農医連携教育研究センター 研究ブランディング事業



Kitasato University
Newsletter of the President Office
September 1, 2007

Newsletter: Agriculture, Environment, and Medicine No.30
The Proceedings of
The Third Agromedicine Symposium in Kitasato University
March 9, 2007

A Look at Avian Influenza from the Perspective of Agriculture, Environment, and Medicine
A Message from the Symposium Organizer  Tadayoshi Shiba
Tadayoshi Shiba
President, Kitasato University

Allow me to make a few remarks as representative of the organizer in relation to Kitasato University's 3rd Agromedicine Symposium.

In 2006, the Science Council of Japan was restructured through consolidation of its 7 earlier divisions-Literature, Law, Economics, Physical Sciences, Engineering, Agriculture, and Medicine-into the 3 divisions of Humanities, Life Sciences, and Physical Sciences and Engineering. In its previous form, the Science Council was supported by the research liaison committees and academic conference activities of the many academic societies that comprised its backbone, but since its reorganization, such society-based activities have declined, giving way to issues-based activities that span a range of fields and bring together experts in specialized areas of different disciplines.

This kind of change has had a significant impact on academic society activities, allocation of research funds, and research trends in each field. For example, the Science Council has from its 20th term organized its committees according to issues and is putting greater emphasis on the contribution that academia can make to society.

The Science Council of Japan is the cornerstone of academia in Japan, and I think that all universities and research institutes need to pay attention to the direction taken by the Council with respect to education and research in Japan. The changing trend of academic conferences is no doubt being driven by a reconsideration of the path taken by science here and a desire to explore new fields, and I think that the initiatives taken in the Council's 20th term give much reason for hope for the future.

To move on to another subject, human activity has had the effect of disturbing the natural order of things on Earth. As a result, ecosystems are beginning to be undermined by a myriad of little invaders, from viruses to weeds.

In September 2001, Japan suffered its first outbreak of BSE (bovine spongiform encephalopathy), a disease that opens holes in the brain tissues of cows and damages the central nervous system. The consumption of parts of cows infected with BSE, particularly the most risky parts such as brain and other nervous tissues and distal ileum, can, albeit very rarely, lead to human infection, causing senility and death. This is just one more little invader.

And now there is a new source of worry. The avian influenza that has broken out here and there in Asia over the past few years has spread to Europe too. The pathogen, a virus, tends to mutate with successive outbreaks, and there is a growing chance of a new influenza virus appearing that will spread like wildfire through human society. This is another case of bioinvasion.

The WHO and many countries have started preparations to guard against such an eventuality, and Japan is no exception. The Ministry of Health, Labour and Welfare on November 14, 2005, announced an action plan that includes its declaration of a state of emergency in the event of an outbreak of a new influenza virus in Japan.

Agriculture is human activity applied to the environment. There is no human activity that does not affect the ecosystem, which could be seen as a huge symphony of life forms. The order of the ecosystem created by the countless organisms within the environment could also be seen as a network of innumerable-and largely invisible-interactions between life forms and resources within the environment. This network and the organisms that comprise it automatically restore equilibrium when that equilibrium is disturbed, and as a result, the natural world can maintain this equilibrium forever.

Unless we seriously tackle such issues as BSE, the current bird flu problem, and other problems caused by these little invaders that are bound to crop up in the future, the human race faces a very dark future. These little invader issues are intimately related to agriculture, environment, and medicine, and cannot be resolved unless we consider agriculture, environment, and medicine as one.

The Science Council of Japan's establishment of a new Life Sciences division is in my mind a vital approach to resolving these little invader issues. Our own new educational and research goal at Kitasato University-the integration of agriculture, environment, and medicine-is very much the same kind of approach. This is an area in which the emphasis is on surmounting disjunction between different areas of knowledge.

It is my sincere wish that holding this Kitasato University 3rd Agromedicine Symposium "A Look at Avian Influenza from the Perspective of Agriculture, Environment, and Medicine" with participation from experts in all three fields will help contribute to the resolution of the issue of bird flu. I hope that the event will be a forum for meaningful and pragmatic discussion that gives rise to new ideas for integrating agriculture, environment, and medicine. I would like to end by expressing my heartfelt thanks to the professors who so readily agreed to speak at this symposium.
Looking at Bird Flu from the Perspective of Agriculture, Environment, and Medicine  Katsu Minami and Shinji Takai
Katsu Minami
Professor, Kitasato University
Shinji Takai
Professor, Kitasato University

Little invaders

There is a book titled Life Out of Bounds(1998) written by Chris Bright, an environmental journalist and magazine editor, while serving as the chief editor of World Watch, a magazine issued by the Worldwatch Institute. The Japanese language edition, titled Little Invaders that Destroy the Ecosystem, was published in 1999 by Ie-no-Hikari Association.

In his acknowledgments at the front of the book, the author writes that he co-hosted a Worldwatch press conference on bioinvasion - "how human activity is 'stirring up' the Earth's organisms - whether viruses, weeds or whatever - and about why the consequent levels of biotic mixing tend to injure our societies and the natural world. The press conference was our way of inviting the public to explore this terrain with us. Life Out of Boundsis a continuation of that process."

Worldwatch founder Lester Brown too writes as follows in a foreword that he contributed to the Japanese edition:

"This book that you are about to read was written with the aim of providing you with a clear picture of how these life forms travel, and the ecological damage they cause. This damage is brought about through the invasion of introduced species that spread at a prolific rate. Introduced species are life forms that have been introduced to ecosystems other than the ecosystem in which they themselves evolved. Once an introduced species gains a foothold in a new location, there is a chance that it will proliferate rapidly and, in the competition for the resources required for survival, overwhelm native species and impede their propagation. If the introduced species is a microorganism, it may trigger an epidemic, and if it is a predator, it may predate on native species to an extent that it eradicates them.

"How can we maintain a balance between trade and the need to protect the world's ecosystems? This is the core issue tackled by this book. The health of our economies clearly depends on a high level of international trade, but it is equally clear that the health of our ecosystems depends on how well we can keep most of this planet's life forms within their native habitats. I think that ensuring a balance between these two needs will become one of the key environmental issues of the new century."

In September 2001, Japan suffered its first outbreak of BSE, a disease that opens holes in the brain tissues of cows and damages the central nervous system. The consumption of parts of cows infected with BSE, particularly the most risky parts such as brain and other nervous tissues and distal ileum, can, albeit very rarely, lead to human infection, causing senility and death. This is just one more little invader.

And now there is a new source of worry, though one of a kind that the world has experienced several times in the past. The avian influenza virus (AIV) that has broken out here and there in Asia over the past few years has emerged in Europe too. This year too, the highly pathogenic H5N1 strain of AIV has emerged in the province of South Chungcheong in Korea, and in the prefectures of Miyazaki and Okayama in Japan. In Korea, 19 H5N1 outbreaks were recorded between December 2003 and March 2004 in poultry farms and other locations, resulting in the death or extermination of 5.3 million chickens and ducks. Four workers involved in the extermination work were also infected by the virus.

Viruses like this tend to mutate with successive outbreaks, and there is a growing chance of a new influenza virus appearing that will spread like wildfire through human society. This is another case of bioinvasion.

The WHO and many countries have launched preparations to guard against such an eventuality, and Japan is no exception. The Ministry of Health, Labour and Welfare in November 2005, announced an action plan that includes its declaration of a state of emergency in the event of an outbreak of a new influenza virus in Japan. This action plan is based on guidelines provided by the WHO, and delineates measures to be taken in the event of both overseas (A) and domestic (B) outbreaks according to 6 phases from interpandemic (normal) to pandemic phases.

Agriculture is human activity applied to the environment. There is no human activity that does not affect the environment or ecosystem, which could be seen as a huge symphony of life forms. AIV or BSE could be seen as evidence that human activity is undermining the natural order and network of interaction created by countless life forms in a diversity of environments.

We need to seriously tackle such issues as BSE, the current bird flu problem, and other new and reemerging infectious diseases that are bound to crop up in the future, considering them in relation to the environment and ecosystem. These issues are intimately related to agriculture, environment, and medicine, and cannot be resolved unless we consider agriculture, environment and medicine as one.

