Avian Influenza - available

Control Tools

Diagnostics availability

Commercial diagnostic kits available worldwide

Yes, but limited. PCR, serology, availability of subtyping tests limited. Technology for characterisation of strains is quite advanced, but sometimes lacking behind in developing countries. Four types of commercial test kits: Antibody detection ELISA, PCR, lateral flow devices and antigens for HI available or in development.

Gap: Cheap, stable and sensitive tests fit for purpose.

Commercial diagnostic kits available in Europe

Yes, but limited. PCR, serology, availability of subtyping tests limited. Technology for characterisation of strains is quite advanced, but sometimes lacking behind in developing countries. Four types of commercial test kits: Antibody detection ELISA, PCR, lateral flow devices and antigens for HI available or in development. Avian Influenza Antibody test kit is on the Register of diagnostic tests certified by the OIE as validated as fit for purpose.

GAPS: Easier to use, field-applicable and specific tests required.

Diagnostic kits validated by International, European or National Standards

Avian Influenza Antibody test kit is on the Register of diagnostic tests certified by the OIE as validated as fit for purpose. Scattered validation data of several commercial tests available in different reference laboratories in EU.

GAP: Meta-analysis of validation data for test kits.

Diagnostic method(s) described by International, European or National standards

Details are contained in the OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals 2009 Chapter 2.3.4 on Avian influenza.

GAP: Specific SOPs.

Commercial potential for diagnostic kits in Europe

Moderate at best; companies focus on Asian markets.

DIVA tests required and/or available

Currently the only approach in Europe that can be applied to differentiate infected from vaccinated birds is the use of a heterologous vaccine (vaccine virus with the same H type as the field strain but a different N type). With such a vaccine, the immune response to the homologous H type ensures protection, while antibodies against the neuraminidase allow differentiation between the field and vaccine strains. The advantage of this method is that a vaccine bank of inactivated oil emulsion heterologous vaccines could be established. However, field applicability and high throughput tools for this method are doubtful.

GAPS: Better DIVA tests are required. Validity of DIVA for HPAI not yet assessed under field conditions; validity of other methods of assessing infectious status of flocks such as testing of routine mortalities

Opportunities for new developments

Multi strain vaccines, diva tests. See specifications made in EFSA and O.I.E. reports.

GAPS: Registration of vaccines through the MS is a new concept which has recently been introduced within the revised text of annex I to Directive 2009/09, and is illustrated in EMEA/CVMP/IWP/105506/2007 (GL on data requirements for multi-strain dossiers for inactivated vaccines against avian influenza, blue tongue and foot and mouth disease). The consistency and coherence of all submitted data should be based on sound scientific arguments. To facilitate the acceptance of an MS dossier, a list of outstanding issues should be taken into account, such as: selection of one uniform dose size for the target species; justification of the selected virus strains, and combination and number of strains included in the final product; the use of fixed amounts of active ingredients and a stable and clear formulation ratio (adjuvant/buffer). Vaccines with a shelf life as long as possible should be foreseen. Taking into account that limited numbers of vaccine batches might be produced, situations might be faced which require to assign a (rather arbitrary) extension of shelf life to such batches in order to cope with sudden, increased requests from field, e.g. as expected under emergency situation or to complete vaccination campaigns.

Vaccines availability

Commercial vaccines availability (globally)

H5, H7, H9 vaccines are available. Vaccination of wild birds seems not feasibla. There are two types of vaccines commercially available at present. Inactivated vaccines and recombinant vaccines (fowl pox). Recombinant vaccines for AI viruses have been produced by inserting the gene coding for the influenza virus haemagglutinin (H5 or H7 for instance) into a live virus vector (e.g. fowl pox virus, Newcastle disease virus, ILTV) and using this recombinant virus to immunise poultry against AI. Recombinant vaccines have been licensed in a number of countries.

Commercial vaccines authorised in Europe

Yes. H5, H7 vaccines for regulated use.

Marker vaccines available worldwide

In principle, yes. DIVA principle with different “N” types. NP antibodies can be used for differentiation in case of recombinant vaccines expressing only H or H and N of AIV. Studies for DIVA using sentinel birds available but information limited.

GAP: Field studies evaluating the DIVA principle using new recombinant vaccines in practise and larger herds.

Marker vaccines authorised in Europe

Not specifically although strains with different N components can be used as markers.

Effectiveness of vaccines / Main shortcomings of current vaccines

International organisations recommend that vaccines used for AI control must be of high quality and that they should meet international standards and guidelines.

GAP: Lack of information about vaccines specially designed for use in ducks although publications available for use of common AI vaccines in ducks.

