FDA H5N1 Update: Classification of H5N1 Viruses and Development of Vaccine Reference Strains

1
FDA H5N1 UpdateClassification of H5N1 Viruses
and Development of Vaccine Reference Strains

• Nancy J. Cox, Ph.D.
• Director, WHO Collaborating Center for
  Surveillance, Epidemiology and Control of
  Influenza
• Centers for Disease Control and Prevention

2
History of H5N1

• Currently 2 discrete lineages of H5 HAs descended
  from the A/Gs/Guangdong/96 have infected humans
• 1997 poultry outbreak in Hong Kong
• 18 human cases, 6 deaths
• Direct avian to human transmission limited H-2-H
  transmission
• 2003 ongoing poultry outbreaks and spread
• 2 human cases, 1 death in Hong Kong
• 1 death in Beijing (from time of SARS)
• End of 2003 - Today
• 258 human cases, 154 deaths
• Azerbaijan, Cambodia, China, Djbouti, Egypt,
  Indonesia, Iraq, Laos, Nigeria, Thailand, Turkey,
  Vietnam

3
Influenza A (H5N1) in Humans, 2003-07
Turkey Cases 12 Deaths 4
275 cases and 167 deaths
Azerbaijan Cases 8 Deaths 5
China Cases 22 Deaths 14
Egypt Cases 22 Deaths 13
Vietnam Cases 93 Deaths 42
Thailand Cases 25 Deaths 17
Djibouti Cases 1 Deaths 0
Cambodia Cases 6 Deaths 6
Iraq Cases 3 Deaths 2
Indonesia Cases 81 Deaths 63
December 2003 February 2007
4
WHO H5N1 Vaccine Development Principles and
Practices

• Development of H5N1 vaccines is one component of
  WHOs overall strategy for pandemic preparedness
• WHOs 4 Collaborating Centers for Influenza
  Reference and Research along with 4 additional H5
  Reference Laboratories share H5N1 antigenic and
  genetic data frequently
• WHO convenes periodic teleconferences of H5
  Reference Laboratory representatives to discuss
  data and apportion tasks required for vaccine
  candidate reference virus production
• Development of appropriate H5N1 vaccines requires
  integration of antigenic, genetic and
  epidemiologic data from human and veterinary
  health sectors
• H5N1 vaccine candidate reference viruses are
  chosen on the basis of antigenic and genetic
  properties and epidemiologic information

5
Circulation of H5N1 Viruses

• HA sequences of the majority of H5N1 viruses in
  avian species segregate into 2 distinct
  phylogenetic clades
• Clade 1 viruses circulated in Cambodia, Thailand
  and Viet Nam and caused human infections during
  2004 and 2005 -and in Thailand in 2006
• Clade 2 viruses circulated in birds in China and
  Indonesia during 20032004 and spread westward
  during 2005 and 2006 to the Middle East, Europe
  and Africa
• Clade 2 viruses have caused the majority of human
  Infections since late 2005
• Multiple sub-clades of clade 2 have been
  distinguished, three of which (subclades 2.1, 2.2
  and 2.3) have been responsible for human cases
  and differ in geographical distribution

6
H5N1 Current Status (Late 2005 to the Present)

• The majority of H5N1 viruses detected in avian
  species in Africa, Asia and Europe and associated
  with sporadic human infections are in Clade 2
• Clade 2.1 viruses circulated in poultry and
  caused human infections in Indonesia clade 2.2
  viruses caused outbreaks in birds in Africa, Asia
  and Europe and were most recently associated
  with human infections in Egypt and Nigeria
  viruses in clade 2.3 caused poultry outbreaks
  and human cases in China
• Viruses outside this classification nomenclature
  were isolated from domestic poultry in Asia two
  emerging clades are represented by
  A/goose/Guiyang/337/06 and A/chicken/Shanxi/2/2006
  viruses