Recent spread of AIV

The risk of highly pathogenic (HP) AIV H5N1 spreading throughout the world has grown since 2004. Up to then, infection had been limited to birds in Asia alone, but from 2004, it began to spread to Europe and Africa. While everyone now recognizes the importance of international pandemic countermeasures, such countermeasures are still imperfect in Asia, and outbreaks cropped up in both Korea and Japan at the end of last year and the beginning of this year.

Outside of East Asia, HPAIV H5N1 has also been identified in Azerbaijan, Djibouti, Egypt, Iraq, Iran, Greece, Turkey, Romania, Kuwait, Russia, Mongolia, Kazakhstan, Tibet, Croatia, Italy, Macedonia, Canada, Sweden, the UK, and the USA, and has been found to infect a wide range of birds, including domestic and wild ducks, turkeys, swans, parrots, chickens, flamingos, and falcons.

Cases of AIV H5N1 infection of humans have occurred in the following 10 countries: Azerbaijan, Cambodia, China, Djibouti, Egypt, Indonesia, Iraq, Thailand, Turkey, Nigeria and Vietnam.

Numbers of people infected (deaths in brackets) between December 2003 and February 6, 2007 are as follows: Vietnam: 93 (42), Indonesia: 81 (63), Thailand: 25 (17), China: 22 (14), Egypt: 19 (12), Turkey: 12 (4), Azerbaijan: 8 (5), Cambodia: 6 (6), Iraq: 3 (2), Nigeria: 1 (1), Djibouti: 1 (0). This makes for a total of 271 persons infected and 166 deaths. The above figures are for cases reported and confirmed, and actual infections and deaths are likely to be higher. (source: Infectious Disease Surveillance Center, National Institute of Infectious Diseases)

Avian influenza epidemics

Pandemics of Spanish flu and other strains of influenza have swept the world several times in the past, causing large numbers of deaths. The following is a brief chronology of such epidemics.

1889-90: Isolation of "influenza germ" from an epidemic, but it was not the real pathogen, which was an H2N2 strain.
1918-19: Spanish flu infects 500 million people and kills 1% of the world's population. H1N1 subtype. In Japan, 23 million infected, 390,000 deaths, though higher estimates also exist.
1933: Type A influenza isolated. Type B isolated in 1940, and type C in 1947
1943: Vaccines for types A and B influenza developed in the USA using embryonated eggs
1946: Italian flu, an H1N1 subtype that went pandemic in Europe
1948: WHO World Influenza Centre established in London
1951: Prototype vaccine developed in Japan. Mass production from 1962
1957-58: Asian flu pandemic. H2N2 subtype. In Japan, 980,000 infected, 7,000 deaths
1968: Hong Kong flu pandemic. H3N2 subtype. In Japan, 140,000 infected, 2,000 deaths
1977: Russian flu. H1N1 subtype
1997: Hong Kong H5N1 outbreak in domestic animals. High fatalities in infected animals
2003-04: H5N1 pandemics among birds in various Asian countries. Human deaths in Thailand and Vietnam
2005-: H5N1 pandemic among wildfowl inhabiting Qinghai Lake, China. Later spreads to Europe and Africa.

(Source: Illume Vol. 18 No.2, 2006)

AIV human infection numbers

An incident occurred in 1997 that forewarned of a global pandemic. At the time, influenza was spreading among chickens and other domestic fowl in Hong Kong, and the causative AIV infected 18 humans, resulting in 6 deaths. This incident shocked the world for the fact that AIV, up to then thought incapable of infecting humans, made a direct jump from domestic fowl to humans, and that it was moreover a highly pathogenic (HP) strain (type A influenza H5N1 subtype).

AIV infection of humans has been reported every year since then, with deaths increasing exponentially every year. Figures for infections and deaths are as follows:

1997: H5N1 China (Hong Kong): 18 infected (6 deaths)
1998: H9N2 China: 9
1999: H9N2 China (Hong Kong): 2
2003: H7N7 Holland: 89 (1)
2003: H9N2 China: 1
2004: H7N3 Canada: 2
2004: H10N7 Egypt: 2
2003-07: H5N1

As of February 6, 2007, there have been 271 humans infected (166 deaths) in 10 countries. Deaths per country are provided above.

Waterfowl are the origin of AIV

AIV has been isolated from over 90 wild bird species so far, a figure that suggests that almost all avians are susceptible to AIV infection.

In the 1970s, AIV was found to be carried by a high percentage of waterfowl around the world, particularly in healthy migrants such as wild ducks, wild geese, swans, curlews, plovers, seagulls, and terns. Wild ducks in particular show a very high percentage of AIV, and wild waterfowl are accordingly now regarded as the natural hosts of the virus in the wild.

Waterfowl carrying AIV at a particularly high level include young mallards just prior to migration in late summer, and other duck species inhabiting ponds and rivers in early winter. A great many waterfowl migrate annually to Japan from Siberia and China, and one study found that 3% of those migrants carry AIV. Curlews and plovers have also been found to carry AIV.

It was shown in the 1970s that a hybrid AIV could be generated by infecting pigs simultaneously with AIV and human influenza. After the discovery that AIV originates in waterfowl such as ducks and swans, the sequencing in the 1980s of the genes of various types of influenza virus proved that wild waterfowl are the natural hosts of AIV and that the original strain spread to various other animals as it mutated.

Impacts of human activity

Human activity has brought about many major changes in the natural world. Such impacts are permissible when kept within limits that enable the ecosystem to recover fairly easily, but we appear to have overstepped those limits.

Up to now, AIV had remained isolated in nature within waterfowl, curlews, and plovers, but owing to international trade, new forms of culture, industrialization of poultry farming and so forth, the virus's ecosystem, distribution, range of hosts, and virulence has changed dramatically. Causative factors include the international trade in pet birds, domestic waterfowl farming, free-range poultry farms, sale of live birds, ornamental and fighting cock trade, and increasing size of poultry farms.

Ducks and geese, which tend to be raised in the open, show a higher prevalence of AIV than chickens do. Because the ponds required for raising waterfowl are normally located outdoors, they are prone to contamination by migrating waterfowl and other wild birds flying overhead or landing on them.

It was previously thought that AIV would crop up only very rarely in the kind of intensive poultry farming practiced in developed countries, but such is no longer the case. Once the virus invades such an intensive environment, it can spread rapidly to affiliated farms, resulting in much more extensive damage. This issue is now deservedly attracting serious consideration.

Countering new strains of influenza

What can we do to prevent the appearance of a new and highly pathogenic H5N1 influenza virus? And what kind of countermeasures do we need to take should such a virus appear? What about choice of vaccine strains, or the production of drugs that fight the influenza virus?

Now that we are already at Phase 3 in the WHO's six public health risk phases and are considering preparedness for Phase 4, what kind of measures should we be thinking about from the perspective of agriculture, environment, and medicine? It is my aim to make this a meaningful symposium that integrates agriculture, environment, and medicine through having experts from various specialized fields provide their views on this subject.

There are of course many related issues, such as national crisis management above and beyond medicine, the issue of balancing crisis management with individual freedom, the role of the media, risk assessment and risk communication issues, household preparedness, and so forth, and I hope that this symposium will also provide opportunities for considering such issues.

Closing comments

It is my fervent hope that a new influenza virus does not emerge, but to such an end I think we need to once more go over the words of Francis Bacon or Rachel Carson and reconsider our relationship with technology and nature.

The ecosystem could be seen as a huge symphony of life forms. The order (or maybe "harmony" would be more appropriate) of the ecosystem created by countless organisms within the environment could also be seen as a network of innumerable - and largely invisible - interactions between life forms and resources within the environment. This network and the organisms that comprise it are designed to automatically restore equilibrium when that equilibrium is disturbed, and as a result, the natural world can maintain this equilibrium forever. However, this "forever" may well now be finite.

