Influenza A virus subtype H5N1 explained

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).^[1] 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.^[2]

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).^[3] 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.^{[4] [5]} 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.^[6] 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.^[7]

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.^[8] As of May 2024, 889 human cases had been identified worldwide, with 463 fatalities, giving a case fatality rate of around 50%;^[9] however, it is likely that this may be an overestimate given that mild infections can go undetected and under-reported.^[10]

A/H5N1 influenza virus was first identified in farmed birds in southern China in 1996.^[11] 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.^[12] Some strains of A/H5N1 which are highly pathogenic to chickens have adapted to cause mild symptoms in ducks and geese,^[13] and are able to spread rapidly through bird migration.^[14] Mammal species that have been recorded with H5N1 infection include cows, seals, goats, and skunks.^[15]

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.^[16] Domestic poultry may potentially be protected from specific strains of the virus by vaccination.^[17] 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.^{[18] [19]}

Signs and symptoms

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.^{[20] [21]} 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.^[22] All subtypes of avian Influenza A have potential to cross the species barrier, with H5N1 and H7N9 considered the biggest threats.^{[23] [24]}

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.^[25]

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.^{[26] [27]} 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.^{[28] [29]}

Virology

Influenza virus nomenclature

To unambiguously describe a specific isolate of virus, researchers use the internationally accepted Influenza virus nomenclature,^[30] 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):

• 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.

Other examples include: A/duck/Hong Kong/308/78(H5N3), and A/shoveler/Egypt/03(H5N2).^[31]

Genetic structure

See main article: H5N1 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.^[32] 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.^[33] 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.^{[34] [35]}

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses.^[36] 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.^{[37] [38]} 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.^{[39] [40]}

Prevention and treatment

Vaccine

Humans - Several "candidate" (unproved) vaccines are available in case an avian virus acquires the ability to infect and transmit among humans; as of July 2024 these include Aflunov, Celldemic and Seqirus/Audenz.^{[41] [42]} Some governments have prepared strategic stockpiles of vaccines against the H5N1 subtype which is considered the biggest risk.^{[43] [44]} However, because the influenza virus is highly variable any vaccine needs to be specifically targeted against the particular strain of virus which is causing concern. Existing influenza vaccine technologies can be adapted to a H5N1 strain causing the pandemic; in the event of an outbreak, the candidate vaccine would be rapidly tested for safety as well as efficacy against the zoonotic strain, and then authorised and distributed to vaccine manufacturers.^[45]

Poultry - it is possible to vaccinate poultry against specific strains of HPAI influenza. Vaccination should be combined with other control measures such as infection monitoring, early detection and biosecurity.^{[46] [47]} In many countries, it is routine to vaccinate poultry against H5N1.^[48] In China, the world's biggest poultry producer, there has been is a mandatory vaccination requirement since 2017; the vaccine is bivalent or trivalent, targeting the H5 and H7 subtypes of influenza A virus. It is manufactured using recombinant influenza virus.^[49]

Treatment

See main article: Treatment of influenza. In the event of an outbreak of human H5N1, the main antiviral drugs recommended are neuraminidase inhibitors, such as zanamivir (Relenza) and oseltamivir (Tamiflu). These drugs can reduce the severity of symptoms if taken soon after infection and can also be taken as prophylaxis to decrease the risk of infection.^{[50] [51] [52] [53]}

Epidemiology

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.^{[54] [55]} 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.^{[56] [57]}

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.^{[58] [59]}

Pandemic potential

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses.^[60] 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.^{[61] [62]} 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.^[63]

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.^[64] A/H5N1 in particular has infected a wide range of mammals and may be adapting to mammalian hosts.^[65]

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.^[66] 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.^[67]

Transmission and prevention

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.^[68] 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.^[69] 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.^{[70] [71]} 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.^[72] 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.^[73] All subtypes of avian Influenza A have potential to cross the species barrier, with H5N1 and H7N9 considered the biggest threats.^{[74] [75]}

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.^[76]

Other animals - a wide range of other animals have been affected by avian flu, generally due to eating birds which had been infected.^[77] There have been instances where transmission of the disease between mammals, including seals and cows, may have occurred.^{[78] [79]}

Mortality

Outbreaks

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.^[80] Subsequently 1.3 million chickens were culled in the territory of Hong Kong. The government also suspended the import of chickens from mainland China.^[81]

