Flaviviruses New Challenges, New Vaccines
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1 Flaviviruses New Challenges, New Vaccines Christian W. Mandl Institute of Virology Medical University of Vienna, AUSTRIA
2 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
3 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
4 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
5 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 Hemorrhagic fever
6 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 Neurological disorders Encephalitis
7 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 Neurological disorders Encephalitis
8 Flaviviruses Yellow fever Dengue Japanese encephalitis Tick-borne encephalitis
9 Flaviviruses West Nile Yellow fever Dengue Japanese encephalitis Tick-borne encephalitis
10 West Nile virus in the United States 1999
11 West Nile virus in the United States 2001
12 West Nile virus in the United States ,862 cases, 264 deaths
13 West Nile virus in the United States : ~ 3,000 cases, 100 deaths per year
14 West Nile virus transmission cycle USA 2003: WN virus found in 43 mosquito species 234 native and captive exotic birds
15 Flaviviruses Usutu virus West Nile Yellow fever Dengue Japanese encephalitis Tick-borne encephalitis Weissenbock, Kolodziejek, Url, Lussy, Rebel-Bauder, Nowotny. Emerg Infect Dis. 2002:652
16 Flaviviruses Usutu virus West Nile Rabensburg virus? Yellow fever Dengue Japanese encephalitis Tick-borne encephalitis Bakonyi, Hubalek, Rudolf, Nowotny. Emerg Infect Dis. 2005:225
17 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 flavivirus infections. There is a big and growing demand for vaccines.
18 Flavivirus particle Small (50 nm), round, enveloped Nucleocapsid (RNA genome and protein C) Two surface proteins (M and E)
19 Flavivirus particle Small (50 nm), round, enveloped Protein E arranged in icosahedral lattice Main target for neutralizing antibodies
20 Distribution map of Japanese encephalitis virus s (1935)
21 JEV transmission cycle Culex tritaeniorhyncus No person-to-person transmission
22 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
23 Travelers to JEV endemic areas USA, ~8 million Europe, ~20 million Australia, ~3 million
24 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
25 Existing JEV vaccines (2/2) Inactivated JE wild-type virus produced in cell culture Live virus vaccine based on attenuated strain SA 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
26 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 SA Vaccinia virus vectored vaccine MVA-BN -JE: Bavarian Nordic JEV surface proteins expressed from Modified Vaccinia Ankara strain Genetically engineered, live viruses
27 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 SA used as seed virus Virus Seed Virus Growth Stabilizers Adjuvant Preservative Formulation Format Vaccination Schedule JE-VAX Virulent Mouse Brain Porcine Gelatin None Thimerosal Lyophilized Vial 3-Dose JE-PIV Attenuated Vero Cells None Alum None Liquid Prefilled Syringe 2-Dose
28 Distribution map of tick-borne encephalitis virus
29 TBEV vaccines Formalininact. Virus Al ( OH ) 3 Stabilizer
30 TBE in Austria and Czech Rep Number of cases Years Czech Rep. Austria
31 Flaviviruses West Nile Yellow fever Dengue Japanese encephalitis Tick-borne encephalitis
32 A new technology to generate attenuated flavivirus strains > Virus particle Subviral particle
33 A new technology to generate attenuated flavivirus strains Capsid deletion mutations < 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
34
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