Rift Valley Fever (RVF)
Overview and Recent
Developments at USDA
Kenneth J. Linthicum
Center Director
Center for Medical
Agricultural and
Veterinary Entomology
USDA-ARS
Gainesville, Florida
Contributors
Kenneth J. Linthicum and Seth Britch, USDA-ARS, Center for Medical, Agricultural &
Veterinary Entomology, Agricultural Research Service, United States Department of
Agriculture, Gainesville, Florida.
Cyril G. Gay, National Program Leader, Animal Health, Office of National Programs,
Animal Production and Protection, USDA-ARS, Beltsville, MD
William Wilson, Kristine Bennett, Arthropod Borne Animal Research Laboratory,
Laramie, Wyoming, L
Assaf Anyamba, Jennifer Small & Compton J. Tucker, NASA/Goddard Space Flight
Center, Biospheric Sciences Branch, Code 614.4, GIMMS Group, Greenbelt,
Maryland.
Jean-Paul Chretien, Clair Witt - Department of Defense, Global emerging Infections
System, Division of Preventive Medicine, Walter Reed Army Institute of Research,
Washington, DC.
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Collaborators
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Pierre Formenty, World Health Organization – Pandemic Alert and Response
Department, Geneva
Stephane DeLaRocque, Food and Agricultural Organization (FAO), Rome.
Overview of Rift Valley
fever (RVF) Topics
1.
2.
3.
4.
RVF Ecology/Epidemiology in
Africa and Arabian Peninsula
Prediction of Recent RVF
Outbreaks in Africa
RVF Threat to U.S.
RVF Interagency Working Group
1. RVF Ecology/Epidemiology
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Disease caused by virus in Family
Bunyaviridae, Genus Phebovirus
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First described in Kenya 1931 after epizootic
in sheep on a farm north of Lake Naivasha
Viral Zoonosis that affects livestock and
humans in Africa
» affects primarily domestic livestock
» horses, pigs, poultry and wild birds nonsusceptible ?
Human symptoms - a flu-like illness with fever,
weakness, back pain, dizziness, and weight
loss – leading to hemorrhage (severe
bleeding), encephalitis (inflammation of the
brain), or severe eye complications
Treatment – None, experimental use of
antiviral ribavirin
No U.S. licensed animal or human vaccine
Mortality – 1-25% in humans, 80-100% in
livestock
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Lake
Naivasha,
Kenya
Rift Valley Fever – Geographic
Distribution
Countries with endemic RVF disease
Countries with isolated outbreaks or serological evidence
RVF is a zoonosis (primarily affects animals, but occasionally causes disease in
human beings). It commonly affects pastoral people who inhabit the Rift Valley
plains and the high plateau grazing lands
Clinical RVF in Cattle
Feature
Characteristics
Incubation period
1-6 days
Clinical signs
Calves:
—Fever of 40°-42°C (104°-106°F)
—Depression
—Icterus
—Anorexia and weakness
—Listlessness
—Evident abdominal pain
Adults:
—Fever of 40°-42°C (104°-106°F)
—Excessive salivation
—Anorexia
—Weakness
—near 100% abortion, Fetid diarrhea
—Fall in milk yield
—Nasal discharge
Case-fatality rate
—Calves: 10%-70%
—Adults: <10% in indigenous breeds
Clinical features in Sheep
and Goats
Feature
Characteristics
Incubation period
Lambs: 12-36 hr
Adults: 1-6 days
Clinical signs
Lambs:
—Fever of 40°-42°C (104°-107°F)
—Anorexia and weakness
—Listlessness
—Evident abdominal pain
Adults:
—Fever of 40°-41°C (104°-106°F)
—Mucopurulent nasal discharge
—Vomiting
—Anorexia
—Listlessness
—Diarrhea
—Icterus
Complications
—Abortion rates can reach 100% (aborted fetus often autolysed)
—Peracute hepatic disease in lambs and kids <1 wk of age
—Hepatitis
—Cerebral infections
—Ocular infections
Case-fatality rate
Lambs
—<1 wk of age: as high as 100%
—>1 wk of age: as high as 20%
Adults: 20%-30%
Clinical Features in Humans
Characteristic
Features
Incubation period
2-6 days
Prodrome
