fda h5n1 update: classification of h5n1 viruses and development of vaccine reference strains fda...
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FDA H5N1 Update:FDA H5N1 Update:Classification of H5N1 Viruses and Classification of H5N1 Viruses and
Development of Vaccine Development of Vaccine Reference StrainsReference Strains
Nancy J. Cox, Ph.D.Nancy J. Cox, Ph.D.
Director, WHO Collaborating Center for Director, WHO Collaborating Center for Surveillance, Epidemiology and Control of Surveillance, Epidemiology and Control of
InfluenzaInfluenza
Centers for Disease Control and PreventionCenters for Disease Control and Prevention
History of H5N1History of H5N1
Currently 2 discrete lineages of H5 HAs descended from Currently 2 discrete lineages of H5 HAs descended from the A/Gs/Guangdong/96 have infected humansthe A/Gs/Guangdong/96 have infected humans
1997 poultry outbreak in Hong Kong1997 poultry outbreak in Hong Kong• 18 human cases, 6 deaths18 human cases, 6 deaths• Direct avian to human transmission: limited H-2-H Direct avian to human transmission: limited H-2-H
transmissiontransmission 2003 ongoing poultry outbreaks and spread2003 ongoing poultry outbreaks and spread
• 2 human cases, 1 death in Hong Kong2 human cases, 1 death in Hong Kong• 1 death in Beijing (from time of SARS)1 death in Beijing (from time of SARS)
End of 2003 - TodayEnd of 2003 - Today• 258 human cases, 154 deaths258 human cases, 154 deaths
• Azerbaijan, Cambodia, China, Djbouti, Egypt, Azerbaijan, Cambodia, China, Djbouti, Egypt, Indonesia, Iraq, Laos, Nigeria, Thailand, Turkey, Indonesia, Iraq, Laos, Nigeria, Thailand, Turkey, VietnamVietnam
VietnamCases: 93Deaths: 42
ThailandCases: 25Deaths: 17
CambodiaCases: 6Deaths: 6
IndonesiaCases: 81Deaths: 63
ChinaCases: 22Deaths: 14
TurkeyCases: 12Deaths: 4
IraqCases: 3Deaths: 2
AzerbaijanCases: 8Deaths: 5
EgyptCases: 22Deaths: 13
Influenza A (H5N1) in Humans, 2003-07Influenza A (H5N1) in Humans, 2003-07**
*December 2003 – February 2007
275 cases and 167 deaths
DjiboutiCases: 1Deaths: 0
WHO H5N1 Vaccine WHO H5N1 Vaccine Development: Principles and Development: Principles and
PracticesPractices Development of H5N1 vaccines is one component of WHO’s overall Development of H5N1 vaccines is one component of WHO’s overall
strategy for pandemic preparednessstrategy for pandemic preparedness
WHO’s 4 Collaborating Centers for Influenza Reference and WHO’s 4 Collaborating Centers for Influenza Reference and Research along with 4 additional H5 Reference Laboratories share Research along with 4 additional H5 Reference Laboratories share H5N1 antigenic and genetic data frequentlyH5N1 antigenic and genetic data frequently
WHO convenes periodic teleconferences of H5 Reference WHO convenes periodic teleconferences of H5 Reference Laboratory representatives to discuss data and apportion tasks Laboratory representatives to discuss data and apportion tasks required for vaccine candidate reference virus productionrequired for vaccine candidate reference virus production
Development of appropriate H5N1 vaccines requires integration of Development of appropriate H5N1 vaccines requires integration of antigenic, genetic and epidemiologic data from human and antigenic, genetic and epidemiologic data from human and veterinary health sectorsveterinary health sectors
