Influenza A virus subtype H5N1

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Influenza A virus subtype H5N1
Colorized transmission electron micrograph of Avian influenza A H5N1 viruses (seen in gold) grown in MDCK cells (seen in green).
Virus classification Edit this classification
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Negarnaviricota
Class: Insthoviricetes
Order: Articulavirales
Family: Orthomyxoviridae
Genus: Alphainfluenzavirus
Species:
Influenza A virus
Serotype:
Influenza A virus subtype H5N1
Notable strains
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).[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.[3] An estimated half a billion farmed birds have been slaughtered in efforts to contain the virus.[2]

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.[5] 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][6] 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.[3][18][19]

Signs and symptoms[edit]

Birds[edit]

Clinical signs of H5N1 in birds range from mild—decrease in egg production, nasal discharge, coughing and sneezing—to severe, including loss of coordination, energy, and appetite; soft-shelled or misshapen eggs; purple discoloration of the wattles, head, eyelids, combs, and hocks; and diarrhea. Sometimes the first noticeable sign is sudden death.[20]

Humans[edit]

Further information: Influenza

In general, humans who catch a humanized influenza A virus (a human flu virus of type A) usually have symptoms that include fever, cough, sore throat, muscle aches, conjunctivitis, and, in severe cases, breathing problems and pneumonia that may be fatal.[20] The severity of the infection depends in large part on the state of the infected persons' immune systems and whether they had been exposed to the strain before (in which case they would be partially immune). No one knows if these or other symptoms will be the symptoms of a humanized H5N1 flu.[citation needed]

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.[21][22] 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.[23][24] As of April 2024, there is no human-adapted form of H5N1 influenza, so all humans who have caught it so far have caught avian H5N1.

Between 2003 and March 2024, the World Health Organization has recorded 888 cases of confirmed H5N1 influenza, leading to 463 deaths.[25] This yields a CFR estimate of 52%. The true fatality rate may be lower because some infections were not identified as H5N1.[26]

Genetics[edit]

The H in H5N1 stands for "hemagglutinin", as depicted in this molecular model
Further information: Influenzavirus A and H5N1 genetic structure

The first known strain of HPAI A(H5N1) (called A/chicken/Scotland/59) killed two flocks of chickens in Scotland in 1959, but that strain was very different from the highly pathogenic strain of H5N1. The dominant strain of HPAI A(H5N1) in 2004 evolved from 1999 to 2002 creating the Z genotype.[27] It has also been called "Asian lineage HPAI A(H5N1)".

Asian lineage HPAI A(H5N1) is divided into two antigenic clades. "Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: Map

  • Subclade 1, Indonesia
  • Subclade 2, Europe, Middle East, and Africa (called EMA)
  • Subclade 3, China[28][29][30]

A 2007 study focused on the EMA subclade has shed further light on the EMA mutations. "The 36 new isolates reported here greatly expand the amount of whole-genome sequence data available from recent avian influenza (H5N1) isolates. Before our project, GenBank contained only 5 other complete genomes from Europe for the 2004–2006 period, and it contained no whole genomes from the Middle East or northern Africa. Our analysis showed several new findings. First, all European, Middle Eastern, and African samples fall into a clade that is distinct from other contemporary Asian clades, all of which share common ancestry with the original 1997 Hong Kong strain. Phylogenetic trees built on each of the 8 segments show a consistent picture of 3 lineages, as illustrated by the HA tree shown in Figure 1. Two of the clades contain exclusively Vietnamese isolates; the smaller of these, with 5 isolates, we label V1; the larger clade, with 9 isolates, is V2. The remaining 22 isolates all fall into a third, clearly distinct clade, labeled EMA, which comprises samples from Europe, the Middle East, and Africa. Trees for the other 7 segments display a similar topology, with clades V1, V2, and EMA clearly separated in each case. Analyses of all available complete influenza (H5N1) genomes and of 589 HA sequences placed the EMA clade as distinct from the major clades circulating in People's Republic of China, Indonesia, and Southeast Asia."[31]

