune escape, receptor binding affini-
ties, pathogenicity and transmissibility. In light of recent
molecular data based on 2014 EBOV outbreak isolates
[59
��

,60,61,65], it will be of interest to further study and to
model such mutations through consecutive passages of
initial/early outbreak variants in human cells. It also
remains to be seen whether adaptation mutations seen
over the course of an outbreak can be in some way
preserved, given the unprecedented scale of the epidemic
and multiple contacts between infected patients, disease
victims and the environment.
A surprising feature of some of the recent outbreaks has
been the appearance of Ebolavirus species in new loca-
tions, including BDBV in DRC and more recently and
more devastatingly, EBOV in West Africa [4]. In this
respect it seems vital that future studies cover the identi-
fication of risk factors linked to the emergence of zoonotic
pathogens and include continuing studies of the molecular
basis of transmission events that allow such breaches of the
animal to human species barrier or that promote efficient
human-to-human transfer. Although we are just beginning
to understand filovirus ecology, it seems clear given the

absence of any current vaccine or proven treatment for
EVD and the difficulty in containing outbreaks in coun-
tries where access to adapted medical and containment
facilities is rare, that for the moment any increased under-
standing of filovirus ecology and surveillance may help to
minimize the risk of future outbreaks.
Acknowledgements
This work was supported by the European Commission (FP7
programme in
the framework of the project ‘Antigone — ANTIcipating the
Global Onset
of Novel Epidemics’, project number 278976) and by Agence
Nationale de
la Recherche (ANR-14-EBOL-002-01). The sponsor had no role
in the
collection, analysis and interpretation of data, in the writing of
this review;
nor in the decision to submit for publication.
References and recommended reading
Papers of particular interest, published within the period of
review,
have been highlighted as:
� of special interest
�� of outstanding interest
1. Groseth A, Eickmann M, Ebihara H, Becker S, Hoenen T:
Filoviruses: Ebola, Marburg and Disease. eLS. John Wiley &

Sons, Ltd.; 2015 http://dx.doi.org/10.1002/
9780470015902.a0002232.pub3 http://www.els.net.
2. Kuhn JH, Yiming B, Sina B, Stephan B, Steven B, Rodney
Brister J,
Bukreyev AA, Yı́ngyún C, Kartik C, Davey RA et al.: Virus
nomenclature below the species level: a standardized
nomenclature for laboratory animal-adapted strains and
variants of viruses assigned to the family Filoviridae. Arch
Virol
2013, 158:1425-1432.
3. Negredo A, Palacios G, Vázquez-Morón S, González F,
Dopazo H,
Molero F, Juste J, Quetglas J, Savji N, de la Cruz Martı́nez M et
al.:
Discovery of an ebolavirus-like filovirus in Europe. PLoS
Pathog 2011, 7:e1002304.
4. Baize S, Pannetier D, Oestereich L, Rieger T, Koivogui L,
Magassouba N, Soropogui B, Sow MS, Keı̈ ta S, De Clerck H et
al.:
Emergence of Zaire Ebola virus disease in Guinea. N Engl J
Med 2014, 371:1418-1425.
5. Centers for Disease Control and Prevention. Outbreaks
Chronology: Ebola Virus Disease (accessed on 05.09.16);
Available online: http://www.cdc.gov.gate2.inist.fr/vhf/ebola/
outbreaks/history/chronology.html.
6. Plowright RK, Foley P, Field HE, Dobson AP, Foley JE, Eby
P,
Daszak P: Urban habituation, ecological connectivity and
epidemic dampening: the emergence of Hendra virus from
flying foxes (Pteropus spp.). Proc Biol Sci 2011, 278:3703-
3712.

7. Patz JA, Olson SH: Climate change and health: global to
local
influences on disease risk. Ann Trop Med Parasitol 2006,
100:535-549.
8. Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M,
Sanchez A, Nichol ST, Ksiazek TG, Rollin PE: Assessment of
the
risk of Ebola virus transmission from bodily fluids and fomites.
J Infect Dis 2007, 196(Suppl. 2):S142-S147.
9. Centers for Disease Control and Prevention. Transmission:
Ebola
Virus Disease (accessed on 03.09.16): Available online: http://
www.cdc.gov.gate2.inist.fr/vhf/ebola/transmission/.
10.
��
Judson S, Prescott J, Munster V: Understanding ebola virus
transmission. Viruses 2015, 7:511-521.
Authors present a thorough overview of our current
understanding of
filovirus transmission and discuss important knowledge gaps for
future
research.
11. Alfson KJ, Avena LE, Beadles MW, Staples H, Nunneley
JW,
Ticer A, Dick EJ Jr, Owston MA, Reed C, Patterson JL et al.:

Particle-to-PFU ratio of Ebola virus influences disease course
and survival in cynomolgus macaques. J Virol 2015,
89:6773-6781.
12. Jaax N, Jahrling P, Geisbert T, Geisbert J, Steele K, McKee
K,
Nagley D, Johnson E, Jaax G, Peters C: Transmission of
Ebola virus (Zaire strain) to uninfected control monkeys in
a biocontainment laboratory. Lancet 1995,
346:1669-1671.
13. Mire CE, Geisbert JB, Agans KN, Deer DJ, Fenton KA,
Geisbert TW: Oral and conjunctival exposure of nonhuman
primates to low doses of Ebola Makona virus. J Infect Dis 2016,
214:S263-S267.
14. Vetter P, Fischer WA II, Schibler M, Jacobs M, Bausch DG,
Kaiser L: Ebola virus shedding and transmission: review of
current evidence. J Infect Dis 2016 http://dx.doi.org/10.1093/
infdis/jiw254.
15. Thorson A, Formenty P, Lofthouse C, Broutet N: Systematic
review of the literature on viral persistence and sexual
transmission from recovered Ebola survivors: evidence and
recommendations. BMJ Open 2016, 6:e008859.
16.
��
Mate SE, Kugelman JR, Nyenswah TG, Ladner JT, Wiley MR,
Thierry C-L, Athalia C, Schroth GP, Gross SM, Davies-Wayne
GJ
et al.: Molecular evidence of sexual transmission of Ebola
virus. N Engl J Med 2015, 373:2448-2454.
This paper shows for the first time that EBOV can be

considered as
sexually transmitted disease and emphasises the need to monitor
EBOV
persistence in semen in survivors to successful control an
epidemic of this
size.
17. Uyeki TM, Erickson BR, Brown S, McElroy AK, Cannon D,
Gibbons A, Sealy T, Kainulainen MH, Schuh AJ, Kraft CS et
al.:
Ebola virus persistence in semen of male survivors. Clin Infect
Dis 2016, 62:1552-1555.
18. Sow MS, Etard J-F, Baize S, Magassouba N’fally, Faye O,
Msellati P, Touré AI, Savane I, Barry M, Delaporte E et al.:
New
evidence of long-lasting persistence of Ebola virus genetic
material in semen of survivors. J Infect Dis 2016 http://
dx.doi.org/10.1093/infdis/jiw078.
19. Chughtai AA, Barnes M, Macintyre CR: Persistence of
Ebola
virus in various body fluids during convalescence: evidence
and implications for disease transmission and control.
Epidemiol Infect 2016, 144:1652-1660.
20. Diallo B, Sissoko D, Loman NJ, Bah HA, Bah H, Worrell
MC,
Conde LS, Sacko R, Mesfin S, Loua A et al.: Resurgence of
Ebola
virus disease in Guinea linked to a survivor with virus
persistence in seminal fluid for more than 500 days. Clin Infect
Dis 2016 http://dx.doi.org/10.1093/cid/ciw601.
21. Arias A, Armando A, Watson SJ, Danny A, Tobin EA, Jia L,
Phan MVT, Umaru J, Wadoum REG, Luke M et al.: Rapid

outbreak
sequencing of Ebola virus in Sierra Leone identifies
transmission chains linked to sporadic cases. Virus Evol 2016,
2:vew016.
22. Abbate JL, Murall CL, Richner H, Althaus CL: Potential
impact of
sexual transmission on Ebola virus epidemiology: Sierra
Leone as a case study. PLoS Negl Trop Dis 2016, 10:e0004676.
23. Darquenne C: Aerosol deposition in health and disease.
J Aerosol Med Pulm Drug Deliv 2012, 25:140-147.
24. Roels TH, Bloom AS, Buffington J, Muhungu GL, Mac
Kenzie WR,
Khan AS, Ndambi R, Noah DL, Rolka HR, Peters CJ et al.:
Ebola
hemorrhagic fever, Kikwit, Democratic Republic of the Congo,
1995: risk factors for patients without a reported exposure.
J Infect Dis 1999, 179(Suppl. 1):S92-S97.
25.
�
Van Kerkhove MD, Bento AI, Mills HL, Ferguson NM,
Donnelly CA:
A review of epidemiological parameters from Ebola outbreaks
to inform early public health decision-making. Sci Data 2015,
2:150019.
The authors present a very detailed analysis of factors driving
transmis-
sion, highlighting differences between the West Africa 2014
epidemic and
previous outbreaks.