Fever, headache, photophobia, retro-orbital pain
Clinical signs/symptoms
—Subclinical infection common
—Four clinical patterns:
~Undifferentiated fever lasting 2-7 days (>90% of cases; often associated with nausea, vomiting, and
abdominal pain)
~Hemorrhagic fever with marked hepatitis and bleeding manifestations (<1% of cases; occurs 2-4 days
after onset of fever)
~Encephalitis (<1% of cases; occurs 1-4 wk after onset of fever)
~Retinitis (up to 10% of cases; occurs 1-4 wk after onset of fever; often bilateral; hemorrhages, exudates,
and cotton wool spots may be visible on macula; retinal detachment may occur)
—Common bleeding manifestations include gastrointestinal bleeding and epistaxis
—Neurologic symptoms include confusion, lethargy, tremors, ataxia, coma, seizures, meningismus, vertigo,
choreiform movements
—Hepatitis, hepatic failure, and renal failure may occur
—A report of the 2000 outbreak in Saudi Arabia identified the following clinical features for 683 laboratoryconfirmed cases:
~Fever: 92.6%
~Nausea: 59.4%
~Vomiting: 52.6%
~Abdominal pain: 38.0%
~Diarrhea: 22.1%
~Jaundice: 18.1%
~Neurologic manifestations:
17.1%
~Hemorrhagic manifestations:
7.1%
Clinical Features in
Humans (Cont)
Characteristic
Features
Laboratory
features
—Initial leukocytosis may occur, followed by leukopenia
—Thrombocytopenia in severe cases
—Laboratory features of DIC in severe cases (prolonged
bleeding time, prothrombin time, and activated partial
thromboplastin time; elevated fibrin degradation products;
decreased fibrinogen)
—Elevated hepatic enzymes (e.g., ALT, AST) and bilirubin
Complications
—Blindness following retinitis
—Neurologic sequelae following encephalitis
Clinical Features in
Humans (Cont)
Characteristic
Features
Case-fatality
rate
—Overall, <1%
—For hemorrhagic disease, about 50%
—In 2000 outbreak in Saudi Arabia, case-fatality rate was reported
as 17% among symptomatic patients and 33.3% among
hospitalized patients admitted to RVFV unit at local referral
hospital
—Death usually due to hepatic necrosis and DIC
Abbreviations: AST: aspartate aminotransferase; ALT, alanine aminotransferase;
DIC, disseminated intravascular coagulation.
Environmental Sensitivity
of RVF
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Acid sensitive
» Shortly after slaughter virus is killed
» pH < 6.2 are effective disinfectants
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Pasteurization of milk kills the virus
Diagnostic Techniques and
Test Selection
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Acute Phase with ELISA,
immunohistochemistry, RT-PCR
Surveillance with ELISA to detect IgM/IgG
» Appropriate test depends on phase of infection
– ID of antigen in viremic phase
– Post viremic phase antibodies increase, detection by
IgM
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Other Diagnotics Technologies
» Molecular diagnosis
» Non-nested PCR works with high viremias
» Nested amplimers can yield sequence data for
phylogenetic analyses
Summary
Patterns of RVF Infection
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Incubation period for RVF is relatively short (35 days in adult humans, 12 hours in young
animals)
Fever coincides with short viremia
Viremia 3-10 days in humans
Viremia 2-5 days in cattle
Amplitude of Viremia High (>108 PFU/ml))
Long lasting immune response
Lifelong IgG and neutralization antibodies in
humans
ENVIRONMENT, HABITAT CONDITIONS AND
EVOLUTION DYNAMICS
Rainfall x Rainy Days
Outbreaks of RVF are known to follow periods of
widespread and heavy rainfall associated with the
development of a strong inter-tropical convergence zone
over Eastern Africa
RVF Epizootics
1950
1961
1968
1977
1982
Vector Dynamics and Ecology
• Emergence
and population
expansion of a number of disease
vectors (mosquitoes, mice, locust)
often tends to follow the trajectory
of the green flush of vegetation in
