Influenza A virus subtype H5N1

Influenza A virus subtype H5N1 (A/H5N1) is a subtype of the influenza A virus, which causes influenza (flu), predominantly in birds. It is enzootic (maintained in the population) in many bird populations, and also panzootic (affecting animals of many species over a wide area). A/H5N1 virus can also infect mammals (including humans) that have been exposed to infected birds; in these cases, symptoms are frequently severe or fatal.

A/H5N1 virus is shed in the saliva, mucous, and feces of infected birds; other infected animals may shed bird flu viruses in respiratory secretions and other body fluids (such as milk). The virus can spread rapidly through poultry flocks and among wild birds. An estimated half a billion farmed birds have been slaughtered in efforts to contain the virus.

Symptoms of A/H5N1 influenza vary according to both the strain of virus underlying the infection and on the species of bird or mammal affected. Classification as either Low Pathogenic Avian Influenza (LPAI) or High Pathogenic Avian Influenza (HPAI) is based on the severity of symptoms in domestic chickens and does not predict the severity of symptoms in other species. Chickens infected with LPAI A/H5N1 virus display mild symptoms or are asymptomatic, whereas HPAI A/H5N1 causes serious breathing difficulties, a significant drop in egg production, and sudden death.

In mammals, including humans, A/H5N1 influenza (whether LPAI or HPAI) is rare. Symptoms of infection vary from mild to severe, including fever, diarrhoea, and cough. Human infections with A/H5N1 virus have been reported in 23 countries since 1997, resulting in severe pneumonia and death in about 50% of cases. As of May 2024, 889 human cases had been identified worldwide, with 463 fatalities, giving a case fatality rate of around 50%; however, it is likely that this may be an overestimate given that mild infections can go undetected and under-reported.

A/H5N1 influenza virus was first identified in farmed birds in southern China in 1996. Between 1996 and 2018, A/H5N1 coexisted in bird populations with other subtypes of the virus, but since then, the highly pathogenic subtype HPAI A(H5N1) has become the dominant strain in bird populations worldwide. Some strains of A/H5N1 which are highly pathogenic to chickens have adapted to cause mild symptoms in ducks and geese, and are able to spread rapidly through bird migration. Mammal species that have been recorded with H5N1 infection include cows, seals, goats, and skunks.

Due to the high lethality and virulence of HPAI A(H5N1), its worldwide presence, its increasingly diverse host reservoir, and its significant ongoing mutations, the H5N1 virus is regarded as the world's largest pandemic threat. Domestic poultry may potentially be protected from specific strains of the virus by vaccination. In the event of a serious outbreak of H5N1 flu among humans, health agencies have prepared "candidate" vaccines that may be used to prevent infection and control the outbreak; however, it could take several months to ramp up mass production.

Humans
Avian flu viruses, both HPAI and LPAI, can infect humans who are in close, unprotected contact with infected poultry. Incidents of cross-species transmission are rare, with symptoms ranging in severity from no symptoms or mild illness, to severe disease that resulted in death. As of February, 2024 there have been very few instances of human-to-human transmission, and each outbreak has been limited to a few people. All subtypes of avian Influenza A have potential to cross the species barrier, with H5N1 and H7N9 considered the biggest threats.

In order to avoid infection, the general public are advised to avoid contact with sick birds or potentially contaminated material such as carcasses or feces. People working with birds, such as conservationists or poultry workers, are advised to wear appropriate personal protection equipment.

The avian influenza hemagglutinin prefers to bind to alpha-2,3 sialic acid receptors, while the human influenza hemagglutinin prefers to bind to alpha-2,6 sialic acid receptors. This means that when the H5N1 strain infects humans, it will replicate in the lower respiratory tract (where alpha-2,3 sialic acid receptors are more plentiful in humans) and consequently cause viral pneumonia.

Influenza virus nomenclature
To unambiguously describe a specific isolate of virus, researchers use the internationally accepted Influenza virus nomenclature, which describes, among other things, the species of animal from which the virus was isolated, and the place and year of collection. For example, A/chicken/Nakorn-Patom/Thailand/CU-K2/04(H5N1): Other examples include: A/duck/Hong Kong/308/78(H5N3), and A/shoveler/Egypt/03(H5N2).
 * A stands for the genus of influenza (A, B or C).
 * chicken is the animal species the isolate was found in (note: human isolates lack this component term and are thus identified as human isolates by default)
 * Nakorn-Patom/Thailand is the place this specific virus was isolated
 * CU-K2 is the laboratory reference number that identifies it from other influenza viruses isolated at the same place and year
 * 04 represents the year of isolation 2004
 * H5 stands for the fifth of several known types of the protein hemagglutinin.
 * N1 stands for the first of several known types of the protein neuraminidase.