26. Prescott J, Joseph P, Trenton B, Robert F, Kerri M, Seth J,
Munster VJ: Postmortem stability of Ebola virus. Emerg Infect
Dis 2015, 21:856-859.
27. Reed DS, Lackemeyer MG, Garza NL, Sullivan LJ, Nichols
DK:
Aerosol exposure to Zaire ebolavirus in three nonhuman
primate species: differences in disease course and clinical
pathology. Microbes Infect 2011, 13:930-936.
28. Piercy TJ, Smither SJ, Steward JA, Eastaugh L, Lever MS:
The
survival of filoviruses in liquids, on solid substrates and in a
dynamic aerosol. J Appl Microbiol 2010, 109:1531-1539.
29. Olival KJ, Hayman DTS: Filoviruses in bats: current
knowledge
and future directions. Viruses 2014, 6:1759-1788.
30. Nkoghe D, Formenty P, Leroy EM, Nnegue S, Edou SYO,
Ba JI,
Allarangar Y, Cabore J, Bachy C, Andraghetti R et al.: Multiple
Ebola virus haemorrhagic fever outbreaks in Gabon, from
October 2001 to April 2002. Bull Soc Pathol Exot 2005,
98:224-229.
31. Nfon CK, Leung A, Smith G, Embury-Hyatt C, Kobinger G,
Weingartl HM: Immunopathogenesis of severe acute
respiratory disease in Zaire ebolavirus-infected pigs. PLoS
ONE 2013, 8:e61904.
32. Genton C, Cristescu R, Gatti S, Levréro F, Bigot E, Caillaud
D,
Pierre J-S, Ménard N: Recovery potential of a western lowland
gorilla population following a major Ebola outbreak: results
from a ten year study. PLoS ONE 2012, 7:e37106.

33.
�
Leroy EM, Kumulungui B, Pourrut X, Rouquet P, Hassanin A,
Yaba P, Délicat A, Paweska JT, Gonzalez J-P, Swanepoel R:
Fruit
bats as reservoirs of Ebola virus. Nature 2005, 438:575-576.
After years of supposition as to the EBOV natural host, the
authors detect
for the first time EBOV RNA in three different species.
34. Moller-Tank S, Maury W: Ebola virus entry: a curious and
complex series of events. PLoS Pathog 2015, 11:e1004731.
35. Simmons G, Graham S: Filovirus entry. Adv Exp Med Biol
2013:83-94.
36.
�
Ng M, Ndungo E, Kaczmarek ME, Herbert AS, Binger T,
Kuehne AI,
Jangra RK, Hawkins JA, Gifford RJ, Biswas R et al.: Filovirus
receptor NPC1 contributes to species-specific patterns of
ebolavirus susceptibility in bats. Elife 2015, 4.
In this study, the authors show the molecular factors driving
EBOV
tropism using VSV recombinant viruses. The identification of
key residues
for EBOV interaction with NPC-1 could help to determine
which bat
species are potential hosts for EBOV.

37. Carette JE, Matthijs R, Wong AC, Herbert AS, Gregor O,
Nirupama M, Kuehne AI, Kranzusch PJ, Griffin AM, Gordon R
et al.:
Ebola virus entry requires the cholesterol transporter
Niemann-Pick C1. Nature 2011, 477:340-343.
38. Albariño CG, Uebelhoer LS, Vincent JP, Khristova ML,
Chakrabarti AK, McElroy A, Nichol ST, Towner JS:
Development
of a reverse genetics system to generate recombinant
Marburg virus derived from a bat isolate. Virology 2013,
446:230-237.
39. Bray M, Davis K, Geisbert T, Schmaljohn C, Huggins J: A
mouse
model for evaluation of prophylaxis and therapy of Ebola
hemorrhagic fever. J Infect Dis 1999, 179(Suppl. 1):S248-S258.
40. Volchkov VE, Chepurnov AA, Volchkova VA, Ternovoj
VA,
Klenk HD: Molecular characterization of Guinea pig-adapted
variants of Ebola virus. Virology 2000, 277:147-155.
41. Ebihara H, Zivcec M, Gardner D, Falzarano D, LaCasse R,
Rosenke R, Long D, Haddock E, Fischer E, Kawaoka Y et al.: A
Syrian golden hamster model recapitulating Ebola
hemorrhagic fever. J Infect Dis 2013, 207:306-318.
42. Mateo M, Carbonnelle C, Reynard O, Kolesnikova L,
Nemirov K,
Page A, Volchkova VA, Volchkov VE: VP24 is a molecular
determinant of Ebola virus virulence in Guinea pigs. J Infect

Dis
2011, 204:S1011-S1020.
43. Geisbert TW, Hensley LE, Kagan E, Yu EZ, Geisbert JB,
Daddario-DiCaprio K, Fritz EA, Jahrling PB, McClintock K,
Phelps JR et al.: Postexposure protection of Guinea pigs
against a lethal Ebola virus challenge is conferred by RNA
interference. J Infect Dis 2006, 193:1650-1657.
44. Gire SK, Goba A, Andersen KG, Sealfon RSG, Park DJ,
Kanneh L,
Jalloh S, Momoh M, Fullah M, Dudas G et al.: Genomic
surveillance elucidates Ebola virus origin and transmission
during the 2014 outbreak. Science 2014, 345:1369-1372.
45. Tong Y-G, Shi W-F, Liu D, Qian J, Liang L, Bo X-C, Liu J,
Ren H-G,
Fan H, Ni M et al.: Genetic diversity and evolutionary dynamics
of Ebola virus in Sierra Leone. Nature 2015, 526:595.
46. Park DJ, Dudas G, Wohl S, Goba A, Whitmer SLM,
Andersen KG,
Sealfon RS, Ladner JT, Kugelman JR, Matranga CB et al.:
Ebola
virus epidemiology, transmission, and evolution during seven
months in Sierra Leone. Cell 2015, 161:1516-1526.
47. Carroll MW, Matthews DA, Hiscox JA, Elmore MJ, Pollakis
G,
Rambaut A, Hewson R, Garcı́a-Dorival I, Bore JA, Koundouno
R
et al.: Temporal and spatial analysis of the 2014–2015 Ebola
virus outbreak in West Africa. Nature 2015, 524:97-101.
48. Hoenen T, Safronetz D, Groseth A, Wollenberg KR, Koita
OA,

Diarra B, Fall IS, Haidara FC, Diallo F, Sanogo M et al.:
Virology.
Mutation rate and genotype variation of Ebola virus from Mali
case sequences. Science 2015, 348:117-119.
49.
�
Ladner JT, Wiley MR, Mate S, Dudas G, Prieto K, Lovett S,
Nagle ER, Beitzel B, Gilbert ML, Fakoli L et al.: Evolution and
spread of Ebola virus in Liberia, 2014–2015. Cell Host Microbe
2015, 18:659-669.
An interesting, in-depth analysis of virus evolution during the
recent
outbreak in Liberia, including a discussion on the selection of
mutations
and patterns of divergence.
50. Kugelman JR, Wiley MR, Mate S, Ladner JT, Beitzel B,
Fakoli L,
Taweh F, Prieto K, Diclaro JW, Minogue T et al.: Monitoring of
Ebola Virus Makona evolution through establishment of
advanced genomic capability in Liberia. Emerg Infect Dis 2015,
21:1135-1143.
51. Blackley DJ, Wiley MR, Ladner JT, Fallah M, Lo T, Gilbert
ML,
Gregory C, D’ambrozio J, Coulter S, Mate S et al.: Reduced
evolutionary rate in reemerged Ebola virus transmission
chains. Sci Adv 2016, 2:e1600378.
52. Pigott DM, Golding N, Mylne A, Huang Z, Henry AJ, Weiss
DJ,
Brady OJ, Kraemer MUG, Smith DL, Moyes CL et al.: Mapping
the

zoonotic niche of Ebola virus disease in Africa. Elife 2014,
3:e04395.
53. Althaus CL: Estimating the reproduction number of Ebola
Virus
(EBOV) during the 2014 outbreak in West Africa. PLoS Curr
2014, 6.
54. Olabode AS, Xiaowei J, Robertson DL, Lovell SC: Ebola
virus is
evolving but not changing: no evidence for functional change
in EBOV from 1976 to the 2014 outbreak. Virology 2015,
482:202-207.
55. Gatherer D, Derek G: The unprecedented scale of the West
African Ebola virus disease outbreak is due to environmental
and sociological factors, not special attributes of the currently
circulating strain of the virus. Evid Based Med 2014, 20:28.
56. de La Vega M-A, Stein D, Kobinger GP: Ebolavirus
evolution:
past and present. PLoS Pathog 2015, 11:e1005221.
57. Liu S-Q, Deng C-L, Yuan Z-M, Rayner S, Zhang B:
Identifying
the pattern of molecular evolution for Zaire ebolavirus in
the 2014 outbreak in West Africa. Infect Genet Evol 2015,
32:51-59.
58.
�
Deng L, Lizong D, Mi L, Sha H, Yousong P, Aiping W,
Xiao-Feng Qin F, Genhong C, Taijiao J: Network of co-
mutations
in Ebola virus genome predicts the disease lethality. Cell Res

2015, 25:753-756.
The authors show the importance of studying mutations in a
virus genome
not individually but as a whole, to detect protein interactions
that are
currently not known to participate in viral replication.
59.
��
Dietzel E, Schudt G, Krähling V, Matrosovich M, Becker S:
Functional characterization of adaptive mutations during the
West African Ebola virus outbreak. J Virol 2016 http://
dx.doi.org/10.1128/JVI. 01913-16.
This paper presents a detailed, functional analysis of commonly
occurring
virus variants from the West African EBOV outbreak using a
series of VLP
and reverse genetics approaches and show that these mutations
can
enhance viral fitness in cell culture.
60. Diehl WE, Lin AE, Grubaugh ND, Carvalho LM, Kim K,
Kyawe PP,
McCauley SM, Donnard E, Kucukural A, McDonel P et al.:
Ebola
virus glycoprotein with increased infectivity dominated the
2013–2016 epidemic. Cell 2016, 167 1088–1098.e6.
61. Urbanowicz RA, McClure CP, Sakuntabhai A, Sall AA,
Kobinger G,
Müller MA, Holmes EC, Rey FA, Simon-Loriere E, Ball JK:
Human
adaptation of Ebola virus during the West African Outbreak.