H5N1 vaccine candidate reference viruses are chosen on the basis H5N1 vaccine candidate reference viruses are chosen on the basis of antigenic and genetic properties and epidemiologic informationof antigenic and genetic properties and epidemiologic information
Circulation of H5N1 Viruses Circulation of H5N1 Viruses
HA sequences of the majority of H5N1 viruses in avian species HA sequences of the majority of H5N1 viruses in avian species segregate into 2 distinct phylogenetic cladessegregate into 2 distinct phylogenetic clades
Clade 1 viruses circulated in Cambodia, Thailand and Viet Nam Clade 1 viruses circulated in Cambodia, Thailand and Viet Nam and caused human infections during 2004 and 2005 -and in and caused human infections during 2004 and 2005 -and in Thailand in 2006Thailand in 2006
Clade 2 viruses circulated in birds in China and Indonesia Clade 2 viruses circulated in birds in China and Indonesia during 2003–2004 and spread westward during 2005 and 2006 during 2003–2004 and spread westward during 2005 and 2006 to the Middle East, Europe and Africa to the Middle East, Europe and Africa
Clade 2 viruses have caused the majority of human Infections Clade 2 viruses have caused the majority of human Infections since late 2005since late 2005
Multiple sub-clades of clade 2 have been distinguished, three Multiple sub-clades of clade 2 have been distinguished, three
of which (subclades 2.1, 2.2 and 2.3) have been responsible for of which (subclades 2.1, 2.2 and 2.3) have been responsible for human cases and differ in geographical distributionhuman cases and differ in geographical distribution
H5N1 Current Status (Late 2005 H5N1 Current Status (Late 2005 to the Present)to the Present)
The majority of H5N1 viruses detected in avian species in The majority of H5N1 viruses detected in avian species in Africa, Asia and Europe and associated with sporadic Africa, Asia and Europe and associated with sporadic human infections are in Clade 2human infections are in Clade 2
Clade 2.1 viruses circulated in poultry and caused human Clade 2.1 viruses circulated in poultry and caused human infections in Indonesia; clade 2.2 viruses caused outbreaks infections in Indonesia; clade 2.2 viruses caused outbreaks in birds in Africa, Asia and Europe and were most recently in birds in Africa, Asia and Europe and were most recently associated with human infections in Egypt and Nigeria; associated with human infections in Egypt and Nigeria; viruses in clade 2.3 caused poultry outbreaks and human viruses in clade 2.3 caused poultry outbreaks and human cases in China cases in China
Viruses outside this classification nomenclature were Viruses outside this classification nomenclature were isolated from domestic poultry in Asia – two emerging isolated from domestic poultry in Asia – two emerging clades are represented by A/goose/Guiyang/337/06 and clades are represented by A/goose/Guiyang/337/06 and A/chicken/Shanxi/2/2006 virusesA/chicken/Shanxi/2/2006 viruses
Hong Kong/156/97
Vietnam/JP14/05 ck/Cambodia/013LC1b/05
Vietnam/1194/04 Vietnam/1203/04
Vietnam/HN30408/05 Thailand/16/04
Vietnam/JPHN30321/05
Clade 1
Hong Kong/213/03 Indonesia/CDC523/06
Indonesia/CDC699/06 Indonesia/CDC326/06
Indonesia/5/05 Indonesia/CDC184/05
Indonesia/7/05 dk/KulonProgoBBVET9/04
ck/Indonesia/CDC25/05 Indonesia/6/05
ck/Brebes/BBVET2/05
Indonesia/CDC594/06* ck/Dairi/BPPVI/05
Clade 2Subclade 1
ck/Yunnan/374/04 ck/Yunnan/115/04
ck/Yunnan/493/05 ck/Yunnan/447/05
dk/Guangxi/13/04 ck/Guangxi/12/04
whooping swan/Mongolia/244/05 bar headed gs/Qinghai/1A/05 *