semi-arid lands
• NDVI data can therefore be
used as a multi-purpose indicator
of conditions associated with
vector-borne disease outbreaks –
in support of disease surveillance
activities
RVF Life Cycle
Climatic factors (heavy
rainfall associated with ENSO)
Dry Season
Aedes mcintoshi infected
with RVF virus
transovarially
Rain
Floodwater Aedes & Culex mosquitoes
+ direct transmission (aerosol, contact)
Deposit RVF
Infected Eggs
Epidemic Cycle
Endemic Cycle
Flooding results in mass
hatching of infected Aedes
eggs and subsequent Culex
mosquitoes leading to
RVF outbreak
Virus persists during dry
season/inter-epizootic
period through vertical
transmission in Aedes
mosquito eggs
Rain
Rainy Season
Culex species - important
secondary vectors of RVF
Anopheles mosquitoes not
involved RVF transmission
2. Prediction of Recent RVF
Outbreaks in Africa
Vector-borne Disease Climate Link
 Building evidence suggests links between El
Niño/Southern Oscillation (ENSO) driven climate
anomalies and infectious diseases, particularly
those transmitted by arthropods:
» Murray Valley encephalitis (Nicholls 1986)
» Bluetongue (Baylis et al. 1999)
» RVF (Linthicum et al. 1999)
» African Horse Sickness (Baylis et al 1999)
» Ross River virus (Woodruff et al. 2002)
» Dengue (Linthicum et al. unpublished)
» Malaria (Bouma & Dye 1996)
» Chikungunya (Chretien et al. 2006)
Operational Application: 1997-1998 Rift
Valley fever Outbreak
•
Convergence of Pacific El Nino event and
WIO Warming
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Wide spread, persistent and rainfall in semi arid
lands
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Flooded dambos – hatching of infected
mosquito eggs, supports several generations of
mosquito populations
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Vegetation green-up – micro-ecological
habitats conducive to mosquito survival and
propagation
•
First human cases identified late December
1997, declared Epizootic late January 1998
•
Impact on Livestock Trade: Ban on livestock
imports from GHA – loss of income ~ $ 100
million in 1998
•
Reported losses of ~70% sheep and goats and
20%-30% ~ cattle and camels
•
estimated 89,000 humans in this region could
have been infected (North Eastern Kenya and
central Somalia)
Largest RVF Outbreak in last
30 years occurred over a large
geographic
•Millions of cattle,
sheep, and goats
•100,000 human cases
Number of flagged pixels in
East Africa exceeded
20,000 (1,280,000 Km2)
Seasonal Summary: SST, OLR SON 2006
September 2006 Actions
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Warning issued in Emerging Disease paper presented at
Society of Vector Ecology Plenary Session, Anchorage,
Alaska
Issued First Alert Mid-October
Wrote GEIS Advisory distributed to DoD Overseas
Laboratory Network – Global Elevated Risk of Outbreaks
of Vector-borne diseases
Advisory submitted to International Journal of Health
Geographics
November 2006 Actions
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Issued Second Alert Early-November
Presented at the WHO Joint Intercountry Workshop on Crimean-Congo
Haemorrhagic Fever (CCHF) Prevention and Control Istanbul, Turkey, 6-8
November 2006
Published on FAO Emergency Prevention System (EMPRES) for
Transboundary Animal and Plant Pests and Diseases EMPRES WATCH
website: Possible RVF activity in the Horn of Africa
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http://www.fao.org/ag/againfo/programmes/en/empres/home.asp
Information transmitted to country and regional offices
Forecast Reported in various global media outlets – AP, Washington Post,
Chicago Tribune, NYT, Nation-Kenya etc
Warning presented at RVF Federal Agency Workshop in Ft. Collins,
Colorado, early December
USAMRU-K/GEIS-Kenya Entomology Team mobilized resource and
personnel for field deployment – mosquito collections and analysis.
