avian influenza

Pictures

Picture	Title	Caption	Copyright
Title External signs Caption Oedema of the wattles Copyright ©USDA-2002/Foreign Animal Diseases Training Set/USDA-Animal and Plant Health Inspection Service (APHIS)	External signs	Oedema of the wattles	©USDA-2002/Foreign Animal Diseases Training Set/USDA-Animal and Plant Health Inspection Service (APHIS)
Title External signs Caption Cyanotic comb of an infected chicken (a) compared with a normal chicken (b). Copyright ©USDA-2002/Foreign Animal Diseases Training Set/USDA-Animal and Plant Health Inspection Service (APHIS)	External signs	Cyanotic comb of an infected chicken (a) compared with a normal chicken (b).	©USDA-2002/Foreign Animal Diseases Training Set/USDA-Animal and Plant Health Inspection Service (APHIS)
Title Signs Caption Cyanosis of comb and wattles Copyright Dirk van Aken	Signs	Cyanosis of comb and wattles	Dirk van Aken
Title Signs Caption Severe (terminal) respiratory distress Copyright Dirk van Aken	Signs	Severe (terminal) respiratory distress	Dirk van Aken
Title Signs Caption Diarrhoea Copyright Dirk van Aken	Signs	Diarrhoea	Dirk van Aken
Title External signs Caption Congestion and petechiae in the skin on the hocks and shanks. Copyright ©USDA-2002/Foreign Animal Diseases Training Set/USDA-Animal and Plant Health Inspection Service (APHIS)	External signs	Congestion and petechiae in the skin on the hocks and shanks.	©USDA-2002/Foreign Animal Diseases Training Set/USDA-Animal and Plant Health Inspection Service (APHIS)
Title Internal signs Caption Opened oedematous wattle. Copyright ©USDA-2002/Foreign Animal Diseases Training Set/USDA-Animal and Plant Health Inspection Service (APHIS)	Internal signs	Opened oedematous wattle.	©USDA-2002/Foreign Animal Diseases Training Set/USDA-Animal and Plant Health Inspection Service (APHIS)
Title Pathology Caption Serofibrinous pericarditis Copyright Dirk van Aken	Pathology	Serofibrinous pericarditis	Dirk van Aken
Title Pathology Caption Fibrinous adhesions, haemorrhages and lung congestion Copyright Dirk van Aken	Pathology	Fibrinous adhesions, haemorrhages and lung congestion	Dirk van Aken
Title Pathology Caption Haemorrhages in the muscle Copyright Dirk van Aken	Pathology	Haemorrhages in the muscle	Dirk van Aken
Title Pathology Caption Necrotic foci in the liver Copyright Dirk van Aken	Pathology	Necrotic foci in the liver	Dirk van Aken
Title Pathology Caption Necrotic foci in the spleen Copyright Dirk van Aken	Pathology	Necrotic foci in the spleen	Dirk van Aken
Title Pathology Caption Severe congestive and haemorrhagic lesions in the lung Copyright Dirk van Aken	Pathology	Severe congestive and haemorrhagic lesions in the lung	Dirk van Aken

Identity

Preferred Scientific Name

• avian influenza

International Common Names

• English: avian influenza, AI in birds; bird flu; bird grippe; Brunswick bird plague; Brunswick disease; fowl disease; fowl grippe; fowl pest; fowl plague; high pathogenicity avian influenza; highly pathogenic avian influenza; low pathogenic avian influenza; low pathogenicity avian influenza; typhus exudatious gallinarium
• French: grippe aviaire; peste aviaire

Local Common Names

• Germany: Geflugelpest

English acronym

• AI
• HPAI
• LPAI

Pathogen/s

Overview

Influenza viruses belong to the family Orthomyxoviridae and are divided on the basis of their antigenic nature into types A, B and C. Only type A influenza viruses are of interest to veterinarians because they can infect birds, pigs, horses, and occasionally seals, whales and mink. Influenza viruses that infect birds are called avian influenza viruses. The first reports of the disease in chickens caused by avian influenza viruses occurred in 1878 in northern Italy. This disease was originally termed 'fowl plague' because of the devastating high mortality rate, but today, this disease is called highly pathogenic avian influenza. The pathogenicity of avian influenza viruses varies widely and clinical signs of disease range from mild respiratory signs to multi-systemic infections with near 100% mortality. Low pathogenicity avian influenza viruses cause the milder forms of avian influenza while highly pathogenic avian influenza viruses cause the more severe form. However, the presence of secondary pathogens or environmental stressors can increase the severity of disease associated with low pathogenicity avian influenza viruses.

Avian influenza viruses can infect most domestic and wild bird species. Influenza viruses have been known to be widely present in waterfowl since the 1970s and most such viruses are of low pathogenicity for poultry. An outbreak of highly pathogenic avian influenza in broilers in Pennsylvania and Virginia, USA, in 1983-1984 led to the slaughter of approximately 11 million birds at a cost of approximately US $61 million. Epidemics of highly pathogenic avian influenza (H5N2) in broilers in Mexico (1993-1995) and of both high and low pathogenic virus (H7N1 and H5N2) in various domestic poultry in Italy between 1997 and 2000 showed that the risk continues. In 1997-1998, avian influenza prompted worldwide concerns after an outbreak of the highly pathogenic H5N1 avian influenza spread from chickens in Hong Kong to humans: six people died and a further 12 were severely affected. The entire population of 1.4 million chickens in Hong Kong was slaughtered. A H5N1 highly pathogenic avian influenza virus reappeared in Hong Kong in 2001 and 2002 resulting in two additional depopulations of chickens in Hong Kong. In 2003, a highly pathogenic virus (H7N7) appeared in the Netherlands resulting in the death or slaughter of 23 million chickens.