Genetic structure
H5N1 is a subtype of Influenza A virus, like all subtypes it is an enveloped negative-sense RNA virus, with a segmented genome. Subtypes of IAV are defined by the combination of the antigenic hemagglutinin and neuraminidase proteins in the viral envelope. "H5N1" designates an IAV subtype that has a type 5 hemagglutinin (H) protein and a type-1 neuraminidase (N) protein. Further variations exist within the subtypes and can lead to very significant differences in the virus's ability to infect and cause disease, as well as to the severity of symptoms.

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The segmentation of its genome facilitates genetic recombination by segment reassortment in hosts infected with two different strains of influenza viruses at the same time. Through a combination of mutation and genetic reassortment the virus can evolve to acquire new characteristics, enabling it to evade host immunity and occasionally to jump from one species of host to another.

Vaccine
There are several H5N1 vaccines for several of the avian H5N1 varieties, but the continual mutation of H5N1 renders them of limited use to date: while vaccines can sometimes provide cross-protection against related flu strains, the best protection would be from a vaccine specifically produced for any future pandemic flu virus strain. Daniel R. Lucey, co-director of the Biohazardous Threats and Emerging Diseases graduate program at Georgetown University has made this point, "There is no H5N1 pandemic so there can be no pandemic vaccine". However, "pre-pandemic vaccines" have been created; are being refined and tested; and do have some promise both in furthering research and preparedness for the next pandemic. Vaccine manufacturing companies are being encouraged to increase capacity so that if a pandemic vaccine is needed, facilities will be available for rapid production of large amounts of a vaccine specific to a new pandemic strain.

Treatment
There is no highly effective treatment for H5N1 flu, but oseltamivir (commercially marketed by Roche as Tamiflu) can sometimes inhibit the influenza virus from spreading inside the user's body. This drug has become a focus for some governments and organizations trying to prepare for a possible H5N1 pandemic. On April 20, 2006, Roche AG announced that a stockpile of three million treatment courses of Tamiflu are waiting at the disposal of the World Health Organization to be used in case of a flu pandemic; separately Roche donated two million courses to the WHO for use in developing nations that may be affected by such a pandemic but lack the ability to purchase large quantities of the drug.

However, WHO expert Hassan al-Bushra has said:

"Even now, we remain unsure about Tamiflu's real effectiveness. As for a vaccine, work cannot start on it until the emergence of a new virus, and we predict it would take six to nine months to develop it. For the moment, we cannot by any means count on a potential vaccine to prevent the spread of a contagious influenza virus, whose various precedents in the past 90 years have been highly pathogenic."

Animal and lab studies suggest that Relenza (zanamivir), which is in the same class of drugs as Tamiflu, may also be effective against H5N1. In a study performed on mice in 2000, "zanamivir was shown to be efficacious in treating avian influenza viruses H9N2, H6N1, and H5N1 transmissible to mammals". In addition, mice studies suggest the combination of zanamivir, celecoxib and mesalazine looks promising producing a 50% survival rate compared to no survival in the placebo arm. While no one knows if zanamivir will be useful or not on a yet to exist pandemic strain of H5N1, it might be useful to stockpile zanamivir as well as oseltamivir in the event of an H5N1 influenza pandemic. Neither oseltamivir nor zanamivir can be manufactured in quantities that would be meaningful once efficient human transmission starts. In September, 2006, a WHO scientist announced that studies had confirmed cases of H5N1 strains resistant to Tamiflu and Amantadine. Tamiflu-resistant strains have also appeared in the EU, which remain sensitive to Relenza.

History
Influenza A/H5N1 was first detected in 1959 after an outbreak of highly pathogenic avian influenza in Scotland, which infected two flocks of chickens. The next detection, and the earliest infection of humans by H5N1, was an epizootic (an epidemic in nonhumans) of H5N1 influenza in Hong Kong's poultry population in 1997. This outbreak was stopped by the killing of the entire domestic poultry population within the territory. Human infection was confirmed in 18 individuals who had been in close contact with poultry, 6 of whom died.

Since then, avian A/H5N1 bird flu has become widespread in wild birds worldwide, with numerous outbreaks among both domestic and wild birds. An estimated half a billion farmed birds have been slaughtered in efforts to contain the virus.

Pandemic potential
Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The segmentation of the influenza A virus genome facilitates genetic recombination by segment reassortment in hosts who become infected with two different strains of influenza viruses at the same time. With reassortment between strains, an avian strain which does not affect humans may acquire characteristics from a different strain which enable it to infect and pass between humans - a zoonotic event.

