|Vesicular Stomatitis Virus-Based Vaccines for Prophylaxis and Treatment
of Filovirus Infections
|Andrea Marzi1*, Heinz Feldmann1, Thomas W. Geisbert2,3 and Darryl Falzarano1
|1Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
|2Galveston National Laboratory University of Texas Medical Branch, Galveston, Texas, USA
|3Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
||Dr. Andrea Marzi
Laboratory of Virology
903 South 4th Street, Hamilton
MT 59840, USA
|Received July 28, 2010; Accepted September 07, 2011; Published September
|Citation: Marzi A, Feldmann H, Geisbert TW, Falzarano D (2011) Vesicular
Stomatitis Virus-Based Vaccines for Prophylaxis and Treatment of Filovirus
Infections. J Bioterr Biodef S1:004. doi:10.4172/2157-2526.S1-004
|Copyright: © 2011 Marzi A, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
|Ebola and Marburg viruses are emerging/re-emerging zoonotic pathogens that cause severe viral hemorrhagic
fever with case-fatality rates up to 90% in humans. Over the last three decades numerous outbreaks, of increasing
frequency, have been documented in endemic regions. Furthermore, as a result of increased international travel filovirus
infections have been imported into South Africa, Europe and North America. Both viruses possess the potential of being
used as bioterrorism agents and are classified as category A pathogens. Currently there is neither a licensed vaccine
nor effective treatment available, despite substantial efforts being dedicated to understanding filovirus pathogenesis as
well as vaccine and drug development. One of the most promising vaccine platforms is based on replication competent
recombinant vesicular stomatitis viruses (rVSV) that express a filovirus glycoprotein as the surface antigen. These
rVSVs have been extensively studied in rodent and nonhuman primate models of filovirus disease and, in general, have
been shown to be 100% protective in pre-exposure prophylaxis. In addition, rVSVs have demonstrated potential for
post-exposure treatment, and thus would be particularly useful in the event of intentional release as well as accidental
exposures in outbreak and laboratory settings.
|Ebola virus (EBOV) and Marburg virus (MARV), members
of the family Filoviridae , are the causative agents of severe
hemorrhagic fever outbreaks that occur mainly in central Africa
[2,3]. More recently, increased worldwide travel has also resulted in
imported cases, underlying an increasingly global threat posed by
these pathogens (Figure 1). Furthermore, filoviruses are classified as
category A agents and thus considered to have the potential to be used
for bioterrorism. Together, this has intensified research on filoviruses
in a number of maximum containment laboratories worldwide. Both
high containment workers and medical personnel in the field are at
risk for potential exposures, which have occurred in the past with fatal
|Filovirus particles are enveloped and contain a nonsegmented,
single-stranded, negative-sense RNA genome of approximately 19 kb
. EBOV and MARV genomes code for seven structural proteins and
in addition EBOV encodes two nonstructural soluble glycoproteins
(GP), soluble GP (sGP) and small sGP (ssGP) [5,6]. All known MARV
strains belong to the Lake Victoria marburgvirus species, while
Ebola virus (EBOV) strains are attributed to four different species:
Zaire ebolavirus (ZEBOV), Sudan ebolavirus (SEBOV), Côte d'Ivoire
ebolavirus (CIEBOV) and Reston ebolavirus (REBOV) . The recently
discovered Bundibugyo ebolavirus (BEBOV) is proposed as a fifth
species . The species vary in their apparent pathogenicity in humans
with ZEBOV being the most pathogenic (up to 90% case fatality rate),
followed by SEBOV (approximately 50% case fatality rate) and BEBOV
(approximately 40% case fatality rate) . CIEBOV and REBOV have
been shown to be lethal in nonhuman primates, but have not yet been
associated with fatal human cases [5,8].
|EBOV and MARV replicate systemically resulting in the release of
high levels of inflammatory cytokines, coagulation abnormalities and
fluid distribution problems. These processes manifest as hemorrhage
and vascular leakage, finally leading to multi-organ failure and shock
[2,5]. Although EBOV and MARV have been extensively studied in
vitro and in various animal models, currently there is neither a licensed vaccine nor approved treatment available. Scientists working in high
containment facilities, healthcare workers in Africa and people residing
in the endemic regions in Africa remain at risk for potential exposures.
