editorial
Virologie 2015, 19 (5) : E1-E7
Anti-Ebola vaccination of humans using a chimeric
virus: rational of a hope
Denis Gerlier
doi:10.1684/vir.2015.0621
Copyright © 2017 John Libbey Eurotext. Téléchargé par un robot venant de 88.99.165.207 le 19/06/2017.
CIRI, Inserm U1111, CNRS UMR5308,
Université Claude-Bernard Lyon 1,
ENS de Lyon, 21, avenue Tony-Garnier,
69007 Lyon, France
<[email protected]>
T
he promising ability of a recombinant vaccine to protect humans against
the risk of getting infected upon contact with Ebola-sick patients comes
as one of the best news from the recent devastating Ebola crisis in Western Africa [1]. This trial is built according to the ring vaccination scheme that
was used in the final stage of the smallpox eradication scheme [2] (figure 1). This
scheme was developed to curtail the limitations of mass vaccination and to reduce
exposure to the risk of severe side effects resulting from the inoculation of the
vaccinia vaccine. It simply relies on vaccinating only the social groups that are
contiguous to a case suffering from the disease in order to create a ring of immunity barrier around infected people [3]. The ring vaccination requires identifying
new cases very shortly after the first symptoms of the disease (the index case) and
all the persons in direct contact with the index case (contacts, such as households)
and persons in contact with the contact (contacts of contacts, such as co-workers)
and to enrol them in the vaccination trial [4]. The cleverly ethically designed
random trial consists in vaccinating cluster of several thousands of contacts and
contacts of contacts of Ebola diagnosed patients either immediately or after a
3-weeks delay [4]. After only four months of survey, the immediate vaccination
with recombinant vesicular stomatitis virus expressing the Ebola virus envelope
glycoprotein showed a striking protective effect with no reported cases of Ebola
after a seven days window in the contact clusters while new cases continued to
occur in the non-vaccinated controls. During this first week window, few Ebola
cases occurred likely because they had been contaminated before having received
the vaccine. In the group in which the vaccination was delayed by three weeks,
a significant number of Ebola cases were observed further on during the 21 days
interval separating the first week window and the seventh day post-vaccination.
This further supports the efficiency of the immediate vaccination schedule as
does the continuous observation of new Ebola cases in non-eligible contacts
from both groups. These results from the Ebola ça Suffit ring vaccination trial
led to implement the trial after four months by pursuing only the immediate vaccination scheme to further document the effectiveness of the vaccine in affording
herd immunity against Ebola transmission. This ring vaccination trial is unconventional and is under the threat of not reaching a much larger size because of the
epidemic waning: these are among the regulatory hurdles to be passed over by
the VSV-ZEBOVGP vaccine in order to get approval by a national health agency
[5].
The vaccine used for this human trial is a recombinant chimeric vesicular stomatitis virus (VSV) in which the coding region of the glycoprotein G has been
substituted by that of the transmembrane glycoprotein of the Zaire Ebola virus
strain (ZEBOV-GP) hence its name VSV-ZEBOVGP (figure 2). VSV-ZEBOVGP
is an attenuated viable viral vaccine that was designed and initially validated in
rodents’ models of Ebola infection a decade ago [6]. It was made available
via licencing and production in good manufacturing practices [7], thus allowing several vaccination trials in non-human primates [8-16], and human trials
including phase I toxicity studies [7, 17].