7
Vietnam/JP14/05
H5 HA
ck/Cambodia/013LC1b/05
Vietnam/1194/04
Clade 1
Vietnam/1203/04
Vietnam/HN30408/05
Thailand/16/04
Vietnam/JPHN30321/05
Hong Kong/213/03
Indonesia/CDC523/06
Indonesia/CDC699/06
Indonesia/CDC326/06
Indonesia/5/05
Clade 2 Subclade 1
Indonesia/CDC184/05
Indonesia/7/05
dk/KulonProgoBBVET9/04
ck/Indonesia/CDC25/05
Indonesia/6/05
ck/Brebes/BBVET2/05
Indonesia/CDC625/06
Indonesia/CDC594/06
Karo cluster
ck/Dairi/BPPVI/05
ck/Yunnan/374/04
ck/Yunnan/115/04
dk/Guangxi/13/04
ck/Guangxi/12/04
ck/Yunnan/493/05
ck/Yunnan/447/05
whooping swan/Mongolia/244/05
bar headed gs/Qinghai/1A/05
Turkey/65596/06
Turkey/15/06
Iraq/207NAMRU3/06
ck/Nigeria/641/06
Clade 2 Subclade 2
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
dk/Laos3295/06
Anhui/1/05
Anhui/2/05
Clade 2 Subclade 3
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
migratory dk/Jiangxi/1653/05
Hong Kong/156/97
gs/Guangdong/1/96
8
HI Reactions of Influenza H5 Viruses
Reference Ferret Antisera
Clade 1
Clade 2-1
A/bhg/QINGHAI/1/05
Clade 2-2
A/dk/HUNAN/15/04
A/ty/TURKEY/1/05
A/ws/MG/244/05
A/GUANGXI/1/05
A/TURKEY/15/05
A/INDO/357/06
A/INDO/625/06
A/ANHUI/1/05
A/VN/1194/04
A/VN/1203/04
A/INDO/5/05
Clade 2-3
A/TH/16/04
1
A/VIETNAM/1194/04
640
nd
nd
20
nd
nd
nd
20
20
lt20
nd
nd
nd
2
A/VIETNAM/1203/04
320
160
160
10
lt10
80
lt10
lt10
40
lt20
160
10
20
3
A/THAILAND/16/04
nd
160
160
10
lt10
40
lt10
lt10
40
nd
80
lt10
10
4
A/INDONESIA/5/05 RG
80
lt10
lt10
320
320
160
40
20
80
40
40
40
20
5
A/INDONESIA/CDC357/06
nd
40
20
320
640
80
40
40
80
nd
20
20
10
6
A/INDONESIA/CDC625/06
nd
40
10
80
40
1280
40
40
160
nd
40
40
20
7
A/TURKEY/15/05
80
20
lt10
40
40
1280
640
640
1280
320
20
40
40
8
A/w.swan/MG/244/05 RG
80
20
10
40
80
640
320
320
640
320
20
10
10
9
A/b-h gs/QINGHAI/1/05 RG
80
10
lt10
40
80
320
80
1260
320
160
40
20
20
10
A/turkey/TURKEY/1/05
80
nd
nd
80
nd
nd
nd
160
160
320
nd
nd
nd
11
A/duck/HUNAN/15/04
nd
80
80
20
20
20
lt10
lt10
20
nd
160
160
nd
12
A/ANHUI/1/05
nd
40
20
lt10
lt10
20
10
10
40
nd
160
640
160
13
A/GUANGXI/1/05
nd
10
20
20
10
10
lt10
lt10
40
nd
nd
320
160
9
HI Reactions of Influenza H5 Viruses
Vietnam/1194/04
Vietnam/1203/04
1
HK/213/03
Indonesia/5/05
2-1
Reference Ferret Antisera
w. swan/Mongolia/244/05
b.h.gs/Qinghai/1A/05
ty/Turkey/1/05
2-2
wsMG24405
GUANGXI05
INDO35706
QINGHAI05
VN120304
Anhui/1/05
INDO505
ANHUI05
2-3
TH1604
HK/156/97
gs/Guangdong/1/96
1
A/VIETNAM/1203/04
160
160
10
lt10
lt10
40
10
20
2
160
160
10
lt10
lt10
40
lt10
10
A/THAILAND/16/04
3
A/INDONESIA/5/05
lt10
lt10
320
320
20
80
40
20
4
A/INDONESIA/357/06
40
20
320
640
40
80
20
10
5
A/w.swan/MG/244/05
20
10
40
80
320
640
10
10
6
A/b-h gs/QINGHAI/1/05
10
lt10
40
80
1260
320
20
20
7
A/ANHUI/1/05
40
20
lt10
lt10
10
40
640
160
8
A/GUANGXI/1/05
10
20
20
10
lt10
40
320
160
10
H5N1 Virus Resistance to M2 Channel Blockers
Clade 1
Resistant Asn-31
Vietnam/1194/04
Vietnam/1203/04
Hong Kong/213/03
Clade 2-1
Indonesia/5/05
80 resistant Asn-31 or Ala-27
whooping swan/Mongolia/244/05
bar headed gs/Qinghai/1A/05
Clade 2-2
Sensitive Ser-31
turkey/Turkey/1/05
Clade 2-3
Anhui/1/05
Sensitive Ser-31
Hong Kong/156/97
gs/Guangdong/1/96
11
H5N1 Resistance to Neuraminidase Inhibitors
Clade 1
Sensitive Several resistant mutants isolated from
treated patients
Vietnam/1194/04
Vietnam/1203/04
Hong Kong/213/03
Indonesia/5/05
Clade 2-1
Sensitive
whooping swan/Mongolia/244/05
bar headed gs/Qinghai/1A/05
Clade 2-2
Generally Sensitive - but moderately resistant
viruses detected
turkey/Turkey/1/05
Clade 2-3
Anhui/1/05
Sensitive
Hong Kong/156/97
gs/Guangdong/1/96
12
HI REACTIONS OF INFLUENZA H5 VIRUSES
13
Evolution of the H5N1 Hemagglutinin Gene
Candidate Vaccine Reference Viruses
ck/Shannxi/62/04
ck/Yunnan/447/05ck/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
Clade 2.1
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
Clade 2.2
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
Clade 2.3
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
Clade 1
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
?
New subgroup
ck/Shanxi/2/06
ck/Myanmar/06010011B/06
ck/Yunnan/71/05
ck/Guiyang/237/06
gs/Guiyang/1325/06
dk/Guiyang/50406
New subgroup
gs/Fujian/bb/03
gs/Vietnam/GZ-3/05
Hong Kong/156/97
gs/Guangdong/1/96
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Conclusions