Terminology[edit]

H5N1 isolates are identified like this actual HPAI A(H5N1) 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), A/avian/NY/01(H5N2), A/chicken/Mexico/31381-3/94(H5N2), and A/shoveler/Egypt/03(H5N2).[32]

Because of the impact of avian influenza on economically important chicken farms, a classification system was devised in 1981 which divided avian virus strains as either highly pathogenic (and therefore potentially requiring vigorous control measures) or low pathogenic. The test for this is based solely on the effect on chickens - a virus strain is highly pathogenic avian influenza (HPAI) if 75% or more of chickens die after being deliberately infected with it. The alternative classification is low pathogenic avian influenza (LPAI).[33] This classification system has since been modified to take into account the structure of the virus' haemagglutinin protein.[34] Other species of birds, especially water birds, can become infected with HPAI virus without experiencing severe symptoms and can spread the infection over large distances; the exact symptoms depend on the species of bird and the strain of virus.[33] Classification of an avian virus strain as HPAI or LPAI does not predict how serious the disease might be if it infects humans or other mammals.[33][35]

Genetic structure and related subtypes[edit]

The N in H5N1 stands for "Neuraminidase", the protein depicted in this ribbon diagram

H5N1 is a subtype of the species Influenza A virus of the genus Alphainfluenzavirus of the family Orthomyxoviridae. Like all other influenza A subtypes, the H5N1 subtype is an RNA virus. It has a segmented genome of eight negative sense, single-strands of RNA, abbreviated as PB2, PB1, PA, HA, NP, NA, MP and NS.[citation needed]

HA codes for hemagglutinin, an antigenic glycoprotein found on the surface of the influenza viruses and is responsible for binding the virus to the cell that is being infected. NA codes for neuraminidase, an antigenic glycosylated enzyme found on the surface of the influenza viruses. It facilitates the release of progeny viruses from infected cells.[36] The hemagglutinin (HA) and neuraminidase (NA) RNA strands specify the structure of proteins that are most medically relevant as targets for antiviral drugs and antibodies. HA and NA are also used as the basis for the naming of the different subtypes of influenza A viruses. This is where the H and N come from in H5N1.

Low pathogenic H5N1[edit]

Low pathogenic avian influenza H5N1 (LPAI H5N1), also called "North American" H5N1, commonly occurs in wild birds. In most cases, it causes minor sickness or no noticeable signs of disease in birds. It is not known to affect humans at all. The only concern about it is that it is possible for it to be transmitted to poultry and in poultry mutate into a highly pathogenic strain.[citation needed]

  • 1966 – LPAI H5N1 A/Turkey/Ontario/6613/1966(H5N1) was detected in a flock of infected turkeys in Ontario, Canada.[37][38]
  • 1975 – LPAI H5N1 was detected in a wild mallard duck and a wild blue goose in Wisconsin.
  • 1981 and 1985 – LPAI H5N1 was detected in ducks by the University of Minnesota conducting a sampling procedure in which sentinel ducks were monitored in cages placed in the wild for a short period of time.
  • 1983 – LPAI H5N1 was detected in ring-billed gulls in Pennsylvania.
  • 1986 – LPAI H5N1 was detected in a wild mallard duck in Ohio.
  • 2005 – LPAI H5N1 was detected in ducks in Manitoba, Canada.
  • 2008 – LPAI H5N1 was detected in ducks in New Zealand.
  • 2009 – LPAI H5N1 was detected in commercial poultry in British Columbia.[39]

"In the past, there was no requirement for reporting or tracking LPAI H5 or H7 detections in wild birds so states and universities tested wild bird samples independently of USDA. Because of this, the above list of previous detections might not be all inclusive of past LPAI H5N1 detections. However, the World Organization for Animal Health (OIE) recently changed its requirement of reporting detections of avian influenza. Effective in 2006, all confirmed LPAI H5 and H7 AI subtypes must be reported to the OIE because of their potential to mutate into highly pathogenic strains. Therefore, USDA now tracks these detections in wild birds, backyard flocks, commercial flocks and live bird markets."[40]