Virologie, Vol 19, n◦ 5, septembre-octobre 2015
Pour citer cet article : Gerlier D. Anti-Ebola vaccination of humans using a chimeric virus: rational of a success. Virologie 2015; 19(5) : 1-7 doi:10.1684/vir.2015.0621
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editorial
Ebola virus (EBOV) was first identified in the seventies, from two outbreaks of hemorrhagic fever in human
populations with high lethality [18, 19]. EBOV is a filamentous enveloped virus that belongs to the Ebolavirus
genus Filoviridae family and Mononegavirales order. It has
a non-segmented negative stranded genome with a length
of ∼19 kilobase long. It contains seven genes coding for
four proteins responsible for viral transcription and replication (nucleoprotein N, VP35, VP30 and large L) and three
genes coding for proteins involved in virus assembly and
packaging (VP40 or matrix, glycoprotein GP and VP24)
(figure 2). In addition, VP35 and VP24 genes also counteract
the intracellular innate immune response that is mediated
by type I interferon. Furthermore, in the absence of RNA
editing, the GP mRNA primarily codes for a soluble form
called sGP that might subvert the GP specific antibody response and has anti-tetherin activity (see for review [20, 21]).
The ubiquitous cholesterol transporter Niemann-Pick C1
(NPC1) serves as the intracellular receptor that mediates
the nucleocapsid delivery from the endosomal compartment to the cytoplasm where the entire virus replication
cycle takes place [22, 23]. The primary capture of the virus
from the extracellular medium is done via the binding of
GP and/or phosphatidylserine to multiple cell surface glycoproteins that allow efficient delivery in the endosomes
via macropinocytosis (see for review [24]).
From putative bat reservoirs, EBOV spill over in wild ape
colonies and in human populations. Alternatively, humans
get infected during butchery of infected ape or from other
unknown intermediate hosts. Inter-human transmission,
primarily among households and as nosocomial disease in
local hospitals, occurs from the contact with body fluids
of sick people. Regular outbreaks limited to at most few
hundreds of people have been observed until the much larger outbreak affecting more than 30,000 people in Guinea
and surrounding countries in 2014-2015 [25]. Clinical signs
appear after a ∼10 days incubation period (interval varies
between 2-21 days). Ebola virus infection is associated with
fever, inflammation, digestive symptoms (vomiting, diarrhea), hemorrhagic syndrome and vascular failure. Since
the recent outbreak is associated with milder hemorrhagic
signs, the Ebola hemorrhagic fever has been renamed Ebola
virus disease. The symptoms are consecutive to the rapid
viral dissemination in macrophages, dendritic cells, endothelial cells, hepatocytes and adrenal cells throughout the
whole body (see for review [26]). Fatal issue can occur in
50 to 70% of Ebola patients with variation according to the
virus strain [25]. Survivals can suffer from the post-Ebola
virus disease syndrome (arthralgia, anorexia, uveitis. . .) for
several months [27]. Viral RNA and sometimes virus can
be detected several months after disease recovery in ocular
fluid [28] and semen [29, 30], thus possibly extending the
E2
period of contagiousness as suggested with the report of one
suspected case of sexual transmission [29]. Survivals exhibit low levels of neutralising antibody [31], and the absence
of any documented case of reinfection in human suggests
that survivors may be effectively protected against a reinfection. A contrario, Ebola virus disease severity has been
associated with little or no production of EBOV-specific
antibodies [32]. Survivors and reported apparent high seroprevalence (up to 32%) in human populations living in
Gabonese rural and forest area [33] indicate that a fraction of the human population can control Ebola infection
with efficient viral clearance.
That a protective immunity can be elicited after immunization with EBOV GP expressing vectors has been
demonstrated in all tested animal models including in nonhuman primates. This solid ground is supported mostly by
data from trials with two major candidate Ebola-specific
vaccines, a recombinant adenovirus [34] and a recombinant VSV [6] coding for EBOV GP. As EBOV, VSV a
member of the Rhabdoviridae family and Mononegavirales
order share a very similar but simpler genome organisation with only five genes, N, P (functional homologue of
EBOV VP35), M, G and L (figure 2). VSV is an arbovirus
pathogenic for horses and cows and there is epidemiological evidence of VSV specific antibodies in farm personals
[35, 36]. VSV uses a very conserved and ubiquitous cellular
receptor, the low-density lipoprotein receptor (LDLR) [37].