Insofar as each and every organism seeks to preserve its line as it evolves, the fight for survival knows no end. The AIV issue is an extension of this struggle, and as such, we need to apply whatever human wisdom we have to prevent and to prepare for outbreaks. Tackling this issue as soon as possible is one way of ensuring a brighter future for humanity.
Current Status and Issues of Zoonotic Viral Diseases  Yasuhiro Yoshikawa
Yasuhiro Yoshikawa
Professor, Graduate School of Agriculture and Life Sciences, University of Tokyo

Opening comments

Human beings are heterotrophic organisms that depend on animals and plants as sources of nourishment. Most of our needs for protein and fat are now met by consumption of the milk, meat, internal organs and other parts of domestic animals. We have had a long relationship with domestic animals, some of which were already living among us when we started farming the land 10,000 years ago. A look at that history shows that almost all current infectious diseases suffered by humans have animal origins. In other words, diseases such as smallpox, measles, and influenza that were once thought to be unique to humans, all pathogens originate in other animals or share common ancestors with viruses infecting other animals. There are also many infectious diseases even today that can be passed between people and domestic animals. We humans do not inhabit a special world separate from that of other animals.

1. From animals to humans

Zoonotic diseases are diseases caused by a pathogen that infects both animals and humans (but natural hosts infected by the pathogen often do not suffer any adverse effects). They consist mostly of diseases passed on to humans from animals, and diseases originally passed on to animals from humans and then back to humans from the infected animals (so-called recurrent infections, e.g. dysentery, tuberculosis, viral hepatitis, and other diseases found in monkeys).

Zoonotic diseases include such well-known examples from ancient times as plague, which is transferred from wild rodents (rats, etc.) to humans through fleas (and is by no means a disease of the past, still being prevalent in the continents of Africa, Asia, and America), and rabies, which is passed on to humans from infected dogs, bats, and other animals. There are of course many other parasitical, rickettsial and chlamydial, bacterial, and viral diseases affecting humans. In 1959, a WHO and FAO joint expert committee listed over 150 such diseases, and now there are thought to be 500-700 noteworthy diseases. Infectious diseases that have sent shockwaves throughout the world in recent times include diseases of wild animal origin such as Ebola hemorrhagic fever (HF), Nipah virus infection, SARS, and West Nile fever; diseases of domestic animal origin such as O-157, BSE, and HPAIV; and diseases of arthropod origin such as dengue fever, dengue hemorrhagic fever, and malaria. About two-thirds of all viral diseases to have emerged in the latter half of the 20th century are zoonotic. Infectious diseases of domestic animal origin such as salmonella, hepatitis E, O-157, and BSE warrant serious consideration also from the food safety perspective since they invariably spread through foodstuffs.

Retrospectively, it was in 1980 that the WHO declared that smallpox had been eradicated. Though it is only one pathogen, this was the first time in history that mankind had defeated a virus (though recently people have voiced concern that it has not been completely eradicated ironically insofar as it continues to exist in the form of samples that might some day be used as pathogens in acts of bioterrorism). With the development of antibiotics, we also became able to suppress bacterial infections, giving rise to optimism about our ability to protect ourselves from infectious diseases. In Japan too, the infectious diseases that were long the top causes of death declined rapidly after the 2nd World war, making way for cancer to become the No.1 cause of death by 1950. As circulatory disorders became the 2nd most prominent cause of death, Japan's healthcare authorities began to focus more on welfare and countering cancer and lifestyle diseases rather than infectious diseases.

However, new infectious diseases such as AIDS and various viral hemorrhagic fevers have emerged worldwide, and diseases such as dengue fever and tuberculosis have reemerged to become serious threats to human health once again. Excessive use of antibiotics has given rise to the spread within hospitals of antibiotic-resistant bacteria such as MRSA, VRE, and VRSA. Given such developments, the WHO has revised its optimistic forecasts regarding the fight against infectious diseases, and countries throughout the world have declared states of crisis with regard to infectious diseases.

2. Factors behind the occurrence and spread of zoonotic diseases

Most zoonotic diseases can be traced to developing countries. The reasons for this include increased contact with pathogens carried by wild animals in tropical rainforest and other natural habitats during development of human production activities (Ebola HF, Marburg disease, monkeypox), disturbance of ecosystems by rodents and other animals whose numbers have been elevated by increased human productivity (Bolivian HF, Lassa fever, Argentine HF, etc.), establishment of infectious disease in cities of developing countries, which is normally circulated between monkeys and mosquitoes in forests owing to rapid urbanization and population concentration combined with poor urban infrastructure (yellow fever, dengue fever, dengue HF, etc.), and rapid spread of infection from developing to developed countries as a result of the rapid air transport of both people and animals (Lassa fever, Marburg disease, SARS).

There are also contributing factors in developed countries, such as the keeping of wild animals as so-called exotic pets (tularemia, plague, monkeypox, etc. transmitted by pet prairie dogs), and contact with wild animals during outdoor recreation such as camping or forest walking (Japanese spotted fever, scrub typhus, Hantavirus pulmonary syndrome and Lyme disease transmitted by such animals as wild rodents and ticks, echinococcosis transmitted by foxes, etc.). New infectious diseases have also emerged in developed countries as a result of the pursuit of economic efficiencies in the form of intensive factory farming and rendering of animal parts as sources of protein (salmonella, BSE, O-157, etc.). In recent years, moreover, we are seeing transmission patterns of a more complicated kind, such as the Hendra and Nipah viruses transmitted from tropical fruit bats - up to now not known to be carriers of pathogens - to humans through domestic animals.

The chances of coming into contact with infectious diseases in humans transmitted by domestic animals such as pigs (Nipah virus), horses (Hendra virus), cattle (BSE), or chickens (HPAIV) are much higher than for those of wild animal origin. Domestic animals are increasingly raised for human consumption in large-scale factory farms, and once a pathogen invades such an intensive rearing environment, it can spread like wildfire, with the likelihood that its frequent transmission among hosts in such an environment will also facilitate genetic mutation, making for a much more dangerous situation than in the past.

Even among wild animals, we might be facing new risks. For example, increasing environmental pollution might reduce host immune functions, as a result of which a virus that has up to now coexisted with a host suddenly begins to spread explosively (North Sea seal virus, etc.), or environmental pollutants might elevate the frequency of virus mutation, because they were frequently mutagenic chemical substances. This kind of possibility suggests a need for conception change and actions different from earlier measures for suppressing zoonoses and avoiding risks. Conservation medicine is a new approach to the control of zoonoses that incorporates the concept of environmental conservation in the consideration human and animal health.

3. Warning to humanity

The way in which zoonoses emerge and spread is changing in connection with the expansion of human production activities, pursuit of economic efficiency, changing lifestyles, and so forth. In this respect, zoonoses have much in common with environmental pollutants such as PCB, DDT, and dioxins. There is nothing evil about pursuing comfort and convenience, but if in our anthropocentric pursuit of ever more advanced technology we continue to ignore the need for balance and continue to destroy the environment and ecosystem, we are doomed to suffer the consequences. Attempts to resolve issues by pushing the contradictions of developed countries onto developing countries or by a country just looking out for itself are already proving to be bankrupt. What is needed is global cooperation between governments on countermeasures to zoonoses led by the WHO and OIE. National governments should also be remind that to avoid covering up or failing to report outbreaks, or all clear declarations under issuing premature. Other acts aimed simply at protecting one's own country's economy or calming the populace will in the end only raise the risks of a global infection (SARS in China, HPAIV in Southeast Asia, BSE in the UK, etc.).

Even the USA, which has the most advanced infectious disease defense system in the world and is home to the Centers for Disease Control and Prevention (CDC) that plays a leading role in controlling infectious diseases worldwide, has not had an easy time controlling zoonoses like West Nile fever that are transmitted through wild animals (birds and mosquitoes). West Nile fever first appeared in eastern New York in 1999, infecting 7 people, but by 2003, it had spread throughout the country and still shows no signs of abating, with infections now standing at over 8,000 and deaths at over 200. The USA is also finding it extremely difficult to suppress plague endemic to arid Midwest regions (being transmitted between prairie dogs and fleas) and rabies transmitted by bats.

Meanwhile, the fact that SARS, which is thought to be of wild animal origin, spread throughout the world in a matter of months demonstrates that national borders and other artificial barriers are no obstacle to modern infectious diseases. HPAIV H5N1, the subject of this symposium, has also spread from Asia to the Middle East, Europe, and Africa. The number of countries affected, the scale of infection, and virulence that has enabled it to directly infect not only pigs but also humans, has prompted the WHO to issue dire warnings about the dangers it poses. In addition to conventional downstream, end-result-oriented infection countermeasures targeting people and animals (Ministry of Agriculture, Forestry and Fisheries [MAFF], Ministry of Health, Labour and Welfare [MHLW]), in the 21st century, zoonoses originating in wild animals need to be investigated from a more upstream perspective that also considers the environment and the ecology of pathogens parasitizing wild animals and natural hosts in order to develop more global countermeasures.

