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Controlling Animal Influenza and Decreasing Animal-to-Human Transmission

Controlling Animal Influenza and Decreasing Animal-to-Human Transmission. David E. Swayne Southeast Poultry Research Laboratory Agricultural Research Service U.S. Department of Agriculture Athens, Georgia. Questions. Studies to assess effectiveness of strategies to control animal influenza

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Controlling Animal Influenza and Decreasing Animal-to-Human Transmission

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  1. Controlling Animal Influenza and Decreasing Animal-to-Human Transmission David E. Swayne Southeast Poultry Research Laboratory Agricultural Research Service U.S. Department of Agriculture Athens, Georgia

  2. Questions • Studies to assess effectiveness of strategies to control animal influenza • Studies to assess optimal approaches to use and to assess impact of AI vaccines • What cross-cutting technologies for control of animal influenza are translatable to human pandemic scenarios • Studies to determine whether the circulating AI H5N1 virus in Asia is likely to cause a human pandemic

  3. 1. Animal Influenza Control Strategies WildBirds Fighting Cocks Meat Turkeys Organic Poultry Village Poultry No single poultry production system in SE Asia – vary by country Captive Birds Ducks & Geese Outdoor Industrial Poultry Humans Live Poultry Markets Other Species Meat Ducks, Geese & Chickens Indoor Industrial Poultry Other Species Thus control will vary with each country & their specific agricultural systems Layer Chickens Breeders AR Health 9-04

  4. 1. Animal Influenza Control Strategies WildBirds Fighting Cocks Meat Turkeys Organic Poultry 1 Village Poultry Epizootic – S. Korea Captive Birds Ducks & Geese Outdoor Industrial Poultry Humans Live Poultry Markets Other Species Meat 3 Ducks, Geese & 1-Chickens Indoor Industrial Poultry Other Species Thus control will vary with each country & their specific agricultural systems 6 -Layer Chickens 8 Breeders AR Health 9-04

  5. 1. Animal Influenza Control Strategies WildBirds Fighting Cocks Meat Turkeys Organic Poultry Village Poultry Epizootic – Malaysia Captive Birds Ducks & Geese Outdoor Industrial Poultry Humans Live Poultry Markets Other Species Meat Ducks, Geese & Chickens Indoor Industrial Poultry Other Species Thus control will vary with each country & their specific agricultural systems Layer Chickens Breeders AR Health 9-04

  6. 1. Animal Influenza Control Strategies WildBirds Fighting Cocks Meat Turkeys Organic Poultry Village Poultry Epizootic –Thailand (1st wave) Captive Birds Ducks & Geese Outdoor Industrial Poultry Humans Live Poultry Markets Other Species Meat Ducks, Geese & Chickens Indoor Industrial Poultry Other Species Thus control will vary with each country & their specific agricultural systems Layer Chickens Breeders AR Health 9-04

  7. 1. Animal Influenza Control Strategies WildBirds Fighting Cocks Meat Turkeys Organic Poultry Village Poultry Epizootic –Thailand (2st wave) Captive Birds Ducks & Geese Outdoor Industrial Poultry Humans Live Poultry Markets Other Species Meat Ducks, Geese & Chickens Indoor Industrial Poultry Other Species Thus control will vary with each country & their specific agricultural systems Layer Chickens Breeders AR Health 9-04

  8. Household Income. Source: UNDP (2003). Dolberg – FAO Study

  9. Many households have poultry – few are commercial * In all countries the large majority of rural households have poultry – even in Thailand. * How to formulate strategies that have them co-exist with commercial units? * Up to 80% no services Dolberg – FAO Study

  10. Duck systems • Of interest because of the ducks’ roles as silent carriers of the virus, but limited data • Ducks are 10-15% of the poultry population in the five countries • Three systems: • Commercial • Migrating, seasonal and large flocks: rice fields, large water bodies • A household system with a few ducks mixed with chicken – frequency not known Dolberg – FAO Study