In the event of an act of bioterrorism involving filoviruses, the atrisk
population could be quite extensive. Thus, countermeasures are
considered an important part of any contingency plan for filoviruses.
|In the past decade great effort has been made to develop vaccine
platforms and treatment strategies against filoviruses. While highly
efficacious treatment options are still lacking there are multiple vaccine
platforms that have demonstrated efficacy against EBOV and MARV
including virus-like-particles (VLPs), Venezuelan equine encephalitis
virus replicons (VEEV RP), replication incompetent adenovirus
serotype 5 vectors, replication competent recombinant human
parainfluenza virus 3 (rHPIV3) and recombinant vesicular stomatitis
virus (rVSV) . These platforms have all been tested in the nonhuman
primate model and were shown to be protective .
|Currently, one of the more promising vaccine approaches against
filoviruses is the rVSV platform. VSV is a nonsegmented, negativestranded
RNA virus in the family Rhabdoviridae . It is primarily
an animal pathogen and is not known to cause severe disease in
humans. There are two known serotypes circulating on the American
continent, serotypes New Jersey and Indiana . Both VSV serotypes
are transmitted by mosquitos, sandflies or blackflies and cause characteristic vesicular lesions on the mouth and teats of livestock
. Humans are rarely infected and even in the event of an infection
the disease course is generally asymptomatic or mild . VSV is the
prototypic rhabdovirus and possesses a number of characteristics that
are important for a vaccine vector: replication in almost all known
mammalian cell lines, growth to very high titers, and a strong induction
of innate and adaptive (humoral as well as cellular) immune responses
[12-14]. In addition, there are very low levels of pre-existing immunity
to VSV in the general population with the neutralizing immune
response primarily directed against the VSV glycoprotein (VSV-G), a
viral protein that is not expressed in the filovirus rVSV vaccine vectors
(Figure 2) [15,16].
||Figure 1: Filovirus outbreaks and cases worldwide. Solid lines indicate introduction of MARV and ZEBOV from central Africa to different non-endemic countries.
Dotted lines indicate introduction of REBOV from the Philippines to Italy and the USA as a result of nonhuman primate shipments. The airplane symbolizes the
introduction of human cases through global travel. The insert displays an enlarged view of the filovirus endemic region of central Africa. Red: Zaire ebolavirus (ZEBOV); blue: Sudan ebolavirus (SEBOV); purple: Côte d'Ivoire ebolavirus (CIEBOV); green: Reston ebolavirus (REBOV); yellow: Bundibugyo ebolavirus (BEBOV);
black: Lake Victoria marburgvirus (MARV).
||Figure 2: Generation of recombinant vesicular stomatitis virus (rVSV) vaccines. The glycoprotein (G) gene in rVSVwt was deleted and replaced by the Ebola
virus glycoprotein (EBOV-GP) resulting in the vector rVSV/EBOV-GP. Co-cultures of 293T and Vero cells were transfected with the following plasmids: full-length
genome plasmid rVSVΔG/EBOV-GP expressing EBOV-GP under control of the bacteriophage T7 polymerase promoter; plasmids expressing the proteins needed for
VSV replication, nucleoprotein (N), phosphoprotein (P) and polymerase (L) under control of the human cytomegalovirus CMV promoter; and the plasmid expressing
the bacteriophage T7 polymerase under control of the CMV promoter. Following incubation of 24-72 hrs rVSV/EBOV-GP particles are harvested and purified from
the cell supernatant.