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.^{[82] [83]}
• 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.^[84]

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.^[85] "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.^[86]

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.^[87]

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.^[88]

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

See main article: List of mammals that can get H5N1. 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.^{[89] [90]}

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.^[91] 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.^[92]

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.^{[93] [94]} 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.^[95]

Research

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.^[96] 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.^[97] 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^[98] for submitting his manuscript, and his research appeared in a special issue of the journal Science devoted to H5N1.^{[99] [100] [101]} 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.^[102]

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.^[103]

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.^{[104] [105]}

See also

• Antigenic shift
• Avian influenza virus
• Favipiravir
• Fujian flu
• H5N1 clinical trials
• H7N9
• Influenzavirus A
• International Conference on Emerging Infectious Diseases
• National Influenza Centers
• Swine influenza
• Zoonosis

References

Sources

• Analysis of the efficacy of an adjuvant-based inactivated pandemic H5N1 influenza virus vaccine. https://link.springer.com/article/10.1007%2Fs00705-019-04147-7 Ainur NurpeisovaEmail authorMarkhabat KassenovNurkuisa RametovKaissar TabynovGourapura J. RenukaradhyaYevgeniy VolginAltynay SagymbayAmanzhol MakbuzAbylay SansyzbayBerik Khairullin

Research Institute for Biological Safety Problems (RIBSP), Zhambyl Region, Republic of Kazakhstan

External links

• Influenza Research Database – Database of influenza genomic sequences and related information.
• WHO World Health Organization
  • WHO's Avian Flu Facts Sheet for 2006
  • Epidemic and Pandemic Alert and Response Guide to WHO's H5N1 pages
  • Avian Influenza Resources (updated) – tracks human cases and deaths
  • National Influenza Pandemic Plans
  • WHO Collaborating Centres and Reference Laboratories Centers, names, locations, and phone numbers
• FAO Avian Influenza portal Information resources, animations, videos, photos
  • FAO Food and Agriculture Organisation – Bi-weekly Avian Influenza Maps – tracks animal cases and deaths
  • FAO Bird Flu disease card
  • FAO Socio-Economic impact of AI Projects, Information resources
• OIE World Organisation for Animal Health – tracks animal cases and deaths
  • Official outbreak reports by country
  • Official outbreak reports by week
  • Chart of outbreaks by country

European Union

• Health-EU Portal EU response to Avian Influenza.

United Kingdom

• Exotic Animal Disease Generic Contingency Plan – DEFRA generic contingency plan for controlling and eradicating an outbreak of an exotic animal disease. PDF hosted by BBC.
• UK Influenza Pandemic Contingency Plan by the National Health Service – a government entity. PDF hosted by BBC
• UK Department of Health

United States

• Center for Infectious Disease Research and Policy Avian Influenza (Bird Flu): Implications for Human Disease – An overview of Avian Influenza
• PandemicFlu.Gov U.S. Government's avian flu information site
• USAID U.S. Agency for International Development – Avian Influenza Response
• CDC, Centers for Disease Control and Prevention – responsible agency for avian influenza in humans in US – Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus
• USGS – NWHC National Wildlife Health Center – responsible agency for avian influenza in animals in US
• Wildlife Disease Information Node A part of the National Biological Information Infrastructure and partner of the NWHC, this agency collects and distributes news and information about wildlife diseases such as avian influenza and coordinates collaborative information sharing efforts.
• HHS U.S. Department of Health & Human Services's Pandemic Influenza Plan