Commercial potential for vaccines in Europe

Depends on disease evolution and willingness to vaccinate, epidemiological situation (e.g. LPAI in Italy or H1N1 in USA), and value of ndividual animals (rare captive birds in zoos & hobby holdings) and the cost of compliance programs.

Regulatory and/or policy challenges to approval

GAP: Need for rapid approval of new seed strains for production.

Commercial feasibility (e.g manufacturing)

Adequate.

Opportunity for barrier protection

Yes.

Opportunity for new developments

• In the recent years a new approach being developed for the creation of inactivated vaccines for AI is based on the application of reverse genetics techniques (Hofmann, 2002).
• Method of application needs to be improved with the long term aim of using spray or drinking water application possible as a single AI vaccine or in combination with Newcastle disease vaccine.
• Development of multiple component “H” vaccines may be advantageous.
• Ability to build in a vaccination regime for AI into normal husbandry practices along with other preventative vaccinations.
• Further development of recombinant vaccines is enyouraged, especially using backbones which favour induction of protection in ducks (e.g. duck herpesviruses etc.)
• In ovo vaccination needs to be further evaluated.
• Revisit live virus vaccines (e.g. work by Perez et al) on temperature sensitive viruses and work by Swayne et al.

GAPS:

• There is need for better quantification of the antigenic content (e.g. quantification of HA) in a vaccine.
• Need for safer adjuvant/adjuvant system(s), improving the efficacy of the vaccines.
• Need for defining the most appropriate vaccination schedules (e.g. in minimum age birds and in breeder birds) capable to induce a prompt and prolonged immune response.

Pharmaceutical availability

Current therapy (curative and preventive)

None. Antivirals (Tamiflu & Relenza) are effective in poultry but their use is prohibited due to the risk of resistance and hazard thereof for human.

GAP: Not applicable at present stage, however, any therapy should be adapted to the provision in the relevant legislation.

Future therapy

None anticipated in the near future. In the longer term virus specific antiviral may be a possibility. Only drugs not for use in human can be considered.

Commercial potential for pharmaceuticals in Europe

None.

GAPS:

• Any scope for si RNA or other methods to increase resistance of poultry to infection and disease?
• Transgenic chickens with increased resistence to AIVs?

Regulatory and/or policy challenges to approval

Not applicable.

GAPS: Resistant poultry? DNA vaccines?

Commercial feasibility (e.g manufacturing)

Not applicable.

Opportunities for new developments

There is a requirement for better understanding of the virus and its pathogenic actions. This understanding along with gene sequencing of the virus may lead to the development strain specific antiviral drugs. This would be in the long term objective.

GAP: Cost of antiviral drugs and some limitations in their use under practical conditions.

New developments for diagnostic tests

Requirements for diagnostics development

Easy to use, usable on farm and mass screening tests are needed. Existing technologies based on nucleic acid amplification work relatively well if properly controlled.

GAP: Development of pen side antibody test in order to detect the optimal age at vaccination (birds could be vaccinated at an age when maternally derived immunity is still present and might have a negative impact on the uptake of the vaccine). May be compensated by good lab infrastructure.

Time to develop new or improved diagnostics

Unknown.

Cost of developing new or improved diagnostics and their validation

Variable.

Research requirements for new or improved diagnostics

Development of pen site tests and alternatives for the simple diagnosis of AI. Rapid ELISA/LFD tests still valid as flock tests if performed on dead birds with H5N1 HPAI.

GAP: “Conventional” methods are rather difficult to be applied under field conditions.

Technology to determine virus freedom in animals

Improved diagnostic tests with higher specificity and sensitivity especially for the early stages of infection.

GAP: Need for virological testing (not just relying on serology especially when dealing with rapidly fatal disease).

New developments for vaccines

Requirements for vaccines development / main characteristics for improved vaccines

Multiple strain coverage, easy to apply, single dose, cheap, marker vaccines, induction and persistence of shedding of virus avoided.

GAPS: It is envisaged that evaluation of MS dossier will not be appropriate in response to an emergency situation.

There is some proof of evidence that live recombinant vectored vaccines are capable to circumvent potentially negative effect on immune response in birds still having maternally derived antibodies. However, antibodies against the recombinant backbone (e.g. NDV or ILTV) in the vaccine may abrogate induction of AI specific immunity; this will be a problem in countries where NDV vaccination is compulsory.

Other vectors – e.g. salmonella; antigens produced in plants.

Time to develop new or improved vaccines

Variable. Depends on vaccine type, product profile, priorities and funding possibilities.

Cost of developing new or improved vaccines and their validation

Variable.