Turkey/65596/06 Turkey/15/06 Iraq/207NAMRU3/06
ck/Nigeria/641/06 mld/Italy/332/06
turkey/Turkey/1/05 Egypt/2782NAMRU3/06 Djibouti/5691NAMRU3/06
ck/Nigeria42/06 migratory dk/Jiangxi/2136/05
gs/Kazakhstan/464/05 ck/Krasnodar/01/06
Azerbaijan/011162/06 swan/Iran/754/06
Clade 2Subclade 2
dk/Laos3295/06 Anhui/1/05
Anhui/2/05 Japanese white-eye/Hong Kong/1038/06 ck/Malaysia935/06
Vietnam/30850/05 Guangxi/1/05
dk/Hunan/15/04 qa/Guangxi/575/05
dk/Vietnam/Ncvdcdc95/05
Clade 2Subclade 3
migratory dk/Jiangxi/1653/05
gs/Guangdong/1/96
* Karo cluster Indonesia/CDC625/06*
H5 HA
HI Reactions of Influenza H5 Viruses
1 A/VIETNAM/1194/042 A/VIETNAM/1203/043 A/THAILAND/16/044 A/INDONESIA/5/05 RG5 A/INDONESIA/CDC357/066 A/INDONESIA/CDC625/06*7 A/TURKEY/15/058 A/w.swan/MG/244/05 RG9 A/b-h gs/QINGHAI/1/05 RG
10 A/turkey/TURKEY/1/0511 A/duck/HUNAN/15/0412 A/ANHUI/1/0513 A/GUANGXI/1/05
640320nd80ndnd80808080ndndnd
nd160160<104040202010nd804010
nd160160<102010
<1010
<10nd802020
201010320320804040408020
<1020
nd<10<1032064040408080nd20
<1010
nd804016080
12801280640320nd202010
nd<10<1040404064032080nd
<1010
<10
20<10<10204040
6403201260160<1010
<10
2040408080160
1280640320160204040
<20<20nd40ndnd320320160320ndndnd
nd16080402040202040nd160160nd
nd10
<10402040401020nd160640320
nd2010201020401020ndnd160160
A/V
N/1
194/0
4
A/V
N/1
203/0
4
A/T
H/1
6/0
4
A/I
ND
O/5
/05
A/I
ND
O/3
57/0
6
A/I
ND
O/6
25/0
6
A/T
UR
KEY
/15/0
5
A/w
s/M
G/2
44/0
5
A/b
hg
/QIN
GH
AI/
1/0
5
A/t
y/T
UR
KEY
/1/0
5
A/d
k/H
UN
AN
/15/0
4
A/A
NH
UI/
1/0
5
A/G
UA
NG
XI/
1/0
5
Reference Ferret Antisera
Clade 2-1
Clade 2-2
Clade 2-3
Clade 1
HI Reactions of Influenza H5 Viruses
Reference Ferret Antisera
1 A/VIETNAM/1203/04 *
2 A/THAILAND/16/04
3 A/INDONESIA/5/05 *
4 A/INDONESIA/357/06
5 A/w.swan/MG/244/05
6 A/b-h gs/QINGHAI/1/05
7 A/ANHUI/1/05 *
8 A/GUANGXI/1/05
160
160
<10
40
20
10
40
10
VN
12
03
04
160
160
<10
20
10
<10
20
20
TH
16
04
<10
320
320
10
10
40
40
20
IND
O5
05
<10
<10
<10
320
640
80
80
10
IND
O3
57
06
<10
<10
20
40
320
1260
10
<10
wsM
G2
44
05
40
40
80
80
640
320
40
40
QIN
GH
AI0
5
10
<10
40
20
10
20
640
320
AN
HU
I05
20
10
20
10
10
20
160
160
GU
AN
GX
I05
HK/156/97
Vietnam/1194/04 Vietnam/1203/04
1 HK/213/03
Indonesia/5/05
2-1
w. swan/Mongolia/244/05 b.h.gs/Qinghai/1A/05
ty/Turkey/1/05 2-2
Anhui/1/05
2-3
gs/Guangdong/1/96
Hong Kong/156/97
Vietnam/1194/04 Vietnam/1203/04
Clade 1
Hong Kong/213/03
Indonesia/5/05
Clade 2-3
whooping swan/Mongolia/244/05 bar headed gs/Qinghai/1A/05 *
turkey/Turkey/1/05
Anhui/1/05
gs/Guangdong/1/96
ResistantAsn-31
SensitiveSer-31
Clade 2-1~80% resistant
Asn-31 or Ala-27
Clade 2-2Sensitive
Ser-31
H5N1 Virus Resistance to M2 Channel Blockers
Hong Kong/156/97
Vietnam/1194/04 Vietnam/1203/04
Clade 1
Hong Kong/213/03
Indonesia/5/05
Clade 2-3
whooping swan/Mongolia/244/05 bar headed gs/Qinghai/1A/05 *
turkey/Turkey/1/05
Anhui/1/05
gs/Guangdong/1/96
SensitiveSeveral resistant
mutants isolated from treated patients
Sensitive
Clade 2-1Sensitive
Clade 2-2Generally Sensitive - but
moderately resistant viruses detected
H5N1 Resistance to Neuraminidase Inhibitors
HI REACTIONS OF INFLUENZA H5 VIRUSES REFERENCE FERRET ANTISERA