4. The path to controlling zoonoses

Including pathogenic microorganisms, there are currently about 1.4 million known species on Earth (approximately 750,000 insects, 280,000 other animals, 250,000 higher plants, 70,000 fungi, 30,000 protozoans, 5,000 bacteria, and 1,000 viruses). When one considers the complexity of the ecosystem that these organisms have built up as the present-day descendants of 3.7 billion years of life on Earth, it is impossible for we humans to completely control zoonoses for the sake of our own convenience. Basically we need to recognize the importance of biodiversity and seek to achieve a balanced coexistence with other life forms.

Even so, we need to do what we can to control infectious diseases that endanger humanity. The organizations charged with the responsibility of controlling infectious diseases on an international level are the Geneva-based WHO for human infectious diseases, and the OIE, headquartered in France, for animal infectious diseases and infectious diseases whose origins can be traced to foodstuffs. Because OIE decisions frequently directly affect domestic animals in various countries and trade in foodstuffs of domestic animal origin, the OIE also serves as an affiliate of the WTO.

The expert committees of these international organizations frequently use risk analysis as an analytical method. This methodology was originally used to decide international safety criteria with respect to humans for drugs, food additives, and so forth, but has come to be used also in the control of food poisoning and infection by microorganisms. Risk analysis is a field that merges natural science with social science, and is made up of three key aspects - risk assessment, risk management, and risk communication. Based on a scientific, quantitative risk assessment, the parties concerned (risk managers) consider cost-effectiveness and draft a realistic plan that they explain to others in easily understandable terms, and attempt to establish a more efficient defense system. In Japan after the BSE panic, the Food Safety Commission was established within the Cabinet Office as a risk assessment organ independent from risk management organs. International organizations are already bringing together infectious disease experts and government officials from different countries or regions in field-specific forums to consider measures for the sustained control of infectious diseases.

However, the control of such diseases is basically a political and economic issue. As long as poverty, famine, and war continue, there is little hope for improving public hygiene globally. The path to controlling infectious diseases is one of international cooperation in the building of standards and systems for global defense against such diseases that also respect diversity in the form of national and regional differences in culture, national character, and everyday life and customs.

5. Japan's new zoonosis countermeasures

After the postwar period of rapid economic growth, dramatic changes in the social system and values fueled the trend towards nuclear families and declining birthrate, and pets as companion animals came to serve as substitutes for people. Then during the economic bubble of the 1980s, in place of the traditional species of pet animals, the import and keeping of exotic animals became very popular. Japan's birthrate declined and population aged at a pace that was exceptional even among the developed countries, and Japan also stood out from the rest in the quantity of its wild animal imports. These changes in society and diversification in lifestyles prompted increasing concern over the possibility that novel zoonoses would emerge, and so when the Infectious Diseases Control Law was enacted (effective from 1999), in addition to diseases transmitted between people, zoonoses too were considered for the first time, and with an expansion of the Rabies Prevention Law, cats, skunks, raccoons, and foxes in addition to dogs became subject to legal quarantine, as did monkeys. However, other infectious diseases and animal species were not subject to regulation, and so when the Infectious Diseases Control Law came up for revision 5 years later, stronger measures were considered.

For this revision, data on infectious diseases, the realities of imported animals, and disease risk assessment was obtained and analyzed. An MHLW zoonotic disease study team carried out a first-ever zoonosis risk analysis. As a result, a total import ban was imposed on all Chiroptera (bats) and rodents of the Mastomys genus (the natural hosts of Lassa fever) from November 2003, and requirements such as import notification, health certificates, and tethering according to risk level were applied to all other animals apart from prairie dogs and civet cats whose import was already prohibited, and monkeys and carnivores already subject to legal quarantine.

In other words, unlike previous revisions which tended to simply increase animal quarantine, the new revision applied import bans to certain species, tethering orders, stronger measures against introduced animals and indigenous wildlife (migratory birds, crows, etc.) including surveillance systems, investigation of animals in the event of outbreak of a zoonosis, and stronger measures to combat zoonoses. Particularly the animal import notification system and requirements for health certificates and furnishing of proof of non-infection with certain pathogens effectively put a stop to the import of wild animals that had gone unchecked up to then, and this has proved to be an effective alternative to quarantine as a means of avoiding risks.

With respect to wild and domestic animals within Japan, everyday surveillance is vital, which means that it is also vital to establish an organization for diagnosing infections in animals. With regard to high-risk infectious diseases, there is a need to identify high-risk localities, localities in which animal intrusion is likely, and habitats of wild animals carrying the infectious diseases concerned, and take comprehensive measures to combat the spread of the disease, curb the number and habitats of natural hosts and animal vectors, exterminate intruders, and so forth. This is a field that calls for cooperation between central and local government, between MAFF and the MHLW, and between doctors and veterinarians.
Highly Pathogenic AIV Infection and Countermeasures Shigeo Yamaguchi
Shigeo Yamaguchi
Research Manager, National Institute of Animal Health,
 National Agriculture and Food Research Organization

Opening comments

Avian influenza (AI) is a disease caused by a type A influenza virus infection. It is one of the most serious infectious diseases of the livestock industry because of certain strains of this virus result in the death of the majority of birds in chicken or turkey poultry farms. AIV was previously thought not to infect and cause illness among humans, but in 1997 in Hong Kong, the H5N1 subtype of highly pathogenic avian influenza (HPAI) virus jump to humans, and killing 6 out of 18 infection. HPAI has been recognized as a important zoonosis ever since this shocking event.

In this symposium, I want to explain the importance of HPAI and the control measures from the agricultural perspective, and also want to reffer to countermeasures to new pandemic of human influenza.

1. Emergence of HPAI

AIV is categolized into two types, low pathogenic and high pathogenic, by the pathogenicity to chickens.

In nature, low pathogenic AIV is found at high levels mainly in waterfowl, and almost all AIV found in the wild birds is of the low pathogenic type. However, as they jump from waterfawl to poultry, a low pathogenic AI viruses mutate into high pathogenic strains that cause 100% fatalities among chickens.

Wild ducks (Anseriformes) harbor low pathogenic AIV at a high level, excreting the virus in feces as they migrate. This virus has an affinity for ducks and does not readily infect other species (orders) such as chickens, turkeys, and other poultry (order Galliformes). However, it can infect such species at a very low rate, and even more rarely establishes itself as a low pathogenic AIV that adopt to poultry and changed to show low infectivity to ducks.

If low pathogenic AIV that has established itself in chickens infects other chickens, certain strains can mutate into high pathogenic AIV capable of causing 100% fatalities in infected chickens. For some reason, up to now low pathogenic AIV that has mutated into high pathogenic AIV has all been of either H5 or H7 subtypes, suggesting that these subtypes are particularly adept at mutating into high pathogenic AIV in chickens.

Because AIV shows the above character, MAFF has defined "highly pathogenic AIV" (HPAIV) for not only high pathogenic AIV infection but also all H5 or H7 subtype infection of even low pathogenic AIV and establishes a movement control zone around affected farms.

2. HPAIV outbreaks in poultry

(1) Outbreaks of low pathogenic types

As stated above, MAFF has classified even low pathogenic AIVs of the H5 and H7 subtypes as HPAIV, labeling them "low pathogenic type" to distinguish them from high pathogenic AIVs.

In May 2005, a type A influenza virus of H5N2 subtype was isolated from specimens collected to investigate a decline in laying at an egg laying farm in Ibaraki Prefecture, Japan. In an experiment to test the pathogenicity of the isolated virus on chickens through intravenous inoculation it was found to be a low pathogenic virus that produced no symptoms in the tested chickens.

Diagnosing the situation as an outbreak of low pathogenic HPAIV, Ibaraki Prefecture ordered the extermination of the chickens on the affected farm, established a 5-km-radius movement control zone around the farm, and inspected all farms within that radius for the presence of AI. This survey turned up a succession of chicken flocks showing no symptoms but possessing antibodies or showing up positive in virus isolation tests. In the end, 40 farms in Ibaraki Prefecture and 1 in Saitama Prefecture proved to be positive, and 5.78 million birds were destroyed before the control order was finally lifted in April 2006.