Research requirements for new or improved vaccines

• Development of recombinant vaccines, sub unit vaccines and possible DNA vaccines.
• Live vaccines would enable improved methods of application such as spray or drinking water would provide major advantages.
• The use of live vaccines which are genetically engineered to avoid the potential disadvantages of reversion to virulence, recombination with field strains or resulting in vaccine induced respiratory disease would be important.
• Use of reverse genetics to generate reassortment marker vaccines.
• Develop live vaccine viruses which only undergo partial replication in the host in order to stimulate an immune response but which cannot progress to full replication of the virus. Need to use replication deficient strains which in turn requires a detailed understanding of the AI virus replication mechanisms and of the functional genetic of the virus Systems
• In ovo vaccination
• DNA vaccines

GAP: Costs relating to the research and development of some types of vaccines in the face of a potentially limited market.

New developments for pharmaceuticals

Requirements for pharmaceuticals development

Not applicable at present.

GAPS: Would it be possible to develop antivirals? Costs of research/development, relating also to the nature of this category of products may constitute a major limit in the availability of this type of pharmaceutical products.

Time to develop new or improved pharmaceuticals

Not applicable at present.

Cost of developing new or improved pharmaceuticals and their validation

Not applicable at present.

Research requirements for new or improved pharmaceuticals

Not applicable at present.

GAP: Not applicable at present stage, however, any therapy should be adapted to the provision in the relevant legislation.

Disease details

Description and characteristics.

Pathogen

The infection is caused by virus strains from the Orthomyxoviridae family, genus Influenzavirus, type A. Influenza A viruses (IAV) are enveloped, spherical-pleomorphic viruses with a diameter of 80-120 nm. The genome, single-stranded RNA of negative polarity, is segmented and encapsidated in eight genome segments which code for up to 11 proteins. The nucleotide sequence as well as the antigenic properties of the hemagglutinin (H) and neuraminidase (N) surface glycoproteins classify type A influenza viruses into 16 hemagglutinin (H1 to H16) and nine neuraminidase (N1 to N9) subtypes. IAV infect a broad range of animal species. Clinical symptoms induced after infection vary considerably according to both viral and host properties. IAV infecting avian hosts are also referred to as avian influenza viruses (AIV). Aquatic wild birds constitute the reservoir of all AIV subtypes known to date. AIV readily cross taxonomic borders between species in the Aves class and occasionally even between classes when infecting mammalian hosts.

Variability of the disease

In addition to subtype classification AIV are distinguished by their pathogenic potential in chickens. Highly pathogenic AIV (HPAIV) induce high mortality rates in gallinaceous poultry while strains of low pathogenicity (LPAIV) induce significantly milder courses or even asymptomatic infections. An intravenous pathogenicity index is used to distinguish between the two pathotypes. Alternatively, the deduced amino acid sequence at the endoproteolytic cleavage site of the HA protein can be used as a surrogate marker of pathogenicity. To date, all naturally occurring HPAIV are representatives of subtypes H5 and H7. However, the majority of H5/H7 circulating is of the LP type.

IAV in general have considerable genetic flexibility through point mutations which accumulate due to an intrinsically high mutation rate of these viruses and through exchange of whole genome segments during co-infection of a single host cell with IAV of different subtypes (reassortment). HPAIV arise by mutation de novo, probably in gallinaceous poultry, from LP precursor viruses maintained in the natural host reservoir.

GAPS:

• Rate of genetic changes and triggers influencing these rates, and their effect on epidemiology, host specificity and pathogenesis.
• How does H5N1 HPAI virus survive between seasons?
• What effect does immunosuppression have on the duration of carriage of H5N1 (and other influenza) viruses in partially immune poultry?
• Does severe transport stress increase susceptibility of poultry to infection even if they are otherwise expected to be immune?

Stability of the agent/pathogen in the environment

Infectivity of AIV depends on the integrity of their lipid envelope; therefore they are sensitive to most detergents and disinfectants,and are inactivated by heating and drying. The pathogen can be inactivated at 56°C/3 hours or 60°C/30 min or 72°C/1min, by acid pH, oxidising agents, sodium dodecyl sulphate, lipid solvents, ß-propiolactone, formalin and iodine compounds. However, depending on environmental conditions, especially temperature and humidity, AI viruses may persist in soil, faeces, and surface waters for varying amounts of time. In lake water at 4°C infectivity remains stable over many months. Freezing does not destroy infectivity.

GAPS:

• What genetic and phenotypic factors influence improved survival at various temperatures (certain H5N1 viruses survive for longer at 30 and 37 degrees)?
• What is the survival at 30 -35 degrees in a range of substrates (water, faeces, in or on feathers etc) (this represents the sorts of temperatures experienced in much of the tropics where H5N1 viruses persist.

