The Threats of Rift Valley Fever and Chikungunya

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The Threats of Rift Valley Fever and Chikungunya

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1. The Threats of Rift Valley Fever and Chikungunya Mark T. Heise The Dept. of Genetic The Carolina Vaccine Institute The University of North Carolina

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3. Rift Valley fever virus Floodwater Aedes sp The Basics Family:Bunyaviridae, genus: Plebovirus Zoonotic pathogen Humans Hemorrhagic fever Encephaltis Retinitis Livestock Transmission/Maintenance Mosquito Known Vectors Floodwater Aedes Sp. Vertical Transmission Culex (Amplified virus) Potential Vectors North American mosquitoes Sand flies Mucosal

4. RVFV Disease Livestock Disease Abortion storms (sheep, cattle, goats). High mortality in young animals High Priority Pathogen for USDA Human Disease Flu like symptoms (majority of cases) Hemorrhagic or encephalitic forms (1%) Hemorrhagic form has hepatic involvement 20-30% case fatality rate in recent outbreaks Retinitis

6. Potential Impact of RVFV in U.S. Livestock industry Direct Loss due to virus induced disease Loss of Export Market Outbreak would cause OIE imposed ban on exports for at least 6 months, and up to 4 years if RVFV is considered endemic. $7.3 billion in beef exports in 2003 Paralysis of Transportation System Human Disease Livestock handlers most at risk Vector borne exposure Mucosal transmission from infected animals Healthcare workers (diagnostic laboratories) General public (Limited direct risk, Panic)

7. Is RVFV a Threat to the United States? Significant Emerging Pathogen OIE List A pathogen USDA/CDC overlap agent #3 agent on Animal Biological Threat Agents and Research Priority list. Several means of potential introduction Intentional Accidental Importation of infected mosquitoes Importation of infected livestock/materials Vector Competence? Multiple mosquito species can transmit experimentally North American Culex and Aedes Species Maintenance and Spread Livestock industry Potential for vertical transmission Susceptibility of North American Wildlife?

8. RVFV: Ongoing Questions/Needs? Surveillance United States (Limited resources for animal testing in U.S.) Worldwide Therapeutics Ribavirin Interferon Vaccines Livestock Existing live attenuated vaccines show promise Elicit long term immunity Generally safe, though contraindicated for pregnant animals Not recommended for non-endemic areas New vaccine alternatives Humans Inactivated vaccine is effective, but requires multiple boosts Live attenuated vaccines (MP-12) Others? Biological Questions Vector potential and transmission Can U.S. Mosquito species efficiently transmit? Can U.S. Mosquito species vertically transmit virus? Susceptibility of North American Wildlife

9. Developing Improved RVFV Vaccines and Diagnostic Agents Develop improved RVFV vaccines for human and livestock use Goals: Safe vaccines that elicit long-lived RVFV immunity, with minimal boost requirements, DIVA compatible (Heise, Ross, and Burt Labs). Alphavirus Replicon-based RVFV vaccines Elicit protective immunity against peripheral and mucosal RVFV challenge in mouse models Elicit protective immunity in vaccinated sheep (Neut titers of 1:32-1:64) DNA vaccines with RVFV Gn protein linked to C3d molecular adjuvant Elicit RVFV specific antibody responses in immunized mice Can be modified for livestock use RVFV virus like particles (VLPs) RVFV Diagnostic Assays (Doms, Burt, and Heise Labs) Goals: Develop non-virus based immunology reagents Experimental RVFV cell fusion and pseudotyping assays developed Virus free RVFV specific neutralization test developed and validated against a standard virus-based RVFV neutralization assay.

10. Summary I: RVFV Potential for significant impact on livestock industry/economy Epizootic would have significant human health impact (potentially more severe than WNV). Endemic potential in Western Hemisphere? Need for improved diagnostics, vaccines, and antivirals.

11. Chikungunya The Basics: Family:Togaviridae, genus: Alphavirus (Semliki Forest virus Complex) Human Disease Rural cycle Ae. Africanus and Ae. Furcifer maintenance with wild primates Urban cycle Ae. Aegypti Ae. Albopictus Related viruses O’nyong-nyong 1959 African epidemic >2 million cases Re-emerged in 1996 Anopheles mosquitoes Ross River virus Australian 1979 epidemic in South Pacific

12. Chikungunya Human Disease Chikungunya (Swahili): That which bends up. Severe arthritis/arthralgia/myalgia High fever (103-104 F) Rash Hemorrhagic manifestations have been reported Severe incapacitating arthritis/arthralgia. Generalized Usually acute (Several days to several weeks, though 20% of individuals have long-term joint complaints) Rarely if ever fatal Apparent-to-inapparent infection ratio varies from 1:3 to 1:50 for CHIK and related viruses Reunion Island: 1:3 or population had clinically apparent disease (approximately 250,000 cases). Infected individuals develop a high titer viremia

14. Are Chikungunya or Related viruses Threats to the United States? Epidemic Chikungunya (2005-2007) Groups within Central/East African CHIK strains* Reunion Island 266,000 cases Approximately 1/3 of population Presumed vector is Aedes albopictus India 1.4 million cases Presumed vector is Aedes aegypti Emergence in new regions due to infected travelers a concern United States: 37 imported cases 2005-2006 Competent vectors present No evidence for transmission Endemic Chikungunya Congo: 2004 (re-emergence after 39 years) Malaysia: 2007 (re-emergence after 7 years) Parola et al., Emerg Infect Dis 2006 12:1393–1399. Schuffenecker, et al., PLoS Med 2006; 3:e263.

15. Threat of CHIK Introduction Sporadic outbreaks Returning Travelers Potential for localized spread Large Scale Epidemic? Risk in areas with competent mosquito vectors Possibility of endemic status? Dengue and YFV as examples

16. What do we need? Surveillance Vaccines Experimental Live attenuated vaccine Therapeutics Non-steroidal anti-inflammatory drugs Basic Biology Viral vector biology Basic pathogenesis of virus induced disease

17. Basic Biology of CHIK and Related Viruses Vector Biology Epidemic on Reunion involved Ae. Albopictus Genetic changes in virus? Other potential vectors? Pathogenesis of virus induced-arthritis Viral factors Host factors Macrophages Complement activation (RRV)

18. Summary II: Chikungunya Potential for large scale epidemics with significant human morbidity Experience with other viruses that use similar mosquito vectors suggests that large scale outbreaks in U.S. may not occur Need for improved therapeutics and vaccines

19. References RVFV Chikungunya

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