Presentation on theme: "Rift Valley Fever (RVF) Overview and Recent Developments at USDA"— Presentation transcript:
1 Rift Valley Fever (RVF) Overview and Recent Developments at USDA Kenneth J. LinthicumCenter DirectorCenter for MedicalAgricultural andVeterinary EntomologyUSDA-ARSGainesville, FloridaRift Valley Fever (RVF)Overview and Recent Developments at USDAAbstract:Global climate greatly influences local conditions that can affect hemorrhagic disease patterns because the viruses, their vectors, and hosts are sensitive to temperature moisture, and other ambient environmental conditions. In this presentation we examine in detail linkages between climate, ecosystems and elevated transmission of Rift Valley fever, dengue, and Ebola viruses. During periods of elevated transmission there is a significantly increased risk of globalization of these and other hemorrhagic viruses.The ability to predict periods of high risk might permit us to design better containment or exclusion strategies to limit globalization.Global climate greatly influences local conditions that can affect hemorrhagic disease patterns because the viruses, their vectors, and hosts are sensitive to temperature moisture, and other ambient environmental conditions. In this presentation we examine in detail linkages between climate, ecosystems and elevated transmission of Rift Valley fever, dengue, and Ebola viruses. During periods of elevated transmission there is a significantly increased risk Globalization of viral hemorrhagic fevers: Importance of identifying linkages between virus, ecosystems and climate” of globalization of these and other hemorrhagic viruses.The ability to predict periods of high risk might permit Globalization of viral hemorrhagic fevers: Importance of identifying linkages between virus, ecosystems and climate”us to design better containment or exclusion strategies to limit globalization.
2 Contributors Collaborators 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, MDWilliam Wilson, Kristine Bennett, Arthropod Borne Animal Research Laboratory, Laramie, Wyoming, LAssaf 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.CollaboratorsPierre Formenty, World Health Organization – Pandemic Alert and Response Department, GenevaStephane DeLaRocque, Food and Agricultural Organization (FAO), Rome.
3 Overview of Rift Valley fever (RVF) Topics RVF Ecology/Epidemiology in Africa and Arabian PeninsulaPrediction of Recent RVF Outbreaks in AfricaRVF Threat to U.S.RVF Interagency Working Group
4 1. RVF Ecology/Epidemiology Disease caused by virus in Family Bunyaviridae, Genus PhebovirusFirst described in Kenya 1931 after epizootic in sheep on a farm north of Lake NaivashaViral Zoonosis that affects livestock and humans in Africaaffects primarily domestic livestockhorses, 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 complicationsTreatment – None, experimental use of antiviral ribavirinNo U.S. licensed animal or human vaccineMortality – 1-25% in humans, % in livestockLakeNaivasha,Kenya
5 Rift Valley Fever – Geographic Distribution Countries with endemic RVF diseaseCountries with isolated outbreaks or serological evidence
6 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
7 Clinical RVF in Cattle Feature Characteristics Incubation period 1-6 daysClinical signsCalves: —Fever of 40°-42°C (104°-106°F) —Depression —Icterus —Anorexia and weakness —Listlessness —Evident abdominal painAdults: —Fever of 40°-42°C (104°-106°F) —Excessive salivation —Anorexia —Weakness —near 100% abortion, Fetid diarrhea —Fall in milk yield —Nasal dischargeCase-fatality rate—Calves: 10%-70% —Adults: <10% in indigenous breeds
8 Clinical features in Sheep and Goats CharacteristicsIncubation periodLambs: hrAdults: 1-6 daysClinical signsLambs: —Fever of 40°-42°C (104°-107°F) —Anorexia and weakness —Listlessness —Evident abdominal painAdults: —Fever of 40°-41°C (104°-106°F) —Mucopurulent nasal discharge —Vomiting —Anorexia —Listlessness —Diarrhea —IcterusComplications—Abortion rates can reach 100% (aborted fetus often autolysed) —Peracute hepatic disease in lambs and kids <1 wk of age —Hepatitis —Cerebral infections —Ocular infectionsCase-fatality rateLambs —<1 wk of age: as high as 100% —>1 wk of age: as high as 20% Adults: 20%-30%
9 Clinical Features in Humans CharacteristicFeaturesIncubation period2-6 daysProdromeFever, headache, photophobia, retro-orbital painClinical 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 laboratory-confirmed 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%
10 Clinical Features in Humans (Cont) CharacteristicFeaturesLaboratory 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 bilirubinComplications—Blindness following retinitis —Neurologic sequelae following encephalitis
11 Clinical Features in Humans (Cont) CharacteristicFeaturesCase-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 DICAbbreviations: AST: aspartate aminotransferase; ALT, alanine aminotransferase; DIC, disseminated intravascular coagulation.