As of June 2024, there is concern about two subtypes of avian influenza which are circulating in wild bird populations worldwide, A/H5N1 and A/H7N9. Both of these have potential to devastate poultry stocks, and both have jumped to humans with relatively high case fatality rates. A/H5N1 in particular has infected a wide range of mammals and may be adapting to mammalian hosts.

Surveillance
The Global Influenza Surveillance and Response System (GISRS) is a global network of laboratories that monitor the spread of influenza with the aim to provide the World Health Organization with influenza control information and to inform vaccine development. Several millions of specimens are tested by the GISRS network annually through a network of laboratories in 127 countries. GISRS monitors avian, swine, and other potentially zoonotic influenza viruses as well as human viruses.

Transmission and prevention
[[File:Main international flyways - bird migration-fr.svg|thumb|400px|The eight major flyways used by shorebirds (waders) on migration

{{Legend|#54A1FF|Pacific}} {{Legend|#EEDCD0|Mississippi}} {{Legend|#EAD27A|West Atlantic}} {{Legend|#CDDBC3|East Atlantic}} {{Legend|#ff187a|Mediterranean and Black Sea}} {{Legend|#D7C6D9|West Asia and Africa}} {{Legend|#FFC6C6|Central Asia and India}} {{Legend|#53F05A|East Asia and Australasia}} ]] Birds - Influenza A viruses of various subtypes have a large reservoir in wild waterfowl, which can infect the respiratory and gastrointestinal tract without affecting the health of the host. They can then be carried by the bird over large distances especially during annual migration. Infected birds can shed avian influenza A viruses in their saliva, nasal secretions, and feces; susceptible birds become infected when they have contact with the virus as it is shed by infected birds. The virus can survive for long periods in water and at low temperatures, and can be spread from one farm to another on farm equipment. Domesticated birds (chickens, turkeys, ducks, etc.) may become infected with avian influenza A viruses through direct contact with infected waterfowl or other infected poultry, or through contact with contaminated feces or surfaces.

Avian influenza outbreaks in domesticated birds are of concern for several reasons. There is potential for low pathogenic avian influenza viruses (LPAI) to evolve into strains which are high pathogenic to poultry (HPAI), and subsequent potential for significant illness and death among poultry during outbreaks. Because of this, international regulations state that any detection of H5 or H7 subtypes (regardless of their pathogenicity) must be notified to the appropriate authority. It is also possible that avian influenza viruses could be transmitted to humans and other animals which have been exposed to infected birds, causing infection with unpredictable but sometimes fatal consequences.

When an HPAI infection is detected in poultry, it is normal to cull infected animals and those nearby in an effort to rapidly contain, control and eradicate the disease. This is done together with movement restrictions, improved hygiene and biosecurity, and enhanced surveillance.

Humans - Avian flu viruses, both HPAI and LPAI, can infect humans who are in close, unprotected contact with infected poultry. Incidents of cross-species transmission are rare, with symptoms ranging in severity from no symptoms or mild illness, to severe disease that resulted in death. As of February, 2024 there have been very few instances of human-to-human transmission, and each outbreak has been limited to a few people. All subtypes of avian Influenza A have potential to cross the species barrier, with H5N1 and H7N9 considered the biggest threats.

In order to avoid infection, the general public are advised to avoid contact with sick birds or potentially contaminated material such as carcasses or feces. People working with birds, such as conservationists or poultry workers, are advised to wear appropriate personal protection equipment.

Other animals - a wide range of other animals have been affected by avian flu, generally due to eating birds which had been infected. There have been instances where transmission of the disease between mammals, including seals and cows, may have occurred.

1959–1997

 * A highly pathogenic strain of H5N1 caused flu outbreaks in 1959 in Scotland in chickens.
 * In 1997, in Hong Kong, 18 humans were infected and 6 died in the first known case of H5N1 infecting humans. Subsequently 1.3 million chickens were culled in the territory of Hong Kong. The government also suspended the import of chickens from mainland China.

2003

 * In 2003 the first cases in humans since 1997 were diagnosed. Three people in one family were infected after visiting Fujian province in mainland China and 2 died.
 * By midyear of 2003 outbreaks of poultry disease caused by H5N1 occurred in Asia, but were not recognized as such. In December animals in a Thai zoo died after eating infected chicken carcasses. Later that month H5N1 infection was detected in 3 flocks in the Republic of Korea.

