Kenneth J' Linthicum

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• Kenneth J. Linthicum
• Center Director
• Center for Medical
• Agricultural and
• Veterinary Entomology
• USDA-ARS
• Gainesville, Florida

Rift Valley Fever (RVF) Overview and Recent
Developments at USDA
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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.

Collaborators

• Pierre Formenty, World Health Organization
  Pandemic Alert and Response Department, Geneva
• Stephane DeLaRocque, Food and Agricultural
  Organization (FAO), Rome.

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Overview of Rift Valley fever (RVF) Topics

• RVF Ecology/Epidemiology in Africa and Arabian
  Peninsula
• Prediction of Recent RVF Outbreaks in Africa
• RVF Threat to U.S.
• RVF Interagency Working Group

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1. RVF Ecology/Epidemiology

• Disease caused by virus in Family Bunyaviridae,
  Genus Phebovirus
• 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
  non-susceptible ?
• 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
  

Lake Naivasha, Kenya
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Rift Valley Fever Geographic Distribution
Countries with endemic RVF disease Countries
with isolated outbreaks or serological evidence
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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
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Clinical RVF in Cattle
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Clinical features in Sheep and Goats
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Clinical Features in Humans
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Clinical Features in Humans (Cont)
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Clinical Features in Humans (Cont)
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Environmental Sensitivity of RVF

• Acid sensitive
• Shortly after slaughter virus is killed
• pH lt 6.2 are effective disinfectants
• Pasteurization of milk kills the virus

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Diagnostic Techniques and Test Selection

• 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
• Other Diagnotics Technologies
• Molecular diagnosis
• Non-nested PCR works with high viremias
• Nested amplimers can yield sequence data for
  phylogenetic analyses

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SummaryPatterns of RVF Infection

• Incubation period for RVF is relatively short
  (3-5 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 (gt108 PFU/ml))
• Long lasting immune response
• Lifelong IgG and neutralization antibodies in
  humans

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• ENVIRONMENT, HABITAT CONDITIONS AND EVOLUTION
  DYNAMICS
• 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
Rainfall x Rainy Days
1950
1982
1961
1977
1968
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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

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RVF Life Cycle
Climatic factors (heavy rainfall associated with
ENSO)
Dry Season
Rain
Aedes mcintoshi infected with RVF virus
transovarially
Floodwater Aedes Culex mosquitoes direct
transmission (aerosol, contact)
Deposit RVF Infected Eggs
Epidemic Cycle Flooding results in mass hatching
of infected Aedes eggs and subsequent Culex
mosquitoes leading to RVF outbreak
Endemic Cycle 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
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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)

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Operational Application 1997-1998 RiftValley
fever Outbreak

• Convergence of Pacific El Nino event and WIO
  Warming
• Wide spread, persistent and rainfall in semi arid
  lands
• Flooded dambos hatching of infected mosquito
  eggs, supports several generations of mosquito
  populations
• 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)

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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)
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Seasonal Summary SST, OLR SON 2006
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September 2006 Actions

• 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

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November 2006 Actions

• 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
• 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.

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FAO Alert issued November 2006
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Sudan NDVI Anomalies, RVF Potential August 2007
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Southern Africa Madagascar Forecast Outbreak
2007 - 2008
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RVF Potential October, December 2007
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Summary

• 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

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3. RVF Threat to U.S.
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Approach to RVF Testing in Animals in US

• 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
• 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

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Programs to Support Rapid RVF Detection

• 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

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Wildlife Issues

• 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

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Human vs. Animal Vaccines

• 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

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Rift Valley Fever Human Vaccines

• 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.
• 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

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Desired Vaccine Profile

• Highly efficacious prevents virus amplification
  in target host efficacy in all target ruminant
  species efficacious in young animals one dose
  quick onset of immunity gt one year duration of
  immunity
• Safe vaccine no reversion to virulence
  non-abortigenic 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

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Rift Valley Fever Veterinary Vaccines

• Modified-live
• Licensed live, attenuated neurotropic strain
  (Smithburn, SNS)(Onderstepoort Biological
  Products, S. Africa)
• Rapid onset of protection with 1 dose and gt1 year
  duration of immunity
• Safety issues, including abortagenic in pregnant
  animals and reversion to virulence concerns

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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 ST currently funding studies to
  further define product profile efficacy in young
  ruminants, vector transmission

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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 ST 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.
  26812691
• 5. Poxvirus vectors
• Vaccinia G1/G2 induces N antibody and protects
  mice and sheep
• 6. Alphavirus replicons
• VEE replicon induces antibodies in mice

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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 vector-borne disease

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Vector-Control - Vaccine Strategies

• 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

• International travel by people
• 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
• 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
• Example
• containers are sealed and may contain mosquitoes
• 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.

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Potential Mechanisms of RVF introduction into the
US (continued)

• 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

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4. RVF Interagency GroupObjectives

• 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

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Conclusions

• 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 vector-borne diseases

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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.

Collaborators

• Pierre Formenty, World Health Organization
  Pandemic Alert and Response Department, Geneva
• Stephane DeLaRocque, Food and Agricultural
  Organization (FAO), Rome.