The isolated virus was a low pathogenic type that had adapted to chickens. It was shown to be highly infective in chickens, but failed in experiments to infect ducks.

(2) Outbreaks of high pathogenic types Between the latter half of 2003 and the end of 2004, outbreaks of HPAI by H5N1 subtype were reported in 10 Asian countries. These outbreaks reportedly resulted in the death or extermination of over 100 million fowl. In Japan, outbreaks occurred on 4 farms in Yamaguchi, Oita, and Kyoto Prefectures, leading to the death or extermination of about 300,000 fowl before all control orders were finally lifted in April 2004.

The isolated virus was a high pathogenic type that caused the death of all 8 test birds within 1 day of intravenous inoculation and within 3 days of nasal inoculation. Gene sequencing showed that all strains isolated in Japan were closely related with each other and with Korean strains, but differed in lineage from those of Thailand, Vietnam, Indonesia, and other Southeast Asian strains, showing that the outbreaks in Japan and Korea were caused by closely related viruses.

Three years later, in January 2007, Japan suffered another outbreak of HPAI by the H5N1 subtype, occurring up to now on 3 farms in Miyazaki Prefecture and 1 in Okayama Prefecture.

The isolated virus is a high pathogenic type that caused the death of all test birds within 1 day of intravenous inoculation. Gene sequencing showed that the strains isolated on each farm were all closely related and belonged to a lineage isolated in 2005 from geese on Qinghai Lake in northern China. Reported to have caused infection and human deaths over an increasing number of regions throughout the world in recent years, this AI virus lineage has been isolated from waterfowl, domestic fowl, and humans who died from infection in 2005-2006 in Mongolia, Russia, the Middle East, Europe, Africa, and Korea.

In Japan, only one-off outbreaks have occurred, with no cases so far of infection spreading beyond the farm concerned in each outbreak. This minimum damage is considered at the present time to be the result of early discovery and response.

3. Measures for controlling HPAI

(1) Disease control guidelines

HPAI control in Japan is carried out according to MAFF's Guidelines for Controlling Specific Livestock Infectious Disease Related to HPAI. The basic aims of these guidelines are to eradicate AI through destruction of infected fowl in accordance with the control policies of affected countries worldwide and to implement measures for preventing the endemic condition. The guidelines accordingly call for the building of stronger surveillance systems for early discovery and crisis management systems for preventing the spread of the disease.

In the event that domestic fowl showing signs of AI infection are discovered on a farm, the discoverer is required by law to notify the local Livestock Hygiene Service Center. On receiving such a notification, the responsible Center staff members immediately carry out an on-site inspection and launch tests to determine the nature of the disease. On receiving the results of virus isolation and other tests carried out by the Livestock Hygiene Service Center concerned, the National Institute of Animal Health (NIAH) conducts tests to determine subtype and pathogenicity. If, as a result of the above tests, the isolated virus is found to be a high pathogenic strain or of H5 or H7 subtypes, MAFF and prefectural authorities announce the outbreak of HPAI, set up a task force, and launch control measures.

Key control measures include the killing and disposal of fowl at the affected farm, disinfection of the farm, isolation of fowl on epidemiologically related farms, and establishment of a zone in principle covering the area within a 10 km radius of the affected farm, within which the movement of domestic fowl and related items is restricted. As the control measures are implemented and the cleanliness of facilities within the movement control zone is confirmed, the control zone area is gradually narrowed down and the control order eventually lifted.

(2) Vaccination-based disease control

An AI vaccine for poultry has been developed and used in several countries. Because low pathogenic H5 and H7 subtypes may mutate into high pathogenic strains with repeated infection of fowl, the low pathogenic live vaccine is not recommended, and vaccines approved up to now around the world have been either inactivated or recombinant live vaccines.

The OIE takes the position that while vaccination can help suppress symptoms and death, reduce the amount of viruses excreted, and increase resistance to infection, it cannot impede the propagation of viruses through infection and is insufficient on its own if one is aiming for eradication, and so should be combined with monitoring of vaccinated flocks, strict hygiene management, and extermination of all infected birds.

In Japan, vaccination is in principle not employed to control AI in poultry. However, in the event that outbreaks occur successively in several farms within a movement control zone and prompt extermination is difficult, MAFF will consider vaccination. For such emergency situations, Japan has accordingly procured a stock of imported vaccine and has also developed its own vaccine.

Countries such as Indonesia, Vietnam, China, and Italy which have suffered repeated outbreaks are using vaccination as a means of control, but they are thought to be still a long way from total eradication.

4. Agricultural countermeasures to new types of influenza

I said that in terms of virulence in chickens, AIV can be divided into low and high pathogenic types, but both have infected people, making AIV a zoonotic disease. The HPAI H5N1 subtype that has been pandemic among bird species in recent years warrants special mention, having claimed 166 human lives between 2004 and early February in 2007.

The WHO fears that the H5N1 subtype of AIV will mutate into a new pandemic influenza virus that can easily infect human beings. Fortunately, it has still not mutated into a form that can be transmitted easily from one human being to another, but it is not hard to imagine such an eventuality should it continue to repeatedly make the jump from birds to humans.

In the cases reported so far, that jump has been from poultry to humans, and continued infection among poultry is a major cause of the emergence of new pandemic influenza viruses. As such, the only way for the agricultural sector to combat the emergence of new pandemic influenza viruses is to eradicate H5N1 HPAI in poultry. HPAI spreads easily across national borders, making strong international cooperation essential to its eradication. Without such cooperation, I don't think that we can prevent the emergence of new pandemic influenza viruses.
Wild Bird Migration and Behavior in Relation to AIV Infection Yutaka Kanai
Yutaka Kanai
Nature Conservation Office,
 Wild Bird Society of Japan

Opening comments

The strongly virulent H5N1 AIV that emerged in Asia in the autumn of 2003 spread in 2005-2006 to Europe and Africa. It also reappeared in 2006 and 2007 in Korea and Japan. Wild birds are suspected of being the vectors in many cases of transmission, and there are cases of wild birds too being infected. However, there have been outbreaks whose location and period do not necessarily match wild bird migration patterns.

I want to take a look here at what current knowledge can tell us about the relationship between wild birds and the spread of AIV infection.

1. The relationship between outbreaks and migration routes

There are many unknowns about what kind of birds become infected with AIV. Even if migratory birds are infected, it would be difficult for them to travel long distances if suffering from the effects of the virus. If symptoms do not emerge, they could carry the virus for the distance that they travel in the approximately 10 days that it takes for the virus to disappear from their bodies. It is for such a reason that many people suspect that migratory birds have played a role in the worldwide spread of AIV. However, since most bird migration is limited to certain fixed periods and flight paths, it would be a mistake to single out migratory birds as the sole cause of the spread of AIV without first considering their behavior patterns.

(1) From Korea to Japan

The AIV outbreak discovered on January 11, 2007 in Kiyotake, Miyazaki Prefecture followed the same pattern as the 2004 outbreaks in Yamaguchi, Oita, and Kyoto Prefectures of occurring during ongoing outbreaks in Korea. In both 2003-2004 and 2006-2007, the Korean outbreaks occurred in late November and early December, continuing into January.

In Japan in 2003-2004, the Yamaguchi Prefecture outbreak occurred in late December, and the Oita and Kyoto prefecture outbreaks occurred in early February, with each outbreak thought to have occurred independently. As for 2007, there have been 4 outbreaks to date (February 13) - 3 in Miyazaki Prefecture, and 1 in Okayama Prefecture.

Both the 2003 and 2006 outbreaks in Korea started in rice growing regions on Korea's west coast. Certain outbreaks occurred in almost identical locations. The outbreaks were not limited just to chicken farms, but occurred also on duck and quail farms. These farms were located near expansive waterfowl habitats, and on December 21, 2006, the same virus was found in wild ducks.

As the provided map shows, outbreaks in Japan have been scattered across southwest Japan. Another difference with Korea is that the majority of outbreaks have occurred at some distance from broad expanses of paddy fields and waterfowl habitats. The 3 Miyazaki outbreaks were close to each other, but occurred in different kinds of environments - one an area of fields with a fair number of houses, another a mountain valley, and the third a terrace bordering a riverside stretch of paddy fields.

