Epidemiology and Disease Burden of Infections with Encephalitic Flaviviruses John T. Roehrig, Ph.D. Arboviral Diseases Branch Division of Vector-Borne Diseases CDC, USA Viruses in the Genus Flavivirus (Family Flaviviridae) Tick-borne viruses Mammalian tick-borne virus group (TBE, POW) Seabird tick-borne virus group Mosquito-borne viruses Aroa virus group Dengue virus group Japanese encephalitis virus group Kokobera virus group Ntaya virus group Spondweni virus group Yellow fever virus group Viruses with no known arthropod vector Entebbe bat virus group Modoc virus group Rio Bravo virus group Tentative Species in Genus Tanama bat virus Cell fusing agent Kamiti River virus Culex flavivirus Serocomplexes of Flaviviruses 1. Tick-borne encephalitis – TBE (Eu, FE, Sib), POW, KFD, OHF 2. Rio Bravo – MOD 3. Japanese encephalitis – JE, SLE, MVE, WN(KUN) 4. Spondweni – ZIK 5. Ntaya – ITM 6. Banzi – EHV 7. Dengue – 1, 2, 3, 4 8. Yellow fever, Rocio, Ilheus, Bussuquara, Sepik, Wesselsbron Flaviviral Encephalitides: General Clinical Description • Asymptomatic or mild flu-like illness • Fever, lymphadenopathy, headache, abdominal pain, vomiting, rash, conjunctivitis • Incubation period usually 5 to 15 days • CNS involvement and death in minority of cases – sequellae can occur • No specific treatment Prevention and Control of Flaviviral Infections • Vector control – source reduction, larvaciding, adulticiding • Exposure control – avoid mosquito and tick bites, repellents • Vaccination – JEV and TBEV TBEV: Background and Epidemiology • First isolated in Russia, 1937 • Commonly found in humans and mammals in Europe, Asia, and North America (Powassan) • Tick (Ixodes)-mammal-tick-human transmission cycle • Can also be transmitted directly by consuming TBEV contaminated food products, e.g., milk, and by aerosol • Biphasic disease (Western TBE); sequellae can occur (Eastern TBE) paralysis including chronic progressive disease • CF ratio = 1-2% for Western TBE; 20-30% for Eastern TBE • 1990-2009 case load: 1000-4000 cases per year in Europe and 6000-13,000 per year in Russia Distribution and Phylogeny of TBEV LaSala and Holbrook, Clin. Lab. Med. 30: 221, 2010 Human TBE Cases in Europe and Russia, 1990-2006 Europe Russia Case Number Case 1990 1 2 3 4 5 6 7 8 9 2000 1 2 3 4 5 6 Lehrer and Holbrook, Tick-Borne Encephalitis, in Vaccine Year for Biodefense and Emerging Infectious Diseases, p. 713, 2009. TBEV Vaccines Type of Vaccine Organ or cells Virus Strain Countries Inactivated Chick embryo Neudorfl (W) Aus, Ger, Swi, fibroblast (CEF) Hun, CRep, UK, cells Canada, Baltics K-23 (W) Aus, Ger, Swi, CRep, Russia, Baltics 205 (E) Russia Sofjin (E) Russia Lehrer and Holbrook, Tick-Borne Encephalitis, in Vaccine for Biodefense and Emerging Infectious Diseases, p. 713, 2009. JEV: Background and Epidemiology • First isolated in Japan, 1934 • Commonly found in humans and birds and other vertebrates in India, SE Asia, China, Japan, Korea, and the islands of the Western Pacific • Mosquito (Culex)-bird (pig)–mosquito-human transmission cycle • 1-3/1000 develop clinical illness (most severe in children) • CFR = 20-30%; 30-50% of recoveries have significant sequellae • Approximately 20,000 cases/yr with 6,000 deaths Expanding Distribution of Japanese Encephalitis,1978- 2010 Nepa l Pakistan Phillipine India s Saipan Sri Lanka