Notes and References

1. Web site: 3 October 2023 . Influenza (Avian and other zoonotic) . 2024-05-06 . who.int. . en.
2. Web site: Bourk . India . 26 April 2024 . 'Unprecedented': How bird flu became an animal pandemic . 2024-05-08 . bbc.com . BBC. en-GB.
3. Web site: 2024-04-19 . Prevention and Antiviral Treatment of Bird Flu Viruses in People Avian Influenza (Flu) . 2024-05-08 . cdc.gov. Centers for Disease Control. US . en-us.
4. Web site: Department of Health & Human Services . Bird flu (avian influenza) . 2024-05-09 . betterhealth.vic.gov.au . Victoria, Australia. en.
5. Web site: 2021-11-18 . Avian influenza: guidance, data and analysis . 2024-05-09 . gov.uk . en-gb.
6. Web site: 2022-06-14 . Avian Influenza in Birds . 2024-05-06 . cdc.gov. Centers for Disease Control and Prevention . US . en-us.
7. Web site: 2022-12-13 . Bird flu (avian influenza): how to spot and report it in poultry or other captive birds . 2024-05-06 . gov.uk. Department for Environment, Food & Rural Affairs and Animal and Plant Health Agency . UK. en-gb.
8. Web site: 2024-02-01 . Influenza Type A Viruses . 2024-05-03 . US. cdc.gov. Centers for Disease Control and Prevention . en-us.
9. News: Devlin . Hannah . 2024-04-18 . Risk of bird flu spreading to humans is 'enormous concern', says WHO . 2024-05-06 . The Guardian . en-GB . 0261-3077.
10. Web site: 2023-02-20 . Avian influenza A(H5N1): For health professionals . 2024-05-22 . canada.ca.
11. Web site: 2023-06-06 . Emergence and Evolution of H5N1 Bird Flu Avian Influenza (Flu) . 2024-05-03 . US. cdc.gov. Centers for Disease Control and Prevention . en-us.
12. Huang . Pan . Sun . Lujia . Li . Jinhao . Wu . Qingyi . Rezaei . Nima . Jiang . Shibo . Pan . Chungen . 3. 2023-06-16 . Potential cross-species transmission of highly pathogenic avian influenza H5 subtype (HPAI H5) viruses to humans calls for the development of H5-specific and universal influenza vaccines . Cell Discovery . en . 9 . 1 . 58 . 10.1038/s41421-023-00571-x . 2056-5968 . 10275984 . 37328456.
13. Web site: 2024-04-22 . Highlights in the History of Avian Influenza (Bird Flu) Timeline – 2020-2024 Avian Influenza (Flu) . 2024-05-08 . US. cdc.gov. Centers for Disease Control and Prevention . en-us.
14. Caliendo . V. . Lewis . N. S. . Pohlmann . A. . Baillie . S. R. . Banyard . A. C. . Beer . M. . Brown . I. H. . Fouchier . R. a. M. . Hansen . R. D. E. . Lameris . T. K. . Lang . A. S. . Laurendeau . S. . Lung . O. . Robertson . G. . van der Jeugd . H. . 2022-07-11 . Transatlantic spread of highly pathogenic avian influenza H5N1 by wild birds from Europe to North America in 2021 . Scientific Reports . en . 12 . 1 . 11729 . 3. 10.1038/s41598-022-13447-z . 35821511 . 9276711 . 2022NatSR..1211729C . 2045-2322.
15. Web site: 2024-05-02 . Bird flu is bad for poultry and cattle. Why it's not a dire threat for most of us — yet . 2024-05-09 . NBC News . en.
16. News: McKie . Robin . 2024-04-20 . Next pandemic likely to be caused by flu virus, scientists warn . 2024-05-09 . The Observer . en-GB . 0029-7712.
17. Web site: 2023-10-10 . Vaccination of poultry against highly pathogenic avian influenza – Available vaccines and vaccination strategies . 2024-05-09 . efsa.europa.eu . en.
18. Web site: 2024-05-01 . Two possible bird flu vaccines could be available within weeks, if needed . 2024-05-09 . NBC News . en.
19. Web site: Avian influenza (bird flu) European Medicines Agency . 2024-05-09 . ema.europa.eu.
20. Web site: CDC . 2024-05-30 . Avian Influenza A Virus Infections in Humans . 2024-06-11 . Centers for Disease Control and Prevention . en-us.