The route from the Korean Peninsula to southwest Japan is a major migration route for wintering birds and is a journey of just 1 day. However migration is at its height between October and early December, and most wintering birds have arrived in Japan by mid-December. Birds arriving after this period tend to do so if the Korean Peninsula is hit by severe cold, with snow and freezing making the finding of food difficult.

There was no direct point of contact in Japan between poultry and the wild ducks considered to be the most likely vectors of the virus. During the 2004 outbreaks, we collected feces of wild ducks in areas surrounding the affected farms and also captured land birds to investigate them for presence of the virus. However, the virus was not detected and there was no sign that infection had spread to land birds.

However, the possibility remains that a very small number of birds carry the virus. Flies and other insects can be found even in winter around the feces and feed boxes in poultry farms, attracting wagtails, thrushes, and other insectivorous birds. It is possible that active viruses accumulate in flies, so we need to look into the possibility that birds feeding on such flies could become infected with AIV.


Locations of strongly virulent AI outbreaks in Japan and Korea

The numbers on the map indicate the order in which outbreaks occurred in 2006-2007. The first AI outbreak in Korea in 2003 occurred in Eumseong, and spread to Cheonan. It was also in Cheonan that the H5N1 AIV was found on December 21, 2006 in the feces of wild ducks.
1,2 Iri 1 Kiyotake
3 Gimje 2 Hyuga
4 Asan 3 Takahashi
5 Cheonan 4 Shintomi
6 Anseong Kokonoe
(2) The spread from Qinghai Lake to Europe In the table below, I show the relationship between the direction of spread of AIV and the period and migration since 2004. In both the 2005 and 2006 outbreaks at China's Qinghai Lake, bar-headed geese suffered infection and death, but there have been no reports suggestive of AIV from the species' wintering area in India. The key wintering areas of birds inhabiting Qinghai Lake are South Asian countries such as India and Bangladesh. In January and February of 2004, outbreaks occurred throughout China, including Lanzhou near Qinghai Lake and around Lhasa on the migration route. It would be natural to assume that the infected bar-headed geese became infected at Qinghai Lake or on the migration route near to the lake.

After the April 2005 outbreak at Qinghai Lake, infection spread to Europe, Africa, and India. There are those who argue that migratory birds are responsible for all of this spread, but such arguments are indefensible from the perspective of the behavior of birds. Before the outbreak in West Siberia, outbreaks had already occurred in the nearby extreme west of China. As stated above, by the winter of 2004, outbreaks had occurred throughout China. This suggests that AIV infection was spread through commerce.

The period when infection spread through West Siberia was the breeding season for birds, a time when they do not venture far from their nests. We should rather pay attention to the way AIV infection advanced along major routes of commerce from West China as the most likely reason behind the spread of infection.

Patterns of AIV spread that overlap with migratory routes and periods are the spread from West Siberia to Romania and other Black Sea coast locations, and from Romania and the Black Sea to North Europe. As for the spread of infection from migratory birds to poultry, it is thought that the shooting of wild birds that are then taken into homes to eat may be responsible.

In February 2005, an AI outbreak occurred in Nigeria. February is a time of the year not for southward migration, but rather for the start of northward migrations. BirdLife International has pointed out that Nigeria was a destination for the export of chicks from areas where outbreaks had occurred.
Location of infection spread Infection period Relationship with bird migration
From Korea to Japan Late December - early February Main migration period is over, but because the distance is short, later migration is also feasible.
From Southeast Asia to Qinghai Lake Mid-April Not a major migration route
From Qinghai Lake to West Siberia July Not a major migration route, and period also differs.
From West Siberia to Black Sea coast and Middle East September - October Major migration route, and migration period overlaps infection period.
From Black Sea coast and Middle East to Nigeria February Migration route, but period differs.
From West Siberia to India February Major migration route, but period differs.
From Black Sea coast and Middle East to North Europe February Major migration route, and migration in February is possible.
From Southeast Asia to Russia, Alaska and Australia - Major migration routes, but no outbreaks along these routes
2. Cases of infection in wild birds

There are increasing reports of wild birds being infected with AIV, but almost no cases in which the infection route has been elucidated. The following are cases in which the circumstances surrounding infection are to a certain extent understood.

(1) Kyoto Prefecture jungle crows (Corvus macrorhynchos)

It has been confirmed that jungle crows were secondarily infected during the February 2004 AIV outbreak in the town of Tanba in Kyoto Prefecture. Corpses of chickens that had died from AIV had been abandoned on the chicken manure dump of the affected poultry farm, and about 1,000 crows are thought to have fed on these corpses.

According to the survey carried out by Kyoto Prefecture and the Ministry of the Environment, there was no significant increase in crow deaths in the 6 roosts within a 30 km radius of the outbreak location. Of the 396 crow specimens found in Kyoto, Osaka, and Hyogo Prefectures from March to mid-April, only 9 were found to be infected, 7 of which were found on March 4 and 5 in Kyoto and Osaka Prefectures. No infected crows were found after April 5.

It appears likely that crows that fed on infected poultry were the only ones affected, and that infection did not spread directly between crows.

(2) Thailand open-billed storks (Anastomus oscitans) At Boraphet, a Thai swamp habitat and wildlife refuge, 496 open-billed storks died between January 18 and February 3, 2005. The outbreak occurred in an area of paddy fields about 30 km north of Bangkok that holds a nesting colony of over 5,000 open-billed storks.

The paddy fields where the storks feed are used also to raise free-range ducks for human consumption. It is thought that some individuals were infected by feeding on snails contaminated with the feces of infected ducks, and that these individuals spread the infection to others in the colony. The nests in the colony are so close together that they can become contaminated with the feces of individuals in surrounding nests, and the storks also gather in groups in ponds near the colony where it is thought that infection could spread easily via water. However, once infection among domestic waterfowl was controlled, infection among the open-billed storks abated.

3. Causes of the spread of infection to wild birds

(1) Infection causes and wild birds

AIV infection of wild birds can take place in the following kinds of circumstances.

Intrusion into facilities for raising domestic fowl: Locations where feed has been scattered and flies and other insects abound tend to attract intrusion by wild birds seeking food. This needs to be prevented by the careful provision of feed and hygiene control. Intrusion can be prevented physically by covering windows and vents with netting or fencing with a mesh of under 3 cm.

Feces: If bird manure that is used as organic fertilizer on farmland contains AIV, infection is likely to spread over a broad area. In Southeast Asia, the scattering of chicken manure is a recommended method for boosting the productivity of fish farms, and there are those who argue that this is another cause of the spread of infection among wild birds. Ducks, herons, plovers, and curlews often visit such fish farms.

Refuse and remains: If refuse and corpses of infected fowl from poultry farms where an outbreak has occurred are left out in the open, crows, kites, vultures, and other wild birds will come to feed on such materials, and the possibility of infection is high. If the meat of infected birds is put on the market, infection in places other than poultry farms might occur.

Wild bird markets: Cases of infection have been discovered in hawk eagles and parrot species during customs inspections. These birds are thought to have become infected while in captivity. There is a high chance of infection spreading in wild bird markets where many different species from different locations are kept in close vicinity.

Other causes of spread of infection: Infected birds shot during hunting would be brought into the vicinity of human households, and hunting of birds also causes birds to scatter, promoting the spread of infection. Bird feeders, tables, and bird baths attract many individuals of different species, creating an environment for the spread of infection.

(2) Research required for preventing infection he following kinds of research are required to reduce the risks of infection from wild birds:

Virus surveys: Surveillance studies to check on the possession of AIV by wild birds are being carried out on an almost worldwide scale.

Tracking of migration routes and periods: Detailed information on migration routes and periods would enable the implementation of a more appropriate emergency response, including the enhancement of measures to prevent wild bird intrusion into poultry farms in areas along migration routes and hunting restrictions according to the time and location of an outbreak. Intensified banding surveys and satellite tracking are being carried in China, Russia, Japan, the USA, and other countries to gather more information on migration routes.