• H5N1 viruses remain a pandemic threat but have
  not yet developed to the ability to be
  transmitted efficiently from person-to-person
• It is not able to predict which if any of the
  H5N1 antigenic/genetic variants might acquire the
  ability to be transmitted efficiently
• Distinct geographical distribution of H5N1
  genetic and antigenic variants have been
  identified
• In this instance, specific WHO pre-pandemic
  vaccine recommendations are not appropriate
  because it is not possible to predict which of
  the viruses in the distinct antigenic/genetic
  groups might acquire the ability to become
  efficiently transmissible

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Availability of Vaccine Viruses and Reagents

• rg A/Viet Nam/1203/2004 (Clade 1) available
  from St. Jude CRH
• Antigen and sheep serum available from CBER
• rg A/Viet Nam/1194/2004 (Clade 1) available
  from NIBSC
• Antigen and sheep serum available from NIBSC
• rg A/Indonesia/05/2005 (Clade 2.1) available
  from CDC
• Antigen and sheep serum - available soon from
  CBER
• rg A/Turkey/turkey/1/2005 (Clade 2.2) available
  from NIBSC
• Antigen and sheep serum available from NIBSC
• rg A/BHG/Qinghai Lake/1A/05 (Clade 2.2)
  available from St. Jude
• Reagents not yet in production
• rg A/whooper swan/Mongolia/244/2005 (Clade 2.2)
  available for research
• Reagents not in production
• rg A/Anhui/1/05 (Clade 2.3) available from CDC

16
Acknowledgements

• WHO National Influenza Centers
• WHO Collaborating Centers and Regulatory
  Authorities in London, Tokyo, Melbourne,
  Canberra, and Memphis
• WHO H5 Reference Laboratories
• WHO Regional Offices
• WHO Headquarters in Geneva
• Many colleagues in Azerbaijan, Cambodia, China,
  Djibouti, Egypt, Indonesia, Iraq, Nigeria,
  Thailand, Turkey, Vietnam and other affected
  countries
• Ministries of Agriculture in affected countries
  and FAO and OIE members
• Members of the Influenza Division, CDC

17
Thank You