|Generation of recombinant vesicular stomatitis virus (rVSV)
|The rVSV vaccine platform is based on the reverse genetics system
for an attenuated strain of VSV serotype Indiana and was developed by
Rose and colleagues . Briefly, the entire VSV genome was cloned
into a plasmid under the control of the bacteriophage T7 polymerase
promoter. Subsequently, the open reading frame for the VSV
glycoprotein (G) gene was excised and unique restriction enzyme sites
for cloning were introduced. The resulting vector can be used to insert
foreign virus glycoproteins in place of VSV-G (Figure 2). The deletion of VSV-G has the added benefit of further attenuating the vector virus
as VSV-G is one of the major virulence factors . Transfection of
the VSV genomic plasmid together with expression plasmids for the
viral replication complex [VSV nucleoprotein (N), phosphoprotein
(P), and polymerase (L)] and the T7 polymerase into a co-culture of
Vero and 293T cells results in viral transcription, protein expression,
genome replication and production of recombinant VSV particles that
bear the foreign glycoprotein on their surface (Figure 2) . Electron
microscopy has shown that these recombinant viral particles possess
the same morphology as VSV wild-type (wt) particles (Figure 2) .
Initially the rVSV vector was used for HIV vaccine development
[15,18], but has since been modified to express the glycoproteins (GP)
of other enveloped viruses such as influenza, Lassa, EBOV and MARV
|To date, two rVSV vaccine vectors have been extensively tested
in filovirus animal disease models : rVSV/ZEBOV-GP expressing
the GP derived from ZEBOV strain Mayinga, and rVSV/MARV-GP
expressing the GP derived from MARV strain Musoke [10,16]. Efficacy
testing of rVSV/ZEBOV-GP as either a vaccine or post-exposure
therapy has been performed with mouse-adapted (MA-) ZEBOV in
mice and hamsters, guinea pig-adapted (GPA-) ZEBOV in guinea pigs,
and ZEBOV, SEBOV, CIEBOV and BEBOV in nonhuman primates
(NHPs) (Table 1-3). Data on protective efficacy of rVSV/MARV-GP against MARV infection has only been published for macaques (Table
2 and 3).
||Table 1: Preventive EBOV rVSV vaccination studies in rodents.
||Table 2: Preventive filovirus rVSV vaccination studies in NHPs.
||Table 3: Post-exposure filovirus rVSV treatment in rodents & NHPs.
|Preventive vaccine approaches
|Rodent models: New EBOV vaccine platforms are commonly
tested in rodent models before they undergo efficacy testing in NHPs.
For EBOV, the rVSV/ZEBOV-GP vaccine has been extensively tested
in BALB/c mice, and to a lesser extent in Syrian golden hamsters and
Hartley guinea pigs. BALB/c mice are completely protected following
a single intraperitoneal (i.p.) vaccination with 2x104 pfu of rVSV/
ZEBOV-GP per mouse at 28, 21, 14, 7 or even one day prior to lethal
challenge with MA-ZEBOV [21-23]. Remarkably, a vaccine dose as low
as 2 pfu resulted in complete protection in the ZEBOV mouse model
. In addition, it was shown that there is no difference in survival
outcome when rVSV/ZEBOV-GP was given 28 days prior to challenge
via the i.p., intranasal (i.n.), intramuscular (i.m.), or oral route .
