A model to control the epidemic of H5N1 influenza at the source

Even developed countries may not be able to withstand a rapidly spreading 1918-like influenza pandemic with a mortality rate of over 50%. Thus early intervention by quarantine of contacts, social distancing and rapid administration of a central stockpile of antiviral and vaccine to the targeted population at the epidemic centre appears to be a reasonable solution [13, 14]. However it may be at least four weeks before cases of human-to-human transmission are reported to WHO due to the lack of infrastructure for epidemiological and virological surveillance in developing countries. Given the wide distribution of the endemicity of H5N1 virus in Asia, Middle East, Africa and Europe, it is not possible to predict the site to emerge a pandemic strain. Moreover, amantadine resistance was found in isolates from some affected areas and oseltamivir resistance have been detected in virus isolates before or after treatment [15–17]. There may not be adequate vaccine available and it is also possible that the stockpiled prototype vaccine may have a poor match to the pandemic strain. Despite the ability to rapidly scale up the vaccine production capacity and the use of potent immuno-adjuvant, at most only a third of the global human population may have the chance of getting the vaccine at least six months after the pandemic strain is identified. These almost insurmountable difficulties in pandemic preparedness and the present toll on poultry strongly suggest that primary attention should be turned to the control of the virus in the poultry while the virus has only limited capability for poultry-to- human transmission and before it changes to a pandemic strain. Until recently, depopulation based on clinical surveillance is the recommended field measure for the control of outbreaks. However such measures rely on the willingness of volunteers to report excess death especially in backyard poultry. Yet these volunteers may not necessarily be as willing to assist in enforcing more extreme preventive measures outside the settings of an impending outbreak, such as a moratorium or an embargo on raising geese and ducks in backyard flocks. Since these measures are associated with considerable losses to families involved, compensation must be given to the affected farmers in order to gain their cooperation and compliance to this intervention. Such extensive and prolonged efforts of surveillance in the field and laboratory will require technical, financial and administrative support from the developed countries, charity funds and international bodies.

Wild waterfowl including migratory ducks and geese are natural hosts of influenza A viruses. They could be asymptomatic despite infection by highly pathogenic H5N1 strains due to their unique immune system, or if they are previously exposed to other H5 viruses. Moreover highly pathogenic H5N1 strains can revert or be selected to lowly pathogenic strains when passaged in domestic ducks in the laboratory. Thus the duck may serve as the "Trojan horse" of H5N1 influenza viruses which continually to spread new strains to other poultry such the chicken wherein the virus may be selected to a highly pathogenic form[18, 19]. The exchange of virus between migratory and domestic water fowls may have accounted for the spread of H5N1 infection over a vast geographic distance. Thus the water fowls especially the ducks and geese should be the focus for control. Many recent human cases were reported without concomitant findings of outbreaks in poultry. Our hypothesis if proven to work at a provincial level with poorly controlled outbreaks, can be adapted to smaller size districts without excess poultry deaths but virologically positive asymptomatic waterfowls. However this will mean a huge burden on laboratory surveillance since regular sampling of dead poultry in districts without excess poultry deaths have to be instituted.

Experience in the control of rinderpest in African cattle showed that it was difficult to achieve an adequate herd immunity by blanket vaccination, which may be wasteful or impractical [20]. Moreover moderate herd immunity with many asymptomatic virus shedders may actually help to sustain viral transmission. Therefore ducks and geese should only be reared in industrial farms where targeted vaccination programme can be fully implemented. The backyard virus is controlled by a one-off moratorium at the hottest month and re-populated by chickens and other minor poultry. As chickens and minor poultry are usually symptomatic if they have not been partially vaccinated or previously exposed to other H5 subtype viruses, they also serve as sentinel in monitoring the efficacy of control of H5N1 virus in ducks and geese. Vaccination programme in backyard farms is unlikely to be very effective unless the coverage is very comprehensive. It could be potentially detrimental since the vaccine giver may be carrying the virus from backyard to backyard. Partial immunity will only fuel the endemicity [20]. Therefore vaccination of chickens and minor poultry in backyards should be done if a good vaccination programme for ducks and geese is already in place.