Hence, it has a very broad cell tropism. In the mouse, VSV
is strongly immunogenic and non-pathogenic unless inoculated in the brain or intra-nasally via the olfactory bulb. The
lack of pathogenicity after peripheral inoculation is linked
to a massive VSV replication restricted to the subcapsular macrophage subset of the draining lymph nodes. This
burst of replication is a source of viral RNA transcripts that
are strong agonists of the RIG-I intracellular receptor. This
results in a massive type I interferon response amplified by
the local recruitment of plasmacytoid dendritic cells that
ultimately protect the local neuron from being infected and
propagating the infection to the brain. Indeed, VSV is highly
sensitive to the interferon and interferon activated cells are
refractory to VSV infection. Furthermore, VSV infection
induces potent antiviral cellular and humoral immunity, and
animals, cured from the infection, are refractory to a second
challenge with VSV (see for review [38]).
Together with the ease to build very stable recombinant
VSV (see for reviews [39]), all these properties make VSV
an attractive vaccine vector. Among several recombinant
VSV expressing EBOV sGP or GP, the chimeric VSVZEBOVGP expressing EBOV GP in replacement of the
VSV glycoprotein was the most studied. VSV-ZEBOVGP
lost the broad host cell range of VSV to adopt that of
EBOV reflecting the ability of the VSV nucleocapsid to
Virologie, Vol 19, n◦ 5, septembre-octobre 2015
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editorial
Neighbours
Coworkers
Contact
Index
Case
Family
(Ebola)
Contact
of
contact
Ring
vaccination
Figure 1. Principle of the ring vaccination trial. A person showing clinical signs of Ebola with biological confirmation is an index case.
People identified as being in direct contact (“contact”) with the index case such as family members and indirectly via a direct contact such
as neighbours (“contact of contact”) are enrolled in the vaccination trial; see [4] for details.
EBOV
N
VP35
VP40
VSV
N
P
M
G
VSV-ZEBOVGP
N
P
M
ZEBOVGP
VP30
sGP, GP
VP24
L
L
L
Figure 2. Genome organization of Ebola virus (EBOV), vesicular stomatitis virus (VSV) and recombinant chimeric VSV-ZEBOVGP
in which the gene coding for the VSV surface glycoprotein has been replaced by the surface glycoprotein GP from Zaire EBOV strain.
Note that VSV-ZEBOVGP produces viral particles enveloped by the EBOVGP; consequently, VSV-ZEBOVGP exhibits the cell host range
of EBOV [6].
Virologie, Vol 19, n◦ 5, septembre-octobre 2015
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editorial
be wrapped into an EBOV GP rich envelope [6]. It provides protection against EBOV challenge even after a single
shot in mice [40] and non-human primates. The protection
extends to several EBOV strains including the Guinea 20142015 strain [10, 14, 16, 41]. Protection is restricted to the
Ebola genus while the equivalent chimeric VSV-MARVGP
protects only against a Marburg virus (MARV) challenge
[8]. VSV-ZEBOVGP is well tolerated by non-human primates immunocompromised due to chronical infection by
the simian immunodeficiency virus (SIV) and protects them
efficiently [9]. Importantly, even when inoculated directly
into the brain of non-human primates, the recombinant vaccine is well tolerated without sign of neurovirulence, while
the parental VSV is neurovirulent [42]. Thus, the change
of the host cell range due to the exchange of the surface
glycoprotein is a factor of attenuation of the VSV vector.
Finally, just few months before the ring vaccine trial, phase
I studies in human have shown good tolerance with acceptable minor and transient side effects although some safety
concerns remain because of the transient viremia [7, 17].
Thus, the VSV-ZEBOVGP vaccine appears to be safe and
very efficient after a single shot.
Remarkably, the biological features of these experimental
trials showed very good agreement with those reported from
the ring vaccine trial in Guinea as schematized in figure 3.