The question of long-term immunity provided by the rVSV vaccine
was analyzed in the ZEBOV mouse model, and showed that a single
i.p. dose of 2x105 pfu rVSV/ZEBOV-GP was still protective 9 months
after immunization . As mice appear to be easily protected it was
necessary to test rVSV vaccine efficacy in other rodent models. The
well-established guinea pig model for ZEBOV was used to confirm the
data obtained in the mouse model. Guinea pigs vaccinated with 2x105
pfu rVSV/ZEBOV-GP were challenged with a lethal dose of GPAZEBOV
three weeks after vaccination. The vaccinated animals showed
no signs of illness, whereas control guinea pigs developed disease and
succumbed to infection between day 7 and 9 . Single rVSV vaccines
expressing BEBOV-, CIEBOV-, REBOV- or SEBOV-GP did not elicit
cross-protective immunity against ZEBOV in the guinea pig model
, indicating that GP is not sufficient as a cross-species protective immunogen for EBOV. In a more recent study, hamsters were also
protected when vaccinated with 1x105 pfu rVSV/ZEBOV-GP 14, 7 or
3 days prior to a lethal challenge with MA-ZEBOV . This study
also determined the protective efficacy of a bivalent vaccine vector
expressing ZEBOV-GP in addition to the Andes virus glycoprotein
(ANDV-GPC), a New World hantavirus, demonstrating that bivalent
rVSV vectors are capable of providing complete protection. In
summary, the rVSV vaccines have proven to be very potent in ZEBOV
|Macaque models: Cynomolgus macaques have been established
as the "gold standard" model for filovirus infections, thus this model
was chosen to test the efficacy of the rVSV/ZEBOV-GP and rVSV/
MARV-GP vaccines. The first study published by Jones et al. showed
that a single dose of 1x107 pfu rVSV/ZEBOV-GP provided complete
protection of all NHPs against a lethal dose of ZEBOV (1,000 pfu i.m.)
4 weeks following vaccination (Table 2) . Furthermore, all animals
were protected from disease and did not show any evidence of ZEBOV
viremia. At the time of challenge the NHPs had low to moderate-IgG
levels and no neutralizing antibodies, but developed a strong cellular
immune response as well as neutralizing antibody titers following
ZEBOV infection . Another study demonstrated that 2x107 pfu
rVSV/ZEBOV-GP administered i.m. protected NHPs against aerosol
infection with 1,000 pfu ZEBOV (Table 2) . The animals developed
similar immune responses after vaccination and aerosol challenge as
described for i.m. ZEBOV infection and were completely protected. A
third study focused on different routes of immunization for the rVSV/
ZEBOV-GP vaccine and no difference in protective efficacy could be
observed after i.n., oral or i.m. administration of a single vaccine dose
containing 2x107 pfu rVSV administered 28 days prior to homologous
challenge (Table 2) .
|Similar studies have been performed using the rVSV/MARV-GP
vaccine and MARV strain Musoke as the challenge virus. A single dose
of 2x107 pfu rVSV/MARV-GP given i.m. was protective against a lethal
i.m. or aerosol challenge (1,000 pfu) with MARV strain Musoke (Table
2) [25,26]. In contrast to EBOV, there is only one MARV species and
the rVSV/MARV-GP vaccine is not only protective against challenge
with the homologous strain (MARV strain Musoke), but also against
MARV strains Angola and Ravn . The IgG and neutralizing
antibody responses induced by the rVSV/MARV-GP vaccine seem to
be cross-protective within species  suggesting that a single MARV
vaccine will be protective against all currently known MARV strains.
|EBOV and MARV overlap in their endemic areas in sub-Saharan
Africa; therefore, a single vaccine that is protective against both
filoviruses is highly desirable. In the first attempt to accomplish this
task, equal amounts (1x107 pfu) of rVSV/MARV-, rVSV/ZEBOV- and
rVSV/SEBOV-GP were combined and a single blended vaccine was
given to cynomolgus macaques . All NHPs survived lethal challenge
with either 1,000 pfu ZEBOV, SEBOV or MARV. Interestingly, three
animals receiving this blended vaccine were infected with 1,000 pfu
CIEBOV and did not develop any signs of disease, despite the lack
of CIEBOV-specific antigen in the vaccine . This is the first study
indicating that the rVSV vaccines can induce cross-species protective
immune responses in nonhuman primates. Falzarano and colleagues
used rVSV/ZEBOV-GP and rVSV/CIEBOV-GP to determine whether
either of these vaccines alone could induce cross-protection against
the newly emerged BEBOV, which is approximately 75% lethal in
cynomolgus macaques [30,31]. Only one out of four animals vaccinated
with rVSV/ZEBOV-GP succumbed to infection while two out of
three animals vaccinated with rVSV/CIEBOV-GP did not survive
(Table 2). Animals surviving BEBOV infection developed signs of
mild to moderate disease and virus could be isolated from their blood
indicating that protection was not complete .