Biosecurity measures at industrial farm and markets must be enforced to ensure that virus trafficking between those epidemic centres is minimized. For the wet markets of HKSAR, the ultimate goal is to go for central slaughtering with no more live chickens in retail markets. In order to decrease the resistance of the public and the poultry stall owners to the change, a series of transitional measures for prevention of avian influenza outbreaks have been implemented in HKSAR since 1997. Live ducks and geese are no longer allowed in the retail markets. Subsequently even live quails are not allowed since they can be the potential intermediate host for all subtypes of influenza viruses. Our local farmed and cross border imported chickens must be vaccinated against influenza virus H5 with sufficient serum HAI titre and negative cloacal swab by H5 RT-PCR before they are allowed into HKSAR or the wet markets. For local farms, biosecurity measures are tightened in terms of sufficient geographical separation and the use of bird-proof net. Chicken farms must not keep any other bird species and pigs. Movement of chickens or feed between farms is tightly controlled. Footwear is disinfected before entry to the farm. All staff must shower and put on protective clothing before entering the production area. Chickens from local farms should only be transported in disinfected cages to a designated local poultry wholesale market. Vehicles that carry chickens from one farm to the wholesale market are not permitted to carry chickens or any other poultry from another farm. No chickens that have been in a wholesale or retail market are allowed to enter local farms to stop a transmission cycle between the markets and the farms. All imported chickens must come from registered farms recognized by the government department. At the wholesale and retail market levels, market rest days (4 rest days for wholesale and 2 matching rest days for retail markets) are set up to break the virus replication cycle and reduce the viral load in the wet markets. During these rest days, all trading activities are stopped, all live poultry in the retail outlet slaughtered and the premises thoroughly cleansed and disinfected. With these comprehensive measures at farms and markets, the perimetric depopulation can be reserved for the control of any missed pockets of infection.

Unlike poultry, the role of wild birds in transmission disease to poultry or human is still poorly defined. Most would agree that the migratory birds are at least partly responsible for spreading the virus to poultry in widely separated geographical regions along their flyways. At least 10 dead birds were found to be infected with the H5N1 virus every winter in HKSAR. Local wild birds, migratory birds from the north and perhaps religiously released birds are implicated as the source of the virus in HKSAR (Personal communicaton by Richard Corlett). Though very few human cases have resulted from exposure to wild birds, the handling, slaughtering, defeathering and preparing of wild birds for consumption in endemic areas are considered as risk factors for acquisition of this disease. Due to outbreaks of disease in recreational park birds of HKSAR and their frequent contacts with human, the publics are advised to avoid contact with recreational park birds or wild birds. They should wash their hands with soap or disinfectant after contact. Though psittacine birds are generally more resistant to the H5N1 virus, pet birds caged in high concentration at pet bird shops should also be put under surveillance for outbreaks. As the religiously released birds are often wild birds caught in the mainland and smuggled into HKSAR, most of them will die after their release due to maladaptation to the new environment. Such activity should be banned on the ground of humanitarianism and public health. At the time of writing there is still no recommendation on the use of vaccine to prevent outbreaks in recreational park bird or pet birds due to the lack of understanding on the highly variable immune response of these highly diversified avian species to vaccination. In one study, some of these pet birds showed poor response to vaccination, whereas others such as the flamingos, ibis, rheas, Congo peafowl, black-winged stilts, Amazon parrots, and kookaburras showed good response to an inactivated H5N9 vaccine[21].

An effective poultry vaccine is one of the pillars in the proposed intervention. Between 1997 and 2001, HKSAR had failed to control outbreaks by relying on intensive clinical and virological surveillance of farms and markets with dedicated staff. Thus vaccination was used as a last resort in addition to other control measures. If a high compliance rate of vaccination can be achieved as in HKSAR, the risk of asymptomatic viral shedding is minimized. However, even among the domestic poultry, there are significant differences in their haemagglutination inhibition antibody response towards the commonly used inactivated H5 vaccines. Generally these vaccines has been found to be quite effective in chickens but the haemagglutination inhibition antibody titer tends to be lower in ducks and geese especially when given during the first few weeks of life when their immune system is relatively immature. Furthermore, H5N1 virus has become moreantigenicallydiversified in the last couple of years, it would be important to select antigenically matched or broadly cross reactive vaccines to maintain the efficacy of vaccination. A surveillance program should be established before and during the intervention to closely monitor the virological and serological results of vaccination. Similar to the human seasonal vaccine, a panel of vaccine candidates should be prepared and tested against many circulating strains before large scale production and field testing are done.

In summary, we proposed an intervention programme based on the successful experience of HKSAR in the control of the H5N1 virus by a combination of targeted immunization with the correct vaccine, segregation of poultry species and a three week moratorium of poultry farming (see additional file 1). This intervention, if successfully demonstrated at the provincial or district level in the developing country with persistent outbreaks, can be adapted at a much smaller scale for early intervention once the virus is found even if there is no excess death in the poultry population. But the later would require a strong laboratory support and regular sampling of all dead poultry. This may solve the present problem of human diseases without excess death in poultry.