Species involved

Animal infected/carrier/disease

AIV infections are widely distributed in aquatic wild bird populations. The majority of infections is transient and clinically mild, if not asymptomatic although an impact of infection e.g. on migration habits have been described. There is no carrier status or persistent infections. Fecal-oral transmission chains dominate. The environment (surface water, sediments) probably acts as an important factor of virus perpetuation. Incidence of infection is cyclic in the natural hosts and peak values of up to 30% correlate with autumn migration of aquatic wild birds in the Northern hemisphere.

GAPS:

• Prevalence of H5-H7 in wild birds largely unknown.
• Transmission modes and factors of transmissibility within the natural host reservoir, in particular, influence of environmental reservoirs for sustainability/seasonality of infection.
• Potential behavioural (individual bird) and ecologic (population) influences through low path AIV infections in natural hosts. Is there a longer term carrier state in partially immune poultry and effects of immunosuppression on excretion (prolonged excretion of human influenza virus in immunosuppressed patients)?

Human infected/disease

Yes. Principal pandemic potential, current risk is limited to close direct contact with infected birds. Exposure to high doses of virus probably required. In general, a rare event so far. No evidence of sustained human to human transmission for the current H5 and H7 strains.

GAPS:

• Relation of virus exposure dose and clinical/immunological effects unknown.
• Predisposing factors of human susceptibility on viral and host side.
• Assess the rate of transmission. Why is there an apparent difference between H5 and H7 viruses?

Vector cyclical/non-cyclical

None identified.

Reservoir (animal, environmental)

Aquatic wild birds and domestic waterfowl are the primary reservoirs for AIV, serving as a source of infection for other birds within their migratory pathway.

GAPS:

• Mode of “environmental” transmissions unknown (virus free floating in surface water, contact with sedimented virus etc.)
• Frequency & risk of contacts between wild birds and poultry.
• Definition of a “risk contact”. What is the role of virus on feathers and is uropygeal gland secretion protective?
• Behaviour of AI viruses in markets and vaccinated flocks – still no good studies on transmission of virus in markets or in flocks of vaccinated poultry.

Description of infection & disease in natural hosts

Transmissibility

Sources of the virus are mainly faeces and respiratory secretions. Transmission is via contact with infected birds or contaminated fomites (surface water!). AIV is highly contagious but does not spread as explosively as velogenic Newcastle disease virus or infectious bronchitis virus. Oral transmission to mammals possible.

GAP: Conjunctival transmission?

Pathogenic life cycle stages

Transmission from acutely infected individuals or contaminated fomites to susceptibles. Infectious period is short. Little evidence for persistent infections/carrier state.

GAP: carrier states in certain species (pheasants) or in immunocompromised birds?

Signs/Morbidity

HPAIV: Symptoms are severe depression, inappetence; drastic decline in egg production; facial oedema with swollen and cyanotic combs and wattles; sudden deaths (mortality can reach 100%). Occasionally petechial haemorrhages on internal membrane surfaces; Lesions in chickens (not pathognonomic):

• Lesions may be absent in cases of peracute death
• Severe congestion of the musculature
• Dehydration
• Subcutaneous oedema of the head and neck area
• Nasal and oral cavity discharge
• Severe congestion of conjunctivae, sometimes with petechiae
• Excessive mucous exudate in the lumen of the trachea, or severe haemorrhagic tracheitis
• Occasional petechiae on the inside of the sternum, on the serosa and abdominal fat, serosal surfaces and in the body cavity
• Severe kidney congestion, sometimes with urate deposits in the tubules
• Haemorrhages and degeneration of the ovary
• Haemorrhages on the mucosal surface of the proventriculus, particularly at the juncture with the gizzard
• Haemorrhages and erosions of the gizzard lining
• Haemorrhagic foci on the lymphoid tissues in the intestinal mucosa
• Pulmonary oedema and congestion
• Splenomegaly
• Pancreatic necrosis

The lesions in turkeys are similar to those in chickens, but may not be as marked due to a high proportion of hyperacute deaths. Ducks infected with HPAI and excreting the virus, may not show any clinical signs or lesions. In HPAIV infected geese neurologic signs may dominate (atactic movement, myoclonus, forced movements, torticollis, somnolence). Also neurological signs in ducks; corneal opacity in ducks.

LPAIV: Symptoms in domestic poultry are extremely variable. Clinical signs (inappetence, respiratory distress, reduced production parameters) most frequently observed in turkeys.