Consideration of measures to prevent infection among wild birds: Research on the types of wild birds living in the vicinity of poultry and their ecology and behavior would help to reveal points of contact between wild birds and poultry or other sources of infection.

Closing comments

Strongly virulent H5N1 AIV poses a threat to wild birds too, and while the culling of wild birds has been carried out on occasion, such measures adversely affect the wild bird population and ecosystem as a whole, and also carry the risk of exacerbating infection.

Controlling AIV requires a detailed understanding of the relationships between the virus, poultry, industry, and wild birds. We need to formulate countermeasures based on the recognition of AIV as a matter of ecosystem management on both a regional and a global scale.

Useful Internet links regarding wild birds and HPAIV
Infection of Wild Birds and Current Status Kumiko Yoneda
Kumiko Yoneda
Senior Research Scientist,
Japan Wildlife Research Center

1. Highly pathogenic avian influenza (HPAI)

Japan has recently suffered its first outbreak of HPAI in three years. AI broke out suddenly in 2004, 79 years after its first appearance in Japan, and spread throughout Southeast Asia in roughly the same space of time, later spreading also to Russia and then Europe and Africa. A great deal of research has been carried out in the past 3 years that has revealed how the virus causing this disease has mutated.

A textbook available at the time of the 2004 pandemic has the following to say about AIV - that it is a virus carried asymptomatically mainly by wild ducks and other waterfowl, and exists in many different strains. In general the AIV harbored by waterfowl displays very weak infectivity with respect to poultry, and is also only weakly pathogenic. However, there are some viruses that, once they have succeeded in making the jump to chickens, mutate over several generations into strongly virulent strains. These strains are known as highly pathogenic avian influenza viruses (HPAIV), and are distinguished as such from other AIV strains in the formulation of poultry infection countermeasures. All HPAIVs to emerge so far have been of either the H5 or H7 type. There is only 1 case so far in which a large number of wild birds have died as a result of infection with AIV - the death in 1961 in South Africa of over 1,300 terns from the H5N3 HPAIV subtype.

As can be gathered from the fact that the vaccine for protecting against human influenza needs to be changed every year to keep in step with the latest strain, the influenza virus mutates very easily, and at the genetic level, no two identical viruses can be found even within the same epidemic. There are also many strains of AIV H5N1. GenBank, a database of gene sequences, shows 1,642 registered strains of AIV H5N1 isolated since 1959 as of July 16, 2007. However, only 11 had been isolated up to 1991, all of those from the UK and the USA. Of these 11, the 4 strains isolated from wild birds were nonpathogenic to chickens, and also produced no symptoms in the wild birds from which they were isolated. Owing to various factors such as advances in gene sequencing technology, increased surveillance, and the fact that researchers register strains on this gene database at their discretion, the number of strains registered does not necessarily reflect the reality at any particular point in time, but since 1997, the number of Asian strains, and particularly those from China, has risen dramatically. Several hundred strains have been registered each year since 2004 when outbreaks in Japan occurred. Strains isolated from wild birds (including captive individuals) number about 240. All of this suggests that some major change occurred around 1997.

2. AIV outbreaks in wild birds

In 1997, an outbreak of HPAIV of the H5N1 subtype killed a great many chickens and other domestic fowl in Hong Kong, and also infected humans. It was determined that this strain had mutated from a strain isolated from domestic geese in the Chinese province of Guangdong in 1996. The same strain further mutated into a different strain that caused the death of 150 waterfowl in two parks in Hong Kong in 2002. This event overturned the widely accepted belief at the time that AIV displays no pathogenicity in wild waterfowls and other wild birds. Both outbreaks happened in parks within the city, with one affecting mostly captive wild birds, as a result of which there is a detailed report on the progress of the outbreak and species that did or did not succumb to the disease. According to this report, waterfowl death rates were high for wild geese and Greater flamingos. Among the captive wild ducks, fatalities were high for New World species and red-crested pochards among Old World species. It was also determined that there were species in the same park ponds that suffered no deaths despite being infected, and other species that suffered neither deaths nor infection, suggesting that pathogenicity of HPAIV to wild geese and ducks differs according to species.

The next incident of mass death among wild waterfowls occurred at Qinghai Lake in inland China in May 2005. Within the space of 2 months, about 6,000 birds died, with bar-headed geese being the main victims, but with deaths also occurring among brown-headed gulls, great black-headed gulls, ruddy shelducks, and great cormorants. In August of the same year at two lakes near Mongolia's border with Russia, about 90 bar-headed geese, whooper swans and other waterfowl died from AIV. Repeated outbreaks occurred in the same areas in 2006, with bar-headed geese deaths in the main being reported in Qinghai Province in April and May, and bar-headed geese and wigeon deaths in Tibet in May. In June, swan, gull and geese deaths were reported at lakes near Mongolia's border with Russia.

Meanwhile in Europe, repeated deaths were reported mainly among mute swans between October 2005 and May 2006. Particularly in Germany, many AIV deaths were reported for swans, wild geese and ducks, raptors, and other types of wild bird. All of the virus strains causing death in wild bird species since the Qinghai Lake outbreak have proven to be very similar and traceable to the so-called Qinghai strain.

3. Susceptibility of wild birds to HPAIV H5N1 subtype

Differences in susceptibility to HPAIV among bird species differ also according to strain. Chickens, turkeys, and other members of the order Galliformes were very susceptible to the pre-2002 H5N1 subtype strains, but domestic ducks and geese showed only low susceptibility. However with the emergence of the HPAIV that spread throughout Southeast Asia in 2004, domestic ducks started to die from AIV infection, and as described above, mass deaths were reported also among wild geese, wild ducks, and gulls. There have also been reports - for example, the Kyoto Prefecture outbreak - of secondary infection of wild bird species during an outbreak among chickens and other poultry.

Pathogenicity with respect to chickens can now be ascertained from the sequence of amino acids in the virus genome, but this is not yet possible for wild geese and ducks. However, it seems reasonable to assume that if pathogenicity experiments were conducted on domestic geese and ducks, results could be used to judge whether the same virus strain would be pathogenic or not to wild geese and ducks. There are only a few reports of infection experiments conducted on wild bird species. This is because it is not only difficult to obtain healthy wild bird specimens, but it is also difficult to keep such specimens in isolator cages for prolonged periods. Reports of HPAIV outbreaks among free-ranging wild birds usually name the species that have suffered deaths, but rarely mention the species living in the same habitat that did not suffer infection or death. It is however possible to deduce the species likely to have been present by referring to habitat reports and other literature published prior to an outbreak. A look at about 130 species that were reported for HPAIV infection, for the circumstances of outbreaks, or for the results of pathogenicity experiments suggests that there are wild bird species with low susceptibility to the HPAIV H5N1 subtype.

There are those who argue that where wild ducks, the original AIV host, are concerned, AIV will evolve to become less and less pathogenic. Any species that can be infected with AIV without suffering any symptoms but shed the virus can become an effective vyytor for spreading the virus.yye need to continue to monitor wild birds for possible infection and carry out further research on species difference in susceptibility in order to develop a clear and accurate picture of how wild birds figure in HPAIV infection.
The Threat Posed by New Types of Influenza: AIV and its Impact on Humans Nobuhiko Okabe
Nobuhiko Okabe
Director, Infectious Disease Surveillance Center,
National Institute of Infectious Diseases

Influenza is a well-known human disease caused by infection with the influenza virus. There are three types of influenza virus - A, B, and C. Types B and C are limited to humans, but type A is found in many different subtypes (currently 144 have been identified), only 2 of which are currently capable of infecting humans. The other influenza type A subtypes infect birds and many other animals.

Type A human influenza viruses

Type A influenza viruses are genetically unstable, and the H3N2 and H1N1 subtypes that are currently transmitted between people continue to mutate very gradually. This kind of gradual change is known as antigenic drift. Once the virus mutates into something new, even people who have suffered influenza previously may once again be susceptible to infection by the new mutation.