Avian influenza viruses are further classified based on their surface proteins; i.e. haemagglutinin and neuraminidase. There are (at least) 16 different haemagglutinin and nine neuraminidase subtypes based on serological testing with the haemagglutinin-inhibition and neuraminidase inhibition tests, respectively. Low pathogenicity avian influenza viruses can be any of the 16 haemagglutinin (H1-16) and nine neuraminidase (N1-9) subtypes. However, highly pathogenic avian influenza viruses have only been of the H5 and H7 haemagglutinin subtypes. The haemagglutinin is the surface protein of greatest immunological significance and provides the basis of immunological protection. Generally, antibodies against one of the haemagglutinins offer little or no protection against a virus with a different haemagglutinin subtype. The virulence of the avian influenza viruses ranges from very low (causing low pathogenicity avian influenza, LPAI) to very high (causing highly pathogenic avian influenza, HPAI). However, some LPAI viral strains are capable of mutating under field conditions to HPAI.

Avian influenza [defined as an infection of poultry caused by any influenza A virus with high pathogenicity and by H5 and H7 subtypes with low pathogenicity] is on the list of diseases notifiable to the World Organisation for Animal Health (OIE). The distribution section contains data from OIE's WAHID database on disease occurrence. For further information on this disease from OIE, see the website: www.oie.int.

Host Animals

Hosts/Species Affected

Wild birds

Since the mid-1970s, avian influenza viruses have been isolated from avian species representing most of the major families of birds throughout the world. Stallknecht and Shane (1988) in their review of surveillance studies listed 88 species of birds, covering 12 orders, which have been found to excrete influenza virus. The actual number of naturally infected or susceptible species is probably much greater because these surveys have been selective with respect to the species sampled, the geographical locations examined and the time of year sampling occurred. Most avian influenza viruses have been isolated from ducks, although other wild birds may also be infected including other waterfowl, shorebirds, and gulls and other seabirds. Wild birds and their excreta are considered to be a major source of avian influenza virus. Most avian influenza virus infections of wild birds are asymptomatic.

Domestic poultry

Turkeys are more commonly infected than chickens probably because of differences in husbandry systems. Preventing direct contact with free-flying birds and protecting domestic poultry from contact with the faeces of wild birds is an important way to prevent initial introduction of avian influenza into domestic poultry. Modern commercial chicken farms are made wild bird-proof. Turkeys, however, are often raised on open ranges, and this has resulted in outbreaks of primarily low pathogenicity avian influenza. Also at risk to avian influenza are poultry raised outdoors for organic or free-range markets, domestic ducks raised on ponds frequented by wild ducks, live poultry markets with multiple bird sources and multi-directional movement of birds, and small farm enterprises that raise multiple poultry species and such birds having access to outdoor areas.

Systems Affected

Distribution

Avian influenza viruses occur worldwide in both wild and domestic birds. Migratory birds, especially waterfowl are believed to be important reservoir hosts, and shed the virus in their respiratory and ocular secretions as well as in faeces. These birds frequently introduce avian influenza viruses into local, non-migratory, wild bird populations. Infected wild birds can transmit the virus to domestic birds such as chickens and turkeys. Asymptomatic carrier birds may also transmit the virus.

Avian influenza notifiable to OIE is defined as an infection of poultry caused by any influenza A virus with high pathogenicity (HPAI) and by H5 and H7 subtypes with low pathogenicity (H5/H7 LPAI). Influenza A viruses with high pathogenicity in birds other than poultry, including wild birds, are also notifiable.

Since 2002 a number of serious outbreaks of HPAI have occurred in different regions of the world with massive disruption to international trade, the culling of millions of birds, and transmission to humans resulting in disease and mortality.

The only country in Africa that reported cases of HPAI to the AU-IBAR in 2011 was Egypt. The country reported a total of 306 outbreaks that involved a morbidity of 218,797 and mortality of 31,851 birds. With the exception of Egypt, there has been a significant reduction in the number of HPAI outbreaks being reported on the African continent. The countries that have reported cases of HPAI in recent years include Egypt (2009, 2010, 2011), South Africa (2010) and Togo (2008).

Countries reporting avian influenza in 2011 to AU-IBAR 

The distribution map associated with this datasheet illustrates occurrence of notifiable avian influenza in poultry.

Distribution Table

The distribution in this summary table is based on all the information available. When several references are cited, they may give conflicting information on the status. Further details may be available for individual references in the Distribution Table Details section which can be selected by going to Generate Report.

Pathology

Highly pathogenic avian influenza in poultry is characterized by subcutaneous haemorrhages and oedema of the head. Vesicles to necrotic foci may be present on the comb and wattles. Haemorrhages can be seen in the serosa of all visceral organs and in the mucosa and lymphoid tissue of the intestinal and respiratory tracts. Low pathogenicity influenza results in tracheitis, pulmonary oedema and air sacculitis. Occassionally, low pathogenicity avian influenza viruses may cause sowllen kidneys (nephrosis), visceral urate deposition ('visceral gout') and exudative inflammation in the lumen of the oviduct.