GAPS:

• No pathognomic symptoms or surrogate markers of infection defined.
• Define trigger points for investigations in different types of flocks including vaccinated flocks.

Incubation period

The incubation period is 1 to 7 days.

GAP: Perhaps longer in vaccinated birds?

Mortality

The “low pathogenic” types may spread undetected and usually cause only mild symptoms. However, the highly pathogenic forms cause disease that affects multiple internal organs and has a mortality rate that can reach 90-100% often within 48 hours in gallinaceous.

GAPS:

• Mechanisms of adaptation of LPAI to poultry; what predisposes an LPAIV to replicate in gallinaceous poultry?
• Transmission rates of LPAIV and HPAIV?

Shedding kinetic patterns

Following infection virus shedding occurs. Effective infectious period is usually short (1-4 days). Shedding mode (fecal versus oropharyngeal) depends on isolate. Vaccination to be fully effective must suppress shedding below the point where it will infect other vaccinated poultry.

GAPS: Virus shedding titers and kinetics of shedding; relation with transmission rates.

Mechanism of pathogenicity

Cellular level: Receptor-bound viruses are taken into the cell by endocytosis. In the low pH environment of the endosome, the viral lipoprotein envelope fuses with the lipid-bilayer of the vesicle releasing viral RNA into the cell cytoplasm from where it is transported into the nucleus. New viral proteins are translated from transcribed messenger RNA (mRNA). New viral RNA is encased in nucleocapsid protein, and together with new matrix protein is then transported to sites at the cell surface where envelope haemagglutinin and neuraminadase components have been incorporated into the cell membrane. Progeny virions are formed and released by budding. The cell does not die initially.

Host level: Dysfunction of infected cells (e.g. lack of ciliary activitiy of respiratory epithelial cells) will cause local symptoms. Replication of LP virus is largely confined to endodermic epithelia. HP virus, in contrast penetrates epithelial borders and will replicate systemically, including the central nervous system. Certain isolates interfere with innate immunity.

GAPS:

• Rate and selection pressure of mutation at the cleavage site. Is it true, and if so, why, are HPAIV usually generated in gallinaceous poultry? Why has HPAI H5N2 not re-emerged in Mexico despite circulation of LP virus for many years?
• Tissue tropism of LPAIV; some strains replicate beyond the basal membranes of respiratory and intestinal tissues (e.g. kidney, adrenals etc.)

Zoonotic potential

Reported incidence in humans

Low, however, unpredictable pandemic potential exits. See WHO statistics for HPAIV H5N1.

GAP: Lack of knowledge of incidence in humans.

Estimated level of under-reporting in humans

Probably low but unknown.

GAPS:

• Changes of clinical course (towards less severe symptoms) in human infections by HPAIV H5N1 in Egypt?
• Reporting depends on likelihood of hospitalisation and cost of hospital treatment precludes many cases in China from attending hospital

Risk of occurence in humans, populations at risk, specific risk factors

Most cases of avian influenza infection in humans have resulted from close contact with high viral doses from infected poultry (e.g., domesticated chicken, ducks, and turkeys) or surfaces contaminated with secretion/excretions from infected birds.

GAP: Genetic resistance/susceptibility of humans.

Symptoms described in humans

Symptoms of avian influenza in humans have ranged from typical human influenza-like symptoms (e.g., fever, cough, sore throat, and muscle aches) to eye infections, pneumonia, severe respiratory diseases (such as acute respiratory distress), and other severe and life-threatening complications. The symptoms of avian influenza depend on which virus caused the infection.

GAP: Are humans more susceptible to H7 than H5 HP viruses and if so why?

Likelihood of spread in humans

The spread of avian influenza viruses from an infected individual to another has only been reported very rarely, and has so far been limited, inefficient and unsustained. Efficient or sustainable transmission has not yet been reported in humans.

GAP: Mechanisms of adaptation in humans.

Impact on animal welfare and biodiversity

Both disease and prevention/control measures related

The effects of HP strains could cause significant suffering in a large number of domestic birds and a wide range of wild bird species.

GAPS:

• Relative advantages and disadvantages of wide area culling versus other control methods.
• Incentives for disease reporting.

Endangered wild species affected or not (estimation for Europe / worldwide)

The H5N1 viruses can also cause disease in mammals of other species, including tigers, leopards, housecats, dogs, palm civets, stone martens, and raptor species. In addition, numerous deaths due to HPAIV H5N1 have been reported in migratory wild birds including highly endangered species, which usually carry avian influenza viruses asymptomatically. Raptor species may be specially threatened due to increased risk of hunting on diseased and weakened prey or by scavenging activities.