21. Web site: 11 June 2024 . Questions and Answers on Avian Influenza . 2024-06-11 . An official website of the European Commission.
22. Web site: 2024-02-01 . Reported Human Infections with Avian Influenza A Viruses Avian Influenza (Flu) . 2024-06-11 . Centers for Disease Control and Prevention . en-us.
23. Web site: Zoonotic influenza . 2024-06-16 . Wordl Health Organization . en.
24. Web site: The next pandemic: H5N1 and H7N9 influenza? . 2024-06-16 . Gavi, the Vaccine Alliance . en.
25. Web site: 2024-06-05 . Highly Pathogenic Avian Influenza A(H5N1) Virus in Animals: Interim Recommendations for Prevention, Monitoring, and Public Health Investigations . 2024-06-13 . Centers for Disease Control . en-us.
26. Bertram S, Glowacka I, Steffen I, Kühl A, Pöhlmann S . Novel insights into proteolytic cleavage of influenza virus hemagglutinin . Reviews in Medical Virology . 20 . 5 . 3. 298–310 . September 2010 . 20629046 . 7169116 . 10.1002/rmv.657 . The influenza virus HA binds to alpha 2–3 linked (avian viruses) or alpha 2–6 linked (human viruses) sialic acids presented by proteins or lipids on the host cell surface..
27. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y . 3. Avian flu: influenza virus receptors in the human airway . Nature . 440 . 7083 . 435–436 . March 2006 . 16554799 . 10.1038/440435a. 2006Natur.440..435S . 9472264 .
28. van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, Osterhaus AD, Kuiken T . 2006 . H5N1 Virus Attachment to Lower Respiratory Tract . Science . 312 . 5772 . 399 . 10.1126/science.1125548 . 16556800 . 33294327 .
29. Bennett . Nicholas John . Avian Influenza (Bird Flu): Background, Pathophysiology, Epidemiology . Medscape Reference . 13 October 2021 . 28 April 2024 . Avian influenza is still primarily a respiratory infection but involves more of the lower airways than human influenza typically does. This is likely due to differences in the hemagglutinin protein and the types of sialic acid residues to which the protein binds. Avian viruses tend to prefer sialic acid alpha(2-3) galactose, which, in humans, is found in the terminal bronchi and alveoli. Conversely, human viruses prefer sialic acid alpha(2-6) galactose, which is found on epithelial cells in the upper respiratory tract..
30. 1980 . A revision of the system of nomenclature for influenza viruses: a WHO Memorandum . Bull World Health Organ . 58 . 4 . 585–591 . 2395936 . 6969132 . This Memorandum was drafted by the signatories listed on page 590 on the occasion of a meeting held in Geneva in February 1980..
31. Payungporn S, Chutinimitkul S, Chaisingh A, Damrongwantanapokin S, Nuansrichay B, Pinyochon W, Amonsin A, Donis RO, Theamboonlers A, Poovorawan T . Discrimination between Highly Pathogenic and Low Pathogenic H5 Avian Influenza A Viruses . Emerging Infectious Diseases . 2006 . 12 . 4 . 16715581. 700–701 . 3294708 . 10.3201/eid1204.051427.
32. Web site: 2024-05-13 . Influenza A Subtypes and the Species Affected Seasonal Influenza (Flu) CDC . 2024-06-17 . Centers for Disease Control and Prevention . en-us.
33. Web site: CDC . 2024-02-01 . Influenza Type A Viruses . 2024-05-03 . Centers for Disease Control and Prevention . en-us.
34. Web site: CDC . 2023-03-30 . Types of Influenza Viruses . 2024-06-17 . Centers for Disease Control and Prevention . en-us.
35. Web site: CDC . 2024-06-11 . Avian Influenza Type A Viruses . 2024-06-17 . Avian Influenza (Bird Flu) . en-us.
36. Márquez Domínguez L, Márquez Matla K, Reyes Leyva J, Vallejo Ruíz V, Santos López G . Antiviral resistance in influenza viruses . Cellular and Molecular Biology (Noisy-le-Grand, France) . 69 . 13 . 16–23 . December 2023 . 38158694 . 10.14715/cmb/2023.69.13.3 . free .