Clade: 1 1 2/1 2/1 2/2 2/2 2/2 2/2 2/3 2/3 2/3 2/3REFERENCE ANTIGENS VN/1203 TH/16 Ind/5 Ind/625 gs/KA TK/15 TK/65 ws/MG Anh/1 ck/HK ck/MY jwe/HKA/VIETNAM/1203/2004 160 160 20 40 20 5 40 20 20 20 20 40A/THAILAND/16/2004 320 320 20 40 40 5 40 20 40 80 40 40A/INDONESIA/5/2005 5 5 320 40 320 20 80 160 160 80 20 40A/INDONESIA/CDC625/2006 20 10 40 320 320 20 160 5 10 10 5 10A/GOOSE/KAZAKHSTAN/464/2005 20 10 80 160 1280 40 320 320 20 40 10 40A/TURKEY/15/2005 40 10 160 320 1280 640 640 1280 40 40 40 80A/TURKEY/65-596/2006 160 80 1280 1280 5120 2560 2560 5120 320 320 320 320A/WHOOPER SWAN/MG/244/2005 1280 320 2560 2560 5120 2560 5120 2560 160 160 80 10A/ANHUI/1/2005 20 40 160 20 20 10 80 10 640 320 320 160A/COMMON/MAGPIE/HK/645/2006 5 5 40 5 5 5 20 5 160 80 160 80A/CHICKEN/MALAYSIA/935/2006 5 10 80 5 10 5 20 5 320 160 320 80A/JAPANESE WHITE EYE/HK/1038/2006 10 10 320 20 160 5 80 20 1280 320 1280 640TEST ANTIGENSA/GOOSE/VIETNAM/GZ-3/2005 80 80 10 40 80 10 80 10 40 40 40 40A/INDONESIA/CDC523T/2006 5 5 640 40 320 20 40 80 320 40 20 20A/INDONESIA/CDC836T/2006 10 20 1280 160 640 80 160 320 320 160 40 80A/INDONESIA/CDC739/2006 10 10 120 160 640 80 160 320 160 160 40 40A/INDONESIA/CDC938E/2006 5 5 640 80 320 40 40 160 160 160 40 20A/INDONESIA/CDC625L/2006 20 10 40 160 80 20 80 40 10 5 5 40A/EGRET EGYPT/1162-NAMRU3/2006 10 5 80 320 640 160 320 640 20 10 10 40A/AZERBAIJIAN/2838-NAMRU3/2006 10 5 80 320 320 160 320 320 20 20 10 40A/CHICKEN/KOREA/IS/2006 10 5 40 160 160 160 320 320 20 20 5 40A/CHICKEN/NINGXIA/70/2005 20 10 160 320 1280 80 320 1280 40 80 40 80A/WHOOPER SWAN/QINGHAI/1/2005 10 10 80 160 640 80 320 320 20 20 10 40A/BARHEADED GOOSE/QINGHAI/12/2005 10 5 40 160 320 40 320 320 20 10 10 40A/SWAN/GUANGDONG/43/2004 10 5 20 160 160 5 80 160 5 10 5 80A/CHICKEN/SHAANXI/62/2004 20 10 160 80 640 40 80 320 10 10 5 20A/CHICKEN/LIAONING/23/2005 10 5 80 320 640 80 320 640 20 20 20 80A/CHICKEN/XINJIANG/27/2004 40 5 80 320 640 80 320 320 10 10 5 20A/CHICKEN/HUNAN/41/2004 20 40 80 20 20 5 40 5 80 160 160 40A/DUCK/JIANGXI/80/2005 10 10 80 5 5 5 20 5 160 160 320 80
ck/Shannxi/62/04 ck/Yunnan/447/05|ck/Yunnan/493/05
dk/Guangxi/13/04 ck/Yunnan/30/04
ck/Yunnan/115/04 ck/Yunnan/374/04
Indonesia/7/05 Indonesia/5/05
Indonesia/CDC742/06 Indonesia/CDC940/06
Indonesia/CDC1031/07 Indonesia/CDC1047/07
Indonesia/CDC887/06 Indonesia/CDC938/06
Indonesia/CDC1032/07 Indonesia/CDC1046/07
Barhdgs/Qinghai/1A/05 ck/Liaoning/23/05
Barhdgs/Qinghai/12/05 ck/Krasnodar/01/06
Azerbaijan/001161/06 swan/Iran/754/06
Turkey/15/06 Iraq/207NAMRU-3/06
ck/Nigeria/641/06 whswan/Mongolia/244/05
tky/Turkey/1/05 Egypt/14724NAMRU-3/06
Djibouti/5691NAMRU-3/06 dk/Egypt/22533/06
Egypt/0636NAMRU-3/07 egret/Egypt/1162NAMRU-3/06
dk/Hunan/15/04 scalybreastedMunia/HongKong/45/07
JapaneseWhiteEye/HongKong/1038/06 Anhui/1/05
dk/Laos/3295/06 ck/Malaysia/935/06
common magpie/Hong Kong/645/06 Guangxi/1/05
House Crow/Hong Kong/719/07 JapaneseWhiteEye/Hong Kong/737/07 WhiteBackedMunia/HongKong/828/07
Thailand/676/05 Vietnam/JP14/05
ck/Cambodia/013LC1b/05 Vietnam/JPHN30321/05
Vietnam/1203/04 Vietnam/1194/04
Vietnam/HN30408/05 Thailand/16/04
Hong Kong/213/03 migdk/Jiangxi/1653/05 ck/Hunan/41/04
ck/Hunan/2292/06 ck/Shanxi/2/06
ck/Myanmar/06010011B/06 ck/Yunnan/71/05 ck/Guiyang/237/06
gs/Guiyang/1325/06 dk/Guiyang/50406
gs/Fujian/bb/03 gs/Vietnam/GZ-3/05
Hong Kong/156/97 gs/Guangdong/1/96
Candidate Vaccine Reference Viruses
Clade 2.1
Clade 2.2
Clade 2.3
Clade 1
Evolution of the H5N1 Hemagglutinin Gene
New subgroup
New subgroup
ConclusionsConclusions H5N1 viruses remain a pandemic threat but have not yet H5N1 viruses remain a pandemic threat but have not yet
developed to the ability to be transmitted efficiently from developed to the ability to be transmitted efficiently from person-to-personperson-to-person