2004

 * In January 2004 a major new outbreak of H5N1 surfaced in Vietnam and Thailand's poultry industry, and within weeks spread to ten countries and regions in Asia, including Indonesia, South Korea, Japan and China.
 * Variants have been found in a number of domestic cats, leopards, and tigers in Thailand, with high lethality. "The Thailand Zoo tiger outbreak killed more than 140 tigers, causing health officials to make the decision to cull all the sick tigers in an effort to stop the zoo from becoming a reservoir for H5N1 influenza.

2005

 * In January 2005 an outbreak of avian influenza affected thirty three out of sixty four cities and provinces in Vietnam, leading to the forced killing of nearly 1.2 million poultry.
 * In April 2005 there begins an unprecedented die-off of over 6,000 migratory birds at Qinghai Lake in central China over three months. Later in the year H5N1 was detected in Kazakhstan, Mongolia and Russia, Turkey, Romania, Croatia and Kuwait.
 * H5N1 was found to be infecting pigs in Indonesia, but without causing symptoms.

2006

 * In the first two months of 2006 H5N1 spread to India, north Africa, and Europe in wild bird populations.


 * February/March 2006 - A dead cat infected with the H5N1 bird flu virus was found in Germany.

2007

 * Significant outbreaks recorded in Japan, Hungary, Russia, United Kingdom, Pakistan, Turkey, Afghanistan, Myanmar, Bangladesh, Saudi Arabia, Ghana, Malaysia, Germany, Czech Republic, Togo, France and India.

2008 to 2019
Many more outbreaks are recorded, in almost every country in the world, affecting both wild birds and poultry, with occasional spillover events infecting humans.

Mammalian infections
In October 2022 an outbreak of H5N1 on a Spanish mink farm showed evidence of being the first recorded case of mammal-to-mammal transmission, with 4 percent of the farm's mink population dying from H5N1-related haemorrhagic pneumonia. This coincided with H5N1 detections in the area among gulls and other seabirds, which are the presumed source of the outbreak.

A mass Caspian seal die-off in December 2022, with 700 infected seals found dead along the Caspian Sea coastline of Russia's Dagestan republic, worried researchers regarding the possibility that wild mammal-to-mammal spread had begun. A similar mass die-off of 95% of southern elephant seal pups in 2023 also raised concerns of mammal-to-mammal spread, as nursing pups would have had less exposure to birds.

In April 2024, spread of H5N1 amongst dairy cow herds in nine states of the USA strongly indicated the presence of cow-to-cow transmission possibly occurring while the animals were being milked. Although mortality in bovines infected with H5N1 is rare, viable virus can be shed in the milk. Around 50% of cats that lived on the affected dairy farms and were fed unpasteurised milk from symptomatic cows died within a few days from severe systemic influenza infection, raising significant concerns of cross-species mammal-to-mammal transmission.

H5N1 transmission studies in ferrets (2011)
Novel, contagious strains of H5N1 were created by Ron Fouchier of the Erasmus Medical Center in Rotterdam, the Netherlands, who first presented his work to the public at an influenza conference in Malta in September 2011. Three mutations were introduced into the H5N1 virus genome, and the virus was then passed from the noses of infected ferrets to the noses of uninfected ones, which was repeated 10 times. After these 10 passages the H5N1 virus had acquired the ability of transmission between ferrets via aerosols or respiratory droplets.

After Fouchier offered an article describing this work to the leading academic journal Science, the US National Science Advisory Board for Biosecurity (NSABB) recommended against publication of the full details of the study, and the one submitted to Nature by Yoshihiro Kawaoka of the University of Wisconsin describing related work. However, after additional consultations at the World Health Organization and by the NSABB, the NSABB reversed its position and recommended publication of revised versions of the two papers. However, then the Dutch government declared that this type of manuscripts required Fouchier to apply for an export permit in the light of EU directive 428/2009 on dual use goods. After much controversy surrounding the publishing of his research, Fouchier complied (under formal protest) with Dutch government demands to obtain a special permit for submitting his manuscript, and his research appeared in a special issue of the journal Science devoted to H5N1. The papers by Fouchier and Kawaoka conclude that it is entirely possible that a natural chain of mutations could lead to an H5N1 virus acquiring the capability of airborne transmission between mammals, and that a H5N1 influenza pandemic would not be impossible.

In May 2013, it was reported that scientists at the Harbin Veterinary Research Institute in Harbin, China, had created H5N1 strains which passed between guinea pigs.

In response to Fouchier and Kawaoka's work, a number of scientists expressed concerns with the risks of creating novel potential pandemic pathogens, culminating in the formation of the Cambridge Working Group, a consensus statement calling for an assessment of the risks and benefits of such research.