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Christian W. MandlInstitute of Virology
Medical University of Vienna, AUSTRIA
Flaviviruses – New Challenges, New Vaccines
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Family Flaviviridae
• Genus Hepacivirus• Genus Pestivirus• Genus Flavivirus (>70 members)
– Yellow fever virus– Dengue virus (types 1 - 4)– Usutu virus– Japanese encephalitis virus– West Nile virus– St. Louis encephalitis virus– Murray Valley encephalitis virus– Rocio virus– Tick-borne encephalitis virus– Louping ill virus– Powassan virus– Omsk hemorrhagic fever virus
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Family Flaviviridae
• Genus Hepacivirus• Genus Pestivirus• Genus Flavivirus (>70 members)
– Yellow fever virus– Dengue virus (types 1 - 4)– Usutu virus– Japanese encephalitis virus– West Nile virus– St. Louis encephalitis virus– Murray Valley encephalitis virus– Rocio virus– Tick-borne encephalitis virus– Louping ill virus– Powassan virus– Omsk hemorrhagic fever virus
Vector: Mosquito
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Family Flaviviridae
• Genus Hepacivirus• Genus Pestivirus• Genus Flavivirus (>70 members)
– Yellow fever virus– Dengue virus (types 1 - 4)– Usutu virus– Japanese encephalitis virus– West Nile virus– St. Louis encephalitis virus– Murray Valley encephalitis virus– Rocio virus– Tick-borne encephalitis virus– Louping ill virus– Powassan virus– Omsk hemorrhagic fever virus
Vector: Tick
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Family Flaviviridae
• Genus Hepacivirus• Genus Pestivirus• Genus Flavivirus (>70 members)
– Yellow fever virus– Dengue virus (types 1 - 4)– Usutu virus– Japanese encephalitis virus– West Nile virus– St. Louis encephalitis virus– Murray Valley encephalitis virus– Rocio virus– Tick-borne encephalitis virus– Louping ill virus– Powassan virus– Omsk hemorrhagic fever virus
Hemorrhagicfever
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Family Flaviviridae
• Genus Hepacivirus• Genus Pestivirus• Genus Flavivirus (>70 members)
– Yellow fever virus– Dengue virus (types 1 - 4)– Usutu virus– Japanese encephalitis virus– West Nile virus– St. Louis encephalitis virus– Murray Valley encephalitis virus– Rocio virus– Tick-borne encephalitis virus– Louping ill virus– Powassan virus– Omsk hemorrhagic fever virus
Neurologicaldisorders
Encephalitis
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Family Flaviviridae
• Genus Hepacivirus• Genus Pestivirus• Genus Flavivirus (>70 members)
– Yellow fever virus– Dengue virus (types 1 - 4)– Usutu virus– Japanese encephalitis virus– West Nile virus– St. Louis encephalitis virus– Murray Valley encephalitis virus– Rocio virus– Tick-borne encephalitis virus– Louping ill virus– Powassan virus– Omsk hemorrhagic fever virus
Neurologicaldisorders
Encephalitis
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Flaviviruses
Yellow feverDengue
Tick-borne encephalitisJapanese encephalitis
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Flaviviruses
Yellow feverDengue
Tick-borne encephalitisJapanese encephalitis
West Nile
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West Nile virus in the United States
1999 …
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West Nile virus in the United States
… 2001 …
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West Nile virus in the United States
… 2003 …
9,862 cases, 264 deaths
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West Nile virus in the United States
… 2005
2004 – 2006: ~ 3,000 cases, 100 deaths per year
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West Nile virus transmission cycle
USA 2003: WN virus found in• 43 mosquito
species• 234 native and
captive exotic birds
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Flaviviruses
Yellow feverDengue
Tick-borne encephalitisJapanese encephalitis
West Nile
Usutu virus
Weissenbock, Kolodziejek, Url, Lussy, Rebel-Bauder, Nowotny. Emerg Infect Dis. 2002:652
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Flaviviruses
Yellow feverDengue
Tick-borne encephalitisJapanese encephalitis
West Nile
Usutu virus
Bakonyi, Hubalek, Rudolf, Nowotny. Emerg Infect Dis. 2005:225
Rabensburgvirus?