In non-human primates, a single shot of VSV-ZEBOVGP
fully protects against a deadly challenge with EBOV performed at least seven days post-vaccination. There is even
indication of a partial protection when the challenge is performed only three days post-vaccination (figure 3A) [14] or
few minutes after the EBOV challenge [10]. That a postexposure vaccination may be effective is also supported by
vaccination in rodent models of Ebola infection [43]. The
one week interval needed between vaccination and EBOV
challenge in non-human primates (figure 3A) required to
establish a sterilising immunity fits well with the seven days
interval during which Ebola cases were still recorded in the
ring vaccination trial (figure 3B) [1]. Another common feature is the transient viremia of the vaccine VSV-EBOVGP
during the first week after vaccination with one case of late
persistence in a peripheral tissue in humans (figure 3B).
What are the mechanisms underlying the impressive efficacy of the VSV-ZEBOVGP vaccine? The sterilising
immunity observed 14 days and later after the vaccination correlates with high neutralising antibody response in
every case. The specificity of the protection restricted to the
Ebola genus correlates also with the poor cross-reactivity
of antibodies directed against the GP of EBOV and MARV
[14]. The vaccination with VSV-ZEBOVGP induces poor
CD8 and CD4 cellular responses to the Ebola GP that
vanish after one week; and the EBOV challenge minimally
reactivates them [44]. Furthermore, depletion of CD8 or
E4
CD4 cells just before the EBOV challenge does not alter
the successful sterilising immunity, while inhibiting antibody production by CD4 depletion during the vaccination
stage does it [12]. A further indication supporting a role of
the antibody response comes from the association of partial
protection and significant antibody response in non-human
primates only six days after being vaccinated with VSVZEBOVGP and challenged with EBOV only three days
thereafter (figure 3A) [14]. The antibody response may not
be the unique major effector responsible for the control of
EBOV since effective protection of non-human primates
consecutive to their vaccination with another Ebola vaccine candidate, the recombinant adenovirus-EBOVGP, is
mostly mediated by CD8+ cells rather than antibodies [45].
Because VSV-ZEBOVGP inoculation induces a strong type
I interferon response in the blood between day 1 and day
6, it is hypothesized that the interferon participates into the
partial protection of non-human primates challenged only
three days after the vaccination. Interferon may dampen
the Ebola viral burst until enough neutralising antibodies
can take the control as shown by the significant antibody
response observed on day 6 in these animals (figure 3A)
[14]. How can VSV-ZEBOVGP induce such a massive IFN
response? Is it related to a strong replication of the VSVZEBOVGP as shown by the transient viremia? To which
extend the change in host cell range due to the use of the
GP of Ebola virus contributes to the interferon response
and/or VSV-ZEBOVGP viremia? Strikingly, inoculation
of STAT1-ko mice with the recombinant chimeric VSVZEBOVGP reveals the strict requirement of a functional
type I interferon system to avoid virus induced lethality as
observed with its parental VSV counterpart [46].
In conclusion, VSV-ZEBOVGP looks a very attractive
and powerful vaccine against Ebola. The preliminary data
from the ring vaccination in Guinea justifies continuing the
immediate vaccination trial. Furthermore, VSV-ZEBOVGP
or VSV-MARVGP may be of some efficacy when used as
emergency post-exposure vaccine after needle-stick contamination [47, 48]. What do we learn from this trial? The
investment in proving the potential of a vaccine against a
rare but dreadful virus in non-human primate models and
phase I studies in human volunteers are key to be ready for
field trials of a candidate vaccine as soon as a new outbreak
of the disease will occur [49]. One can easily imagine how it
would have been rewarding to be ready for vaccine trials in
the field at the very beginning of the largest Ebola outbreak
ever observed, with the potential to have it rapidly curtailed.
