Dr. Ramon Flick
BioProtection Systems Corporation
2901
South Loop
Dr. Suite 3360 Ames, IA 50010 Tel: +1-515-598-5017 Fax: +1-515-296-3820 E-mail: rflick@bpsys.net
Received December 30, 2010; Accepted April 21, 2011; Published April 23, 2011
Citation: Mandell RB, Flick R (2011) Rift Valley Fever Virus: A Real Bioterror
Threat. J Bioterr Biodef 2:108. doi:10.4172/2157-2526.1000108
Rift Valley fever virus is recognized as an important bioterror and agroterror threat to Western countries including
the United States. Once introduced, the virus would be readily spread by native mosquito populations and potentially
become endemic. While infection often results in severe morbidity and mortality in both humans and livestock, there
are currently no FDA or USDA-licensed vaccines. The development of effective countermeasures and implementing
surveillance and diagnostic capabilities are critical. Ultimately, the presence of RVFV would lead to severe long-term
negative impacts for healthcare, agricultural and travel economic sectors.
Introduction
Rift Valley fever virus (RVFV) is a zoonotic arthropod-borne
pathogen that often results in severe morbidity and mortality in
both humans and livestock. The lack of prophylactic and therapeutic
measures, the potential for human-to-human transmission, and the
significant threat to livestock associated with RVFV make this pathogen
a serious bioterror threat.
RVFV can be propagated easily and efficiently with simple cell
culture systems in vitro [1]. The potential to use RVFV as a bioweapon
is further enhanced by the ability to manipulate the virus through
either rational genetic approaches or through various passaging
schemes to produce altered agents that could escape detection and/
or existing prevention and control methods [1]. As such, RVF virus is
considered a potential threat as a biological weapon [2] that could have
dramatic direct (morbidity and death) and indirect (international trade
restrictions) impact in countries that are currently free of the virus.
Because of its clear disease potential, aerosolized RVFV could be used
as a bioterror or agroterror weapon to threaten humans and ruminants
and devastate the economy [3]. Importantly, unlike other potential
bioterror agents (i.e., Crimean-Congo hemorrhagic fever virus, Nipah
virus and Ebolavirus), the vectors for RVFV transmission are present in
the Western hemisphere.
Background
New highly fatal diseases have emerged or reappeared during the
last 4 decades such as severe acute respiratory syndrome (SARS) [4-5], Legionella [6], hantavirus pulmonary syndrome (Sin Nombre virus)
[7], Nipah virus encephalitis [8-9], avian influenza [10-11], West Nile
encephalitis [12-13] and Rift Valley fever with adverse global or regional
public health and economic impact [14]. Most emerging infectious
diseases are the result of epizoonotic transmission from animals to
man [15-16]. RVFV presents one of the most important non-endemic
bioterror threats to the Western hemisphere. RVFV was first identified
in 1931 as the causative agent of enzootic hepatitis of sheep in Kenya
[17] and has since then spread across most of the African continent
and more recently emerged on the Arabian peninsula [18-19]. RVF
manifests itself in the vast majority of individuals (90% show clinical
signs of disease) that become infected, unlike a WNV infection, which
has no clinical manifestation in 80% of infected individuals. Historically,
while infections in humans are typically mild and present as selflimiting
febrile illnesses, RVFV infections progress to more severe
disease including fulminant hepatitis, encephalitis, retinitis, blindness,
or a hemorrhagic syndrome in approximately 2% of affected individuals
[20-21]. However, statistics from recent outbreaks suggest that the case fatality rate from RVFV infections is significantly increasing (>30%) in
naive populations [1,14,22-23]. For example, during the 2006-2007
Rift Valley fever outbreak in East Africa, RVF was diagnosed in over
1000 patients in multiple locations in Kenya, Somalia and Tanzania [24-27] and over 300 patients died [28]. As recently as 2010, there was a
RVFV outbreak in South Africa with at least 237 human cases reported
including twenty-six deaths [29-30] http://www.nicd.ac.za/outbreaks/
rvf/docs/RVF_Interim_Report_2010_10_01.pdf.
There are similarities between the public's awareness of RVFV
and its perception of the West Nile virus (WNV) threat before 1999.