37. Kou Z, Lei FM, Yu J, Fan ZJ, Yin ZH, Jia CX, Xiong KJ, Sun YH, Zhang XW, Wu XM, Gao XB, Li TX . 2005 . New Genotype of Avian Influenza H5N1 Viruses Isolated from Tree Sparrows in China . J. Virol. . 79 . 24 . 15460–15466 . 10.1128/JVI.79.24.15460-15466.2005 . 1316012 . 16306617.
38. The World Health Organization Global Influenza Program Surveillance Network. . 2005 . Evolution of H5N1 avian influenza viruses in Asia . Emerging Infectious Diseases . 11 . 10 . 1515–1521 . 10.3201/eid1110.050644 . 3366754 . 16318689.
    Figure 1 shows a diagramatic representation of the genetic relatedness of Asian H5N1 hemagglutinin genes from various isolates of the virus
39. Shao . Wenhan . Li . Xinxin . Goraya . Mohsan Ullah . Wang . Song . Chen . Ji-Long . 2017-08-07 . Evolution of Influenza A Virus by Mutation and Re-Assortment . International Journal of Molecular Sciences . 18 . 8 . 1650 . 10.3390/ijms18081650 . 1422-0067 . 5578040 . 28783091 . free.
40. Eisfeld AJ, Neumann G, Kawaoka Y . January 2015 . At the centre: influenza A virus ribonucleoproteins . Nature Reviews. Microbiology . En . 13 . 1 . 28–41 . 10.1038/nrmicro3367 . 5619696 . 25417656.
41. Web site: Vaccines for pandemic influenza . 30 July 2024 . European Medicines Agency . en.
42. Web site: January 31, 2020 . Audenz . live . https://web.archive.org/web/20200806022227/https://www.fda.gov/vaccines-blood-biologics/audenz . August 6, 2020 . February 5, 2020 . U.S. Food and Drug Administration (FDA) . STN: 125692.
43. Web site: Vaccines for pandemic influenza . 2024-06-15 . European Medicines Agency.
44. Web site: February 4, 2020 . FDA Approves Seqirus' Audenz as Vaccine Against Potential Flu Pandemic . live . https://web.archive.org/web/20200205184348/https://www.biospace.com/article/seqirus-wins-fda-approval-of-vaccine-for-potential-flu-pandemic/ . February 5, 2020 . February 5, 2020 . BioSpace . Keown A.
45. Web site: 2024-06-03 . Making a Candidate Vaccine Virus (CVV) for a HPAI (Bird Flu) Virus . 2024-06-22 . U.S. Centers for Disease Control and Prevention (CDC) . en-us.
46. Web site: 2023-10-10 . Vaccination of poultry against highly pathogenic avian influenza – Available vaccines and vaccination strategies . 2024-05-09 . efsa.europa.eu . en.
47. Web site: 2024-06-03 . Making a Candidate Vaccine Virus (CVV) for a HPAI (Bird Flu) Virus . 2024-06-15 . U.S. Centers for Disease Control and Prevention (CDC) . en-us.
48. News: 17 February 2023 . Bird flu vaccination policies by country . 30 July 2024 . Reuters.
49. Wu . Jie . Ke . Changwen . Lau . Eric H.Y. . Song . Yingchao . Cheng . Kit Ling . Zou . Lirong . Kang . Min . Song . Tie . Peiris . Malik . Yen . Hui-Ling . January 2019 . Influenza H5/H7 Virus Vaccination in Poultry and Reduction of Zoonotic Infections, Guangdong Province, China, 2017–18 . Emerging Infectious Diseases . 25 . 1 . 116–118 . 10.3201/eid2501.181259 . 1080-6040 . 6302570 . 30355435.
50. Peteranderl C, Herold S, Schmoldt C . August 2016 . Human Influenza Virus Infections . Seminars in Respiratory and Critical Care Medicine . 37 . 4 . 487–500 . 10.1055/s-0036-1584801 . 7174870 . 27486731.
51. Web site: 2017-10-19 . Bird flu . 2024-07-30 . National Health Service (NHS) UK . en.
52. Web site: CDC . 2024-07-29 . Avian Influenza (Bird Flu) - Emergency Use Instructions (EUI) for Oseltamivir . 2024-07-30 . Centers for Disease Control and Prevention . en-us.
53. Stiver . Grant . 2003 . The treatment of influenza with antiviral drugs . Canadian Medical Association Journal . 168 . 1 . 49–57 . 139319 . 12515786 . Pub Med.