Cell 2016, 167:1079-1087 e5.
62. Mahale KN, Patole MS: The crux and crust of ebolavirus:
analysis of genome sequences and glycoprotein gene.
Biochem Biophys Res Commun 2015, 463:756-761.
63. Mänz B, de Graaf M, Mögling R, Richard M, Bestebroer
TM,
Rimmelzwaan GF, Fouchier RAM: Multiple natural
substitutions
in avian influenza A virus PB2 facilitate efficient replication in
human cells. J Virol 2016, 90:5928-5938.
64. Dowall SD, Matthews DA, Garcia-Dorival I, Taylor I,
Kenny J,
Hertz-Fowler C, Hall N, Corbin-Lickfett K, Empig C,
Schlunegger K
et al.: Elucidating variations in the nucleotide sequence of
Ebola virus associated with increasing pathogenicity. Genome
Biol 2014, 15:540.
65. Albariño CG, Guerrero LW, Chakrabarti AK, Kainulainen
MH,
Whitmer SLM, Welch SR, Nichol ST: Virus fitness differences
observed between two naturally occurring isolates of Ebola
virus Makona variant using a reverse genetics approach.
Virology 2016, 496:237-243.
66. Du X, Wang Z, Wu A, Song L, Cao Y, Hang H, Jiang T:
Networks of genomic co-occurrence capture
characteristics of human influenza A (H3N2) evolution.
Genome Res 2007, 18:178-187.
67. Rimmelzwaan GF, Berkhoff EGM, Nieuwkoop NJ, Smith
DJ,
Fouchier RAM, Osterhaus ADME: Full restoration of viral

fitness
by multiple compensatory co-mutations in the nucleoprotein
of influenza A virus cytotoxic T-lymphocyte escape mutants.
J Gen Virol 2005, 86:1801-1805.
68. Shabman RS, Jabado OJ, Mire CE, Stockwell TB, Edwards
M,
Mahajan M, Geisbert TW, Basler CF: Deep sequencing
identifies
noncanonical editing of Ebola and Marburg virus RNAs in
infected cells. MBio 2014, 5:e02011.
69. Samuel CE: Adenosine deaminases acting on RNA (ADARs)
are
both antiviral and proviral. Virology 2011, 411:180-193.
70. Volchkov VE, Becker S, Volchkova VA, Ternovoj VA,
Kotov AN,
Netesov SV, Klenk HD: GP mRNA of Ebola virus is edited by
the
Ebola virus polymerase and by T7 and vaccinia virus
polymerases. Virology 1995, 214:421-430.
71. Mohan GS, Li W, Ye L, Compans RW, Yang C: Antigenic
subversion: a novel mechanism of host immune evasion by
Ebola virus. PLoS Pathog 2012, 8:e1003065.
72. Volchkov VE, Volchkova VA, Muhlberger E, Kolesnikova
LV,
Weik M, Dolnik O, Klenk HD: Recovery of infectious Ebola
virus
from complementary DNA: RNA editing of the GP gene and
viral cytotoxicity. Science 2001, 291:1965-1969.
73. Volchkova VA, Dolnik O, Martinez MJ, Reynard O,
Volchkov VE:

RNA editing of the GP gene of Ebola virus is an important
pathogenicity factor. J Infect Dis 2015, 212(Suppl. 2):S226-
S233.
74. Volchkova VA, Vorac J, Repiquet-Paire L, Lawrence P,
Volchkov VE: Ebola virus GP gene polyadenylation versus
RNA
editing. J Infect Dis 2015, 212(Suppl. 2):S191-S198.
75. Volchkova VA, Dolnik O, Martinez MJ, Reynard O,
Volchkov VE:
Genomic RNA editing and its impact on Ebola virus adaptation
during serial passages in cell culture and infection of guinea
pigs. J Infect Dis 2011, 204(Suppl. 3):S941-S946.
76. Trefry JC, Wollen SE, Nasar F, Shamblin JD, Kern SJ,
Bearss JJ,
Jefferson MA, Chance TB, Kugelman JR, Ladner JT et al.:
Ebola
virus infections in nonhuman primates are temporally
influenced by glycoprotein poly-U editing site populations in
the exposure material. Viruses 2015, 7:6739-6754.
77. Dolnik O, Volchkova VA, Escudero-Perez B, Lawrence P,
Klenk H-D, Volchkov VE: Shedding of Ebola virus surface
glycoprotein is a mechanism of self-regulation of cellular
cytotoxicity and has a direct effect on virus infectivity. J Infect
Dis 2015, 212(Suppl. 2):S322-S328.
78. Escudero-Pérez B, Volchkova VA, Dolnik O, Lawrence P,
Volchkov VE: Shed GP of Ebola virus triggers immune

activation and increased vascular permeability. PLoS Pathog
2014, 10:e1004509.
79. Singh SK, Ruzek D: Viral Hemorrhagic Fevers. CRC Press;
2016.
80. Gouy M, Guindon S, Gascuel O: SeaView version 4: a
multiplatform graphical user interface for sequence
alignment and phylogenetic tree building. Mol Biol Evol 2010,
27:221-224.
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© Van Zuiden Communications B.V. All rights reserved.
S P E C I A L R E P O R T
Ebola virus disease: a review on epidemiology,
symptoms, treatment and pathogenesis
M. Goeijenbier1, J.J.A. van Kampen1, C.B.E.M. Reusken1,
M.P.G. Koopmans1,2, E.C.M. van Gorp1*
1Department of Viroscience, Erasmus MC, Rotterdam, the
Netherlands, 2National Coordination Centre
for Communicable Disease Control (CIb), National Institute for
Public Health and the Environment
(RIVM) the Netherlands, *corresponding author: email:
[email protected]

A B S T R A C T
Currently, West Africa is facing the largest outbreak of
Ebola virus disease (EVD) in history. The virus causing
this outbreak, the Zaire Ebolavirus (EBOV), belongs
to the genus Ebolavirus which together with the genus
Marburgvirus forms the family of the Filoviridae. EBOV
is one of the most virulent pathogens among the viral
haemorrhagic fevers, and case fatality rates up to 90% have
been reported. Mortality is the result of multi-organ failure
and severe bleeding complications. By 18 September 2014,
the WHO reported of 5335 cases (confirmed, suspected and
probable) with 2622 deaths, resulting in a case fatality rate
of around 50%. This review aims to provide an overview
of EVD for clinicians, with the emphasis on pathogenesis,
clinical manifestations, and treatment options.
K E Y W O R D S
Ebola virus disease, viral haemorrhagic fever, filovirus,
pathogenesis, treatment
I N T R O D U C T I O N
On 8 August 2014 the World Health Organisation (WHO)
declared the Ebola virus disease (EVD) outbreak in
West Africa a Public Health Emergency of International
Concern (PHEIC),1 stressing the need for international
attention and collaboration to control the outbreak. At
this moment (18 September 2014) a total of 5335 cases
with 2622 reported deaths have been notified, in Guinea,
Liberia, and Sierra Leone. The imported EVD case in
Nigeria that resulted in a relatively small outbreak,
and similar imported cases in the USA and Spain
which at first appeared to have been well contained, but

eventually lead to infection of healthcare workers, show
the importance of adequate isolation methods, training
of personnel and the adequate use of personal protective
equipment (PPE).2 For the West Africa outbreak the total
number of cases is subject to change due to ongoing
reclassification, retrospective investigation and the
availability of laboratory results. A second, non-related,
EVD outbreak has been reported in the Democratic
Republic of Congo with currently a total of 62 confirmed
and suspected cases.3,4
V I R O L O G Y
The virus causing the outbreak has been characterised
as Zaire Ebolavirus (EBOV). EBOV belongs to the genus
Ebolavirus which together with the genus Marburgvirus
forms the family of Filoviridae. This family belongs
to the order of the Mononegavirales which further
contains members of Bornaviridae, Paramyxoviridae
and Rhabdoviridae. Ebolaviruses are linear, negative-
stranded, RNA viruses with a genome of approximately 19
kilobases. Morphologically, when studied under an electron
microscope, the viral particles look like long stretched
filaments with some particles tending to curve into an
appearance looking like the number 6. At this moment
the genus Ebolavirus consists of five species: EBOV,
Sudan ebolavirus (SUDV), Tai forest ebolavirus (TAFV),
Bundibugyo ebolavirus (BDBV) and Reston ebolavirus
(RESTV). RESTV is considered to be non-pathogenic to
humans.5 The genus is named after the first recognised
outbreak that took place in the village of Yambuku, in Zaire
(now Democratic Republic of Congo), close to the Ebola
river.6 Since then there have been multiple EVD outbreaks,
mostly with EBOV and SUDV. The EBOV responsible for