Diagnosis

Editor's note: the clinical signs table in this datasheet refers to highly pathogenic avian influenza (HPAI).

Avian influenza (AI) is difficult to diagnose and false positives are not uncommon in preliminary tests. Virus isolation in specific-pathogen-free embryonated eggs or cell cultures is conventionally considered the method of choice for the detection and identification of avian influenza viruses. This is a reliable and specific technique although it is time-consuming and expensive. However, the time between clinical suspicion and laboratory confirmation of AI can be long because of the logistics of sending samples to laboratories and their capacity for providing high throughput of sensitive and specific assays is often limited. Although very accurate, virus isolation is of limited value for control and eradication purposes, because avian influenza is a highly contagious disease and the prompt identification of infection is crucial. In order to shorten the time between receipt of samples in a laboratory and diagnosis there has been widespread application of molecular techniques based on the amplification of specific nucleic acid sequences by polymerase chain reaction (PCR), ligase chain reaction and nucleic acid sequence-based amplification (NASBA). Real-time PCR (Brown, 2006) is increasingly being used, as it enables rapid diagnosis in part due to automation, and also because the PCR products are detected, and quantified, during the DNA amplification process, without requiring a subsequent separate detection process. The development of portable instruments for application of molecular technologies in field offers prospects for radically changing diagnostic approaches for AI in the future (Cattoli and Capua, 2006).

Clinical Diagnosis

Clinical signs of avian influenza vary according to the host, strain of virus, vaccinal immunity, secondary infections and environmental conditions. In some flocks the only evidence of the infection is seroconversion, i.e. the birds infected with a LPAI virus may only develop a detectable antibody titre to avian influenza virus. Birds infected with LPAI virus often develop respiratory, enteric, or reproductive disease. Decreased feed intake and a drop in egg production are some of the earliest and most predictable signs of disease. Birds infected with LPAI may show mild depression with a significant decrease in egg production. Other clinical signs for LPAI include excessive lacrimation, sinusitis, diarrhoea, coughing and sneezing.

Birds with HPAI may show some of the clinical signs of LPAI, but infected poultry usually have swollen heads, facial oedema with swollen and cyanotic unfeathered skin (comb, wattles, snood, feet and legs) and nervous signs such as paresis, paralysis, torticollis, and opisthotonus. Other clinical signs include severe depression and inappetence as well as a significant decline in egg production. Infection with the HPAI virus may cause sudden death with little or no overt signs (mortality can reach 100%). However, none of these signs can be considered pathognomonic. Differential diagnosis should consider acute fowl cholera, velogenic Newcastle disease, and respiratory diseases such as infectious laryngotracheitis.

Laboratory Diagnosis

Diagnosis of avian influenza is made by the isolation of the virus, molecular detection of specific nucleic acids or identification of specific proteins. Serological methods may be used as additional diagnostic tools, but, used alone, are unsuitable for a detailed identification.

The virus can be isolated from variety of sources including faeces, tracheal swabs and cloacal swabs. Inoculation of embryonated SPF chicken eggs is the preferred method of growing avian influenza A viruses but avian cell tissue culture can be used. The presence of haemagglutination activity in allantoic fluids of inoculated 9- to 11-day-old embryonating chicken eggs after incubation for 4-7 days at 35-37°C indicates a high probability of either influenza A virus or Newcastle disease virus infection.

The presence of influenza A virus can be confirmed in the allantoic fluid using agar gel immunodiffusion tests by demonstrating the presence of the nucleocapsid or matrix antigens, which are common to all influenza A viruses. The method for definitive antigenic sub-typing of influenza A viruses recommended by the WHO Expert Committee (1980) involves the use of highly specific antisera against haemagglutinin and neuraminidase subtypes, generally in a reference laboratory. Alternatively, the allantoic fluid can be tested for avian influenza virus type A nucleoprotein or matrix protein by solid phase ELISA test such as Directigen or by detection of avian influenza viral nucleic acids in a reverse transcriptase polymerase chain reaction assay. The antigen or nucleic acid detection tests can also be used to identify avian influenza virus directly in respiratory or cloacal swabs, or tissue homogenates from affected birds.

Further information concerning the pathogenicity of avian influenza subtypes may be obtained by sequencing part of the genome of the virus, where the amino acid make-up of the cleavage site of the haemagglutinin has great significance as an indicator of pathogenicity. Essentially, high pathogenicity H5 and H7 subtype strains have one or more pairs of basic amino acids (arginine, lysine) at the HA1-HA2 cleavage site, rendering the haemagglutinin cleavable by ubiquitous furin proteases present in many cells of organs throughout the body of poultry species. Consequently AIVs with such cleavage sites can replicate in many visceral and other organs and are consequently highly pathogenic. In contrast, low pathogenicity strains generally have only individual basic amino acids, not pairs, in the cleavage site. Proteases able to cleave such cleavage sites are not present in organs throughout the body, thereby restricting replication largely to respiratory and enteric organs where these proteases are present.