|The fact that rVSVs are replication-competent vectors raises
questions regarding their safety. In addition, potential filovirus
vaccine target populations in Africa may be immunocompromised
especially as a result of HIV infection, which could increase the risk
of adverse effects following vaccination. Geisbert et al. have addressed
this issue through vaccination of simian-human immunodeficiency
virus (SHIV)-infected, immunocompromised rhesus macaques with
rVSV/ZEBOV-GP . Six animals received a single dose of 1x107
pfu VSV/ZEBOV-GP i.m. and three animals received saline as control.
None of the animals showed clinical signs of illness indicating that no adverse effects were associated with vaccination. All nine subjects were
subsequently challenged with 1,000 pfu ZEBOV (strain Kikwit) on
day 31 after immunization. The three control animals succumbed to
lethal ZEBOV infection while four of six vaccinated animals survived.
Two of the surviving NHPs in the vaccinated group developed mild
but characteristic signs of Ebola hemorrhagic fever (EHF), while the
other two animals showed no signs of disease. Interestingly, the two
non-survivors in the vaccinated group had the lowest CD4+ cells count
and highest SHIV viremia, indicating that CD4+ T cell responses
may be important for protection . This data suggests that even in
immunocompromised individuals, rVSV vectors seem to be safe and
|In summary, the rVSV vaccine vectors have provided complete and
largely sterile protection in filovirus NHP models against homologous
challenge when administered prophylactically. Moreover, protective
immunity against multiple EBOV and MARV species/strains has
been achieved with a blended vaccine approach. The single-shot,
blended vaccine currently presents the most feasible vaccine strategy
for implementation in endemic regions of Africa while also being
suitable for the protection of maximum containment laboratory
workers worldwide. In the event of an act of bioterrorism involving
filoviruses, these vaccine vectors might also prove useful as time-toprotection
appears to be relatively rapid, thus they could be used to
limit secondary spread of infections to susceptible populations.
|Post-exposure treatment approaches
|Rodent models: In the event of an intentional filovirus release,
post-exposure vaccination (or treatment) would be highly desirable as
there is little to no time for wide-coverage preventative vaccination.
It had been demonstrated that a single dose of 2x104 pfu of rVSV/
ZEBOV-GP was completely protective in mice as a preventive vaccine
when administered as late as 24 hrs prior to lethal MA-ZEBOV
infection (Table 3) [21,22]. This finding suggested that the rVSV
vectors could be used for post-exposure treatment. The same rVSV
dose was subsequently tested in mice for its protective efficacy when
administered either 30 min or 24 hrs post challenge with 1,000 LD50
of MA-ZEBOV . The mice developed mild clinical symptoms
including slight weight loss, indicative of virus replication, but all
treated animals survived. Encouraged by this outcome, the experiment
was repeated in guinea pigs. Groups of six animals were treated with a
single dose of 2x105 pfu rVSV/ZEBOV-GP 1 hr or 24 hrs post infection
with 1,000 LD50 of GPA-ZEBOV (Table 3) . None of the groups
were fully protected; however, 83% of guinea pigs in the 1 hr post challenge group and 50% of guinea pigs in the 24 hr post infection group
survived after developing signs of disease . A similar study was
performed in hamsters with a single dose of 1x105 pfu rVSV/ZEBOVGP
administered immediately following MA-ZEBOV challenge (day
0), or 24 hrs or 48 hrs after challenge . All hamsters treated up to
24 hrs post lethal infection with rVSV/ZEBOV-GP survived, whereas
all animals succumbed in the 48 hrs treatment group despite showing
delayed time to death. Taken together, rVSV/ZEBOV-GP has the
potential to be used for post-exposure treatment and thus was tested
in the macaque models.