Slaughter necessity according to EU rules or other regions

No, for HP infected poultry culling and destruction demanded (marketing of products prohibited). Yes, for LP H5/H7 infected poultry if culling and destruction is economically/ethically not considered.

Geographical distribution and spread

Current occurence/distribution

Global. Low pathogenic strains are found worldwide. HPAI viruses have been eradicated from domesticated poultry in most developed countries.

The current avian HPAIV H5N1 outbreak began during 2003 in poultry in Southeast Asia. Between 2003 and 2008, it spread epizootically into domesticated or wild birds in other regions of Asia as well as parts of Europe, the Pacific, the Middle East and Africa. Some countries have eradicated the virus from their domesticated poultry but eradication of HPAIV H5N1 on a global scale is not expected in the short term as pockets of endemic infection, especially in domestic waterfowl, continue to exist in several countries (e.g. Indonesia, Egypt, probably others).

Eradication of LPAIV is impossible due to the reservoir function of aquatic wild bird populations.

GAPS:

• Persistence and duration of excretion of H5N1 by wild bird species.
• Relative contribution of factors that lead to persistence of H5N1 HPAI in countries with endemic infection.

Epizootic/endemic- if epidemic frequency of outbreaks

Variable, depending on the effectiveness of the control measures. In Europe the rapid implementation of harsh controls (stand still-culling-C+D) can prevent spread within the domestic populations of birds.

Seasonal cycle (seasonality)

Possible link to bird migration patterns (LPAIV). HPAIV: Annual shifts in incidence in endemic regions (SE Asia, Egypt) linked to cooler/more humid times of the year or to increased poultry production and trading movements during nation-wide celebrations/holidays (e.g. Tet/Vietnam, Ramadan/Egypt, Indonesia).

Speed of spatial spread during an outbreak

Variable, depending on initial identification and diagnosis and the speed of implementation of effective controls.

Transboundary potential of the disease

High. Uncontrolled and illegal trading activities with live poultry and all kinds of poultry products. Spill-over into wild bird population and (secondary) spread with migratory species possible.

GAP: Trade control.

Seasonal cycle linked to climate

LPAIV: Yes. HPAIV: Possibly.

Distribution of disease or vector linked to climate

Suspected for HPAIV in wild birds (0°C isotherm).

GAP: Not true followed 0 C isotherm in most recent years (e.g., summer 2007 Central Europe!)

Outbreaks linked to extreme weather

Suspected for HPAIV in wild birds (extreme cold spells).

Sensitivity of disease or vectors to the effects of climate change (environmental changes/land use)

Not known.

Route of Transmission

Usual mode of transmission (introduction, means of spread)

Direct contact with secretions from infected birds, especially faeces, saliva and nasal secretions or contaminated fomites is the most common.

GAPS:

• Role of aerosol or neighbourhood transmission and relative contributions of various routes of transmission.
• Role of contaminated/infected feathers (H5).

Occasional mode of transmission

Clinically normal waterfowl and sea birds may introduce directly or indirectly the virus into flocks.

Conditions that favour spread

Close contact with infected wild species and domesticated birds (free range poultry holdings), dense populations of susceptible species, mixed populations of susceptible poultry (waterfowl and gallinaceous fowl). Uncontrolled poultry trading movements.

GAP: Mode and frequency of contacts between wild birds and poultry.

Detection and Immune response to infection

Mechanism of host response

Slightly complex. Humoral antibodies are protective but are subtype- and even strain-specific. Local protection less understood. Immunology in waterfowl not really known very well. In mammals many immunology questions remain, particularly for human HPAIV H5N1 infections immunopathological mechamisms are discussed.

GAP: Lack of knowledge on resistance mechanisms in different bird species.

Immunological basis of diagnosis

Detection of IAV generic and subtype-specific antibodies.

GAPS:

• High-throughput generic and subtype-specific multiplex serological tools.
• On-site serological tools
• Validation of serological DIVA in the field for H5N1 HPAI

Main means of prevention, detection and control

Sanitary measures

Avoidance of contact between poultry and wild birds, in particular waterfowl. Avoidance of the introduction of birds of unknown disease status into flock. Control of human traffic. Proper cleaning and disinfection procedures. One age group per farm (all in-all out) breeding. Single species per holding. Compartmentalization.

Phase 1:

• Implementation of restriction measures at a farm level
• Establishment of protection and surveillance zones

Phase 2: Enlargement of restriction zones (ban of restocking in large areas).

Phase 3: Implementation of vaccination plan.

GAPS:

• Which measures on farm offer the best value for money?
• Decision trees for vaccination in endemically infected countries such as Bangladesh.