List of Symptoms/Signs

Disease Course

The virus is transmitted rapidly to susceptible birds through inhalation or ingestion of influenza particles in nasal and respiratory secretions and by direct contact with faeces of infected birds. Viral replication occurs in the intestinal and respiratory tracts for both low and high pathogenicity avian influenza viruses. The highly pathogenic strains spread to vascular endothelium with replication, causing viraemia and multi-focal necrosis in many visceral organs, skin and brain. These necrobiotic lesions may be accompanied by inflammatory lesions in many organs including heart, skeletal muscle, brain and pancreas. In addition, chicken and turkey succumb after several days of clinical signs, exhibiting petechial haemorrhages and serous exudates in respiratory, digestive and cardiac tissues. Neutralizing antibodies are detectable within 3-7 days after the onset of both high and low pathogenicity avian influenza viruses, reaching a peak during the second week and persisting for up to 18 months in all avian species. Most poultry infected with high pathogenicity avian influenza viruses do not survive but many infected with low pathogenicity viruses recover.

Morbidity is apparent following exposure to either low or high pathogenicity avian influenza viruses. Mortality is consistently high with high pathogenicity avian influenza viruses, but mortality is variable for low pathogenicity avian influenza viruses depending on climatic factors, the presence of secondary pathogens, and environmental conditions.

The avian influenza virus does not persist in individual birds, but within a large population of birds, the virus may spread slowly throughout a production facility; depending on level of immunity, transmissibility of the virus, infectivity of the virus, housing type and host species. A farm cannot be assumed avian influenza virus-free until the infected flock has been removed by depopulation or controlled marketing, and the facility has been thoroughly cleaned and disinfected.

Epidemiology

Avian influenza viruses are highly infectious. Most poultry flocks affected with avian influenza are infected directly or indirectly from other infected poultry flocks. Wild waterfowl, seabirds and shorebirds serve as a reservoir of avian influenza virus, but once it enters the poultry population, these birds no longer have a role in its spread.

Avian influenza viruses show host adaptation with greatest amount of virus replication and easiest transmission occurring between birds in the same or closely related species. However, with repeated infection cycles in a new host species, the avian influenza virus adapts to a new host making transmission easier and faster. Avian influenza virus is periodically introduced into susceptible poultry flocks from wild birds, especially wild ducks. Avian influenza viruses have also been isolated in many countries from imported cage birds. The epidemiological importance of live poultry markets should not be underestimated. They serve as a reservoir and source of introduction to other commercial poultry. Influenza virus is transmitted by direct contact with respiratory secretions and faeces where the virus can survive for long periods, especially in water at low temperatures. Influenza in turkeys is principally seen in countries where they are raised in facilities where wild birds can have access or use drinking water obtained from ponds frequented by wild birds. An important way of preventing exposure to the virus is preventing contact of domestic birds with wild and migratory birds that may carry the virus. For commercial farming operations, preventing exposure to wild birds is also important, but preventing exposure to other domestic poultry that may have had direct or indirect contact with wild birds is more important. Such exposure could be through using dirty chicken crates from live poultry markets, partial load-out of poultry, employees owning backyard poultry or fighting chickens, sharing equipment between farms, lack of visitor restrictions, and failure to disinfect boots and equipment and launder dedicated work clothing on the farm.

Avian influenza is most often transmitted from infected to susceptible flocks by personnel and their equipment. Once introduced into the poultry of an area it can spread rapidly and be extremely difficult to control and/or eradicate.

Impact: Economic

Outbreaks of high pathogenicity avian influenza result in severe losses in production, and high costs associated with disease control and prevention. The cost of the 1983-1984 eradication programme in Pennsylvania and surrounding states far exceeded any other losses attributable to avian influenza. Lasley (1987) estimated that this outbreak cost the government and farmers US $75 million. Subsequent rises in food prices may have cost the consumers an additional US $349 million. An outbreak of HPAI in Australia in 1985 was estimated to have cost more than AUS $2 million (Cross, 1987). The 1997 outbreak of H5N1 highly pathogenic avian influenza in Hong Kong cost US $13 million. The 2000 outbreak of H7N1 high pathogenicity avian influenz cost the Italian government US $100 million in conpensation to farmers (Swayne and Halvorson, 2003).

Low pathogenicity avian influenza leads to a reduction in egg production and exacerbates secondary bacterial infections. Carcass and egg quality declines following infection. Losses in trade due to embargoes and restrictions imposed by importing countries are more devastating economically for some countries than the direct losses caused by an epizootic of avian influenza. In Minnesota alone, a 1978 outbreak cost US $5 million in losses to producers. From 1978 to 1996, losses to producers in Minnesota exceeded US $22 million (Swayne and Halvorson, 2003).

Zoonoses and Food Safety

Most avian influenza virus strains do not infect humans, even when high-risk exposures occur (Swayne and King, 2003). However, avian influenza virus can occasionally infect mammals. Seroepidemiological and virological studies since 1889 have indicated that human influenza infections were caused by H1, H2 and H3 subtypes of influenza A viruses. However, unlike previous outbreaks, an outbreak of H5 subtype of avian influenza virus in Hong Kong in 1997-1998 affected both chickens and humans. Six people died and a further 12 were severely affected in this outbreak, and the entire chicken population of Hong Kong (1.4-1.5 million birds) was slaughtered. The cause of this outbreak was avian influenza A virus, strain H5N1, which was previously thought only to infect birds. These cases represent the first documented human infections with avian influenza A (H5N1) virus. The virus appeared to have been transmitted directly from chickens to humans from contact with live birds and not from consumption of or handling poultry meat. Since then, more than 500 human cases of avian influenza virus infection due to H5, H7 and H9 subtypes have been reported, mainly as a result of poultry-to-human transmission with a fatality rate of over 50% for H5N1 infections. In 1998, seven people were infected with low pathogenicity H9N2 avian influenza virus in China and Hong Kong, but all had uneventful recoveries