  11. The market • Played a role in spreading the disease • Farmers sell sick animals • Women keep birds in more than one household as a safety measure for “a bad day”. Dolberg – FAO Study

  12. 1. Animal Influenza Control Strategies • Veterinary infrastructure • Adequate GDP • Low rural population in animal agriculture • Education on disease control • Financial incentives to seek control • Successes (eradication): Japan, S. Korea, Malaysia, (Taiwan) • Successes in management: Hong Kong, China, (Thailand)

  13. 1. Animal Influenza Control Strategies • Country specific epidemiological studies – FAO, OIE, EU, and others • Surveillance: agricultural systems, captive birds and wild birds • Understanding pathogenesis in affected bird species – domestic, captive and wild birds • Could pigs play a future role in pandemic virus generation? • Creative solutions for smallholder: education, economic incentives, changes in agricultural systems IOM-NAS 2005

  14. 2. Animal-to-Human Transmission Potential Modes of Transmission to Humans • Inhalation: • Contaminated dust from farming operations • Fine water droplets generated during slaughtering, defeathering, eviscerating and preparing • Contact with oral/nasal mucus membrane or conjunctiva: • Hand-transplantation of virus from contaminated surface (poultry feces, respiratory secretions or other contaminated products) • Direct oral exposure in cleaning fighting cocks? • Consumption of raw products? • Duck blood pudding & internal organs • No epidemiological evidence at this time

  15. 2. Animal-to-Human Transmission • Exposure Risks for Infection: Assessment of H5N1 HPAI - human cases [HK 1997, Vietnam & Thailand early 2004] (Mounts et al., J. Inf. Dis, 180:505-508, 1999; Tran et al., NEJM 350 [12]:1179-88, 2004; Chotpitayasunondh et al., EID 2005 11(2):201-9) • Risk: exposure 1 week before illness to live poultry, direct contact w/sick poultry • Not a risk: travel, preparing or eating poultry meat, or exposure to human AI cases • Not involved in organized culling or large poultry farms • Cases were associated with Village (smallholder) poultry or Live Poultry Market

  16. 2. Animal-to-Human Transmission • Occupational risk for exposure & infection (HK 1997): poultry farmers, depopulation crews & processors (Bridges et al., J. Inf. Dis. 185:1005-1010, 2002). • Some suspected limited human-to-human transmission – family clusters • January 2004 cases in Hanoi (Liem et al., EID 2005 11(2):210-5): no health careworker cases • Needs: • Timely epidemiological studies and sharing of data with veterinary medical sector which will assist in focusing control efforts in animal agricultural sector

  17. 3. Disease Control Basics • Strategies for dealing with poultry disease are developed to achieve one of 3 goals or outcomes: • Prevention: preventing introduction • Management (Control): reducing losses by minimizing negative economic impact through management practices • Eradication: total elimination • These goals are achieved through various strategies developed using universal components: • Biosecurity (exclusion and inclusion) including quarantine • Diagnostics and surveillance • Elimination of AI virus infected poultry • Decreasing host susceptibility to the virus (vaccines and host genetics) • Education IOM-NAS 2005

  18. Avian Influenza Vaccines: Poultry • Vaccination not routine in most of the world • No single vaccine for AI viruses • Anti-HA antibodies are protective, but NA also protective, less effective • Types of Vaccines • Inactivated whole AI virus (C,E) • Recombinant live virus vectors: Fowl Pox (C), VEE (E), ALV (E), Vaccinia (E), ILT (E), NDV (E) • Subunit AI proteins (E) - HA, NA: Baculovirus, Yeast, Bacterial, Plant • Naked DNA vaccines (E) • Critical: safety, purity, potency & economy IOM-NAS 2005