Mechanical and biological control

Biosecurity, contact prevention migratory birds and bridge species, movement control poultry, eradication, stamping out eventually combined with vaccination, vaccination.

GAP: Role of bridging species in transmission of AIV between wild aquatic birds and poultry farms.

Diagnostic tools

Avian influenza can be diagnosed by virus isolation in embryonated eggs with confirmation of the virus by AGID or ELISA. RT-PCR assays can identify avian influenza viruses in clinical samples, and can replace virus isolation. These tests combined with nucleotide sequencing can also distinguish sub- and pathotypes. As of 2008, (OIE) recommended that antigen detection tests be used to identify avian influenza only in flocks and not in individual birds.

Serological tests including agar gel immunodiffusion, hemagglutination, hemagglutination inhibition and ELISAs are useful. Serology can be valuable for surveillance and to demonstrate freedom from infection with LPAIV. Gallinaceous will be dead from HPAIV infection before mounting antibodies. AGID tests and generic competitive ELISAs can recognize all avian influenza subtypes in poultry, but hemagglutination inhibition tests are subtype specific and may miss some infections due to high specificity of this assay which does not necessarily include all strains within one subtype.

GAP: Antigenic & molecular variations.

Vaccines

H5, H7, H9 vaccines available, no vaccination of wild birds possible. Inactivated whole virus vaccines, recombinant vaccines (fowl pox, NDV recombinants). There are five types of AI vaccines possible, inactivated, live, subunit, recombinant vectors expressing AI genes, and DNA vaccines. Each of which has both advantages and disadvantages to its use. Although various types of AI vaccines have been tested in experimental conditions, only relatively few have been licensed in industrialized countries. Traditionally, inactivated vaccines have been based on antigens produced from naturally low pathogenic (LP) AI isolates. The antigenic relatedness between the vaccine strain and the field virus against protection is targeted should be as close as possible to ensure a high efficacy of vaccination.

GAPS:

• Problems with induction of sterile immunity.
• Lack of markers of protection.
• Vaccines that are easy to administer and offer broader cross protection than current killed antigen vaccines.
• Vector vaccines that offer protection against more than one agent (especially needed for ducks).
• Is there scope to use live modified virus vaccines as used in humans?

Therapeutics

None.

Biosecurity measures effective as a preventive measure

Poultry producers should maintain a high level of biosecurity on farms and hatcheries.

GAPS:

• What is a sufficient level of biosecurity?
• Needs to be divided down into specific measures.

Border/trade/movement control sufficient for control

Control on the movement of birds and products from infected regions.

Prevention tools

Vaccines.

Surveillance

AI viruses appear to be evolving antigenically and a constant monitoring system of the antigenic characteristics of circulating AI viruses by testing new viruses isolates should be installed. Surveillance should first aim at early detection and eradication, then adaptation of vaccination Veterinary authorities may use information provided through surveillance to guide decision-making when establishing vaccine banks for use in avian species (Beato et al., 2009).

GAP: Systems for rapid incorporation of antigenic variants to vaccines (only China has done so in a timely manner).

Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

Costs of above measures

GAP: Compensations to farmers.

Disease information from the OIE

Disease notifiable to the OIE

Yes.

http://www.oie.int/animal-health-in-the-world/update-on-avian-influenza/2011/

OIE disease card available

http://www.oie.int/fileadmin/Home/eng/Media_Center/docs/pdf/Disease_cards/AI-EN.pdf

OIE Terrestrial Animal Health Code (reference)

http://www.oie.int/index.php?id=169&L=0&htmfile=chapitre_1.10.4.htm

OIE Terrestrial Manual (reference)

http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.03.04_AI.pdf

Socio-economic impact

Zoonosis: Impact on affected individuals and/or aggregated DALY figures

Unknown.Low with current incidence and apparent inability of HPAI to spread to and within the human population. However, mortality among rural backyard poultry in developing countries may challenge local animal protein resources.

GAPS:

• Only if virus becomes human pandemic strain or more readily transmissible from birds to humans will this be significant.
• Socio-economic impact of control measures often outweigh cost of the disease.
• Unintended consequences on the poor of changes to marketing and farming practices introduce for disease prevention/control (e.g. closure of LBMs).

Zoonosis: cost of treatment and control of the disease in humans

Potentially high with the need for vaccination and antiviral treatment if the incidence in humans increases. But not at present.

Potentially huge if severe pandemic strain emerges but likelihood appears low based on experiences from past 15 years.