The H5N1 virus re-emerged in South Korea in 2003. In that year four cases were reported in China and Viet Nam, a number that increased 10-fold in the following year, with cases in Thailand and Viet Nam. During the next year (2005) the number of reported cases doubled again, Thailand and Viet Nam being joined by Indonesia. The peak number of reports was in 2006 (115 cases, 79 deaths), with Cambodia, Djibouti, Egypt, Iraq and Turkey joining the list of affected countries. Since then the number of cases reported annually has declined, there being 48 and 53 in 2010 and 2011, respectively (as of 2^ndNovember 2011), Egypt reporting more cases than any other country in each year from 2007 to 2011, inclusive. In total 569 cases had been reported from all countries since 2003, 334 of them fatal (59%). The H5N1 virus arrived in Europe in October 2005, but no human cases have been reported. Over 100 people were infected with H7N7 highly pathogenic avian influenza in the Netherlands, with one death. These outbreaks have prompted the governments of many countries to start developing contingency plans for the emergence of an influenza virus that can readily transmit between humans.

Cumulative number of confirmed human cases of avian influenza A/(H5N1) from January 2003 to 2 November 2011 (only laboratory-confirmed cases are included). Taken from the website of the World Health Organization (WHO, http://www.who.int).
 

Disease Treatment

There is no approved effective treatment for infected birds. Drugs for treatment of influenza in humans are expensive and not approved for use in birds. Treatments for secondary pathogens, such as antibiotics for bacteria, and improving environmental conditions can hasten natural recovery of birds from low pathogenicity avian influenza viruses.

In human medicine, the influenza virus-specific antiviral drugs oseltamivir (brand name Tamiflu®) and zanamivir (brand name Relenza®) may reduce clinical signs and accelerate recovery. Both drugs inhibit the neuraminidase (NA) and are active against various subtypes of influenza virus. They are about 70% to 90% effective. Previously several adamantane drugs were used to fight influenza A infections in humans, but these are no longer recommended, due to high levels of resistance among circulating influenza A viruses. (Source, Centres for Disease Control, USA). Jefferson et al. (2006) reviewed the efficacy and safety of registered antiviral drugs against naturally occurring influenza in healthy adults.

Scientists also believe that immunoglobulins obtained from recovered flu patients could be used as an alternative treatment if an avian influenza virus strain develops resistance to antiviral drugs.

Prevention and Control

Prevention is based on biosecurity measures that include avoiding contact between poultry and wild birds, in particular waterfowl, avoiding introduction of birds of unknown disease status into flocks, control of human traffic, proper cleaning and disinfection procedures, and one age group per farm ('all in-all out') breeding systems.

When outbreaks have occurred, all birds in the flock must be slaughtered and the carcasses disposed. Restocking should not occur for at least 21 days.

Immunization and vaccines

Antibodies against the haemagglutinin play the major role in protection following immunization or exposure. These antibodies are protective against the homologous haemagglutinin subtype but not against heterologous subtypes; i.e. H5 vaccine protects against an H5 but not an H7 avian influenza virus.

Several types of commercial vaccines are available, listed though not necessarily endorsed by the Food and Agriculture Organisation (see: Avian Influenza Vaccine Producers and Suppliers for Poultry, June 2009). The largest type is inactivated whole AIV oil emulsion vaccines of H5 or H7 subtypes. These consist of various AIV isolates i.e. all eight genes from the respective AIV isolate, or comprise the H5 and N1 or N3 genes from AIVs plus the six internal protein genes from human A/Puerto Rico/8/34 virus, known as PR8. The PR8 virus has been used for many decades as the basis for human inactivated influenza vaccines, containing the HA and NA genes of a prevailing human influenza virus. PR8 genes confer high productivity in embryonated chicken eggs. There are also some live recombinant virus vectored vaccines against AIV. Two such vaccines comprise an avian poxvirus as the vector, producing H5 or both an H5 and N1 proteins. Another vectored vaccine comprises live Newcastle disease virus (LaSota) producing H5 haemagglutinin.

The use of AI vaccines around the world in poultry is not well documented. It is believed that the largest single use of inactivated avian influenza vaccine (H5N2 strain) has occurred in China (since December 2003 to present). Indonesia has also used H5 inactivated AI vaccine. In Mexico, both inactivated and recombinant fowlpox vaccines have been used since January 1995. Pakistan began using H7 inactivated AI vaccine following epizootics (in 1995, 1998, 2000 and 2003) of H7N3 HPAI and H9N2 LPAI (Naeem and Siddique, 2006). H9N2 inactivated vaccines are used in many countries in Asia, the Middle East and Eastern Europe. The USA also has considerable experience with the use of killed vaccines, primarily in turkeys. In the state of Minnesota in the 1980s and early 1990s vaccines were used successfully to control outbreaks of AI in turkeys. More recently, several large layer flocks have been vaccinated in Connecticut after an H7N2 LPAI outbreak (Suarez et al., 2006). H7 inactivated vaccine has been used in a high-risk area of northern Italy.