12 Environmental Sensitivity of RVF Acid sensitiveShortly after slaughter virus is killedpH < 6.2 are effective disinfectantsPasteurization of milk kills the virus
13 Diagnostic Techniques and Test Selection Acute Phase with ELISA, immunohistochemistry, RT-PCRSurveillance with ELISA to detect IgM/IgGAppropriate test depends on phase of infectionID of antigen in viremic phasePost viremic phase antibodies increase, detection by IgMOther Diagnotics TechnologiesMolecular diagnosisNon-nested PCR works with high viremiasNested amplimers can yield sequence data for phylogenetic analyses
14 Summary Patterns 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 viremiaViremia 3-10 days in humansViremia 2-5 days in cattleAmplitude of Viremia High (>108 PFU/ml))Long lasting immune responseLifelong IgG and neutralization antibodies in humans
15 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 AfricaRVF EpizooticsRainfall x Rainy Days19501961197719821968
16 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 landsNDVI data can therefore be used as a multi-purpose indicator of conditions associated with vector-borne disease outbreaks – in support of disease surveillance activities
17 RVF Life Cycle Climatic factors (heavy rainfall associated with ENSO) Dry SeasonRainAedes mcintoshi infectedwith RVF virus transovariallyFloodwater Aedes & Culex mosquitoes+ direct transmission (aerosol, contact)Deposit RVFInfected EggsEpidemic CycleFlooding results in masshatching of infected Aedeseggs and subsequent Culexmosquitoes leading toRVF outbreakEndemic CycleVirus persists during dryseason/inter-epizootic period through vertical transmission in Aedes mosquito eggsRainRainy SeasonCulex species - importantsecondary vectors of RVFAnopheles mosquitoes notinvolved RVF transmission
18 2. Prediction of Recent RVF Outbreaks in Africa Vector-borne Disease Climate LinkBuilding 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)
19 Operational Application: 1997-1998 Rift Valley fever Outbreak Convergence of Pacific El Nino event and WIO WarmingWide spread, persistent and rainfall in semi arid landsFlooded dambos – hatching of infected mosquito eggs, supports several generations of mosquito populationsVegetation green-up – micro-ecological habitats conducive to mosquito survival and propagationFirst human cases identified late December 1997, declared Epizootic late January 1998Impact on Livestock Trade: Ban on livestock imports from GHA – loss of income ~ $ 100 million in 1998Reported losses of ~70% sheep and goats and 20%-30% ~ cattle and camelsestimated 89,000 humans in this region could have been infected (North Eastern Kenya and central Somalia)
20 Largest RVF Outbreak in last 30 years occurred over a largegeographicMillions of cattle,sheep, and goats100,000 human casesNumber of flagged pixels inEast Africa exceeded20,000 (1,280,000 Km2)
22 September 2006 ActionsWarning issued in Emerging Disease paper presented at Society of Vector Ecology Plenary Session, Anchorage, AlaskaIssued First Alert Mid-OctoberWrote GEIS Advisory distributed to DoD Overseas Laboratory Network – Global Elevated Risk of Outbreaks of Vector-borne diseasesAdvisory submitted to International Journal of Health Geographics
23 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 2006Published on FAO Emergency Prevention System (EMPRES) for Transboundary Animal and Plant Pests and Diseases EMPRES WATCH website: Possible RVF activity in the Horn of AfricaInformation transmitted to country and regional officesForecast Reported in various global media outlets – AP, Washington Post, Chicago Tribune, NYT, Nation-Kenya etcWarning presented at RVF Federal Agency Workshop in Ft. Collins, Colorado, early DecemberUSAMRU-K/GEIS-Kenya Entomology Team mobilized resource and personnel for field deployment – mosquito collections and analysis.
28 SummaryThe fall-winter development of El Niño conditions in 2006, extending into 2007 and 2008 had significant implications for global public healthExtremes in climate events with above normal rainfall and flooding in some regions and drought periods in other regions occurredForecasting disease is critical for timely and efficient planning of operational control programsUnderstanding 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
30 RVFV Vector Competence Transovarial Transmission RVFV Control – Priority VectorsRVFV Vector CompetenceTransovarial TransmissionAedes vexansYesUnknownAedes taeniorhynchusAedes sollicitansAedes CanadensisYes*Aedes excruciansAedes triseriatusAedes albopictusAnopheles speciesNoCulex salinariusCulex tarsalisCulex territansCulex pipiensUnknown**Culex quinquefasciatusPsorophora columbiae*Probably of lower importance**Varies from inefficient to efficient for various African and European strains. Little to no data on North American strains.