Direct impact (a) on production

Losses to the poultry and allied industries in an outbreak can be severe. A major outbreak could reduce the supply of meat and eggs produced within the country. Highly pathogenic avian influenza (HPAI) virus spreads rapidly, may cause serious disease and result in high mortality rates (up to 100% within 48 hours).

GAP: Market shocks due to consumer fears.

Direct impact (b) cost of private and public control measures

Costs of eradication, vaccination and biosecurity.

Indirect impact

High and severe. Trade implications. Impact on backyard poultry and protein supply of developing countries. Negative impact for tourism in a severely affected region although so far very little evidence that H5N1 HPAI has had any effect on tourism – but would if became pandemic – unlike SARS which did.

Trade implications

Impact on international trade/exports from the EU due to existing regulations

If an outbreak of HPAI occurred, exports of live birds, eggs and poultry products would initially be prohibited from the affected Member state and possibly from others in the EU into third countries. Details of standards are contained in the OIE Terrestrial Animal Health Code 2009 chapter 10.4 Avian influenza.

GAP: Need for pre-approved compartments with on-going monitoring.

Impact on EU intra-community trade due to existing EU regulations

If an outbreak of HPAI occurred, exports of live birds, eggs and poultry products would initially be prohibited from the affected country into other Member States of the EU.

Impact on national trade due to existing regulations

If an outbreak of HPAI occurred, movement of live birds, eggs and poultry products within a country would initially be prohibited and then strictly controlled depending on the protection and surveillance zones and the epidemiological investigations.

Main perceived obstacles for effective prevention and control

• Inability of developing countries to control disease,
• Nature of virus (antigenic drift, antigenic shift),
• Natural reservoir host,
• Increasing demands for outdoor poultry production,
• Potential of the virus to change from low to high pathogenic,
• Lack of sufficient cross protection of different H types,
• Lack of induction of sterile immunity by vaccination; birds which have been vaccinated may shed the virus while remaining asymptomatic. Effective surveillance and movement controls are critical in a vaccination campaign
• Lack of fit-for-purpose DIVA tools (and lack of validation of existing tools for HPAI in field conditions) - but in many cases sterile immunity is achieved experimentally
• Lack of mass applicable easy to administer vaccines; lack of sufficient global influenza vaccine production capacity.
• Lack of control over live bird markets and backyard poultry raising.
• Public resistance against mass culling.
• Economic and trade implications of vaccination policies. Lack of transparency of certain countries.
• Lack of incentive for industry to develop vaccines with a non vaccination policy in place.
• Limited insight in trade implications and consistent global coordination.
• Vaccination may put selection pressures on avian influenza viruses, and might eventually result in the evolution of new strains or variants (but selection pressure might also occur in unvaccinated populations of poultry that survive infection such as domestic ducks).

GAPS:

• Lack of sufficient level and consistency of surveillance, lack of adequate compensation and lack of education of farmers, traders and veterinarians
• Structure and nature of poultry sector (usually rapid uncontrolled growth).

Main perceived facilitators for effective prevention and control

• Pandemic scare and increased funds for research.
• Food security considerations.
• Production facilities.
• Global organisation of commercial poultry companies. Better global surveillance of wild birds and migration patterns.
• Antigen banks.

GAPS: Early detection and timely notification.

Risk

Vaccination is an important method for controlling avian influenza but can pose some risks. It would be possible to stimulate antigenic drift if vaccines are not applied properly and under controls. Likewise, without proper marker systems, it will be difficult to differentiate infection from vaccine seroresponses. This is turn will impact on epidemiological investigations. Problems of available vaccines to induce sterile immunity implies risks of silent spread of virus by healthy appearing infected vaccinated poultry.

GAPS: Need to weigh up advantages of vaccination against these disadvantages in endemically infected countries in places where it will not be possible to eliminate virus in the foreseeable future due to the structure of the sector, quality of vet services and the limited commitment at all levels to measures required for disease elimination.

Conclusion

Classical as well as recombinant technology is widely available with reverse genetics system available for influenza. The following are required.

1. Task 1: Develop better early detection methods.
2. Task 2: efficient cell system for production
3. Task 3: increase knowledge on virus biology
4. Task 4: cell signalling, maturation, budding
5. Task 5: antigen presentation and processing
6. Task 6: immunology mediators of cell mediated

GAP: Route of inoculation: mass vaccination = drinking water or spray. Field studies on these parameters are lacking.

Sources of information

Name of expert group leader

Timm Harder - Head OIE and National Reference Laboratory for Avian Influenza, Friedrich-Loeffler Institute.

Name of reviewers

Project Management Board.

Date of preliminary approval

22nd January 2011.

Date of final approval

26th April 2011.