In areas where inadequate resources preclude eradication, flocks may be immunized using autogenous inactivated vaccines or recombinant vectored products. These vaccines are effective in preventing disease and reducing the amount of virus shed into the environment, but have the disadvantage of making it difficult to distinguish between infected and vaccinated birds. Vaccination suppresses clinical occurrence of disease but the virus may persist in the poultry population of the affected region unless adequate biosecurity and surveillance measures are undertaken. In most developed countries, vaccines are banned or discouraged because they may interfere with control policies and may also result in export bans on poultry products. However, during the devastating epidemics of HPAI in the 1990s and early 2000s, the mass slaughter of animals raised serious ethical questions. These epidemics showed that the use of emergency vaccination is an essential element in disease control (Clercq and Goris, 2004). With the development of tests or vaccines that will allow differentiation of vaccinated birds from those infected with the field virus, vaccines may come into greater use (Capua et al., 2003; Ellis et al., 2004; Swayne et al., 2006; Zhao et al., 2006).

Table: Types of vaccines available

Information from the Food and Agriculture Organisation (FAO), June 2009.

Vaccines and vaccination to control avian influenza - update 2005

By kind permission of the author, Dr David Swayne, Laboratory Director, Southeast Poultry Research Laboratory, USDA/ARS, and ProMED-mail (http://www.promedmail.org), the following is provided as background information on the use of vaccines for control of avian influenza (AI) in poultry (first published as: ProMED-mail. Avian influenza, poultry vaccines: a review. ProMED-mail 2005; 7 March: 2005 16:32:05 -0500 (EST). <http://www.promedmail.org>. Accessed 7 March 2005).

"1. Vaccination should be viewed and used only as a single tool in a comprehensive control strategy that includes: 1) biosecurity, 2) education, 3) diagnostics and surveillance, and 4) elimination of AI virus infected poultry. One or more of these components are used to develop AI control strategies to achieve one of 3 goals or outcomes (Swayne, 2004): 1) Prevention - preventing introduction of AI; 2) Management - reducing losses by minimizing negative economic impact through management practices; or 3) Eradication - total elimination of AI.

2. Protection against avian influenza is the result of immune response against the hemagglutinin protein (HA), of which there are 15 different HA subtypes, and to a lesser extent against the neuraminidase protein (NA), of which there are 9 different NA subtypes (Suarez & Schultz, 2000; Swayne & Halvorson, 2003). Immune responses to the internal proteins, such as nucleoprotein or matrix protein, are insufficient to provide field protection. Therefore, there is no one universal AI vaccine. Practically, protection is provided against the individual hemagglutinin subtype(s) included in the vaccine.

3. Experimental and field studies have shown that properly used vaccines will accomplish several goals: 1) protect against clinical signs and death, 2) reduced shedding of field virus if vaccinated poultry become infected, 3) prevent contact transmission of the field virus, 4) provide at least 20 weeks protection following a single vaccination for chickens (this may require 2 or more injections in turkeys or longer-lived chickens), 5) protect against challenges by low to high doses of field virus, 6) protect against a changing virus and 7) increase a birds resistance to avian influenza virus infection (Swayne, 2003; Capua et al., 2004). These positive qualities are essential in contributing to AI control strategies. Most AI vaccine studies and field use have focused on chickens and turkeys because of their high death rates and the high concentrations of Highly Pathogenic Avian Influenza (HPAI) virus excreted into the environment by these species. However, with the changing epidemiology of the H5N1 HPAI virus in Asia, the infection of domestic ducks and geese has become a very important contributor to the maintenance and spread of the H5N1 HPAI virus. Experimentally, vaccines have been shown to significantly reduce AI virus replication and shedding in domestic ducks and geese and thus decrease environmental contamination (especially in ponds, lakes and rivers) and prevent contact transmission. Proper vaccination of domestic ducks and geese will have a positive impact on control of H5N1 HPAI in Asia.

4. A wide variety of vaccines have been developed and examined in the laboratory for potential use in the field. However, only vaccines from 2 technologies are licensed and used in poultry: inactivated whole avian influenza virus vaccines and a recombinant fowlpox virus vectored vaccine with an H5 AI gene insert (from AI virus A/turkey/Ireland/83 (H5N8)). These 2 vaccine technologies have been shown to produce safe, pure and potent vaccines. Both vaccine technologies require handling and injection of individual birds.

5. The quantity of AI vaccine used around the world in poultry is not well documented, but reliable information suggests the largest single use has been 2 billion doses of inactivated H5N2 avian influenza vaccine in China (December 2003 - present). Indonesia also uses H5 inactivated AI vaccine. In Mexico, an AI vaccination program has been used since January 1995, with over 1.3 billion doses of inactivated vaccine and 850 million doses of recombinant fowlpox have been used. H5N2 HPAI has been eradicated (last isolate was in June 1995), but H5N2 LPAI (low pathogenic avian influenza) still circulates in central Mexico. Pakistan began using H7 inactivated AI vaccine in 1995, with use in 3 regions following epizootics of H7N3 HPAI (1995, 2001 and 2004). By contrast, with low pathogenicity (LP) AI, H9N2 inactivated vaccines have been and are used in many countries within Asia, the Middle East and Eastern Europe, but the number of doses is unknown. Vaccines for control of LPAI have been used sporadically. Recently, H7 inactivated vaccine is being used in a high risk area of Northern Italy and in one chicken layer company in the USA to control LPAI.