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N O V E M B E R 2 0 1 4 , V O L . 7 2 , N O 9
the current outbreak was introduced into West Africa from
Central Africa in the last few decades.7
E P I D E M I O L O G Y A N D W E S T A F R I C A
O U T B R E A K
Figure 1 summarises the current area of the West Africa
EVD outbreak. This region is known to be endemic for two
additional viral haemorrhagic fever viruses (VHF), namely
the rodent-borne Lassa fever virus and the mosquito-borne
Yellow fever virus.8,9 Furthermore, a single case of EVD,
caused by TAFV, has been reported from this area
concerning a female researcher investigating (autopsy)
infected chimpanzees.10 Historically, EVD outbreaks often
occurred in small villages close to or located in tropical
rainforests. This partly explains why the first outbreaks
of EVD, due to EBOV and SUDV, remained restricted to a
limited area.11 No EVD outbreaks were reported between
1979 and 1994, but after 1994 the number of recognised
outbreaks increased, leading to the discovery of two new
Ebolavirus species (BDBV and TAFV).12 Multiple causes
of this increase in EVD outbreaks have been mentioned
in the literature, with the most likely being increased
bush meat consumption and transportation to previously
inaccessible areas.5,12 EVD is a zoonotic disease and each
EVD outbreak in the human population is initiated by a
(single) introduction from an animal reservoir. For the
current outbreak this introduction occurred in Guinea

in December 2013, but it is not known with certainty
how the index case became infected.7 The index case of
the unrelated outbreak in the Democratic Republic of
Congo had consumed bush meat, which is considered
the most likely source of infection.7,13 Species implicated
in introduction of EBOV into the human population are
chimpanzee, gorillas, duikers and specific species of fruit
bats, all found to be infected with EBOV during targeted
studies ( figure 2). Given the lack of overt disease, bats
are considered the most likely reservoir host.14,15 Once
introduced into the population EBOV may spread rapidly,
due to the rapid uncontrolled rate of high levels of viraemia
and virus shedding in body fluids (saliva, urine, faeces
and sweat) by EVD patients.16 When hygiene and personal
protective measures are not adequate, the risk for infection
of healthcare workers is considerable, as illustrated in the
Figure 1. Overview of the area of the current EVD
outbreak as per 8 September 2014
Figure 2. Transmission of Ebola virus disease (EVD)
Ebolaviruses enter the human body via mucosal
surfaces, abrasions and injuries in the skin or by direct
parental transmission. For each outbreak of EVD a
single introduction from the animal kingdom is needed.
It is likely that, as for the index case, infection occurs
after human contact with primates, e.g. due to hunting
or consuming of infected animals, while also other
mammals such as antelopes and rodents have been
mentioned as potential reservoirs.61 Another potential
cause for human infection was described in 2005 where
data from a large study in bats showed three fruit bat
species to be a potential reservoir for Ebolaviruses.14 This
was later confirmed by an EVD outbreak that resulted
after direct contact with bats.12,15 Due to the high viral
loads seen in the body fluids of EVD patients human to

human transmission can easily occur. This transmission
seems to take place through body fluid contact and not
by airborne transmission (e.g. infective aerosols)
444
N O V E M B E R 2 0 1 4 , V O L . 7 2 , N O 9
current outbreak.17 Furthermore cultural aspects, such as
local funeral ceremonies with potential contact with body
fluids from patients who have died from EVD, contribute
to the magnitude of this outbreak.18
C L I N I C A L M A N I F E S T A T I O N S
Symptoms in EVD patients normally occur after an
incubation period of 4-10 days, with a range of 2-21
days.19,20 After a sudden onset of ‘flu-like’ symptoms
(fever, myalgia, chills) and vomiting and diarrhoea, the
disease can rapidly evolve into a severe state with a rapid
clinical decline. This disease phase is characterised by
potential haemorrhagic complications and multiple organ
failure.19,21 EVD patients may present with gastro intestinal
symptoms (nausea, stomach ache, vomiting and diarrhoea),
neurological symptoms (headache, profound weakness
and coma), respiratory symptoms (coughing, dyspnoea
and rhinorrhoea), and generalised symptoms related to
failure of the cardiovascular system resulting in shock and
oedema.5,20,21 The most commonly described symptoms
are fever in combination with anorexia, asthenia and
a maculopapular rash between day 5 and 7 after the
onset of the disease,5,20,21 but in the current outbreak

the primary clinical presentation is gastro intestinal.
Clinical symptoms and chemical laboratory tests confirm
multi-organ involvement. Most common haematological
changes are leucopenia and lymphopenia, with a
specific decreased neutrophil count, and an increase in
liver enzymes. With progression of the disease, EVD
patients develop thrombocytopenia, lengthening of the
pro-thrombin time and activated partial thromboplastin
time. The lengthening of the clotting times together
with the observed increase in fibrin degradation products
suggest a consumptive coagulopathy due to disseminated
intravascular coagulation, which contributes to multi-organ
failure. Lethal EVD cases generally succumb between day
6 and 16 after the onset of symptoms. Patients die due to
shock, haemorrhage and multi-organ failure.5 If patients
recover, clinical improvement arises simultaneously with
the development of the antibody response. In lethal cases
the antibody response sometimes remains absent.22,23
Long-term complications of EVD have not been studied
extensively, but available literature suggests that patients
recovered from EVD could develop long-term symptoms
and disorders such as recurrent hepatitis, myelitis,
prolonged hair loss, psychosis and uveitis.5,19,21
D I A G N O S I S
The diagnosis of acute EVD is made by viral genome
detection via RT-PCR. The virus is generally detectable 48
hours after infection in both lethal and non-lethal cases.
This means that a negative test result within the first 48
hours after exposure does not rule out EBOV infection.
Due to the rapidity of the acute disease, serology does not
play a role in diagnosis of acute EVD patients but may
be of use in epidemiological and surveillance studies. In
general, IgM antibodies can be detected starting from two

days after the first symptoms appear and disappear after
30-168 days.24 IgG response is generally considered to start
between day 6 and 18 post onset of illness and remains
detectable for years. The antibody profile of the sera from
patients with lethal disease as compared with those that
survive is markedly distinct. This difference can serve as
a prognostic marker for the management of the patient
since antibody responses strongly differ between lethal and
survivor cases and it has been shown that deceased patients
show a much lower or even absent antibody response
compared with survivors.25,26
P A T H O G E N E S I S A N D T R A N S M I S S I O N
After infection, development of disease is a complex
interplay between virus, host and environment. Different
case fatality rates (CFR) have been reported between
the four human-pathogenic Ebolaviruses. For EBOV the
CFR ranges from 50-90% of the EVD cases.27 For the
current outbreak, CFR is estimated to be around 50%,28
although there is some evidence of improved outcomes
with intense symptomatic treatment. There is an indication
of differences in the CFR for different EBOV species, but
these data are hard to interpret as they rely on reporting,
which may be suboptimal.29 Ebolaviruses enter the human
body via mucosal surfaces, abrasions and injuries in the
skin or by direct parental transmission. Infection through
intact skin is considered unlikely, although not excluded.
The virus has been successfully isolated from skin (biopsy)
and body fluids.30 Several laboratory associated infections
have been reported in the past decades, often after needle
accidents or direct contact with infectious materials.31
The route of transmission seems to affect the disease
outcome; in the early EBOV outbreak in 1976, CFR
after transmission by injection was 100% versus 80%
in contact exposure cases.5 This has been confirmed in

a non-human primate model, showing faster disease
progression in animals infected via injection versus those
that received an aerosol challenge.32 Due to the high CFR
in EVD and the potential use of EBOV as a biodefense
weapon, the pathogenesis of EVD has been relatively well
studied during the past 15 years.33 Most studies have been
performed in rodent, guinea pig, primate and in vitro
models. Since the virus needs to adapt to cause disease
in rodent and guinea pig experimental study models, the
most relevant data representing human disease come
445
N O V E M B E R 2 0 1 4 , V O L . 7 2 , N O 9
from non-human primate studies.34 Upon entry, EBOV
have proven to be able to infect numerous cell types. Post
mortem studies of patients and experimentally infected
animals showed infection of immune cells (macrophages,
monocytes and dendritic cells), epithelial and endothelial
cells, fibroblasts, hepatocytes and adrenal gland tissue.35
Replication in infected cells is very efficient resulting
in a rapid and high peak viraemia.35 Furthermore, cell
death of infected cells has been hypothesised to play
an important role in the signs and symptoms seen in
EVD patients, for instance the decreased ability of the
immune system to respond to the infection due to necrosis
of infected lymphocytes or a decreased production of
clotting factor due to the loss of hepatocytes.5 Hallmark
characteristics of EVD, as in any VHF, are the bleeding
manifestations although these are infrequently observed in
the current outbreak.36 Studies addressing the mechanism