54. Charostad . Javad . Rezaei Zadeh Rukerd . Mohammad . Mahmoudvand . Shahab . Bashash . Davood . Hashemi . Seyed Mohammad Ali . Nakhaie . Mohsen . Zandi . Keivan . September 2023 . A comprehensive review of highly pathogenic avian influenza (HPAI) H5N1: An imminent threat at doorstep . Travel Medicine and Infectious Disease . 55 . 102638 . 10.1016/j.tmaid.2023.102638 . 1477-8939. free . 37652253 .
55. Web site: CDC . 2024-06-10 . 1880-1959 Highlights in the History of Avian Influenza (Bird Flu) Timeline . 2024-07-08 . Avian Influenza (Bird Flu) . en-us.
56. Web site: CDC . 2024-06-10 . 1960-1999 Highlights in the History of Avian Influenza (Bird Flu) Timeline . 2024-07-08 . Avian Influenza (Bird Flu) . en-us.
57. Chan . Paul K. S. . 2002-05-01 . Outbreak of Avian Influenza A(H5N1) Virus Infection in Hong Kong in 1997 . Clinical Infectious Diseases . 34 . Supplement_2 . S58–S64 . 10.1086/338820 . 11938498 . 1537-6591.
58. Web site: Bourk . India . 26 April 2024 . 'Unprecedented': How bird flu became an animal pandemic . 2024-05-08 . www.bbc.com . en-GB.
59. Web site: CDC . 2024-07-05 . H5N1 Bird Flu: Current Situation . 2024-07-08 . Avian Influenza (Bird Flu) . en-us.
60. Sanjuán R, Nebot MR, Chirico N, Mansky LM, Belshaw R . October 2010 . Viral mutation rates . Journal of Virology . 84 . 19 . 9733–48 . 10.1128/JVI.00694-10 . 2937809 . 20660197.
61. Kou Z, Lei FM, Yu J, Fan ZJ, Yin ZH, Jia CX, Xiong KJ, Sun YH, Zhang XW, Wu XM, Gao XB, Li TX . 2005 . New Genotype of Avian Influenza H5N1 Viruses Isolated from Tree Sparrows in China . J. Virol. . 79 . 24 . 15460–15466 . 10.1128/JVI.79.24.15460-15466.2005 . 1316012 . 16306617.
62. The World Health Organization Global Influenza Program Surveillance Network. . 2005 . Evolution of H5N1 avian influenza viruses in Asia . Emerging Infectious Diseases . 11 . 10 . 1515–1521 . 10.3201/eid1110.050644 . 3366754 . 16318689. Figure 1 shows a diagramatic representation of the genetic relatedness of Asian H5N1 hemagglutinin genes from various isolates of the virus
63. Web site: CDC . 2024-05-15 . Transmission of Bird Flu Viruses Between Animals and People . 2024-06-10 . Centers for Disease Control and Prevention . en-us.
64. Web site: 29 July 2020 . Global AIV with Zoonotic Potential . 2024-06-24 . The Food and Agriculture Organization (FAO) of the United Nations . en.
65. Plaza . Pablo I. . Gamarra-Toledo . Víctor . Euguí . Juan Rodríguez . Lambertucci . Sergio A. . 2024 . Recent Changes in Patterns of Mammal Infection with Highly Pathogenic Avian Influenza A(H5N1) Virus Worldwide . Emerging Infections Diseases . en-us . 30 . 3 . 444–452 . 10.3201/eid3003.231098 . 10902543 . 38407173.
66. Book: Lee . Kelley . Historical Dictionary of the World Health Organization . Fang . Jennifer . Rowman & Littlefield . 2013 . 9780810878587.
67. Web site: 19 September 2022 . 70 years of GISRS – the Global Influenza Surveillance & Response System . 2024-06-13 . World Health Organization . en.
68. Web site: 2024-05-15 . Transmission of Bird Flu Viruses Between Animals and People . 2024-06-10 . U.S. Centers for Disease Control and Prevention (CDC) . en-us.
69. Web site: Avian Influenza . 2024-06-10 . WOAH - World Organisation for Animal Health . en-GB.
70. Web site: August 2020 . Prevention and Control of H5 and H7 Avian Influenza in the Live Bird Marketing System . 15 June 2024 . United States Department of Agriculture.
71. Web site: 11 June 2024 . Questions and Answers on Avian Influenza . 2024-06-11 . An official website of the European Commission.
72. Web site: 2024-05-30 . Avian Influenza A Virus Infections in Humans . 2024-06-11 . U.S. Centers for Disease Control and Prevention (CDC) . en-us.
73. Web site: 2024-02-01 . Reported Human Infections with Avian Influenza A Viruses . 2024-06-11 . Centers for Disease Control and Prevention . en-us.