  19. Vaccines in AI Control • LPAI outbreaks - • Waterfowl - origin viruses: Meat Turkeys (Minnesota: 22 million doses over 20 years) – • Swine influenza (H1N1, H1N2, H3N2): Turkey Breeders (2.6 million USA 2001): other subtypes in world used • H7 & H5 in Italy – use in areas high risk since 2000 • H9N2 Middle East and Asia: billions (?) doses • Layers - rare use USA (inactivated H6N2 & H7N2) • HPAI – outbreaks • Mexico (1995-2001) - H5N2: >1.3 billion doses inactivated & >1 billion doses Fowlpox recombinant • Pakistan (1995-04) - H7N3: inactivated (? Doses) • Hong Kong (2002-04) – H5N1: inactivated; China & Indonesia for unknown period (2 billion doses) IOM-NAS 2005

  20. Avian Influenza Vaccines in Asia • Inactivated vaccine strains: • A/turkey/England/73 (H5N2) LPAIV • A/chicken/Mexico/94 (H5N2) LPAIV • A/chicken/Indonesia/03 (H5N1) HPAIV • A/turkey/Wisconsin/68 (H5N9) LPAIV • Infectious clone: H5 & N1 genes of A/goose/Guangdong/96, 6 internal genes PR8 • Fowlpox recombinants with cDNA inserts of AI viral genes • H5 gene - A/turkey/Ireland/83 • H5 & N1 - A/goose/Guangdong/96 IOM-NAS 2005

  21. Components of Effective Inactivated AI Vaccines • Proper adjuvant system (major) • High antigen mass in each dose (major) • Proper transportation, storage & administration in high proportion of population to get effective immunization (major) • Proper vaccine strain – homologous hemagglutinin and sufficient sequence similarity (minor contribution) IOM-NAS 2005

  22. Priorities for Vaccination Decreasing Order of Priority • High risk situations; e.g. in an outbreak zone as ring or suppressor vaccination • Valuable genetic stock such as pure lines or grandparent stocks whose individual value is high • Rare captive birds • Long-lived birds, such as egg layers or parent breeders • Meat birds IOM-NAS 2005

  23. Properly Used AI Vaccines Protection • Increase resistance to AIV infection • Prevent clinical signs and death • Reduced shedding of field virus when infected • Prevent or reduce contact transmission • Provide long protection from single vaccination • Protect against high exposure dose of field virus • Protect against a changing virus, but vaccine strains will have limited life span • NO STERLIZING IMMUNITY outside the laboratory IOM-NAS 2005

  24. Recombinant Fowlpox & Inactivated H5N9 AI Vaccine Protection Against H5N1 Chickens vaccinated SQ 1d with fowlpox-AIV-H5 recombinant* or inactivated whole AIV vaccine** and IN challenged at 3 wks with low challenge dose (103.3 EID50 of HPAIV A/chicken/South Korea/2003 [H5N1]). *H5 gene of A/turkey/Ireland/83 ** A/turkey/Wisconsin/68 (H5N9) Swayne, Develop. Biol. 119:219-228, 2004 IOM-NAS 2005

  25. Recombinant Fowlpox & Inactivated H5N9 AI Vaccine Protection Against H5N1 Chickens vaccinated SQ 1d with fowlpox-AIV-H5 recombinant* or inactivated whole AIV vaccine** and IN challenged at 3 wks with low challenge dose (103.3 EID50 of HPAIV A/chicken/South Korea/2003 [H5N1]). *H5 gene of A/turkey/Ireland/83 ** A/turkey/Wisconsin/68 (H5N9) Swayne, Develop. Biol. 119:219-228, 2004 IOM-NAS 2005

  26. Vaccine Protection Against Asian H5N1 • Chickens vaccinated SQ 3 wks with inactivated whole AIV vaccine and IN challenged 3 wks later with 106.0 EID50 of HPAIV (A/chicken/Indonesia/7/2003 [H5N1]) • 1994 North American vaccine virus • 1986 Eurasian vaccine virus HA1 A.A. similarity with challenge virus, Mexican Strain 84.8% & European 91.9% IOM-NAS 2005

  27. Protect Against a Changing Virus • Fowl pox with H5 AIV gene insert • Different challenge viruses (87.3-100% aa sequence similarity) * challenge viruses (Swayne et al., Vaccine 18:1088-1095. 2000) IOM-NAS 2005