WNV was not considered a threat to the USA prior to its emergence
in New York in 1999 [31]. However, within six years, WNV had
become endemic across the USA [13]. Interestingly, while the WNV
transmission route is limited to two mosquito genera [32] (Aedes
and Culex) and has a limited effective host range, RVFV is readily
transmitted through a broad range of mosquito genera including Aedes,
Anopheles, Culex, Eretmapoites and Mansonia, and by other vectors
including sand flies [33]. Importantly, RVFV has a much broader
effective host-range compared to WNV, capable of causing severe
disease in sheep, goat, cattle, water buffalo, and humans. Recent studies
have illustrated the ability of RVFV to utilize the dominant mosquito
species of a given geographical location [34-37], which indicates that
there is no natural blockade to protect naive countries from the spread
of the virus. This presents a real threat for RVFV incursions into other
parts of the world, including Europe [34] and the United States [38].
However, differences in RVFV transmission rates can be affected by
local mosquito populations [39].
Human RVFV infections are usually preceded by transmission from
wild to domestic animal hosts, recognized by sudden and devastating
impact on livestock [20,40-41]. In sheep, mortality in lambs under
2 weeks of age approaches 100%, reaches 30% in older animals and
abortions approach 100%. Cattle also show high abortion rates (up to
100%) with adult mortality averaging 10% [21,42].
Threat
Because of the potential for severe consequences during such
outbreaks, RVFV is considered a major zoonotic threat to the US.
Homeland Security Presidential Directive/HSPD-9 established a
national policy to defend the agriculture and food system against terrorist
attacks, major disasters, and other emergencies (http://merln.ndu.edu/
archivepdf/hls/WH/20040203-2.pdf), including the establishment of a
National Veterinary Stockpile (NVS). RVFV is #3 on the list of the 17
most dangerous animal threats, behind only highly pathogenic avian
Influenza and Food and mouth disease (http://www.aphis.usda.gov/vs/
ep/functions.html). RVFV is classified as an Overlap Select Agent by
the Department of Health and Human Services (HHS), US Department
of Agriculture (USDA) [43-44] and as a high-consequence pathogen
with the potential for international spread by the World Organization
for Animal Health (Office International des Épizooties) [45]. RVFV is
also classified as a Category A High Priority Pathogen by the National
Institute for Allergy and Infectious Diseases (NIAID) (http://www3.
niaid.nih.gov/topics/BiodefenseRelated/Biodefense/research/CatA.
htm) and is on the Center for Disease Control (CDC) Bioterror Agent
list (http://www.bt.cdc.gov/agent/agentlist-category.asp#a) [44]. As
described previously [46], RVFV is clearly recognized as a biothreat by
The US Commission on the Prevention of Weapons of Mass Destruction
(WMD) Proliferation and Terrorism [47] and several risk assessment
studies have illustrated the potential spread of RVFV once introduced
into Europe or the USA [48-52] (http://ppmq.ars.usda.gov/research/
publications/Publications.htm?seq_no_115=235466&pf=1) (http://
nabc.ksu.edu/assets/uploads/rift_valley_report.pdf). RVFV working
groups have produced scientific opinions, threat assessments and
recommended action plans (surveillance, diagnostics, vector control),
for the management of RVFV including the European Food Safety
Authority (EFSA) [48], the Animal and Plant Health Inspection Service
(APHIS) Centers for Epidemiology and Animal Health multi-agency
and university working group on RVFV (reviewed in Kasari et al [49],
the USDA's Agricultural Research Service's (ARS) Arthropod-Borne
Animal Diseases Research Laboratory (ABADRL) in collaboration with
ARS, Center for Medical, and Veterinary Entomology and the USDA,
APHIS.
(http://ppmq.ars.usda.gov/research/publications/Publications.
htm?seq_no_115=235466&pf=1), the Global Disease Detection
Division at CDC-Kenya along with the Regional Emergency Office
for Africa (REOA) Food and Agriculture Organization (FAO) and
the Global Emerging Infections Surveillance Systems office of the
U.S. Army Medical Research Unit in Nairobi, in collaboration with
the Kenya Ministries of Health and of Livestock (reviewed in [14])
and ARBO-ZOONET [53], reviewed in Korketaas et al [23]. Taken
together, these works strongly conclude that RVFV is a real threat and it
is only a matter of when - not if - RVFV is intentionally or accidentally
introduced into the Western hemisphere.
