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

1. 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

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

3. 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

4. 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

5. Rift Valley Fever – Geographic Distribution Countries with endemic RVF disease Countries 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

8. Clinical features in Sheep and Goats

9. Clinical Features in Humans

10. Clinical Features in Humans (Cont)

11. Clinical Features in Humans (Cont)

12. Environmental Sensitivity of RVF • Acid sensitive • Shortly after slaughter virus is killed • pH < 6.2 are effective disinfectants • Pasteurization of milk kills the virus

13. 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

14. 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 (>108 PFU/ml)) • Long lasting immune response • Lifelong 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 Africa RVF Epizootics Rainfall x Rainy Days 1950 1961 1977 1982 1968

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 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

17. RVF Life Cycle Climatic factors (heavy rainfall associated with ENSO) Dry Season Rain Aedesmcintoshi 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

18. 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)

19. 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)

20. 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)

21. Seasonal Summary: SST, OLR SON 2006

22. 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

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 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.

24. FAO Alert issued November 2006

25. Sudan NDVI Anomalies, RVF Potential : August 2007

26. Southern Africa & Madagascar Forecast & Outbreak 2007 - 2008

27. RVF Potential : October, December 2007

28. 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

29. 3. RVF Threat to U.S.

31. 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

32. 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

33. 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

34. 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

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 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

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 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

37. 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

38. 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 >1 year duration of immunity • Safety 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 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

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 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

41. OIE Standards for RVF • Four years after RVF activity required to resume trade • Minimum 6 months without virus • Extensive documentation required

42. Economic Impact Due to Trade Restrictions • Trade restrictions – documentation • Kenya 1997, 2007 – stopped livestock trade • US 2003 – END resulted in Trade Restrictions

43. 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

44. 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?

45. 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.

48. 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

49. 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

50. 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