Avian Influenza

Disease Analysis

Description and characteristics.

Pathogen

The disease is caused by a virus from the family of the Orthomyxoviridae, genus Influenzavirus A, B and C. Influenzavirus are 80-120 nm diameter, segmented RNA viruses, with a helical symmetry. Two surface antigens, the hemagglutinin (H) and neuraminidase (N) proteins, are used to classify type A influenza viruses into subtypes. There are 16 hemagglutinin antigens (H1 to H16) and nine neuraminidase antigens (N1 to N9). . To date, all highly pathogenic isolates have been influenza A viruses of subtypes H5 and H7. Avian influenza is broadly divided into highly pathogenic (HPAI) and low pathogenic (LPAI) strains based on its ability to cause disease in poultry.

Variability of the disease

Influenza virus has a high rate of genetic recombination meaning that new serological and pathological subtypes frequently appear. This makes it extremely difficult to develop reliable assays that can detect all types of Influenzavirus.

Stability of the agent/pathogen in the environment

Avian influenza (AI) viruses are sensitive to most detergents and disinfectants, and heating and drying will inactivate them. However, AI viruses may persist in soil, faeces, and pond water for varying amounts of time, depending on environmental conditions. The ability of AI viruses to survive in the environment depends on temperature and humidity. The pathogen can be inactivated by 56°C/3 hours or 60°C/30 min, by acid pH, oxidising agents, sodium dodecyl sulphate, lipid solvents, ß-propiolactone, by formalin and iodine compounds. It can remain viable for long periods in tissues, faeces and also in water.

Species involved

Animal infected/carrier/disease

Wild bird population endemic, oral transmission to mammals. Many species of waterfowl are asymptomatic carriers of AIV.

Human infected/disease

Yes. Pandemic potential, current risk is limited to close direct contact with no evidence of human to human transmission.

Vector cyclical/non-cyclical

 None.                                                                                                    

Reservoir

Waterfowl are believed to be the primary reservoirs for influenza A, serving as a source of infection for other birds within their migratory path.

Description of infection & disease in natural hosts

Transmissibility

Readily. Highly infectious, via contact, faeces, contact with wild birds, virus can survive in faeces and water. Oral transmission to mammals possible

Pathogenic life cycle stages

Transmission from carriers to susceptible species.

Signs / Morbidity

Sources of the virus are mainly faeces and respiratory secretions. The symptoms are: severe depression, inappetence; Drastic decline in egg production; Facial oedema with swollen and cyanotic combs and wattles; Petechial haemorrhages on internal membrane surfaces; Sudden deaths (mortality can reach 100%);

Lesions in chickens :

• Lesions may be absent in cases of sudden 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
• 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

The lesions in turkeys are similar to those in chickens, but may not be as marked. Ducks infected with HPAI and excreting the virus, may not show any clinical signs or lesions. 

Incubation period

1 to 7 days.

Mortality

The “low pathogenic” form may go undetected and usually causes only mild symptoms (such as ruffled feathers and a drop in egg production). However, the highly pathogenic form spreads more rapidly through flocks of poultry. This form may cause disease that affects multiple internal organs and has a mortality rate that can reach 90-100% often within 48 hours.

Shedding kinetic patterns

Virus shedding occurs following infection. Vaccination to be fully effective must eliminate this shedding.

Mechanism of pathogenicity

Receptor-bound viruses are taken into the cell by endocytosis. In the low pH environment of the endosome, RNA is released from MP1, and 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 the capsid 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 (at least not initially).

Zoonotic potential

Reported incidence in humans

As of  end of June 2009 HPAI H5N1 has been responsible for approximately 436  human infections, generally as the result of close contact with poultry; of which 262 cases were fatal.

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 infected poultry (e.g., domesticated chicken, ducks, and turkeys) or surfaces contaminated with secretion/excretions from infected birds.

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 may depend on which virus caused the infection.

Level of under-reporting in humans

Low.     

Likelihood of spread in humans

The spread of avian influenza viruses from one ill person to another has been reported very rarely, and has been limited, inefficient and unsustained. Efficient or sustainable transmission has not been reported in humans.

Impact on animal welfare and biodiversity

Both disease and prevention/control measures related

The effects of pathogenic strains could cause significant suffering in a large number of birds.

Endangered wild species affected or not

The H5N1 viruses can also cause disease in mammals of other species, including tigers, leopards, housecats, dogs, palm civets and stone martens. In addition, numerous deaths have been reported in migratory wild birds, which usually carry avian influenza viruses asymptomatically and lethal infections have been reported in songbirds.

Slaughter necessity

Yes especially with the LPAI strains which have the potential to become highly virulent.