6. Historically, AI virus strains selected for manufacturing of inactivated vaccines have been based on LPAI viruses obtained from field outbreaks that have homologous hemagglutinin protein; i.e. H5 vaccine virus obtained from an H5 LPAI outbreak. Rarely, HPAI strains have been used to manufacture inactivated vaccines, because, to be done properly, such production requires specialized high biocontainment manufacturing facilities which are uncommon in the world. Contrary to rumor, HPAI strains do replicate to sufficient titer in embryonating eggs to be used in inactivated AI vaccines, but their use is discouraged because of biosecurity and biosafety manufacturing concerns. Furthermore, LPAI strains, with fewer biosecurity and biosafety concerns for manufacturing, protect against HPAI viruses of the same hemagglutinin subtype.

7. Vaccine strains have been shown to provide protection against diverse field viruses (88-100 percent similarity to the challenge virus hemagglutinin) isolated over a 38 year period (Swayne et al., 2000b). Recently, both North American and Eurasian lineages of AI vaccine viruses from 1968-1986 have been shown to be protective against the most recent 2003-2004 Asian H5N1 HPAI viruses (Swayne, 2004). This broad and longer-term protection efficacy of poultry AI vaccines, as compared to the need for frequent change of human influenza vaccine strains, is potentially the result of the following: 1) poultry vaccines use proprietary oil-emulsion-adjuvant technology which elicits more intense and longer-lived immune response in poultry than alum-adjuvant influenza vaccines, 2) the AI virus immune response in poultry appears to be broader than in humans, 3) the immunity in the domestic poultry population is more consistent because of greater host genetic homogeneity than is present in the human population, and 4) vaccine use in poultry is targeted to a relatively young, healthy population as compared to humans, in whom the vaccine is optimized for groups with the highest risk of severe illness and death.

8. The protection efficacy of individual poultry AI vaccines should be evaluated every 2-3 years to assure they are still protective against circulating virus strains. For example, a recent study demonstrated the 1994 Mexican H5N2 vaccine strain is no longer protective against circulating H5N2 LPAI viruses in Central America, and a change in vaccine strains is needed (Lee et al., 2004a). With the H5N1 AI virus in Asia circulating as only an HP strain, future vaccines may require the use of reverse genetics (Liu et al., 2003; Lee et al., 2004b) to generate new LPAI vaccine strains, or, other molecular techniques to produce vectored vaccine products, such as new recombinant fowlpox virus vaccines. Some of these products use patented technologies and will require legal clarification before use in the field.

9. "Sterilizing immunity" is not feasible in the field. Some experiments have reported "sterilizing immunity," but closer examination indicated such studies used very few experimental birds without statistical evaluation, used a very low virus challenge, or used low sensitive virus isolation/detection methods. In the field, vaccines will reduce replication of challenge virus in respiratory and GI tracts and thus reduce the environmental load of virus and virus transmission. However, the protection in conventional poultry in the field will always be less than that seen in specific-pathogen-free poultry under laboratory conditions because of other factors, such as improper vaccination technique, reduced vaccine dose, immunosuppressive viruses and improper storage & handling of vaccines. The other 4 components of a control strategy, as presented in item 1, are essential, because vaccines and their use are not perfect.

10. Economics and animal health control drive the use of vaccines in poultry. Vaccines are used in geographic areas of highest risk and in the agricultural sector affected, or at greatest risk to be affected. In the USA, inactivated AI vaccines cost on average USD 0.05/dose and another USD 0.05-0.07 for labor and equipment to administer. In examining new vaccine technologies, such adoption will only occur when protection is as good as or better than existing technologies, and the product is cost effective (Swayne, 2004). If the cost is prohibitively high, the farmer or company will not be able to use the vaccine.

11. When deciding to use AI vaccine in poultry, a simple animal health algorithm, in decreasing order of application, should be used: 1) high risk situations - e.g. as suppressor vaccine in the outbreak zone or as ring vaccination outside the outbreak zone; 2) rare captive birds, such as those in zoological collections; 3) valuable genetic poultry stock, such as pure lines or grandparent stocks whose individual value is high; 4) long-lived poultry, such as egg layers or parent breeders; and, lastly, 5) meat production poultry.

12. Several issues which must be resolved before deciding to use AI vaccines: 1) the vaccine strain must be of the same hemagglutinin subtype and be shown in animal studies to be protective against the circulating field virus, 2) standardized manufacturing of vaccines must be followed to produce consistent and efficacious vaccines, 3) policies must be established for proper storage, distribution and administration of the vaccine; 4) adequate serological or virological surveillance must be done to determine whether the field virus is circulating in vaccinated flocks; and 5) an exit strategy must be developed to prevent permanent use of vaccine. In addition, for inactivated whole AI vaccines, the following should be addressed: 1) the need for adequate AI viral antigen content to elicit a protective immune response, either by establishing a minimum hemagglutinin protein content in the vaccine (e.g. minimum of 1-5 micrograms/dose if using generic adjuvant system, less antigen is needed if a proprietary systems gives higher titers) or by demonstration of a high level of protection as measured by _in vivo_ challenge studies or the presence of a minimal hemagglutination inhibition (HI) antibody titer in vaccinated birds (e.g. minimum of 1:32-1:40 HI test); 2) the need for a good oil emulsion adjuvant system; and 3) the establishment of a high level of biosecurity practice for vaccination crews that enter farms to prevent accidental spreading of field virus. If using recombinant fowlpox vaccine, the vaccine should only be administered to one day-old chickens in hatchery, which will give good protection, improved biosecurity and a high degree of quality control. Before new vaccine technologies should be used in the field, assessment of safety in target species, environmental impact to non-target species, purity and efficacy must be demonstrated.