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Flaviviruses ...
… are pathogens of global importance.… are emerging pathogens that can conquer new
ecological niches.… are considered potential bioterroristic
weapons.
• There is no specific treatment for flavivirusinfections.
• There is a big and growing demand for vaccines.
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Flavivirus particle
• Small (50 nm), round, enveloped• Nucleocapsid (RNA genome and protein C)• Two surface proteins (M and E)
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Flavivirus particle
• Small (50 nm), round, enveloped• Protein E arranged in icosahedral lattice –• Main target for neutralizing antibodies
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Distribution map of Japanese encephalitisvirus
1983
1955
1970
1990
1985
1935
1965
1960
1952
1949
1947
1998
1990
1995
1870s (1935)
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JEV transmission cycle
No person-to-person transmissionCulex tritaeniorhyncus
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Japanese encephalitis fact sheet
• Most important recognised cause of viral encephalitis in Asia
• ~ 50,000 cases reported annually (probably heavily underreported)
• Only 1 in ~ 250 infections results in clinical disease
• Case-fatality rate: 30%
• Serious neurologic sequelae: 30%
• 3 Billion people live in endemic areas
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Travelers to JEV endemic areas
USA, ~8 million
Europe, ~20 million
Australia,~3 million
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Existing JEV vaccines (1/2)
Inactivated JEV wild-type virus from suckling mouse brain
• JE-VAX®: Biken / SanofiPasteur (and other local manufacturers)• Very successful (JE nearly eliminated in several countries)
However• Traces of myelin basic protein• Local reactions (20%)• Systemic symptoms, headache, fever etc. (20%)• Sporadic cases of acute disseminated encephalomyelitis??• 2005: Recommendation for childhood vaccination withdrawn in
Japan• 2004: Production in Japan discontinued
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Existing JEV vaccines (2/2)
Inactivated JE wild-type virus produced in cell culture
Live virus vaccine based on attenuated strain SA14-14-2
• Many million doses of both vaccines used in China.
However• Unresolved safety issues• Primary hamster kidney cells not approved by WHO for human
vaccine production• Production lacks purification steps• Not used in Western world
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New JEV vaccines (1/2)
Live virus vaccine based on a YFV-JEV chimeric strain
• Chimerivax®-JE: Acambis• Surface proteins M and E of YF-17D vaccine strain replaced
by the corresponding proteins from JEV strain SA14-14-2
Vaccinia virus vectored vaccine• MVA-BN®-JE: Bavarian Nordic• JEV surface proteins expressed from Modified Vaccinia Ankara
strain
Genetically engineered, live viruses
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New JEV vaccines (2/2)
Inactivated JEV produced in Vero cells• JEV-IC51: Intercell• Vero cells (originally from African green monkey kidney) are used
worldwide for human, e.g. polio, vaccine production.• Attenuated strain SA14-14-2 used as seed virus
2-Dose3-DoseVaccinationSchedule
Prefilled SyringeVialFormatLiquidLyophilizedFormulationNoneThimerosalPreservativeAlumNoneAdjuvantNonePorcine GelatinStabilizers
Vero CellsMouse BrainVirus GrowthAttenuatedVirulentVirus Seed
JE-PIVJE-VAX®
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Distribution map of tick-borne encephalitis virus
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TBEV vaccines
Formalin-
inact. Virus
Al ( OH )3
Stabilizer
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TBE in Austria and Czech Rep.1979 - 2005
1979 81 83 85 87 89 91 93 95 97 99 01 03 050
100
200
300
400
500
600
700
Years
Number of cases
Czech Rep. Austria
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Flaviviruses
Yellow feverDengue
Tick-borne encephalitisJapanese encephalitis
West Nile
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A new technology to generate attenuated flavivirus strains
Virus particle
>
Subviral particle
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A new technology to generate attenuated flavivirus strains
Virus particle
<Subviral particle
This strategy is currently applied to West Nile virus in a preclinical collaborative study between Intercell and the Institute of Virology
Capsiddeletion
mutations
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