FAO Alert issued
November 2006
Sudan NDVI Anomalies, RVF Potential :
August 2007
Southern Africa & Madagascar Forecast
& Outbreak 2007 - 2008
RVF Potential : October, December 2007
Summary
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The fall-winter development of El Niño
conditions in 2006, extending into 2007 and
2008 had significant implications for global
public health
Extremes in climate events with above
normal rainfall and flooding in some regions
and drought periods in other regions
occurred
Forecasting disease is critical for timely and
efficient planning of operational control
programs
Understanding the ecology of vector-borne
disease permits better assessment of risk:
give decision makers additional tools to
make rational judgments concerning
disease prevention and mitigation strategies
3. RVF Threat to U.S.
RVFV Control – Priority Vectors
RVFV Vector Competence
Transovarial
Transmission
Aedes vexans
Yes
Unknown
Aedes taeniorhynchus
Yes
Unknown
Aedes sollicitans
Yes
Unknown
Aedes Canadensis
Yes*
Unknown
Aedes excrucians
Yes*
Unknown
Aedes triseriatus
Yes*
Unknown
Aedes albopictus
Yes*
Unknown
No
Unknown
Culex salinarius
Yes*
Unknown
Culex tarsalis
Yes
Unknown
Culex territans
Yes*
Unknown
Culex pipiens
Unknown**
Unknown
Culex quinquefasciatus
Unknown**
Unknown
Psorophora columbiae
Unknown
Unknown
Anopheles species
*Probably of lower importance
**Varies from inefficient to efficient for various African and European strains. Little to
no data on North American strains.
Approach to RVF Testing
in Animals in US
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Develop an awareness for breeders,
veterinarian, and foreign animal disease
diagnosticians
Piggy backing on existing surveillance systems
like those in California, Florida, and other states
Establish parameters to trigger a RVF test
» Abortion storm
» Favorable climate for mosquito vectors
» Fetus with necrotic liver
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Integrate RVF in existing battery of tests in
regional labs and distribute testing supplies and
reagents
IgM is less expensive than RT-PCR
IgM detected 10 days after infection
Programs to Support Rapid
RVF Detection
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Disease modeling and syndromic surveillance
Electronic reporting system for animal abortions
Definitive diagnosis of livestock abortions
Sentinel animals or multiplex vector
surveillance near ports of entry or international
airports
Goal of programs is to restrict an RVF event to
an controlled area
Immediacy of detection and effective vector
control may be best measures to mitigate
spread
Wildlife Issues
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RVF has a broad host profile, including
North American species
Little is know about role that wildlife
could play as a reservoir of virus
Can infect ticks (Hyalomma;
Rhipichepalus, Ixodes species ?)
Domestic Culex mosquitoes are good
vectors
Ochlerotatus possible T/O transmission
RVF isolated from Culicoides and sand
flies
Human vs. Animal Vaccines
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Vaccines are a key disease control issue
Efficacy primary concern for animal vaccine
Safety primary concern for human vaccine
Vaccine strategy must be integrated into
disease control and eradication programs
Private sector and research community needs
to energized to deliver vaccines
Wildlife vaccines need to be considered for
disease eradication program
» Novel food delivery system may be required
Rift Valley Fever – Human
Vaccines
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Inactivated (non licensed)
» formalin inactivated vaccine prepared by U.S. Army Medical
Research Institute for Infectious Diseases (USAMRIID)
» Requires 3 immunizations over a 28 day period
» Limited supply and is not licensed or commercially
available.
» Used experimentally to protect veterinary and laboratory
personnel at high risk of exposure to RVF.