It is not able to predict which if any of the H5N1 It is not able to predict which if any of the H5N1 antigenic/genetic variants might acquire the ability to be antigenic/genetic variants might acquire the ability to be transmitted efficientlytransmitted efficiently
Distinct geographical distribution of H5N1 genetic and Distinct geographical distribution of H5N1 genetic and antigenic variants have been identifiedantigenic variants have been identified
In this instance, specific WHO pre-pandemic vaccine In this instance, specific WHO pre-pandemic vaccine recommendations are not appropriate because it is not recommendations are not appropriate because it is not possible to predict which of the viruses in the distinct possible to predict which of the viruses in the distinct antigenic/genetic groups might acquire the ability to become antigenic/genetic groups might acquire the ability to become efficiently transmissibleefficiently transmissible
Availability of Vaccine Viruses and Availability of Vaccine Viruses and ReagentsReagents
rg A/Viet Nam/1203/2004 (Clade 1) – available from St. Jude CRHrg A/Viet Nam/1203/2004 (Clade 1) – available from St. Jude CRH• Antigen and sheep serum available from CBERAntigen and sheep serum available from CBER
rg A/Viet Nam/1194/2004 (Clade 1) – available from NIBSCrg A/Viet Nam/1194/2004 (Clade 1) – available from NIBSC• Antigen and sheep serum available from NIBSCAntigen and sheep serum available from NIBSC
rg A/Indonesia/05/2005 (Clade 2.1) – available from CDCrg A/Indonesia/05/2005 (Clade 2.1) – available from CDC• Antigen and sheep serum - available soon from CBERAntigen and sheep serum - available soon from CBER
rg A/Turkey/turkey/1/2005 (Clade 2.2) – available from NIBSCrg A/Turkey/turkey/1/2005 (Clade 2.2) – available from NIBSC• Antigen and sheep serum available from NIBSCAntigen and sheep serum available from NIBSC
rg A/BHG/Qinghai Lake/1A/05 (Clade 2.2) – available from St. Juderg A/BHG/Qinghai Lake/1A/05 (Clade 2.2) – available from St. Jude• Reagents not yet in productionReagents not yet in production
rg A/whooper swan/Mongolia/244/2005 (Clade 2.2) – available for rg A/whooper swan/Mongolia/244/2005 (Clade 2.2) – available for researchresearch• Reagents not in productionReagents not in production
rg A/Anhui/1/05 (Clade 2.3) – available from CDCrg A/Anhui/1/05 (Clade 2.3) – available from CDC• Reagents not yet in productionReagents not yet in production
AcknowledgementsAcknowledgements
WHO National Influenza CentersWHO National Influenza Centers WHO Collaborating Centers and Regulatory WHO Collaborating Centers and Regulatory
Authorities in London, Tokyo, Melbourne, Canberra, Authorities in London, Tokyo, Melbourne, Canberra, and Memphisand Memphis
WHO H5 Reference LaboratoriesWHO H5 Reference Laboratories WHO Regional OfficesWHO Regional Offices WHO Headquarters in GenevaWHO Headquarters in Geneva Many colleagues in Azerbaijan, Cambodia, China, Many colleagues in Azerbaijan, Cambodia, China,
Djibouti, Egypt, Indonesia, Iraq, Nigeria, Thailand, Djibouti, Egypt, Indonesia, Iraq, Nigeria, Thailand, Turkey, Vietnam and other affected countriesTurkey, Vietnam and other affected countries
Ministries of Agriculture in affected countries and Ministries of Agriculture in affected countries and FAO and OIE membersFAO and OIE members
Members of the Influenza Division, CDCMembers of the Influenza Division, CDC
Thank You