OIE Regional Expert Group Meeting for the Control of Avian influenza in Asia Sapporo, 3-5 October 2017 For the control of avian influenza Hiroshi Kida Hokkaido University Research Center for Zoonosis Control OIE Reference Laboratory for Avian Influenza WHO Collaborating Centre for Zoonoses Control National Research Centre for the Control and Prevention of Infectious Diseases, Nagasaki University
For the control of avian influenza 1. How do highly pathogenic avian influenza viruses emerge? 2. Why have the H5 HPAIVs persisted in poultry for 20 years? 3. Why are antigenic variants of different clades circulating in poultry birds? 4. Will the HPAIVs that have returned to migratory birds persist in nature? 5. Then, how should we control HPAI?
Duck influenza Each of the known subtypes (H1-16, N1-9) of influenza A virus has been isolated from ducks. In ducks, viruses replicate in the colon, being shed with feces in a week, and non-pathogenic. Water-borne fecal-oral transmission Viruses are preserved in frozen water of the lakes, where ducks nest in summer, in winter in Alaska, Siberia etc. Ducks carry and provide viruses during migration and over-wintering. Influenza viruses circulating in ducks are highly stable antigenically and genetically. Migratory duck is the natural host of influenza A viruses. Kida et al (1980) Infect Immun; (1987) Virology; Ito et al (1995) Arch Virol
Acquisition of pathogenicity of avian influenza viruses in chickens APAIV 6~9 Months LPAIV HPAIV (H5 or H7)
Return of the HPAIV from domestic poultry to migratory water birds APAIV > 6 months LPAIV HPAIV (H5 or H7)
HPAI viruses isolated from wild birds in Mongolia Awhooper swanmongolia305 (H5N1) Abar-headed goosemongolia105 (H5N1) Acommon goldeneyemongolia1206 (H5N1) Ugii Lake Awhooper swanmongolia206 (H5N1) Qinghai Lake Awhooper swanmongolia209 (H5N1) Awhooper swanmongolia909 (H5N1) Abar-headed goosemongoliax5309 (H5N1) Arubby sholduckmongoliax422009 (H5N1) Acommon goldeneyemongoliax6009 (H5N1) Awhooper swanmongolia110 (H5N1) Awhooper swanmongolia710 (H5N1)
03 04 05 06 07 08 09 10 11 12 13 14 15 16 03 04 05 06 07 08 09 10 11 12 13 14 15 16 Confirmed human cases of H5N1 HPAIV infection Country DeathCases China 中国 Egypt China Vietnam Indonesia Egypt Cambodia Lao PDR Thailand Iraq Azerbaijan Turkey Djibouti Nigeria Myanmar Pakistan Bangladesh Canada 31 64 167 120 37 2 17 2 5 4 0 1 0 1 1 1 53 127 199 359 56 2 25 3 8 12 1 1 1 3 8 1 Viet Nam インドネシア Indonesia Thailand タイカンボジア Cambodia Total 453 859 As of 25 July 2017 WHO
Bird flu vaccines Vietnam: H5N2 and H5N1 (Adjuvant inactivated vaccines) China: H5N1 and recombinant NDV ( Reverse genetics inactivated vaccines) Indonesia: H5N1, H5N2, H5N9 and recombinant H5N1 (inactivated vaccines) Egypt: since 2006 Thailand: Officially prohibited vaccination in 2006 As a stockpile, Singapore: H5N2 ( Inactivated, adjuvanted vaccine) Japan: H5N1 and H7N7 (Oil-adjuvanted inactivated vaccines) Pakistan: H5N1, H5N2, H5N9, and H5N3 (Water based with alum hydroxide and oil based with mineral oil)
Selection of antigenic variants of an H5 HPAIV strain in vaccinated chickens Study-I Challenge strain: WsHok11 (H5N1) Vaccine strain: WsHok11 (H5N1) Y VacP1 Y VacP2 Y VacP3 Y VacP9 VacP8 1 st passage 2 nd passage 3 rd passage 9 th passage Challenge strain: WsHok11-VacP9 (H5N1) Study-II Vaccine strain: WsHok11-VacP9 (H5N1) Y VacP9 VacP1 Y VacP9 VacP2 Y VacP9 VacP3 Y VacP9 VacP4 1 st passage 2 nd passage 3 rd passage 4 th passage WsHok11 (H5N1): Awhooper swanhokkaido42011 (H5N1) Lam et al (2017) Virology
Antigenicity and amino acid substitutions on the hemagglutinin of passaged viruses in Study-I Viruses NT titers a HI titers a Amino acid positions on the hemagglutinin b,c 131 179 WsHok11-P0 (H5N1) 32 32 Q G WsHok11-VacP1 (H5N1) 32 32 WsHok11-VacP2 (H5N1) 32 32 WsHok11-VacP3 (H5N1) <2 2 D WsHok11-VacP4 (H5N1) <2 2 R D WsHok11-VacP5 (H5N1) <2 2 R D WsHok11-VacP6 (H5N1) <2 2 R D WsHok11-VacP7 (H5N1) <2 2 R D WsHok11-VacP8 (H5N1) <2 2 R D WsHok11-VacP9 (H5N1) <2 2 R D WsHok11-NonvacP9 (H5N1) 32 32 a Neutralization (NT) and hemagglutinin inhibition (HI) titers of the chicken antiserum against WsHok11-P0 (H5N1). Homologous titers were underlined. b Methionine encoded by AUG start codon is defined as position 1 (H5 numbering). c indicates the same amino acids with original virus of WsHok11-P0 (H5N1). Lam et al (2017) Virology