Surveillance and diagnosis
The capacity for surveillance, handling large numbers of samples
and diagnostics is extremely limited in the US and other Western
nations should RVFV be introduced/emerge, with a low probability
of early detection and response with control measures. Physicians and
veterinarians are unaccustomed to the clinical signs of RVFV which
will likely delay a positive diagnosis. The ability to handle human and
animal samples and specimens is problematic because RVFV must be
handled under high containment, and a very limited number of such
facilities are available.
In endemic areas, RVFV infection is most often diagnosed using
a combination of clinical judgment (recognition of acute hemorrhagic
fever cases) and available diagnostic testing [54]. Newer, multiplexed
PCR and reverse-transcription (RT)-PCR enzyme hybridization assays
are being developed that can simultaneously detect multiple pathogens,
including many hemorrhagic fever viruses [55-56], and should be used
in conjunction with ELISA-based [57] methodologies. A focus on
practical field deployable diagnostics is critical since RVF outbreaks
occur most commonly in remote locations. Importantly, the real-time
RT-loop-mediated isothermal amplification (RT-LAMP) assay for
RVFV presents a similar sensitivity and specificity as real-time PCR,
but is a single-step reaction that is faster and less expensive, and can be
assessed with the unaided eye [58-59].
Vaccines
Public health and animal health agencies agree that it is now a
priority to develop RVFV countermeasures (whether for humans,
animals, or both: the "One Health" initiative [60]) that will yield highly
effective, long-term protective immunity [1,54]. The ideal RVF vaccine
would confer protection after a single dose, be nonpathogenic with
no potential for reversion to wild-type virus, be safe for production in
standard vaccine facilities, and present long-term stability at ambient
temperatures. The development of safe and efficacious RVFV vaccines
has proven to be quite difficult (summarized in Bouloy and Flick 2009
[1] and Bird et al. 2009 [21] and references therein). Unfortunately,
there is currently no licensed vaccine available for human use in the
USA or Europe.
In addition, because of the animal-trade embargoes imposed
during RVF epizootics, the design of commercial livestock vaccines
should allow for the differentiation of naturally infected and vaccinated
animals (DIVA) [1,61]. A vaccine to prevent the amplification cycle
of RVFV in livestock would greatly reduce the risk of human infection
by preventing livestock epizootics. The partially attenuated Smithburn
modified live virus vaccine was developed for livestock applications, but
it can lead to abortions or teratology in pregnant animals. In addition,
the risk of reversion to full virulence precludes its use in countries where
RVFV is not known to be endemic. A formalin-inactivated version of
this vaccine is available, but increased production costs combined with
the need of multiple inoculations to protect animals present critical
disadvantages in outbreak situations [46]. A formalin-inactivated
RVFV vaccine, TSI-GSD-200, has limited availability in the US for
protection of military personnel and laboratory workers. As with most
inactivated antiviral vaccines, several inoculations (including annual
boosters) are needed to maintain immunity. In addition, this vaccine is
in short supply and expensive.
While live attenuated and genetically engineered RVFV strains
are highly immunogenic and do not require boosting, they do present
safety concerns regarding reversion to virulence [1,62]. MP12 is
efficacious in livestock and was recently tested in human clinical trials
with promising results [63]. However, one study showed that abortion
(4%) and teratogenic effects (14%) occurred in pregnant sheep [64],
and since MP12 attenuation is based on several single point mutations,
concerns about reversion are valid. Clone 13, a natural RVFV isolate [65-66], a MP12/Clone 13 reassortant, R566 (M. Bouloy et al., unpublished
data) and a ΔNSs/ΔNSm ZH501 strain are being developed that have
excellent preclinical safety profiles [67]. These vaccine candidates have
NSs or both NSs/NSm gene partial or complete deletions which prevent
the virus from hijacking the type 1 IFN pathway, make reversion almost
impossible, and satisfy the DIVA concept. Other approaches include
expression of RVFV glycoproteins by recombinant Lumpy skin disease virus (LSDV) and adenovirus-based platforms and alphavirus replicon
vectors [1,21].
Recent RVFV vaccine developments focus on virus-like particle
(VLP)-based platforms which avoid issues associated with liveattenuated
vaccines. Expression of structural proteins of many nonenveloped
and enveloped viruses leads to the formation of VLPs
[68] and references therein). Structural similarity with the wild type
virus combined with the lack of viral genetic material makes this
vaccine platform ideal to generate safe vaccine candidates [68-69].