Geographical distribution and spread

Current occurence/distribution

Global. Low pathogenic strains are global HPAI viruses have been eradicated from domesticated poultry in most developed nations, but reservoirs for these viruses occur worldwide in wild birds.

The current (2003-2009) avian H5N1 outbreak began in poultry in Southeast Asia in 2003. From 2003 to 2008, it spread into domesticated or wild birds in other regions of Asia as well as parts of Europe, the Pacific, the Middle East and Africa. Although some countries have eradicated the virus from their domesticated poultry, this epidemic is ongoing and worldwide eradication is not expected in the short term.

Epizootic/endemic- if epidemic frequency of outbreaks

Variable depending on the effectiveness of the control measures. In Europe the rapid implementation of controls can prevent spread within the domestic populations of bird. Failure to control with result in spread from bird to bird and via vehicles, people equipment  etc.

Seasonal cycle

Comments NA

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. Via Wild birds migration.

Seasonal cycle linked to climate

Comments NA

Distribution of disease or vector linked to climate

No

Outbreaks linked to extreme weather

No

Sensitivity of disease or vectors to the effects of climate change

Not known

Route of Transmission

Usual mode of transmission

Transmission via Direct contact with secretions from infected birds, especially faeces, saliva and nasal secretions.

Occasional mode of transmission

Contaminated feed, water, equipment and clothing. Clinically normal waterfowl and sea birds may introduce the virus into flocks; Broken contaminated eggs may infect chicks in the incubator.

Conditions that favour spread

Close contact infected wild species and domesticated birds, dense populations of susceptible species.

Detection and Immune response to infection

Mechanism of host response

Slightly complex. Humoral antibodies are protective but strain specific. Local protection less understood.  Immunology in waterfowl not really known very well. In mammal disease many immunology questions remain.

Immunological basis of diagnosis

Detection of antibodies.

Main means of prevention, detection and control

Sanitary measures

Comments NA

Mechanical and biological control

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

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 in some cases. These tests can also distinguish some subtypes. 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 as supplemental tests. Although most poultry and other susceptible birds die before developing antibodies, serology can be valuable for surveillance and to demonstrate freedom from infection. AGID tests can recognize all avian influenza subtypes in poultry, but hemagglutination inhibition tests are subtype specific and may miss some infections. In wild birds, some serologic tests may underestimate the prevalence of H5N1 infections.

Vaccines

H5, H7, H9 vaccines available, no vaccination of wild  birds possible. Inactivated vaccines, recombinant vaccines (fowl pox). There are five general types of AI vaccines (i.e., 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.

Therapeutics

None.

Biosecurity measures

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

Border/trade/movement control

Comments NA

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 might be obtained through surveillance. Veterinary authorities may use information provided in this to guide decision-making when establishing vaccine banks for use in avian species (Beato et al., 2009).

Experiences/success (and failures) of prevention, control, eradication in other countries

Eradication of the disease in poultry relies on early detection and rapid response mechanisms in front of any outbreak and through the slaughter of infected or in contact birds, Countries where national veterinary services do not comply with OIE standards on quality are often not yet capable to detect nor to respond rapidly to massive avian influenza outbreaks. In these cases, vaccination should be systematically used as an intermediate control tool until the Veterinary Services comply with the relevant OIE quality standards.

Costs of above measures

Comments NA

Disease outbreaks reported to OIE in last 18 months

Number of reports

Comments NA

Date

Comments NA

Delay between first suspicion / first confirmation and OIE first emergency notification

Depends on the status of the country. Often the first outbreak is not detected quickly. Also depends on the effectiveness of the veterinary services.

Frequency of follow-up reports

Depends on the country but generally follow up reports at least monthly intervals and in some cases more frequently.

Level of under-reporting

High in certain parts of the world where the surveillance systems are not well developed.                                                                                                     

Socio-economic impact

Human

Low with current incidence and apparent inability of HPAI to spread to and within the human population.

Impact on affected individuals and/or aggregated DALY figures

Unknown.

Cost of treatment and control of the disease in humans

Potentailly high with the need for vaccination and antiviral treatment but not at present.

Animal

Comments NA

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).

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

Costs of eradication, vaccination, biosecurity.

Indirect impact

High and severe. Trade implications Impact on backyard poultry and protein supply of developing countries.

Trade implications

Impact on international trade/exports from the EU

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.

Impact on EU intra-community trade

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

Impact on national trade

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 and frequent mutations, waterfowl carriers migration, outdoor production, potential of the virus to change from low to high pathogenic. Lack of cross protection of different H types. 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. Economical implications 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.

Vaccines can allow birds to shed virus while remaining asymptomatic, good surveillance and movement controls are critical in a vaccination campaign

Vaccination may place selection pressures on avian influenza viruses, and might eventually result in the evolution of new strains or variants.