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Modified-live (experimental)
» Live, attenuated strain (MP-12) derived from virulent isolate
(ZH-548) through serial passages in mice and tissue culture
» Large body of published and unpublished data obtained
from sheep, lambs, pregnant ewes, cattle, pregnant cattle
and fetal bovids, rhesus monkeys and human phase I
(open IND)
» Safe (no reversion to virulence), immunogenic (induces
serum neutralizing antibodies) and efficacious (various
ruminants)
» Starting point for 2nd generation ML vaccine candidates
using reverse genetic technology
Desired Vaccine Profile
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Highly efficacious: prevents virus amplification
in target host; efficacy in all target ruminant
species; efficacious in young animals; one
dose; quick onset of immunity; > one year
duration of immunity
Safe vaccine: no reversion to virulence; nonabortigenic; all species; pure vaccine; no vector
transmission
DIVA compatible
Manufacturing method yields high number of
doses
No maternal antibody interference
Mass vaccination compatible
Rapid speed of production and scale-up
Reasonable cost
Short withdrawal period for food consumption
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Rift Valley Fever – Veterinary
Vaccines
Inactivated
» Licensed formalin inactivated alum adjuvanted vaccine
(Onderstepoort Biological Products, S. Africa) based on
S. African ruminant isolate from 1953
» Modestly immunogenic, relatively slow onset to
protection, and requires booster
» Non-licensed, formalin inactivated adjvunted vaccined
(Egypt Veterinary Serum and Vaccine Research
Institute) based on human isolate (ZHB01)
» Ongoing production problems, including presence of
residual virus
Rift Valley Fever – Veterinary
Vaccines
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Modified-live
1. Licensed live, attenuated neurotropic strain
(Smithburn, SNS)(Onderstepoort Biological
Products, S. Africa)
– Rapid onset of protection with 1 dose and >1 year
duration of immunity
– Safety issues, including abortagenic in pregnant
animals and reversion to virulence concerns
Rift Valley Fever – Veterinary
Vaccines
2. Experimental live, attenuated strain (MP-12)
– Uniformly safe and effective in sheep and cattle in controlled
studies in the U.S.
– No reversion demonstrated in new born lambs
– Possibly lower immunogenicity in field tests in Africa (serology
done with ELISA and IFA)
– One South African study claimed fetal abnormalities in ewes;
none seen in U.S., U.K., or another African study
– Safe for humans manufacturing or administering (select agent
exempt)
– USDA ARS and DHS S&T currently funding studies to further
define product profile –efficacy in young ruminants, vector
transmission
Rift Valley Fever – Veterinary
Vaccines
3. Experimental live, attenuated strain (Clone
13)
– In late development in S. Africa (Onderstepoort Biological
Products)
– USDA ARS and DHS S&T engaged in discussions to
assist in importation license and to further define product
profile – efficacy in young ruminants, vector transmission
4. Live NSs gene-deleted reverse genetic platform
– Bird et. al. Journal of Virology, Mar. 2008, p. 2681–2691
5. Poxvirus vectors
– Vaccinia G1/G2 induces N antibody and protects mice and
sheep
6. Alphavirus replicons
– VEE replicon induces antibodies in mice
OIE Standards for RVF
Four years after RVF activity
required to resume trade
 Minimum 6 months without virus
 Extensive documentation required
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Economic Impact Due to
Trade Restrictions
Trade restrictions – documentation
 Kenya 1997, 2007 – stopped
livestock trade
 US 2003 – END resulted in Trade
Restrictions
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Epidemiology Considerations
in U.S.
Zoonotic agent
 Wide variety of mammals (deer,
rodents, birds?)
 Mosquito species
 Vertical transmission in mosquito
 Few US Veterinarians have
experience with controlling vectorborne disease
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Vector-Control - Vaccine
Strategies
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Vaccine protect immunized cattle and
reduce number of amplifying hosts
such as humans
» Can be risky during an outbreak due to
contaminated needles
Vector control in US is strong but focal
 Repellent spraying of livestock?