31 Approach to RVF Testing in Animals in US Develop an awareness for breeders, veterinarian, and foreign animal disease diagnosticiansPiggy backing on existing surveillance systems like those in California, Florida, and other statesEstablish parameters to trigger a RVF testAbortion stormFavorable climate for mosquito vectorsFetus with necrotic liverIntegrate RVF in existing battery of tests in regional labs and distribute testing supplies and reagentsIgM is less expensive than RT-PCRIgM detected 10 days after infection
32 Programs to Support Rapid RVF Detection Disease modeling and syndromic surveillanceElectronic reporting system for animal abortionsDefinitive diagnosis of livestock abortionsSentinel animals or multiplex vector surveillance near ports of entry or international airportsGoal of programs is to restrict an RVF event to an controlled areaImmediacy of detection and effective vector control may be best measures to mitigate spread
33 Wildlife IssuesRVF has a broad host profile, including North American speciesLittle is know about role that wildlife could play as a reservoir of virusCan infect ticks (Hyalomma; Rhipichepalus, Ixodes species ?)Domestic Culex mosquitoes are good vectorsOchlerotatus possible T/O transmissionRVF isolated from Culicoides and sand flies
34 Human vs. Animal Vaccines Vaccines are a key disease control issueEfficacy primary concern for animal vaccineSafety primary concern for human vaccineVaccine strategy must be integrated into disease control and eradication programsPrivate sector and research community needs to energized to deliver vaccinesWildlife vaccines need to be considered for disease eradication programNovel food delivery system may be required
35 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 periodLimited 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 cultureLarge 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
36 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; > one year duration of immunitySafe vaccine: no reversion to virulence; non-abortigenic; all species; pure vaccine; no vector transmissionDIVA compatibleManufacturing method yields high number of dosesNo maternal antibody interferenceMass vaccination compatibleRapid speed of production and scale-upReasonable costShort withdrawal period for food consumptionDesired Vaccine Profile
37 Rift Valley Fever – Veterinary Vaccines InactivatedLicensed formalin inactivated alum adjuvanted vaccine (Onderstepoort Biological Products, S. Africa) based on S. African ruminant isolate from 1953Modestly immunogenic, relatively slow onset to protection, and requires boosterNon-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
38 Rift Valley Fever – Veterinary Vaccines Modified-liveLicensed live, attenuated neurotropic strain (Smithburn, SNS)(Onderstepoort Biological Products, S. Africa)Rapid onset of protection with 1 dose and >1 year duration of immunitySafety issues, including abortagenic in pregnant animals and reversion to virulence concerns
39 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 lambsPossibly 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 studySafe 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
40 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 transmission4. Live NSs gene-deleted reverse genetic platformBird et. al. Journal of Virology, Mar. 2008, p. 2681–26915. Poxvirus vectorsVaccinia G1/G2 induces N antibody and protects mice and sheep6. Alphavirus repliconsVEE replicon induces antibodies in mice
41 OIE Standards for RVFFour years after RVF activity required to resume tradeMinimum 6 months without virusExtensive documentation required
42 Economic Impact Due to Trade Restrictions Trade restrictions – documentationKenya 1997, 2007 – stopped livestock tradeUS 2003 – END resulted in Trade Restrictions
43 Epidemiology Considerations in U.S. Zoonotic agentWide variety of mammals (deer, rodents, birds?)Mosquito speciesVertical transmission in mosquitoFew US Veterinarians have experience with controlling vector-borne disease
44 Vector-Control - Vaccine Strategies Vaccine protect immunized cattle and reduce number of amplifying hosts such as humansCan be risky during an outbreak due to contaminated needlesVector control in US is strong but focalRepellent spraying of livestock?Efficacy of adulticide control?
45 Potential Mechanisms of RVF introduction into the US International travel by peoplemany people travel back and forth between US and RVF endemic countriesmany FNs travel from endemic countries to the UStravelers/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 areasReturning US military forces previously deployed in RVF endemic areasBy Mosquitoeson an airplane where there is a direct flight between endemic region and the US – not common but can happen – also by military flightsmaritime containers/shipsincreased where you have plants-water with rodentsmay take weeks but you have life cycle going on including virus transmissionthere are maritime container ports near JKI - KenyaExample:containers are sealed and may contain mosquitoesin a day or two the container is put on a truck driven to Mombasaput on a shipship could go to multiple US portse.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.
48 Potential Mechanisms of RVF introduction into the US (continued) Movement of infected animals into the USRare from Africa but could enter easily via MexicoIntentional introductionsomebody in EA knows an outbreak is going on,Does not have to be sophisticatedCould bring infected animal tissueIf more sophisticated could bring the virus in containerInfect domestic animal by inoculation
49 4. RVF Interagency Group Objectives: Develop plans for local, national and international organizations to participate in the prevention and control of arthropod-borne animal and human emerging diseaseUtilize 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 outbreakDevelop 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 agenciesImplement 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 diseaseDevelop plans to aggressively respond to disease outbreaks
50 ConclusionsThreat from globalization of various arboviruses, like RVF, is real and ever present dangerSurveillance and control preparations are criticalResearch on disease ecology, vector biology and control, genetics, vaccines, etc to is essential to react quickly and effectively control disease and limit spreadVector control, quarantine and vaccine containment stategies must continually be developed and testedEnhanced preparation will reduce human and animal health risk, and limit economic lossesMuch more research, operational preparation, and agency coordination is needed to either prevent or contain vector-borne diseases
51 Contributors Collaborators 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, MDWilliam Wilson, Kristine Bennett, Arthropod Borne Animal Research Laboratory, Laramie, Wyoming, LAssaf 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.CollaboratorsPierre Formenty, World Health Organization – Pandemic Alert and Response Department, GenevaStephane DeLaRocque, Food and Agricultural Organization (FAO), Rome.