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.

Diagnostics availability

Commercial diagnostic kits available worldwide

Yes, but limited. PCR, serology, availability of differentiation tests limited. Technology for characterisation of strains is quite advanced, but sometimes lacking behind in developing countries.

Commercial diagnostic kits available in Europe

BioChek Avian Influenza Antibody test kit  is on the Register of diagnostic tests certified by the OIE as validated as fit for purpose. An ELISA.

Diagnostic kits validated by National or International Standards

BioChek Avian Influenza Antibody test kit  is on the Register of diagnostic tests certified by the OIE as validated as fit for purpose.

Diagnostic method(s) described by International Standards (e.g. OIE, EU)

FAO Guideline and OIE Manual.

Commercial potential for diagnostic kits in Europe

Medium.

DIVA tests required and/or available

Yes. Sentinel birds can be used for ‘DIVA’ strategies. Sentinel birds are non-vaccinated birds that are kept in vaccinated flocks and routinely inspected and tested for AI infection.

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: heterologous neuramidase). With such a vaccine, the immune response to the homologous H type ensures protection, while antibodies against the neuramidase of the field virus can be used as a marker through the application of a suitable companion discriminatory test. The advantage of this method is that a vaccine bank of inactivated oil emulsion heterologous vaccines could be established.

Opportunities for new developments

Multiple strain vaccines, diva tests.

Vaccines availability

Commercial vaccines availability (globally)

Yes. H5, H7, H9 vaccines available, no vaccination of wild birds possible. Inactivated vaccines, recombinant vaccines (fowl pox). Killed and recombinant vaccines. 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 and using this recombinant virus to immunise poultry against AI.

Commercial vaccines authorised in Europe

Yes. H5, H7 vaccines, regulated use.

Marker vaccines available worldwide

Yes. DIVA principle with different N types.

Marker vaccines authorised in Europe

Not specifically although strains with different N components can be sued 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 respect international standards and guidelines. The standards of OIE and the minimum requirements indicated by EMEA for vaccines to be used in birds against HPAI viruses (ref. Committee for Medicinal Products for Veterinary Use (CVMP) guideline EMEA/CVMP/IWP/222624/2006) should be respected.

Commercial potential for vaccines in Europe

Regulatory and/or policy challenges to approval

Depends on disease evolution and willingness to vaccinate.

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 drininking water application possible as a single AI vaccine or in combination with Newcastel 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.

Pharmaceutical availability

Current therapy (curative and preventive)

None.

Future therapy

Future therapy

None anticipated in the near future. In the longer term virus specific antiviral may be a possibility.

Commercial potential for pharmaceuticals in Europe

None.

Regulatory and/or policy challenges to approval

Not applicable.

Commercial feasibility (e.g manufacturing)

Not applicable.

Opportunities for new developments

Based on an understanding of the virus and its pathogenic actions along with gene sequencing of the virus it may eventually be possible to develop strain specific antiviral drugs. This would be in the long term.

New developments for diagnostic tests

Requirements for diagnostics development

Easy to use, usable on farm and mass screening tests are needed.

Time to develop new or improved diagnostics and their validation

Unknown.

Cost of developing new or improved diagnostics and their validation

Variable.

Research requirements for new or improved diagnostics

Development of pen side tests and alternatives for the simple diagnosis of AI.

Technologies to determine virus freedom in animals

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

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.

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. The development of live vaccines which may 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. 

New developments for pharmaceuticals

Requirements for pharmaceuticals development

Not applicable at present.

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.

Risks

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. Equally without proper marker systems it will be difficult to differentiate infection from vaccine responses. This is turn will impact on epidemiological investigations.    

5 critical gaps

Conclusion

Money is needed for research requirements.

Classical as well as recombinant technology is widely available, reverse genetics system available for influenza

Task 1; Develop better early detection methods.

Task 2: efficient cell system for production

Task 3: increase knowledge on virus biology

Task 4: cell signalling, maturation, budding

Task 5: antigen presentation and processing

Task 6: immunology mediators of cell mediated

Sources of information: 

Defra http://www.defra.gov.uk/animalh/diseases/vetsurveillance/az_index.htm

OIE   http://www.oie.int/eng/normes/MMANUAL/A_index.htm

http://www.oie.int/eng/maladies/fiches/a_a080.htm

http://www.oie.int/eng/ressources/en_diseasecards.htm

http://www.oie.int/eng/maladies/en_alpha.htm?e1d7

http://www.oie.int/eng/info_ev/en_AI_avianinfluenza.htm

WHO

http://www.who.int/csr/disease/avian_influenza

References