74. Web site: Zoonotic influenza . 2024-06-16 . Wordl Health Organization . en.
75. Web site: The next pandemic: H5N1 and H7N9 influenza? . 2024-06-16 . Gavi, the Vaccine Alliance . en.
76. Web site: 2024-06-05 . Highly Pathogenic Avian Influenza A(H5N1) Virus in Animals: Interim Recommendations for Prevention, Monitoring, and Public Health Investigations . 2024-06-13 . U.S. Centers for Disease Control and Prevention . en-us.
77. News: 2023-02-02 . Bird flu 'spills over' to otters and foxes in UK . 2024-06-11 . BBC News . en-GB.
78. Web site: 2023-03-15 . Study of H5N1 avian flu seal deaths reveals multiple lineages . 2024-06-13 . Center for Infectious Disease Research and Policy . en.
79. Kozlov M . June 2024 . Huge amounts of bird-flu virus found in raw milk of infected cows . Nature . 10.1038/d41586-024-01624-1 . 38840011.
80. Web site: WHO . October 28, 2005 . H5N1 avian influenza: timeline . dead . https://web.archive.org/web/20051129155319/http://www.who.int/csr/disease/avian_influenza/Timeline_28_10a.pdf . November 29, 2005.
81. Web site: 香港禽流感大事记 . dead . https://web.archive.org/web/20081007173436/http://www.yangtse.com/epaper/yzwb/2007-06/28/content_9354072.htm . October 7, 2008 . June 12, 2008.
82. J.S. Peiris . W.C Yu . C.W. Leung . C.Y. Cheung . W.F. Ng . J.M. Nicholls . T.K. Ng . K.H. Chan . S.T. Lai . W.L. Lim . K.Y. Yuen . Y. Guan . February 21, 2004 . Re-emergence of fatal human influenza A subtype H5N1 disease . Lancet . 363 . 9409 . 617–9 . 10.1016/S0140-6736(04)15595-5 . 7112424 . 14987888.
83. Web site: 6 June 2023 . Emergence and Evolution of H5N1 Bird Flu Avian Influenza (Flu) . live . https://web.archive.org/web/20240307155551/https://www.cdc.gov/flu/avianflu/communication-resources/bird-flu-origin-infographic.html . 7 March 2024 . 10 March 2024 . Centers for Disease Control and Prevention . en-us.
84. Web site: WHO . Confirmed Human Cases of Avian Influenza A(H5N1) . dead . https://web.archive.org/web/20060423065725/http://www.who.int/csr/disease/avian_influenza/country/en/ . April 23, 2006.
85. T. Tiensin . P. Chaitaweesub . T. Songserm . A. Chaisingh . W. Hoonsuwan . C. Buranathai . T. Parakamawongsa . S. Premashthira . A. Amonsin . M. Gilbert . M. Nielen . A. Stegeman . November 2005 . Highly pathogenic avian influenza H5N1, Thailand, 2004 . Emerg Infect Dis . 11 . 11 . 1664–72 . 10.3201/eid1111.050608 . 3367332 . 16318716.
86. Web site: Henry L Niman . October 22, 2004 . Thailand: Up to 100 Tigers in Sri Racha Zoo Now Affected by Avian Influenza . dead . https://web.archive.org/web/20090422193601/http://www.promedmail.org/pls/otn/f?p=2400:1202:45722282341019::NO::F2400_P1202_CHECK_DISPLAY,F2400_P1202_PUB_MAIL_ID:X,26990 . April 22, 2009 . February 19, 2008.
87. http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/may2705avflu.html CIDRAP
88. News: February 28, 2006 . German cat gets deadly bird flu . October 8, 2006 . BBC News.
89. News: Nuki . Paul . How worried should we be about avian flu? . 5 February 2023 . The Telegraph . 2 February 2023 . https://web.archive.org/web/20230202100423/https://www.telegraph.co.uk/global-health/science-and-disease/avian-flu-jumping-mammals-experts-fear-humans-will-next/ . 2 February 2023.
90. News: Pelley . Lauren . Bird flu keeps spreading beyond birds. Scientists worry it signals a growing threat to humans, too . 5 February 2023 . CBC News . 2 February 2023 . https://web.archive.org/web/20230202120256/https://www.cbc.ca/news/health/bird-flu-keeps-spreading-beyond-birds-scientists-worry-it-signals-a-growing-threat-to-humans-too-1.6732287 . 2 February 2023.