|Macaque models: Three different rVSVs expressing the GP from
either MARV (strain Musoke), SEBOV (strain Boniface), and ZEBOV
(strain Mayinga) have been tested for post-exposure treatment in the
rhesus macaque model of filovirus infections (Table 3). The rhesus
macaque model was chosen for these experiments because the mean
time to death following lethal filovirus infections is generally longer
than with cynomolgus macaques [4,5]. Interestingly, rVSV/MARVGP
(strain Musoke) displays the greatest potential for post-exposure
treatment. When given 20-30 min following MARV (strain Musoke,
1,000 pfu) infection this vector protected 100% of rhesus macaques
from viremia and disease . This experiment was followed up
by another study where two groups of six animals were treated with
rVSV/MARV-GP 24 or 48 hrs following lethal MARV (strain Musoke)
infection . Treatment 24 hrs post-infection resulted in 83% survival,
with one out of six animals showing signs of disease and three of the
six testing positive for viral RNA in the blood. When treatment was
delayed until 48 hrs post infection, the survival rate dropped to 33%
and all animals showed moderate to severe signs of disease, and 83%
developed viremia .
|However, the rVSV/SEBOV-GP vector also protected 100% of
the animals from lethal outcome when administered 20-30 min post
challenge with SEBOV . All four treated animals showed signs
of illness and two NHPs developed viremia . By comparison, the
rVSV/ZEBOV-GP seems to be the least potent vector for post-exposure
treatment as 50% of rhesus macaques infected with ZEBOV (strain
Kikwit, 1,000 pfu) and subsequently treated with rVSV/ZEBOV-GP
20-30 min later, succumbed to infection. All survivors developed
moderate signs of illness and were viremic. While it appears that this
vector is highly effective as a preventive vaccine, it seems less effective
as a post-exposure strategy . However, MARV (strain Musoke)
and particularly SEBOV infections typically progress slower in NHPs
than infections with ZEBOV [4,5], which likely contributes to the
greater success of the rVSV/MARV-GP and rVSV/SEBOV-GP in postexposure
treatment. It would be interesting to determine post-exposure
treatment efficacy against infection with MARV, strain Angola, which
shows the fastest disease progression of all known filoviruses .
|Correlates and mechanisms of protection
|The mechanisms of protection of the rVSV vectors in pre-exposure
vaccination are not understood. It also appears that there might
be differences between the rodent models, in particular the mouse,
and the NHP models. The humoral immune response is certainly
sufficient to protect mice from lethal challenge as was clearly shown
with successful plasma transfer studies  as well as treatment studies
with neutralizing antibodies [37-39]. For prophylactic vaccination of
NHPs, it appears that adaptive immune responses, both cellular and
humoral, are required. The MARV rVSV vector seems to elicit stronger
non-neutralizing antibody responses whereas the EBOV rVSV vectors
induce stronger cellular immune responses. Further studies, such as specific depletion of T and B cells, should better define the mechanism
of protection. Nevertheless, a strong non-neutralizing antibody
response appears to correlate with protection and could be used as a
marker for successful vaccination.
|The mechanisms of protection for post-exposure rVSV treatment
also remain unknown. VSV is known to act as a very strong inducer
of innate immune responses, which might be sufficient to overcome
filovirus-driven suppression of these responses , thus inhibiting
filovirus replication and spread of infection. It has been shown that
rVSVs infect the same target cells as filoviruses  resulting in a
block in EBOV and MARV replication potentially as a result of viral
interference. Again, the development of a humoral non-neutralizing
immune response is associated with survival but is unlikely to be the
mechanism of protection as its development would be too late .