Antigenicity and amino acid substitutions on the hemagglutinin of passaged viruses in Study-II Viruses NT titer a HI titer a Amino acid positions on the hemagglutinin b,c 144 256 339 WsHok11-VacP9 (H5N1) 16 16 S H R WsHok11-VacP9VacP1 (H5N1) 16 16 G WsHok11-VacP9VacP2 (H5N1) 16 16 G WsHok11-VacP9VacP3 (H5N1) <2 <2 R G WsHok11-VacP9VacP4 (H5N1) <2 <2 P R G? WsHok11-VacP9NonvacP4 (H5N1) 16 16 a Neutralization (NT) and hemagglutinin inhibition (HI) titers of the chicken antiserum against WsHok11-VacP9 (H5N1). Homologous titers were underlined. b Methionine encoded by AUG start codon is defined as position 1 (H5 numbering). c indicates the same amino acids with parental virus of WsHok11-VacP9 (H5N1). Lam et al (2017) Virology
Antigenic characterization of cloned variants isolated from Study-I and Study-II by cross-reactivity Viruses a HI titers b Amino acid positions on the hemagglutinin c,d P0 VacP9 131 144 179 256 339 WsHok11-P0 (H5N1) #1 32 <2 Q S G H R WsHok11-VacP3 (H5N1) #1 4 16 D WsHok11-VacP9 (H5N1) #1 4 16 R D WsHok11-VacP9VacP1 (H5N1) #1 4 16 R D G WsHok11-VacP9VacP3 (H5N1) #1 4 <2 R D R G WsHok11-VacP9VacP4 (H5N1) #10 4 <2 R P D R G WsHok11-VacP9NonvacP4 (H5N1) #1 4 16 R D a # indicates cloned identification number. b Chicken antisera against WsHok11-P0 (H5N1) and WsHok11-VacP9 (H5N1) were used. Homologous titers were underlined. c Methionine encoded by AUG start codon is defined as position 1 (H5 numbering). d indicates the same amino acids with original virus of WsHok11-P0 (H5N1). Lam et al (2017) Virology
143 237 179 144 (0.96) 256 131 (0.59) Antigenic sites Receptor binding site Lam et al (2017) Virology
Influenza Vaccine for bird flu prevent manifestation of disease signs and decrease the amount of virus shed, but does not confer complete protective immunity from infection. Stamping-out policy is recommended for the control of avian influenza. Vaccination was not primarily recommended, and later approved as one of the options applied when the control of avian influenza is difficult. Country where vaccine is used is not designated as HPAI-free. leads silent spread of virus.
26TH CONFERENCE OF THE OIE REGIONAL COMMISSION FOR ASIA, THE FAR EAST AND OCEANIA Shanghai, People s Republic of China, 16-20 November 2009 RECOMMENDATION FOR THE CONTROL OF AVIAN INFLUENZA It is considered that; Highly pathogenic avian influenza H5N1 virus strains have persisted in domestic poultry for 14 years and antigenic variants have been selected mainly due to the misuse of vaccine. HPAI has been put under control in several countries. Stamping out policy has been the most effective measures for the control HPAI. Vaccine is used in 4 countries where HPAI has not been controlled. Vaccine is used instead of stamping out in 2 countries and in the other 2 countries, basically in addition to stamping out. Sentinel birds are put in the vaccinated poultry population in Viet Nam and not in the other 3 countries where vaccine is used. Compensation for livestock owners is done in most countries in case of stamping out. It is recommended that; Since stamping out is the best and ultimate measure for the control of HPAI, vaccine should be used in addition to, not instead of stamping out. The OIE should continue and develop standards on animal influenza surveillance, prevention and control. Surveillance of swine flu is crucial in the countries where avian flu has not been controlled.
For the control of avian influenza 1. How do Highly Pathogenic Avian Influenza viruses emerge? Live bird markets play a role of transmission of LPAIVs from water birds to terrestrial birds such as chickens and quails who select HPAIVs. 2, Why have the H5 HPAIVs persisted in poultry for 20 years and been antigenic variants selected? Because of misuse of vaccine. 3. Will the HPAIVs that returned to migratory birds persist in nature? Contamination of HPAIVs in the nesting lakes of migratory ducks have occurred. Prompt eradication of the H5 HPAIVs from poultry birds in Asia is urgently needed. 4. Does influenza vaccine confer complete protective immunity? No. 5. How should we control HPAI? Containment and eradication of HPAIVs in the poultry flocks infected, early detection, culling the flock, movement restriction, and strengthening hygienic measures without misuse of vaccine. Vaccine should be carefully used in addition to, not instead of stamping out. International coordination and cooperation are essential.
Thank you for your kind attention.