91. News: Merrick . Jane . Mass death of seals raises fears bird flu is jumping between mammals, threatening new pandemic . 15 February 2023 . The i newspaper . 1 February 2023 . https://web.archive.org/web/20230203230815/https://inews.co.uk/news/politics/mass-death-of-seals-raises-fears-bird-flu-is-jumping-between-mammals-threatening-new-pandemic-2121376 . 3 February 2023.
92. News: Kwan . Jacklin . Bird flu wipes out over 95% of southern elephant seal pups in 'catastrophic' mass death . 23 January 2024 . livescience.com . 22 January 2024 . en.
93. Kozlov . Max . 2024-06-05 . Huge amounts of bird-flu virus found in raw milk of infected cows . Nature . en . 10.1038/d41586-024-01624-1 . 0028-0836 . 38840011.
94. Mallapaty . Smriti . 2024-04-27 . Bird flu virus has been spreading in US cows for months, RNA reveals . Nature . en . 10.1038/d41586-024-01256-5. 38678111 .
95. Burrough . Eric . Magstadt . Drew . Main . Rodger . Highly Pathogenic Avian Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Domestic Dairy Cattle and Cats, United States, 2024 . Emerging Infectious Diseases . 29 April 2024 . 30 . 7 . 1335–1343 . 10.3201/eid3007.240508 . 38683888 . 11210653 . 30 April 2024.
96. Harmon . Katherine . 2011-09-19 . What Will the Next Influenza Pandemic Look Like? . live . https://web.archive.org/web/20120302235202/http://www.scientificamerican.com/article.cfm?id=next-influenza-pandemic . 2012-03-02 . 2012-01-23 . Scientific American.
97. News: David Malakoff . March 30, 2012 . Breaking News: NSABB Reverses Position on Flu Papers . dead . https://web.archive.org/web/20120630154419/http://news.sciencemag.org/scienceinsider/2012/03/breaking-news-nsabb-reverses-pos.html . June 30, 2012 . June 23, 2012 . Science Insider.
98. News: Nell Greenfieldboyce . April 24, 2012 . Bird Flu Scientist has Applied for Permit to Export Research . live . https://web.archive.org/web/20120622123109/http://www.npr.org/blogs/health/2012/04/24/151292681/bird-flu-scientist-has-applied-for-permit-to-export-research . June 22, 2012 . June 23, 2012 . NPR.
99. News: Nell Greenfieldboyce . June 21, 2012 . Journal Publishes Details on Contagious Bird Flu Created in Lab . live . https://web.archive.org/web/20120622181156/http://www.npr.org/blogs/health/2012/06/21/155504336/journal-publishes-details-on-controversial-bird-flu-experiments . June 22, 2012 . June 23, 2012 . National Public Radio (NPR).
100. June 21, 2012 . H5N1 . live . Special Issue . . https://web.archive.org/web/20120625000009/http://www.sciencemag.org/site/special/h5n1/ . June 25, 2012 . June 23, 2012.
101. Herfst . S. . Schrauwen . E. J. A. . Linster . M. . Chutinimitkul . S. . De Wit . E. . Munster . V. J. . Sorrell . E. M. . Bestebroer . T. M. . Burke . D. F. . Smith . D. J. . Rimmelzwaan . G. F. . Osterhaus . A. D. M. E. . Fouchier . R. A. M. . 2012 . Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets . Science . 336 . 6088 . 1534–1541 . 2012Sci...336.1534H . 10.1126/science.1213362 . 4810786 . 22723413.
102. News: Brown . Eryn . June 21, 2012 . Scientists create bird flu that spreads easily among mammals . live . https://web.archive.org/web/20120623022726/http://www.latimes.com/news/science/la-sci-h5n1-bird-flu-20120622,0,4539172.story . June 23, 2012 . June 23, 2012 . Los Angeles Times.
103. Keim . Brandon . 2013-05-02 . Chinese Scientists Create New Mutant Bird-Flu Virus . 2023-02-07 . Wired . en-US . 1059-1028.
104. Web site: Scientists Resume Efforts to Create Deadly Flu Virus, with US Government's Blessing . Forbes.
105. Web site: 18 July 2014 . From anthrax to bird flu – the dangers of lax security in disease-control labs . TheGuardian.com.