Another lesson is the advantage of the ring vaccination schedule for trials. It has proved efficiency in the containment of
smallpox [2]. It limits the number of people to be vaccinated
hence limiting both the stockpile of vaccines to be ready for
use and the number of people at risk of possible side effects
Virologie, Vol 19, n◦ 5, septembre-octobre 2015
editorial
A
VSV-ZEBOVGP
at d0
EBOV at d7, 14, 21 or 28
EBOV
at d3
12/12 free from EBOV
Non-human primate
VSV-ZEBOVGP
Viremia
Anti-EBOV antibodies after EBOV at d7 or later
Anti-EBOV antibodies after EBOV at d3
IFNα
0
3
7
15
28
days
B
VSV-ZEBOVGP
At risk of Ebola2
Ring vaccination trial,
Lancet 2015
Protected from Ebola2
Anti-EBOVGP
antibodies (100%)3
Human
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1/3 death, 1/3 survival, 1/3 free
VSV-ZEBOVGP
Viremia (94%)3
0
1
VSV-ZEBOVGP
in peripheral tissue3
6
7(-10)
15
Phase I trial in Africa
& Europe volunteers,
NEJM 2015
Anti-EBOV
neutralizing antibodies (84%)3
28
days
Figure 3. Convergent observations made in vaccination trials with VSV-ZEBOVGP done in non-human primates (A) and humans
(B) according to vaccination trial in macaques against the 2014-2015 Ebola virus outbreak strain1 , the ring vaccination trial in Guinea2 , and
the phase I trial in humans3 . A) VSV-ZEBOVGP partially protects macaques against EBOV challenge done only three days after vaccination
and protects all individual challenged with EBOV at 7, 14, 21 or 21 days post-vaccination1 . The type I interferon (IFN␣) response and VSVZEBOVGP viremia were measured in blood drew every three days for nine days then every week1 . Note that in the group challenged
on day 3, EBOVGP specific antibodies were already detectable three days after the challenge (green dotted line) while antibodies were
below the detection threshold in the other groups challenged later (green line). B) The “at risk of Ebola” and “protected from Ebola” periods
reflect the actual observations in the ring vaccination trials in the group of contacts and contacts of contacts having received immediate
vaccination2 . In the phase I trial, EBOLA specific antibodies (green star) were determined only at 28 days post-vaccination3 . Note the
reported observation times lasted about 40-45 days post-vaccination.
1 data from [14]. 2 data from [1]. 3 data from [7].
of the vaccination. It allows preparation and information of
the small community at immediate risk of being contaminated with expected high level of consent and compliance
[4]. One crucial question remains: how to deal with the persons that are ethically considered to be ineligible because
of young age, pregnancy and breast-feeding? Indeed the
passive protection they could get from the herd immunity
of their vaccinated contacts does not seem to prevent them
being contaminated with the virus [1]. Should we perform
vaccination trials in corresponding animal models including
non-human primate? A solution may come from the use
of further attenuated VSV platform obtained by changing
Virologie, Vol 19, n◦ 5, septembre-octobre 2015
the gene order of the replication machinery and mutating
the M gene [41]. Finally, three other observations raise
further hopes. The duration of the protection afforded by
VSV-MARVGP lasts several months in non-human primates [15]. The recombinant VSV platform can be used
to express GP of other viruses with reported protection in
non-human primates and such VSV-GP vaccines can be
used consecutively to protect against another virus thus
affording a bivalent protection [13]. Should it be confirmed,
the appealing effectiveness exhibited by VSV-ZEBOVGP
in protecting humans against Ebola virus would certainly
boost the usage of recombinant VSV as a vaccine vector
E5
editorial
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for other transmissible diseases. A rational (re)appraisal of
the parameters that governs the Ebola vaccine primary success would guide vaccine developers to focus recombinant
VSV usage against infectious agents for which the chance
of success appears the greatest. In particular, the ability of
the pathogen to induce naturally a protective immunity with
neutralising antibodies and the ability of the vaccine vector
to result in abundant expression of a native form of viral
surface proteins appear to be good predictors of the likely
vaccine efficacy.
Acknowledgements. The author thanks O Reynard,
S. Baize, C. Mathieu, K. Dhont, Y Gaudin and A. Vabret
for helpful comments.
Conflict of interest : there are no conflicts of interest.
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