  28. Fowlpox Recombinant Virus: Protection Against Changing Virus *Fowlpox-AI HA had TK/Ireland/83 as insert (Swayne et al., Vaccine 18:1088-1095. 2000) IOM-NAS 2005

  29. Protection in the Face of Changing AIV (Swayne et al., Vaccine 18:1088-1095. 2000) • 100% protection from clinical signs and death • Variable reduction in shedding of challenge virus IOM-NAS 2005

  30. Broad and longer-term protection efficacy of poultry AI vaccines • Proprietary oil-emulsion-adjuvant technology → intense & long-lived immune response • AI virus immune response in poultry appears to be broader than in humans • Greater genetic homogeneity in poultry gives more consistent immunity • Young, healthy poultry population are immunized verses in humans with emphasis on population at highest risk of severe illness and death • Limit to how long a vaccine strain can be used – evaluated biennially IOM-NAS 2005

  31. Limitations and Disadvantages of Avian Influenza Vaccines • Best protection is in experimental studies with specific pathogen free chickens • Field protection less than in laboratory • High challenge exposure • Improper vaccination technique • Reduced vaccine dose • Immunosuppressive viruses • Improper storage & handling of vaccines • Unable to vaccinate 100% of poultry population IOM-NAS 2005

  32. Cross Protection of Commercially Vaccinated Birds to Different LPAI Challenge • Mexico: use of vaccination to control both LPAI and HPAI started in 1995 using killed and in 1998 using recombinant Fowl poxvirus (TK/Ireland/83 H5 gene insert) • Has field strain drifted from vaccine? Is protection still adequate? (Lee et al., J. Virol. 78:8372-8381, 2004) IOM-NAS 2005

  33. HA CK/Jalisco/14585-660/94 CK/Jalisco/28159-600/95 CK/Hidalgo/28159-460/95 Mexican H5 Phylogenetic Lineage CK/Guanajuato/28159-331/95 CK/Michoacan/28159-530/95 CK/Queretaro/14588-19/94 CK/Queretaro/7653-20/95 CK/Queretaro/22019-853/96 CK/Mexico/31381-1/94 CK/Mexico/31381-2/94 Jalisco CK/Mexico/31381-4/94 CK/Mexico/31381-3/94 CK/Mexico/31382-1/94 CK/Mexico/31381-5/94 CK/Hidalgo/28159-232/95 (VACCINE) CK/Queretaro/26654-1373/94 CK/Morelos/28159-538/95 CK/Hidalgo/26654-1368/94 CK/Mexico/26654-1374/94 CK/VeraCruz/28159-398/95 CK/Mexico/31381-6/94 CK/Mexico/31381-8/94 CK/Mexico/31381-7/94 CK/Mexico/15407/97 CK/Mexico/28159-541/95 CK/Chiapas/28159-488/95 CK/Mexico/37821-771/96 CK/Chiapas/15406/97 A CK/Chiapas/15408/97 CK/Vera Cruz/232-6169/98 A CK/Puebla/231-5284/98 CK/Morelos/FO22189/98 CK/Morelos/227-4353/98 CK/Jalisco/229-4592/98 CK/Aguascalientes/124-3705/98 CK/Puebla/14585-622/94 Puebla CK/Puebla/14586-654/94 CK/Puebla/8623-607/94 CK/Puebla/8624-604/94 CK/Puebla/28159-474/95 CK/Chiapas/15224/97 CK/Chiapas/15405/97 CK/Tabasco/234-8289/98 CK/FO/22066/98 B CK/Guatemala/45511-1/00 B CK/Guatemala/45511-2/00 CK/Guatemala/45511-3/00 CK/Guatemala/45511-4/00 CK/El Salvador/102711-1/01 CK/El Salvador/102711-2/01 CK/Guatemala/45511-5/00 CK/Guatemala/194573/02 5 changes (Lee et al., J. Virol. 78:8372-8381, 2004) IOM-NAS 2005