behind these coagulation abnormalities first showed
that haemorrhage was most likely not a direct effect
of endothelial cell infection, followed by cytolysis.37 A
more likely explanation seems to be an overexpression
of tissue factor in monocytes/macrophages resulting in
(over)activation of the extrinsic pathway of coagulation
followed by a consumptive coagulopathy and eventually
a disseminated intravascular coagulation.38 Furthermore
antibody enhancement has been hypothesised to play
a role in the later phase of the EVD course.39 Although
data on this theory are still limited, antibody-dependent
enhancement seems to enhance infectivity of the virus
in vitro not only for EBOV but also the closely related
Marburgvirus.38,40 A similar disease mechanism has been
hypothesised for the development of dengue haemorrhagic
fever.41,42 Interesting data about EVD pathogenesis come
from asymptomatic cases and EVD patients who survived
infection. A cluster of asymptomatic infections have been
described after EBOV infection. Of these 24 contacts, 11
were asymptomatically infected and developed an IgM
and IgG response plus a mild viraemia between day 7 (first
day of sampling) and day 16.43 The other 13 patients had
high levels of plasma viraemia associated with high levels
of pro-inflammatory cytokines. These data suggest that
a correlation exists between the height of peak viraemia
and levels of pro-inflammatory cytokines contributing to
disease severity.
C L I N I C A L M A N A G E M E N T A N D
( E X P E R I M E N T A L ) T R E A T M E N T
The first step is to identify patients with symptoms
consistent with the case definition as outlined by the
WHO and the Centers for Disease Control and Prevention
(CDC), Atlanta, Georgia, USA specially for patients in
geographical areas where Ebolavirus infections have

previously been reported and/or patients in other
countries with similar symptoms who have travelled
to these countries within the past 21 days. These
patients need to be rapidly isolated and the patient
contacts identified and appropriate containment and
preventive measures instituted. Blood samples need to
be immediately obtained and submitted to the nearest
clinical laboratory certified to conduct diagnostic
evaluation for Ebolavirus. Currently, the treatment of
EVD includes the administration of ‘supportive care’ and
treatment strategies. EVD patients benefit most from
managing the haemodynamics and haemostasis. When
started in the early phase of the disease, fluid replacement
therapy drastically increases the chance of survival.44
Ribavirin, the only known antiviral that is effective
against certain VHF pathogens such as Lassa fever, is
not effective against Ebolaviruses.45,46 Various drugs with
a potential effect in EVD are in the experimental phase
and have shown beneficial effects against Ebolaviruses
(mainly EBOV and SUDV) in animal models and have
been used in small numbers to treat EVD patients.
The WHO declared that, considering the magnitude
and severity of the current outbreak, it is ethical to use
experimental drugs for treatment and prevention of
EVD. Table 1 shows the most promising experimental
compounds with activity against EBOV, and the degree
of available information from preclinical and clinical
trials published in peer-reviewed journals. ZMapp is a
cocktail of monoclonal antibodies and is being used to
treat some victims of the current EBOV outbreak. Its role
in treatment of EVD still needs to be established since
efficacy data in humans have not been published yet.
The strongest evidence that ZMapp is indeed effective in
EVD comes from experiments in non-human primates
in which ZMapp was able to revert advanced EVD

when administered up to five days post infection.47
Unfortunately, there is a limited supply of ZMapp at this
moment. Of the non-antibody based antiviral preparations,
only the nucleoside analogue favipiravir has been tested
extensively in humans. Recently the drug gained approval
in Japan for use in humans infected with novel and
re-emerging influenza viruses. Besides activity against
influenza virus infection, this drug also has documented
activity against a wide variety of RNA viruses including
Ebolaviruses.48, 49 Favipiravir prevented death in mice
infected with EBOV when treatment was started six days
post infection.50 These results are promising, but need to
be confirmed in a non-human primate model. BCX-4430
is also a nucleoside analogue with broad spectrum activity
against RNA viruses and has proven to be effective against
the Marburg virus in a non-human primate model and
Ebola virus in a mouse model.51 Finally, TKM-ebola and
AVI-6002 are under development for the treatment of
EVD and exert their action via gene silencing. Both drugs
446
N O V E M B E R 2 0 1 4 , V O L . 7 2 , N O 9
have proven to be effective in mouse and primate models,
and some safety and pharmacokinetic data in humans are
available for AVI-6002.52-54 In earlier outbreaks attention
was paid to potential treatment of EVD patients with
blood transfusion from EVD survivors. For instance,
in the EVD outbreak in Kikwit (Democratic Republic
of Congo) in 1995, patients receiving convalescent

serum from EVD survivors showed a much lower CFR.55
However these results were based on a small number of
patients with a potential treatment bias. Furthermore,
this passive immunotherapy did not seem to be effective
in a non-human primate model.56 Due to the potential
for antibodies to enhance viral infections via antibody-
enhancement mechanisms,59 a note of caution is in order
Table 1. Experimental treatments for Ebola viral disease
Drug Drug type Mode of
action
In vitro
data on
Ebola
Non-primate
animal data on
Ebola
Primate data on
Ebola
Drug tested
in humans
Drug
tested
in Ebola
infected
humans
Approval
status

Favipiravir
(T-705)
(Fujifilm
Holdings
Corp)
Nucleoside
analogue
– broad
spectrum
activity
against RNA
viruses
RNA chain
termination
and/or lethal
mutagenesis
Yes
EC
50
31-63
mg/l48
IC
50
10
mg/l50
Yes
300 mg/kg/d
started 1 hour

post infection
prevented death
in 100% of Ebola
infected mice48
300 mg/kg/d
started 6 days
post infection
prevented death
in 100% of Ebola
infected mice50
Ongoing at
USAMRIID
[personal com-
munication M.
Koopmans and
S. Gunther]
Phase-2
completed
(influenza)
and phase-3
ongoing
(influenza)
No Approved
in Japan
for novel
and re-
emerging
influenza
viruses49
TKM-Ebola
(Tekmira

Pharma-
ceuticals
Corp)
Lipid nano-
particle with
siRNA –
Ebolavirus
specific
compound
Gene
silencing
Yes Yes
TKM-Ebola
started 1 hour
post infection
resulted in
survival of 3/5
guinea pigs (2
deaths unrelated
to Ebola)57
Yes
TKM-Ebola
started 30
minutes post
infection resulted
in survival of 6/8
rhesus monkeys
(2 Ebola related
deaths)52
Phase-1
study

partially on
hold9
No Not
approved
BCX-4430
(BioCryst
Pharma-
ceuticals)
Nucleoside
analogue
– broad
spectrum
activity
against RNA
viruses
RNA chain
termination
Yes
EC
50
3,4
– 11,8
microM
Yes No, but
activity against
Marburgvirus
in cynomolgus
macaques58

No No Not
approved
AVI-6002
(Sarepta
Thera peutics)
Phosporo-
diamidate
morpholino
oligomer –
Ebolavirus
specific
compound
Gene
silencing
Yes59 Yes Yes
AVI-6002 started
30-60 minutes
post infection
resulted in
survival of rhesus
monkeys in
dose dependent
manner (5/8
survived using
high dose)53
No No Not
approved
ZMapp
(Mapp

Biopharma-
ceuticals)
Cocktail of 3
monoclonal
antibodies –
Ebolavirus
specific
compound
Most likely
virus neu-
tralisation
Yes Yes Yes
started 24-48
hours post
infection
prevented death
in cynomolgus
macaques and
Zmapp is able to
revert advanced
EVD when
administered up
to five days post
infection47;60
Currently
being
used to
treat small
number of
victims of
the current
EBOV

outbreak
Yes Not
approved
447
N O V E M B E R 2 0 1 4 , V O L . 7 2 , N O 9
for the use of passive immunotherapeutic strategies.
However, there have been studies using such passive
immunotherapeutic protocols, especially with monoclonal
antibody treatment, which have been shown to be quite
effective in non-human primate models of Ebolavirus
infection and need to be considered.
C O N C L U S I O N
Rapid and wide geographic spread of the current EBOV
outbreak are reasons for increased alertness of clinicians
dealing with returning travellers from the outbreak
areas. Due to the initial non-specific presentation of
EVD, the combination of fever (and/or EVD symptoms
such as nausea, flu-like illness, headache, diarrhoea,
myalgia, conjunctival effusion and redness of the oral
and pharyngeal mucosa) in combination with high-risk
exposure (contact with EVD patient or body fluids, wild
animals, attendance of a funeral, visit to a local healthcare
facility or preparing and/or consuming bush meat) is
enough to proceed with isolation and management
protocols in patients who visited endemic areas in the
last 21 days. Currently treatment strategies rely solely on

the early start of supportive care, where aggressive fluid
replacement therapy is proven to drastically improve the
survival rates. Specific antiviral EVD treatment strategies
are still in the experimental phase. The current EVD
outbreak stresses the already weak healthcare and public
health systems in the affected countries, but also triggers
increased awareness in countries at risk for EVD import
cases. Given the ongoing outbreak, countries and clinical
centres should be aware of the potential for admission of
an EBOV infected person.
D I S C L O S U R E
The authors declare no conflicts of interest in the
preparation of this manuscript.
R E F E R E N C E S
1. Briand S, Bertherat E, Cox P, et al. The International Ebola
Emergency. N
Engl J Med. 2014;371:1180-3.
2. Leroy EM, Labouba I, Maganga GD, Berthet N. Ebola in
West Africa: The
outbreak able to change many things. Clin Microbiol Infect.
2014 [Epub
ahead of print].
3.
http://apps.who.int/iris/bitstream/10665/133833/1/roadmapsitrep
4 _eng.
pdf?ua=1
4. Nunes-Alves C. Ebola update. Nat Rev Microbiol.
2014;12:656.

5. Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet.
2011;377:849-62.
6. Johnson KM, Lange JV, Webb PA, Murphy FA. Isolation and
partial
characterisation of a new virus causing acute haemorrhagic
fever in Zaire.
Lancet. 1977;1:569-71.
7. Baize S, Pannetier D, Oestereich L, et al. Emergence of Zaire
Ebola Virus
Disease in Guinea – Preliminary Report. N Engl J Med.
2014;371:1418-25.
8. Paessler S, Walker DH. Pathogenesis of the viral hemorrhagic
fevers.
Annu Rev Pathol. 2013;8:411-40.
9. Goeijenbier M, Wagenaar J, Goris M, et al. Rodent-borne
hemorrhagic
fevers: under-recognized, widely spread and preventable –
epidemiology,
diagnostics and treatment. Crit Rev Microbiol. 2013;39:26-42.
10. Le GB, Formenty P, Wyers M, Gounon P, Walker F, Boesch
C. Isolation
and partial characterisation of a new strain of Ebola virus.
Lancet.
1995;345:1271-4.
11. Cox NJ, McCormick JB, Johnson KM, Kiley MP. Evidence
for two subtypes
of Ebola virus based on oligonucleotide mapping of RNA. J
Infect Dis.
1983;147:272-5.

12. Muyembe-Tamfum JJ, Mulangu S, Masumu J, Kayembe JM,
Kemp
A, Paweska JT. Ebola virus outbreaks in Africa: past and
present.
Onderstepoort J Vet Res. 2012;79:451.
13. Gire SK, Goba A, Andersen KG, et al. Genomic surveillance
elucidates
Ebola virus origin and transmission during the 2014 outbreak.
Science.
2014;345:1369-72.
14. Leroy EM, Kumulungui B, Pourrut X, et al. Fruit bats as
reservoirs of Ebola
virus. Nature. 2005;438:575-6.
15. Leroy EM, Epelboin A, Mondonge V, et al. Human Ebola
outbreak
resulting from direct exposure to fruit bats in Luebo,
Democratic Republic
of Congo, 2007. Vector Borne Zoonotic Dis. 2009;9:723-8.
16. Gatherer D. The 2014 Ebola virus disease outbreak in West
Africa. J Gen
Virol. 2014;95:1619-24.
17. Bausch DG, Bangura J, Garry RF, et al. A tribute to Sheik
Humarr Khan
and all the healthcare workers in West Africa who have
sacrificed in
the fight against Ebola virus disease: Mae we hush. Antiviral
Res.
2014;111C:33-5.
18. Frieden TR, Damon I, Bell BP, Kenyon T, Nichol S. Ebola
2014--new

challenges, new global response and responsibility. N Engl J
Med.
2014;371:1177-80.
19. Kortepeter MG, Bausch DG, Bray M. Basic clinical and
laboratory features
of filoviral hemorrhagic fever. J Infect Dis. 2011;204:S810-6.
20. Jeffs B. A clinical guide to viral haemorrhagic fevers:
Ebola, Marburg and
Lassa. Trop Doct. 2006;36:1-4.
21. Hartman AL, Towner JS, Nichol ST. Ebola and Marburg
hemorrhagic fever.
Clin Lab Med. 2010;30:161-77.
22. Baize S, Leroy EM, Georges-Courbot MC, et al. Defective
humoral
responses and extensive intravascular apoptosis are associated
with fatal
outcome in Ebola virus-infected patients. Nat Med. 1999;5:423-
6.
23. Leroy EM, Baize S, Debre P, Lansoud-Soukate J,
Mavoungou E. Early
immune responses accompanying human asymptomatic Ebola
infections.
Clin Exp Immunol. 2001;124:453-60.
24. Rowe AK, Bertolli J, Khan AS, et al. Clinical, virologic,
and immunologic
follow-up of convalescent Ebola hemorrhagic fever patients and
their household contacts, Kikwit, Democratic Republic of the
Congo.
Commission de Lutte contre les Epidemies a Kikwit. J Infect
Dis.

1999;179:S28-35.
25. McElroy AK, Erickson BR, Flietstra TD, et al. Ebola
hemorrhagic
Fever: novel biomarker correlates of clinical outcome. J Infect
Dis.
2014;210:558-66.
26. Baize S, Leroy EM, Georges AJ, Georges-Courbot MC,
Capron M,
Bedjabaga I, Lansoud-Soukate J, Mavoungou E. Inflammatory
responses
in Ebola virus-infected patients. Clin Exp Immunol
2002;128:163-8.
27. Baize S, Pannetier D, Oestereich L, et al. Emergence of
Zaire Ebola Virus
Disease in Guinea – Preliminary Report. N Engl J Med.
2014;371:1418-25.
28. WHO situation report
http://apps.who.int/iris/bitstream/10665/133833/1/
roadmapsitrep4 _eng.pdf?ua=1
29. Miranda ME, Miranda NL. Reston ebolavirus in humans and
animals in
the Philippines: a review. J Infect Dis. 2011;204:S757-60.
30. Hofmann-Winkler H, Kaup F, Pohlmann S. Host cell factors
in filovirus
entry: novel players, new insights. Viruses. 2012;4:3336-62.
448

N O V E M B E R 2 0 1 4 , V O L . 7 2 , N O 9
31. Feldmann H, Jones SM, Daddario-DiCaprio KM, et al.
Effective
post-exposure treatment of Ebola infection. PLoS Pathog.
2007;3:e2.
32. Geisbert TW, Daddario-DiCaprio KM, Geisbert JB, et al.
Vesicular
stomatitis virus-based vaccines protect nonhuman primates
against aerosol challenge with Ebola and Marburg viruses.
Vaccine.
2008;26:6894-900.
33. Leroy EM, Gonzalez JP, Baize S. Ebola and Marburg
haemorrhagic fever
viruses: major scientific advances, but a relatively minor public
health
threat for Africa. Clin Microbiol Infect. 2011;17:964-76.
34. Bray M, Hatfill S, Hensley L, Huggins JW. Haematological,
biochemical
and coagulation changes in mice, guinea-pigs and monkeys
infected
with a mouse-adapted variant of Ebola Zaire virus. J Comp
Pathol.
2001;125:243-53.
35. Mahanty S, Bray M. Pathogenesis of filoviral haemorrhagic
fevers. Lancet
Infect Dis. 2004;4:487-98.
36. Goeijenbier M, van Wissen M, van de Weg C, et al. Review:
Viral

infections and mechanisms of thrombosis and bleeding. J Med
Virol.
2012;84:1680-96.
37. Geisbert TW, Young HA, Jahrling PB, et al. Pathogenesis of
Ebola
hemorrhagic fever in primate models: evidence that hemorrhage
is not a
direct effect of virus-induced cytolysis of endothelial cells. Am
J Pathol.
2003;163:2371-82.
38. Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E,
Hensley LE.
Mechanisms underlying coagulation abnormalities in ebola
hemorrhagic
fever: overexpression of tissue factor in primate
monocytes/macrophages
is a key event. J Infect Dis. 2003;188:1618-29.
39. Takada A, Feldmann H, Ksiazek TG, Kawaoka Y. Antibody-
dependent
enhancement of Ebola virus infection. J Virol. 2003;77:7539-44.
40. Nakayama E, Tomabechi D, Matsuno K, et al. Antibody-
dependent
enhancement of Marburg virus infection. J Infect Dis.
2011;204:S978-85.
41. Mairuhu AT, MacGillavry MR, Setiati TE, et al. Is clinical
outcome of
dengue-virus infections influenced by coagulation and
fibrinolysis? A
critical review of the evidence. Lancet Infect Dis. 2003;3:33-41.
42. van Gorp EC, Setiati TE, Mairuhu AT, et al. Impaired

fibrinolysis in the
pathogenesis of dengue hemorrhagic fever. J Med Virol.
2002;67:549-54.
43. Leroy EM, Baize S, Volchkov VE, et al. Human
asymptomatic Ebola
infection and strong inflammatory response. Lancet.
2000;355:2210-5.
44. Fowler RA, Fletcher T, Fischer Ii WA, et al. Caring for
Critically Ill Patients
with Ebola Virus Disease: Perspectives from West Africa. Am J
Respir Crit
Care Med. 2014;190:733-7.
45. Jahrling PB, Geisbert TW, Geisbert JB, et al. Evaluation of
immune
globulin and recombinant interferon-alpha2b for treatment of
experimental Ebola virus infections. J Infect Dis.
1999;179:S224-34.
46. Huggins JW. Prospects for treatment of viral hemorrhagic
fevers with
ribavirin, a broad-spectrum antiviral drug. Rev Infect Dis.
1989;11:S750-61.
47. Qiu X, Wong G, Audet J, et al. Reversion of advanced Ebola
virus disease
in nonhuman primates with ZMapp. Nature. 2014;514:47-53.
48. Smither SJ, Eastaugh LS, Steward JA, Nelson M, Lenk RP,
Lever MS.
Post-exposure efficacy of oral T-705 (Favipiravir) against
inhalational Ebola
virus infection in a mouse model. Antiviral Res. 2014;104:153-
5.

49. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF,
Barnard DL.
Favipiravir (T-705), a novel viral RNA polymerase inhibitor.
Antiviral Res.
2013;100:446-54.
50. 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.
51. Warren TK, Wells J, Panchal RG, et al. Protection against
filovirus diseases
by a novel broad-spectrum nucleoside analogue BCX4430.
Nature.
2014;508:402-5.
52. Geisbert TW, Lee AC, Robbins M, et al. Postexposure
protection of
non-human primates against a lethal Ebola virus challenge with
RNA
interference: a proof-of-concept study. Lancet. 2010;375:1896-
905.
53. Warren TK, Warfield KL, Wells J, et al. Advanced antisense
therapies for
postexposure protection against lethal filovirus infections. Nat
Med.
2010;16:991-4.
54. Heald AE, Iversen PL, Saoud JB, et al. Safety and
Pharmacokinetic Profiles
of Phosphorodiamidate Morpholino Oligomers with Activity

against Ebola
Virus and Marburg Virus: Results of Two Single Ascending
Dose Studies.
Antimicrob Agents Chemother. 2014 [Epub ahead of print].
55. Mupapa K, Massamba M, Kibadi K, et al. Treatment of
Ebola hemorrhagic
fever with blood transfusions from convalescent patients.
International
Scientific and Technical Committee. J Infect Dis.
1999;179:S18-S23.
56. Jahrling PB, Geisbert JB, Swearengen JR, Larsen T,
Geisbert TW. Ebola
hemorrhagic fever: evaluation of passive immunotherapy in
nonhuman
primates. J Infect Dis. 2007;196:S400-3.
57. Geisbert TW, Hensley LE, Kagan E, et al. Postexposure
protection of
guinea pigs against a lethal ebola virus challenge is conferred
by RNA
interference. J Infect Dis. 2006;193:1650-7.
58. Warren TK, Wells J, Panchal RG, et al. Protection against
filovirus diseases
by a novel broad-spectrum nucleoside analogue BCX4430.
Nature.
2014;508:402-5.
59. Swenson DL, Warfield KL, Warren TK, et al. Chemical
modifications of
antisense morpholino oligomers enhance their efficacy against
Ebola
virus infection. Antimicrob Agents Chemother. 2009;53:2089-
99.

60. Pettitt J, Zeitlin L, Kim DH, et al. Therapeutic intervention
of Ebola virus
infection in rhesus macaques with the MB-003 monoclonal
antibody
cocktail. Sci Transl Med. 2013;5:199ra113.
61. Leirs H, Mills JN, Krebs JW, et al. Search for the Ebola
virus reservoir in
Kikwit, Democratic Republic of the Congo: reflections on a
vertebrate
collection. J Infect Dis. 1999;179:S155-63.
Assignment Criteria
Points
%
Description
Introduction of disease
20
20%
Provide a brief description of the disease/disorder. This part of
the paper should not be limited to the definition of the disease.
Include epidemiology as appropriate.
Etiology
20
20%
Identify common causes and risk factors for the disease, to
include age, gender, environmental, genetic, and lifestyle.
Pathophysiological processes
20
20%
Describe how the disease begins by describing the cause and
mechanisms of the disease that give rise to signs and symptoms.
Remember pathophysiology should be on a cellular level.
Include information on how the body attempts to

overcome/correct the disease, if applicable.
Clinical Manifestations & Complications
20
20%
Describe the physical signs and symptoms that are important in
considering the presence of the disease.
Diagnostics
10
10%
Describe common laboratory and diagnostic tests used to
determine the presence of the disease. Provide information on
significant findings for these diagnostic studies associated with
the disease.
APA Style and Organization
10
10%
The assignment should be a 2-3 page (excluding title and
reference pages) typed paper and presented in APA format. This
includes an APA title, page and references with in-text
citations. Spelling and grammar will be evaluated with this
assignment.
Must include at least two (2) scholarly, primary sources from
the last 5 years, excluding the textbook.
Total
100
100%
1) Write a 2-3 page paper (excluding title and reference pages).
Include the following information (also outlined in the grading
rubric) about the selected disease process:
a. Introduction of disease
b. Etiology and risk factors
c. Pathophysiological processes
d. Clinical Manifestations & Complications
e. Diagnostics

2) Provide a reference list in APA format.
a. A minimum of two (2) scholarly, primary sources are
required.
b. Given the nature of the research, current literature (within 5
years).
Introduction of disease (20)
Provides a one-paragraph description of the disease/ disorder
and is not limited to the definition of the disease. Includes
complete description of the disease epidemiology.
19-20 points
Etiology (20)
Identifies ALL of the following: common causes and risk
factors for the disease including age, gender, environmental,
genetic, and lifestyle.
19-20 points
Pathophysiological processes (20)
Comprehensively describes the cause(s) of the disease and the
disease mechanisms that give rise to signs and symptoms.
Comprehensively describes processes at the cellular level and
information related the body’s attempts to overcome the
disease.
19-20 points
Clinical Manifestations & Complications (20)
Comprehensively describes the physical signs and symptoms
that are important in considering the presence of the disease.
Comprehensively describes significant and common
complications associated with the disease if left untreated.
19-20 points
Diagnostics (10)
Comprehensively describes common laboratory and diagnostic

tests used to determine the presence of the disease.
Comprehensively describes information on significant findings
for these diagnostic studies associated with the disease.
10 points
APA Style and Organization (10)
· References are submitted with assignment.
· Used appropriate APA format (6th ed.) and are free of errors.
· Grammar and mechanics are free of errors.
· Paper is 2-3 pages, excluding title and reference pages
· At least two (2) scholarly, primary sources from the last 5
years, excluding the textbook, are provided
10 points

Ebola Virus Disease: An Update On Current Prevention and
Management Strategies
MSF Field
Research
Authors Trad, MA; Naughton, W; Yeung, A; Mazlin, L;
O'sullivan,
M; Gilroy, N; Fisher, DA; Stuart, RL
Citation Ebola Virus Disease: An Update On Current Prevention
and Management Strategies. 2016, 86:5-13 J. Clin. Virol.
DOI 10.1016/j.jcv.2016.11.005
Publisher Elsevier
Journal Journal of Clinical Virology: The Official Publication
of
the Pan American Society for Clinical Virology

Rights Archived with thanks to Journal of Clinical Virology :
The
Official Publication of the Pan American Society for
Clinical Virology
Downloaded 18-May-2018 15:58:06
Link to item http://hdl.handle.net/10144/618818
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Journal of Clinical Virology 86 (2017) 5–13
Contents lists available at ScienceDirect
Journal of Clinical Virology
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c
a t e / j c v
bola virus disease: An update on current prevention and
anagement strategies
.A. Trad a,b,c,∗ , W. Naughton g, A. Yeung g, L. Mazlin d,
M. O’sullivan i,j, N. Gilroy i,
.A. Fisher e,f, R.L. Stuart g,h

Department of Infectious Diseases, Wollongong Hospital,
Wollongong, NSW, Australia
Graduate School of Medicine, University of Wollongong,
Wollongong, Australia
Medecins Sans Frontieres, Paris, France
Medecins Sans Frontieres, Brussels, Belgium
Division of Infectious Diseases, University Medicine Cluster,
National University Hospital, Singapore
Yong Loo Lin School of Medicine, National University of
Singapore, Singapore
Department of Infectious Diseases, Monash Health, Clayton,
Victoria, Australia
Department of Medicine, Monash University, Victoria,
Australia
Centre for Infectious Diseases and Microbiology, Pathology
West, Westmead Hospital, NSW, Australia
Marie Bashir Institute for Infectious Diseases and Biosecurity,
University of Sydney, NSW, Australia
r t i c l e i n f o
rticle history:
eceived 11 June 2016
eceived in revised form 6 October 2016
ccepted 8 November 2016
a b s t r a c t
Ebola virus disease (EVD) is characterised by systemic
viral replication, immuno-suppression, abnormal
inflammatory responses, large volume fluid and electrolyte
losses, and high mortality in under-resourced
settings. There are various therapeutic strategies targeting
EVD including vaccines utilizing different
antigen delivery methods, antibody-based therapies and
antiviral drugs. These therapies remain experi-