Efficient generation of RVF VLPs has been demonstrated by several
groups using either mammalian cell or insect cell derived systems.
Promising immunological data (e.g., high neutralizing antibody titers)
and full protection in mice and rat challenge studies were achieved,
demonstrating that VLP-based RVFV vaccine candidates are a
promising RVFV vaccine approach [1,70-73].
Alternatively, DNA-based (virus-free) vaccines such as gene-gun
immunizations with cDNA encoding RVFV structural proteins have
been shown to induce neutralizing antibody titers in mice, but some
immunized animals still developed clinical signs of infection after
sublethal challenge [74].
Therapeutics
For treatment of symptomatic RVF, no highly effective RVFVspecific
therapeutics currently exist [1]. However, beyond supportive
care, there is hope that viable antiviral therapeutic options will emerge.
With the exception of ribavirin as an approved drug, few compounds
are licensed as approved antiviral drugs for the hemorrhagic fever
viruses [75]. Furthermore, the effectiveness of ribavirin is limited due
to side effect complications and lack of specificity [1,76-78]. The arylmethyldiene
rhodanine derivative LJ001 prevents virus-cell fusion
and has broad-spectrum activity against enveloped viruses such as
RVFV, and might provide utility as a therapeutic [79]. Potential broadspectrum
therapeutic activity has also been suggested for bavituximab
which targets phosphatidylserine on enveloped viruses and virusinfected
cells [80]. Pyrazinecarboxamide compounds have also
been shown to be useful for post exposure antiviral therapy as broad
spectrum antiviral inhibitors [81-83].
Outbreak prediction and control
RVF presents an informative model for assessing the impact
of climate and ecology on its periodic reemergence and spread, as
well as for the potential that modern technologies and public health
advancements can contribute to disease forecasting, prevention,
and control [28]. While important risk assessment and surveillance
strategies for RVFV in Western countries that rely on statistical tools
including landscape epidemiology and phylogeography have been
suggested [84], to date no plans have been officially implemented. As
described in Breiman et al. 2010, RVF is a disease associated with a
complex set of factors that make disease outbreaks likely including
animals, mosquitoes, climate, ecology, and commercial trade [14]. Its
prevention and control is not straightforward. Livestock trade practices
has moved the virus long distances [19,85] (potentially including the
movement of infected mosquitoes), creating the potential for disease
in regions without previous exposure to the virus [14]. Landscape
attributes influence spatial variations in disease risk or incidence. As
described by Lambin et al. 2010, integrated analyses at the landscape
scale allows a better understanding of interactions between changes
in ecosystems and climate, land use and human behavior, and the
ecology of vectors and animal hosts of infectious agents [86]. As noted in LaBeaud et al. 2010 [54], because RVFV outbreaks generally follow
anomalous heavy rainfall in endemic areas [87-89], meteorological
forecasting of extreme weather events has been shown to be a useful
tool to predict RVFV activity [90]. Future research will need to focus
on providing early warnings so that prediction can have greater impact
on mobilization of preventive interventions and outbreak management
[54].
Conclusions
RVFV was reportedly weaponized by the US offensive biological
weapons program, illustrating the real threat and utility of RVFV as
a bioweapon (http://cns.miis.edu/cbw/possess.htm). Bioterrorism,
trade, world travel and the presence of mosquito species capable of
transmitting the virus make RVFV a major threat to Western countries
[46]. Coupled with the fact that there is currently no FDA-or USDAapproved
RVFV vaccine for human or veterinary use, there is a clear
need for more RVFV vaccine research and development [1,21,62].
It has been proposed that a single infected person or animal which is
able to enter Europe or the USA would be sufficient to initiate a major
outbreak before RVFV would be detected. This would quickly lead to
the spread of RVFV and cause a severe strain on health care systems
as human infections become more common. Wide-spread public panic
might also ensue because of the knowledge that a hemorrhagic fever is
circulating in the population. A severe economic impact is inevitable
and will be felt in almost all economic sectors, from agriculture to
healthcare and travel, likely for years post-identification. Although
important strides have been made regarding awareness and preparation
for RVFV, this pathogen still presents one of the most important viral
disease threats to the Western hemisphere.
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