|Vaccine safety & environmental impact
|Since rVSV filovirus vaccines are replication competent, vaccine
safety has been a significant concern and as such was taken into account
during vector design. Importantly, there has been no indication of
potential safety issues using multiple rVSV vectors despite being used
in a large number of animal studies. The rVSV vectors are based on
an attenuated strain of VSV serotype Indiana and in addition the
VSV glycoprotein, a key determinant for VSV pathogenicity ,
has been replaced with a filovirus glycoprotein. This has resulted in
replication competent vectors that are attenuated both in vitro 
and in vivo (Marzi et al., unpublished data). Safety concerns have also
been addressed through evaluation of the rVSV filovirus vaccines in
two immunocompromised animal models. Non-obese diabetic severe
combined immunodeficiency (NOD/SCID) mice and SHIV-infected
macaques showed no indication of adverse effects following rVSV
vaccination and in fact the vaccines were efficacious against lethal
challenge (albeit not completely) [22,32]. Based on efficacy and safety
data in animal models, the rVSV/ZEBOV-GP vaccine was recently
used for post-exposure treatment of a laboratory exposure with only
moderate reactions being reported .
|While all rVSV animal studies performed so far have only resulted
in low level transient rVSV viremia with no detectable shedding of
infectious vaccine virus, the potential impact of live attenuated vaccine
vectors on the environment should not be underestimated [25-30,32].
Furthermore, this vector is not expected to cause disease in livestock as
a result of the lack of VSV-G, however, further safety testing should be
performed in animals of interest (cattle, donkeys, mules, horses, swine,
etc.). In addition, VSV has a very low transmission rate in nature ,
and there is no evidence that rVSV vectors would accumulate mutations
that would result in increased virulence or transmissibility to a broader
host range. In this regard, the currently used live measles vaccine
that has been widely used for five decades has shown no evidence of
acquiring increased virulence [41,42]. Together, the efficacy and safety
data strongly support further development of these vaccine vectors for
|Most filovirus outbreaks have been reported in sub-Saharan Africa,
but with increased global travel EBOV and MARV have the potential to
be imported worldwide (Figure 1). Although, larger epidemics in Africa
have been prevented as a result of patient isolation, contact tracing and
extensive surveillance efforts, the threat of filovirus infection remains
ever present particularly with the potential misuse of these viruses as
agents of bioterrorism. Significant progress has been made over the last 15 years towards filovirus vaccine development, with multiple potential
vaccine candidates that are highly efficacious.
|The rVSV vectors have been evaluated in a variety of rodent and
NHP models, clearly demonstrating their safety and efficacy as a
prophylactic vaccine platform for filoviruses and perhaps other viral
hemorrhagic fever pathogens [9,10]. A single shot, blended rVSV
approach is currently the best strategy to provide broad coverage
for filoviruses in overlapping endemicity zones in Africa (Figure 1).
Multi-dose regimens with rVSV vectors seem possible due to the
lack of neutralizing antibody responses to the vector backbone (VSVG-
deficient) opening the opportunity for continuing vaccination
programs. In addition to its efficacy as a preventive vaccine, the rVSV
vectors have also shown value in post-exposure treatment. This is an
important asset of a vaccine platform in the event of a bioterrorism
attack or an accidental laboratory exposure as was shown in 2009
when rVSV/ZEBOV-GP was first used as a post-exposure treatment
in a laboratory accident . Thus, the next obvious step for the
rVSV filovirus vaccine platform is the move into phase I clinical trials.
For this to occur, vaccine stocks need to be produced to GLP/GMP
standards and the correlates and mechanisms of protection need to be
better defined to allow licensing. Currently, the rVSV filovirus vectors
seem to be the most promising choice for a fast-acting preventive and
therapeutic vaccine platform.
|The authors thank Anita Mora and Austin Athman (Visual and Medical Arts Unit,
Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases,
National Institutes of Health) for support with graphics. Filovirus work at the Rocky
Mountain Laboratories is funded by the Intramural Research Program, NIAID, NIH.
Work on rVSV-based filovirus vaccines at UTMB Galveston is supported in part by
the Department of Health and Human Services, NIH grant AI082197.
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