13. Surveillance must be conducted on vaccinated flocks to determine whether the field virus is circulating and the control strategy is working. This should be done by both serological and virological surveillance of vaccinated and non-vaccinated flocks. For serological surveillance, several methods can be used to identify infections by field virus in vaccinated populations: 1) placement of unvaccinated sentinel birds and looking for antibodies against AI viruses, such as in ducks, 2) if using inactivated vaccine, looking for specific antibodies against the neuraminidase of the circulating field virus in vaccinated birds (if using an inactivated vaccine strain with a different neuraminidase subtype than the circulating field virus (Capua et al., 2003)) or looking for antibodies against the non-structural protein (Tumpey et al., 2005), or 3) if using recombinant fowlpox vaccine, looking for antibodies to nucleoprotein/matrix protein. For virological surveillance, examination for specific AI viral nucleic acids or proteins, or isolation of the virus, could be used to determine whether the field virus is circulating. This is best done on sentinel birds that are showing clinical signs or who die. Alternatively, examination of dead poultry from vaccinated populations will give an indication of whether the field virus is circulating.

14. Recently, 2 new vaccines for use in China have been reported (ProMED 20050207.0415 and 20050210.0456): 1) recombinant fowlpox-H5N1 AI vaccine, and 2) a reverse genetic produced influenza A inactivated vaccine. The new recombinant fowlpox vaccine is a live, injectable vaccine for chickens and uses the same technology as the previously licensed recombinant-fowlpox-virus-AI-H5 vaccine (cDNA copy of the AI hemagglutinin gene from A/turkey/Ireland/83 (H5N8)), but includes inserted cDNA copies of AI hemagglutinin (H5) and neuraminidase (N1) genes (both from A/goose/Guangdong/3/96 (H5N1)) (Qiao et al., 2003). This type of vaccine can only be used in one-day-old chickens and not in older birds in which immunity to fowlpox virus will inhibit replication of the vaccine virus and prevent development of effective immunity (Swayne et al., 2000a). The other new vaccine is a traditional inactivated oil emulsion AI vaccine, but unlike current inactivated AI vaccines, the new vaccine virus is not an H5 LP or HPAI field virus. The vaccine virus was produced by reverse genetics using the 6 internal genes from a human influenza vaccine strain (PR8) and the hemagglutinin and neuraminidase genes from A/goose/Guangdong/3/96 (H5N1) AI virus. The use of PR8 internal genes imparts the characteristic of growth to high virus content in embryonating chicken eggs used in the manufacturing process and thus produces a high concentration of the protective hemagglutinin protein in the vaccine. Another change in the vaccine virus: the portion of the gene that codes the hemagglutinin proteolytic cleavage site has been changed from a sequence of an HP to an LPAI virus, thus, the vaccine virus is a LPAI virus and can be manufactured at a lower level of biosafety. Both vaccines require handling and injection of individual birds. Data published or presented at scientific meetings indicate that these new vaccines are as efficacious as the existing licensed vaccines, but no data have been presented to demonstrate they provide superior protection."

National and international control policy

The virulent form of avian influenza (fowl plague) is included in the OIE (World Organisation for Animal Health) list of notifiable diseases, which means that outbreaks are notifiable to the OIE and restrictions to movement of birds and poultry products are enforced.

Many countries have regulations aimed at preventing avian influenza, which involve trade embargoes on importation of birds and avian products from countries not declared highly pathogenic avian influenza (HPAI) -free. HPAI virus is considered an exotic pathogen in most European countries, the USA and Australia. Exotic outbreaks of HPAI are eradicated by implementing an intensive programme comprising rapid diagnosis, slaughter and disposal of affected flocks, quarantine of the affected area and concurrent surveillance with disposal of flocks with positive antibody titres to avian influenza. Restrictions on movement of flocks and poultry products from infected areas are imposed.

Farm-level control

It is important to have adequate biosecurity to prevent AI introduction from other poultry flocks. Preventing direct contact with wild and migratory birds that may carry the virus, and protecting domestic poultry from contact with the faeces of wild birds are also ways of preventing avian influenza. Implementation of strict biosecurity measures at the local farm level can limit dissemination of avian influenza virus. However, the prevention of avian influenza in developing countries is extremely difficult because feed is delivered in bags, and because small-scale producers distribute eggs and live broilers through dealers to regional markets.

Cleaning and disinfection

The virus remains viable for a long time in tissues and faeces. Effective disinfection procedures involve complete removal of all organic material because influenza viruses are well protected from inactivation in such material. Disinfectants of many types (glutaraldehyde plus formaldehyde; glutaraldehyde and quaternary ammonium salts; chlorocresols; oxidising disinfectants; iodophores; quaternary ammonium salts) are effective against influenza virus. However, professional advice should be sought as these differ with respect to efficacy in the presence of organic matter and in relation to low temperatures.

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