Papua New Guinea Australia Distribution and Phylogeny of JEV Solomon, J. Neourovirology 9:274, 2003 Yun et al., Virology J. 7:127, 2010 WPRO and SEARO Total Reported JE Cases, 1991-2000 35000 30000 25000 20000 15000 10000 5000 0 cases cases cases cases cases cases cases cases cases cases deaths deaths deaths deaths deaths deaths deaths deaths deaths deaths 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 SEARO WPRO Total Courtesy of P. Namgyal, IVR, WHO Data, WHO JEV Vaccines Type of Vaccine Organ or cells Virus Strain Countries Inactivated Mouse brain Beijing-1 Japan, Thailand Nakayama Japan, Taiwan, Vietnam, India Primary hamster P3 China kidney (PHK) cells Vero cells P3 China SA-14-14-2 Austria, USA- (Ixiaro) Beijing 1 Japan Live attenuated PHK cells SA14-14-2 China Vero cells SA14-14-2* USA Vero cells YF/SA14-14-2* France (IMOJEV) * In development Kurane, Japanese Encephalitis, in Vaccine for Biodefense and Emerging Infectious Diseases, p. 527, 2009. West Nile Virus in the Western Hemisphere West Nile Virus: Background and Epidemiology • First isolated in West Nile district, Uganda, 1937 • Commonly found in humans, birds, and other vertebrates in Africa, Eastern Europe, West Asia, and the Middle East, but has not previously been documented in the Western Hemisphere • Mosquito (Culex)-bird-mosquito-human (horse) transmission cycle • Transmitted by blood and tissue • 20 % of cases are symptomatic; sequellae can occur • 1% of clinical cases are neuroinvasive (NI); CFR for NI WNV = 10% • 1999-2010 in the U.S. >30,000 cases; exposure rate=2.5% West Nile Outbreaks • Israel - 1951-1954, 1957, 1997-2003 • Egypt – 1950s • France – 1962, 2000 • South Africa – 1974 • North Africa – 1994-96 • Romania – 1996 • Italy 1998 • Russia - 1999 • United States –1999-2010 Epidemic/Epizootic West Nile Virus 1937 1950-75 1994 - 1999 Adapted from Gubler, 2007 U.S. WNV human, veterinary, bird and mosquito (Cases by year) Number ofcases Number Year Phylogeny of North American WNV Bertolotti et al., Virology 360: 143, 2007 Distribution and Phylogeny of WNV KUNV 1 West Nile Viruses (60 viruses) 5 India 1980 human Nigeria 1965-70 Wengler 2 Uganda 1937 human B956 Rabensburg 1997 3 Volgograd 2005 Uranotaenia 4 Caucasus 1988 dermacentor Courtesy of R. Lanciotti, DVBD, CDC 200 WNV Vaccines • Horses (approved) • Humans (in development) – TC killed vaccine – WNV/YF ChimeriVax – Avipoxvirus – DNA – DNA - Birds – Subunit (E protein) SLEV: Background and Epidemiology • First isolated in the United States, 1933 • Found in North, Central, and South America • Mosquito (Culex)-bird-mosquito-human transmission cycle • CFR = 5-30%; greatest in elderly • Approximately 80 cases/yr; 4,232 cases in U.S. (1964-2008) Distribution and Phylogeny of SLEV E protein VI IV VII VA VB III IIG SLEV IIA IIC IID MVEV 1951 IIB IB IA May et al., J. Gen. Virol. 89: 1901, 2008 SLEV Neuroinvasive Disease U.S. Cases Reported by State, 1964-2008 CDC Website – www.cdc.gov Conclusions • Five medically important encephalitic flaviviruses: TBEV, JEV, WNV, SLEV, and MVEV • World-wide distribution • Zoonoses: mammal and bird vertebrate reservoirs • Transmitted to humans by the bite of infected ticks or mosquitoes • Disease ranges from inapparent infection to frank encephalitis and death • Approved human vaccines only for TBEV and JEV • No known treatment.