eywords:
bola
anagement
accines
herapeutics
mental, but received attention following their use
particularly in cases treated outside West Africa during
the 2014–15 outbreak, in which 20 (80%) out of 25 patients
survived. Emerging data from current trials
look promising and are undergoing further study, however
optimised supportive care remains the key
to reducing mortality from EVD.
Crown Copyright © 2016 Published by Elsevier B.V. All
rights reserved.
utbreak
bolavirus
ontents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.1. Practicalities of clinical trials for Ebola virus disease
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . 6
2. Vaccines against Ebola virus disease . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . 6
2.1. Recombinant vesicular stomatitis virus vector vaccines .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 6
2.2. Adenovirus vector vaccines . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . 9
2.3. Vaccine use post exposure to ebola virus . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . 9
2.4. Other antigen and vaccine delivery methods . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . 9
3. Antibody based therapies . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . 9
3.1. Convalescent blood products . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . 9
3.2. Monoclonal antibody combinations (ZMapp, MB-003,
and ZMab) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 9
3.3. Other antibody based therapies . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . .
4. Drugs and small molecules . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Favipiravir . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Phosphorodiamidate morpholino oligomers and small
interfering
∗ Corresponding author at: Department of Infectious Diseases,
Lawson House, Level 1, W
E-mail address: [email protected] (M.A. Trad).
ttp://dx.doi.org/10.1016/j.jcv.2016.11.005
386-6532/Crown Copyright © 2016 Published by Elsevier B.V.
All rights reserved.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
RNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
ollongong Hospital, Wollongong NSW 2500, Australia.
6 M.A. Trad et al. / Journal of Clinical Virology 86 (2017) 5–13
4.3. Brincidofovir CMX001 . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . 10
4.4. BCX443 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . 10
5. Supportive care . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
5.1. Authors’ remarks . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . 11
5.2. Mental health . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . 11
6. Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . 11
7. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Conflict of interest statement . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . 12
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . 13

. . . . . .
1
e
s
p
C
r
A
o
a
s
l
i
(
A
p
i
e
t
1
a
b
g
s
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i

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Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . .
. Introduction
Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV),
Bundibugyo
bolavirus (BDBV), Taï Forest ebolavirus (TAFV), and the only
Asian
pecies Reston ebolavirus (RESTV) [1]. The first three of these
have
reviously caused large outbreaks in the Democratic Republic of
ongo, Sudan, Gabon, Republic of Congo, and Uganda [2]. The
most
ecent and largest outbreak involving over 28,000 cases in West
frica was caused by a variant strain of EBOV with an estimated
verall case fatality rate of around 40% [3].
EVD is primarily a diarrheal illness that requires copious

mounts of fluid and electrolyte replacement [4]. Failure to
address
uch requirements contributes to mortality and thus an intensive
evel of support is required to optimize outcomes. This is
challeng-
ng in resource limited settings.
There were no approved therapeutics to treat Ebola virus
disease
EVD) during the 2014–15 outbreak, that devastated three West
frican countries [5]. A small number of cases were treated with
utative therapeutics in the U.S and Europe before formalised
clin-
cal trials were established late in the outbreak [6]. Potentially,
an
ffective therapeutic available in large quantities could not only
reat individual cases but halt outbreaks.
.1. Practicalities of clinical trials for Ebola virus disease
Although a number of experimental vaccines and antivirals
gainst Ebola virus had been developed prior to the large EVD
out-
reak in West Africa in 2014-15, phase II/III field studies did not
et underway until late in the epidemic [6]. Consequently, some
tudies will now have insufficient recruitment to establish
efficacy
40]. This highlights the unique difficulties encountered in
conduct-
ng clinical trials in the midst of a health emergency,
particularly
n resource poor settings. Nevertheless, for a disease such as
EVD,
hich has such a high mortality and no proven directed therapy,

it
s imperative that an integral part of the international response
be
o facilitate clinical trials of therapeutic agents.
International agencies setting up treatment centres must be
illing to recruit patients into clinical trials, and have structures
in
lace to manage the ethical and medico-legal requirements to
facil-
tate their conduct [6]. Ethical considerations around the design
of
linical trials in such settings can be complex, and it has been
argued
hat randomized, placebo controlled designs are not ideal as they
ay lead to withholding of potentially beneficial treatment (albeit
xperimental) from those with a condition that otherwise has a
ery poor outcome [6]. Using historical controls can circumvent
this
ssue, but calls into question the robustness of the study
outcomes.
daptive trial designs where ongoing planned interim monitoring
f the outcome data can be used to alter the trial design after
com-
encement to maximize the potential benefit to study participants
hile maintaining statistical reliability, have also been advocated
or such studies [55]. Other challenges to conducting clinical tri-
ls in such settings are the need for study personnel to enter the
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

“red zone” of Ebola treatment centres (ETCs) to consent
patients,
thereby risking exposure to Ebola themselves, obtaining consent
from very unwell patients for complex studies when next of kin
are
unable to be present at the bedside, and co-ordinating and
expedit-
ing the ethical review process between multiple governmental
and
non-governmental healthcare organisations and research institu-
tions. [55] Consent procedures can be further complicated by
the
cultural and linguistic barriers.
This paper will review proposed therapeutics (including vac-
cines, antibody based therapies, and small molecules) – many of
which have only been tested in vivo on rodents or non-human
primates (NHPs) [2].
2. Vaccines against Ebola virus disease
Vaccines are a potential cornerstone for limiting or fully pre-
venting an EVD outbreak. There are numerous vaccine trials
including two leading candidates in phase 3 trials (Table 1)
rVSV-
EBOV vaccines (recombinant vesicular stomatitis virus vector)
and
ChAd3-ZEBOV (adenovirus vector) [7,8]. Other potential
candidates
have been described elsewhere [9].
2.1. Recombinant vesicular stomatitis virus vector vaccines
When vesicular stomatitis virus was used in antigen delivery in
NHPs, 50% protection was observed which was still effective
up to

thirty minutes post acquiring infection [7]. Recently, the interim
results of a cluster randomized phase III trial of rVSV-EBOV in
Guinea have been published [10]. The difficult logistics of
conduct-
ing such a trial were mitigated effectively by a ring vaccination
strategy, where adult contacts and contacts of contacts of
patients
with EVD were included. Clusters of participants were
randomized
1:1 into immediate versus delayed (21 days) vaccination. Out
of
2014 participants from 48 clusters in the immediate group, there
were no EVD cases after 10 days post vaccination, compared to
16
cases occurring in the delayed group of 2380 participants
allocated
to 42 clusters. Only one case had a febrile illness associated
with the
vaccine, which resolved without sequelae. Although the study
did
not provide measures of antibody titres, it concluded that it
might
take up to 6 days for the vaccine to provide protection.
Prior phase 1 trials of rVSV-EBOV vaccine, including patients
from various sites in the U.S, Africa and Europe, found a high
num-
ber of adverse events in 90% of the study population [11,12].
The
majority of events were reported as mild or moderate, appeared
and subsided early (≤24 h), and were alleviated with simple
anal-
gesics. Rapid onset and transient haematological changes were
observed in all participants including transient leukocytopenia
and

lymphocytopenia. By 4 weeks, all vaccine doses produced
EBOV-
glycoprotein specific antibodies, although it could not be
concluded
whether higher vaccine doses would be required for optimal
pro-
tection.
M
.A
.
Tra
d
et
a
l.
/
Jo
u
rn
a
l
o
f
C

lin
ica
l
V
iro
lo
gy
8
6
(2
0
1
7
)
5
–
1
3
7
Table 1
Experimental: treatment approaches evaluated for efficacy
against Ebola virus disease in mammals.
Approach Target/mechanism of action Demonstrated Efficacy

Comments Ref.
Rodent NHP Human
Vaccines
Plasmid DNA based vaccine
VRC-EBODNA023-00-VP
DNA immunisation with
boosting adenoviral vector
– Y Phase I (Uganda) Process takes 6 months to provide
protection in NHP
[37]
Accelerated vaccine of plasmid
DNA based vaccine:
ChAd-EBOV, Ad5-EBOV,
cAd3-EBOV (GSK) and
Ad26 and MVA-EBOV (J&J)
Adenoviral vector delivers DNA
encoding Ebola GP
MVA used as a second dose
booster
Y – Y Y Phase I (UK, U.S, China, Mali,
Uganda, Switzerland)
Phase II/III* : Liberia
Phase I* : UK, II/III* US
Process takes 28 days to provide
pre-exposure protection in NHP.
Potential for outbreaks. Booster
induces longer term protective

immunity
* NCT02509494
* NCT02240875, NCT02598388
[16,46,47]
rGP nanoparticle (Novavax) Recombinant Ebola GP
admistered with a saponin
based adjuvant (Matrix-M)
– – Phase I: Australia Requires 2 injections [48]
rVSV-EBOV (Merck),
rVSV�G-EBOV
VSV delivers Antigen – Y Phase I (Kenya, U.S,
Switzerland)
STRIVE: Phase II/III
Randomized trial in HCWs
(Sierra Leone), PREVAIL: Phase
II (Liberia). Ca Suffit: Phase III
(Guinea)
Up to thirty minutes post infection
(protection against Ebola −50%,
Marburg 100%) 33% protection
after 48 h, in NHP
Geneva phase I trial halted for
safety concerns. Less side effects
with the newer strains.
Potentially could provide
protection after 6 days of
vaccinations in humans. No
booster required. Duration of
protective antibodies unknown

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