 Efficacy of adulticide control?
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Potential Mechanisms of RVF
introduction into the US
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International travel by people
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many people travel back and forth between US and RVF endemic countries
many FNs travel from endemic countries to the US
travelers/visitors on commercial flights from RVF endemic areas can reach
virtually any US city in 36hrs (shorter than the incubation period of RVF)
Immigrants - many people immigrate to the US from RVF endemic areas
Returning US military forces previously deployed in RVF endemic areas
By Mosquitoes
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on an airplane where there is a direct flight between endemic region and the US
– not common but can happen – also by military flights
maritime containers/ships
increased where you have plants-water with rodents
–
–
may take weeks but you have life cycle going on including virus transmission
there are maritime container ports near JKI - Kenya
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Example:
containers are sealed and may contain mosquitoes
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in a day or two the container is put on a truck driven to Mombasa
put on a ship
ship could go to multiple US ports
e.g.. New Orleans, may be open there or remain closed and be transported to thousands
of inland ports via truck rail or ship and open virtually at any city in the US.
Potential Mechanisms of RVF
introduction into the US (continued)
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Movement of infected animals into the US
» Rare from Africa but could enter easily via Mexico
Intentional introduction
» somebody in EA knows an outbreak is going on,
» Does not have to be sophisticated
» Could bring infected animal tissue
» If more sophisticated could bring the virus in container
» Infect domestic animal by inoculation
4. RVF Interagency Group
Objectives:
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Develop plans for local, national and international organizations to
participate in the prevention and control of arthropod-borne animal
and human emerging disease
Utilize international disease surveillance efforts and forecasting
models to identify potential threats to the U.S.
Implement focused and timely disease control prevention strategies
before an outbreak
Develop Geographic Information System (GIS) - based remotely
sensed early warning system to identify spatial and temporal
distribution of potential mosquito vectors in the U.S.
Develop data on distribution of vertebrate hosts in U.S.
Distribution of vector and vertebrate host forecast information can be
disseminated to U.S. health and agriculture agencies
Implement plans, several months before conditions are suitable for
elevated vector populations, permitting targeted implementation of
vector control, animal quarantine and vaccine strategies in time to
lessen or prevent animal and human disease
Develop plans to aggressively respond to disease outbreaks
Conclusions
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Threat from globalization of various arboviruses, like RVF, is
real and ever present danger
Surveillance and control preparations are critical
Research on disease ecology, vector biology and control,
genetics, vaccines, etc to is essential to react quickly and
effectively control disease and limit spread
Vector control, quarantine and vaccine containment
stategies must continually be developed and tested
Enhanced preparation will reduce human and animal health
risk, and limit economic losses
Much more research, operational preparation, and agency
coordination is needed to either prevent or contain vectorborne diseases
Contributors
Kenneth J. Linthicum and Seth Britch, USDA-ARS, Center for Medical, Agricultural &
Veterinary Entomology, Agricultural Research Service, United States Department of
Agriculture, Gainesville, Florida.
Cyril G. Gay, National Program Leader, Animal Health, Office of National Programs,
Animal Production and Protection, USDA-ARS, Beltsville, MD
William Wilson, Kristine Bennett, Arthropod Borne Animal Research Laboratory,
Laramie, Wyoming, L
Assaf Anyamba, Jennifer Small & Compton J. Tucker, NASA/Goddard Space Flight
Center, Biospheric Sciences Branch, Code 614.4, GIMMS Group, Greenbelt,
Maryland.
Jean-Paul Chretien, Clair Witt - Department of Defense, Global emerging Infections
System, Division of Preventive Medicine, Walter Reed Army Institute of Research,
Washington, DC.
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Collaborators
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Pierre Formenty, World Health Organization – Pandemic Alert and Response
Department, Geneva
Stephane DeLaRocque, Food and Agricultural Organization (FAO), Rome.