  34. Limitations and Disadvantages of Avian Influenza Vaccines • Must be able to differentiate infected from vaccinated animals (DIVA): • Must detect “silent” infections and eliminate immediately • All vaccinated flocks must have surveillance • Specific serological tests, or • Unvaccinated sentinel animals – serology and virus detection, and • Virus detection (virus isolation or RT-PCR) on dead birds IOM-NAS 2005

  35. Interference of AI Vaccination with Surveillance Serological Test Homo. Hetero. NA (NI) - - X - - HA (HI) X X X X - NA (NI) X X - - - NP/M (AGP/ELISA) X X X - - NS X - - - - AI Field Virus Homologous NA inactivated AIV vaccine Heterologous NA inactivated AIV vaccine Recombinant Fowlpox, subunit HA & DNA HA vaccines Unvaccinated sentinels IOM-NAS 2005

  36. Needs in Vaccines and Vaccination • Standards in purity, safety & potency of AI vaccines • Studies to confirm efficacy of AI vaccines in ducks, geese and other minor poultry species • Effective vaccines that can be applied by mass immunization method • Metabolizable oil adjuvant systems • Sterilizing immunity? • Effective DIVA strategies that will be used to identify infected flocks for elimination • Periodic evaluation of vaccine strains for efficacy against predominate circulating strains IOM-NAS 2005

  37. 4. Will the H5N1 Be the Next Pandemic Virus? • Lesion distribution and infection in mice similar to humans Dybing et al., J. Virol 74(3):1443-1450, 2000 • Experimentally, some AIV cause infection and disease in mice, but not all AIV do! • Value of Ferret and Primate models (Dybing et al., 2000) IOM-NAS 2005

  38. Not all Asian H5N1 AIV have same potential to infect and cause disease in humans Three H5N2 HPAIV in intranasally inoculated BALB/c mice (Tumpey et al., J. Virol. 76:6344-6355, 2002) • 2003-2004: Cases only in Thailand, Vietnam and Cambodia, but not other Asian countries with H5N1 poultry cases • Differences in virus strains • Exposure differences IOM-NAS 2005

  39. Groups Mouse Strain BALB/c (Mx1-) CAST/Ei (Mx1+ & Mx1-) Mortality Virus Isolationb Mortality Virus Isolationb Trachea Lung Trachea Lung Control 0/2 0/2 0/2 0/2 0/2 0/2 PA/11767/97 (H7N2) 0/5 1 /2(102.5) 0/2 0/5 0/2 0/2 PA/19241/97 (H7N2) 0/5 2/2(106.2) 2/2(105.2) 0/5 0/2 0/2 HK/156/97 (H5N1) 5/5 2/2(106.0) 2/2(107.8) 5/5 2/2(104.0) 2/2(107.2) Do LPAIV have the potential to infect and cause disease in humans? (Henzler et al., Avian Diseases 47:1022-1036, 2003) IOM-NAS 2005

  40. Human Pandemic Influenza • Which one of the avian influenza viruses could contribute genes to the next human pandemic virus? • LP verses HPAI as contributor of genes • Asian H5N1 HPAI • Asian H9N2 LPAI • H7N3 HPAI • H7N7 HPAI • H7N2 LPAI • H2N2 – the old nemesis?

  41. Needs: Determine What AI Virus(es) Have Greatest Potential to be the Next Pandemic Virus! • Develop, evaluate and use animal models to predict and understand human infection and transmission potential for circulating AI viruses including H5N1 Asian viruses • Determining in vitro anti-viral susceptibility and in vivo vaccine protection against circulating H5N1 AI viruses as prelude to human prevention • Reverse genetic studies to identify avian genes from specific strains with greatest pandemic potential (reassortants) - Caution should be exercised as to the appropriate biosafety level for reassortant studies to generate a potentially pandemic strain by reverse genetics IOM-NAS 2005

  42. Thank You For Your Attention! IOM-NAS 2005

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