Rather than remaining the same subtype for tens or hundreds of years, type A influenza virus has tended to change suddenly into another subtype every few years or decades. These changes are not small-scale changes within any one subtype, but rather changes on a scale that produces a new subtype. This is called antigenic shift, and could be thought of as something like a full model change in auto industry parlance, a totally new human influenza virus. Since it is new, nobody has any resistance to it, and so for a while widespread pandemics ensue. Spanish flu (H1N1) swept the world in 1918 as a huge pandemic, but then became established as ordinary influenza for the next 39 years, until replaced suddenly by Asian flu (H2N2) in 1957. This type reigned for 11 years before being ousted by Hong Kong flu (H3N2) in 1968, a new influenza virus that was subsequently joined in 1977 by Russian flu (H1N1). These two subtypes cause ordinary flu to this day while continuing to mutate very gradually.

Avian influenza virus

Birds are the leading example of animals that are susceptible to infection by type A influenza virus. The influenza viruses that infect birds are of the same type A that also infect humans, but their genetic structure differs slightly. Another difference is that AIV tends to replicate mainly in the intestines, which means that large quantities of virus are expelled with feces. Response differs according to type of bird. Wild ducks and other waterfowl can be infected by all 144 type A subtypes, but do not show symptoms. Because infected migratory ducks remain healthy as they fly from here to there throughout the world, excreting viruses along with their feces as they go, it is thought that ducks are the most likely cause of the spread of AIV. Some of the viruses expelled by ducks are thought to infect chickens, domestic ducks, and other poultry at watersides and feeding areas. In most cases such infections are by low pathogenic viruses (LPAIV) that produce only light or no symptoms at all in most chickens and ducks, but certain subtypes (H5 and H7 subtypes known as highly pathogenic AIV) are extremely pathogenic in chickens, with H5N1 in particular causing severe symptoms that rapidly kill almost all infected chickens.

Infection of humans by AIV

It was thought for a long time that AIV could never directly infect humans, but during the 1997 outbreak of AIV H5N1 in Hong Kong, the first ever case of human AIV infection occurred, with 18 people being infected, 6 of whom died. After the Hong Kong government exterminated the 1.5 million chickens thought to have been the source of infection, no further cases of human AIV infection occurred for a while, but then in 2003 in Holland, an outbreak of H7N7 AIV occurred among chickens that also produced symptoms (mostly conjunctivitis) in about 100 humans, and caused 1 human death. In 2005 there was an outbreak of AIV H5N2 in Ibaraki Prefecture, Japan, but no people fell ill on this occasion.

When it directly infects humans, AIV H5N1 produces very severe symptoms (60% death rate). However the virus does not readily infect humans, and almost all of the victims to date had close contact with birds that were suffering or had died from the virus. There was no spread of the infection in hospitals caring for AIV-infected patients or transmission from people to people in the vicinity of outbreaks, and nor was there any transmission through poultry food products. In short, in a country like Japan, for example, no one leading a normal life has any reason to fear catching AIV just because they happened to spot some birds flying past their windows.

The threat posed by the emergence of a new influenza virus

As mentioned earlier, Spanish flu (H1N1 subtype) continued to circulate for 39 years from 1918, and then Asian flu (H2N2) for 11 years from 1957. In 1968, Hong Kong flu (H3N2) appeared, joined in 1977 by Russian flu (H1N1), and they remain in circulation to this day, the former for almost 40 years, the latter for almost 30. Both types continue to mutate slightly, but they are still basically the same type A influenza viruses that they started out as. If you look at the history of change of influenza up to now, it would not be in least surprising for the type A virus to undergo another full model change at any time to give rise to a new influenza virus, but no one can forecast with any scientific accuracy whether this event will take place next year or 5 years or more from now.

However, if a completely new influenza virus does appear, humans will not have any resistance to it, and there are consequently fears that it will cause a worldwide pandemic. While medicine too has advanced, the development of transport, increase and concentration of human population, changes in lifestyles, and so forth make this a very different world from the one in which previous pandemics occurred, and if and when a new virus appears, it is sure to spread at an unprecedented pace and become a huge pandemic. This is giving rise to serious concern over increases in human illness and the severe impact that a major pandemic would have on human society.

Theories regarding the emergence of a new influenza virus include: (1) a genetic mutation of AIV may result in a new subtype that can easily infect humans; and (2) AIV and the human influenza virus may simultaneously infect either pigs or humans (pigs are able to be infected by both human and avian influenza), and as a result of mixing of the genes of both viruses (gene exchange), a new subtype may be created. The occurrence of major outbreaks of AIV among birds and the concomitant rise in number of human infections, rare and coincidental though they might be, is thought to point to an increased risk of a new influenza virus emerging.

Currently H5N1, which is the cause of increasing outbreaks of AI among poultry, is seen as the most likely precursor of a new human influenza virus. The possibility of the emergence of such a virus through pigs remains, so we are continuing to monitor occurrences of influenza in pigs.

AIV and new influenza virus countermeasures and preparations

To regard the appearance of a new influenza virus as unlikely is an excessively optimistic view. At the same time it is unrealistic, given our current capabilities, to think that we can totally prevent such an eventuality. I think we have to accept it as a part of the natural order of things. However, just as we prepare for earthquakes and other disasters, we should of course take steps to curb the scale of any epidemic that occurs, and minimize damage to health and impact on society.

If we keep going on endlessly about the possibility of a new influenza virus appearing, we run the risk of being seen as Aesop's fabled "boy who cried wolf", but whatever preparations we make need not be limited just to countering a new influenza virus. We will be able to apply them equally to other new threats such as SARS, and so they are vital as countermeasures to all infectious diseases, whether known or as yet unknown.
Highly Pathogenic AIV and Vaccination Measures Tetsuo Nakayama
Tetsuo Nakayama
Professor, Control of Viral Infections
Deputy Director, Kitasato Institute of Life Sciences, Kitasato University

In 1997 in Hong Kong, 18 people were infected with AIV H5N1, and 6 of those died. It was determined that the virus had been transmitted from chickens, and the spread of the infection was prevented by the extermination of the chickens thought to have been its source. Later, H5N1 transmitted from wild ducks spread among domestic ducks and geese in China and other parts of Southeast Asia, and then came to infect poultry such as chickens and quails, and also wild birds. As a result, H5N1 spread to the Middle East and Europe and became a global issue.

Since 2003, human infection with AIV has been reported in Vietnam and Thailand, and the number of human infections has risen to almost 270, with a death rate of over 50%. There are cases in which human-to-human transmission could be suspected, but because these cases involved members of the same family sharing the same environment, there is little strong support for the human-to-human infection argument. In Japan too, AIV outbreaks resulting in chicken deaths occurred at poultry farms in Kyoto, Yamaguchi, and Oita Prefectures in 2004, and occurred again in 2006 in Miyazaki and Okayama Prefectures, prompting fears of human infection. Anti-influenza drugs have been developed, but as a preventive measure, the development of vaccines is fundamental to combating influenza.

Influenza vaccine is manufactured using fertilized eggs containing 15 μg of HA protein respectively for A/H1, A/H3 and B strains. Because HPAIV kills fertilized eggs, conventional production methods are difficult. A phase I study has been completed in which pharmaceutical companies have each developed prototype HPAIV vaccines from vaccine seeds of recombinant viruses created by using genetic engineering techniques to modify HA protein genes related to pathogenicity and reduce their virulence, and then combining them with genes other than HA and NA replicated in eggs. Each company conducted clinical trials in which 6 groups of 20 (subcutaneous and intramuscular; 1.7-, 5- and 15-μg HA dose groups respectively) were vaccinated twice with whole inactivated viruses to which aluminum adjuvant had been added. The subcutaneous groups showed strong local reactions, but overall reactions were much the same as for existing vaccines. Immunogenicity was confirmed for doses of 5 μg and above. Based on the phase I study results, the three front-running companies conducted phase II and phase III studies. The results of clinical trials using 4 groups (subcutaneous and intramuscular; 5- and 15-μg dose groups respectively) and a total of 900 subjects, cleared the EU's immunogenicity criteria for inactivated influenza vaccines.

The prototype vaccine HA protein was of a strain isolated in Vietnam in 2004 (clade 1), but the influenza virus mutates rapidly, and the strain currently circulating is a clade 2 strain which is further subdivided into subclades 1, 2, and 3 as its antigenicity changes. We are currently manufacturing a store of pandemic prototypes using a strain derived from clade 2.

I would like to explain the limitations of current influenza vaccines and the global status of development of vaccines against new influenza viruses.
編集・発行 北里大学学長室
発行日 2007年9月1日