High mutation rate[edit]

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.[41][42] A previously uncontagious strain may then be able to pass between humans, one of several possible paths to a pandemic.[citation needed]

The ability of various influenza strains to show species-selectivity is largely due to variation in the hemagglutinin genes. Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells. Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types.[43] This doesn't mean that one amino acid substitution can cause a pandemic, but it does mean that one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans.[citation needed]

Influenza A virus subtype H3N2 is endemic in pigs in China, and has been detected in pigs in Vietnam, increasing fears of the emergence of new variant strains. The dominant strain of annual flu virus in January 2006 was H3N2, which is now resistant to the standard antiviral drugs amantadine and rimantadine. The possibility of H5N1 and H3N2 exchanging genes through reassortment is a major concern. If a reassortment in H5N1 occurs, it might remain an H5N1 subtype, or it could shift subtypes, as H2N2 did when it evolved into the Hong Kong Flu strain of H3N2.

Both the H2N2 and H3N2 pandemic strains contained avian influenza virus RNA segments. "While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the 'Spanish flu' in 1918 appears to be entirely derived from an avian source".[44]

Prevention[edit]

See also: Yarding

Vaccine[edit]

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".[45] 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.[46][47][48] 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.

Public health[edit]

Further information: Influenza pandemic

"The United States is collaborating closely with eight international organizations, including the World Health Organization (WHO), the Food and Agriculture Organization of the United Nations (FAO), the World Organization for Animal Health (OIE), and 88 foreign governments to address the situation through planning, greater monitoring, and full transparency in reporting and investigating avian influenza occurrences. The United States and these international partners have led global efforts to encourage countries to heighten surveillance for outbreaks in poultry and significant numbers of deaths in migratory birds and to rapidly introduce containment measures. The U.S. Agency for International Development (USAID) and the U.S. Department of State, the U.S. Department of Health and Human Services (HHS), and Agriculture (USDA) are coordinating future international response measures on behalf of the White House with departments and agencies across the federal government".[49]

Together steps are being taken to "minimize the risk of further spread in animal populations", "reduce the risk of human infections", and "further support pandemic planning and preparedness".[49]

Ongoing detailed mutually coordinated onsite surveillance and analysis of human and animal H5N1 avian flu outbreaks are being conducted and reported by the USGS National Wildlife Health Center, the Centers for Disease Control and Prevention, the World Health Organization, the European Commission, and others.[50]

Treatment[edit]

Further information: Flu research

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.[51] 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.[52]

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".[53]

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".[54] 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.[55] 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.[56] In September, 2006, a WHO scientist announced that studies had confirmed cases of H5N1 strains resistant to Tamiflu and Amantadine.[57] Tamiflu-resistant strains have also appeared in the EU, which remain sensitive to Relenza.[58][59]

Epidemiology[edit]

Further information: Transmission and infection of H5N1 and Global spread of H5N1

The earliest infections of humans by H5N1 coincided with an epizootic (an epidemic in nonhumans) of H5N1 influenza in Hong Kong's poultry population in 1997. This panzootic (a disease affecting animals of many species, especially over a wide area) outbreak was stopped by the killing of the entire domestic poultry population within the territory. However, the disease has continued to spread; outbreaks were reported in Asia again in 2003. On December 21, 2009, the WHO announced a total of 447 cases which resulted in the deaths of 263.[20][60]

Contagiousness[edit]

Highly pathogenic H5N1
  Countries with humans, poultry and wild birds killed by H5N1
  Countries with poultry or wild birds killed by H5N1 and has reported human cases of H5N1
  Countries with poultry or wild birds killed by H5N1

H5N1 is easily transmissible between birds, facilitating a potential global spread of H5N1. While H5N1 undergoes mutation and reassortment, creating variations which can infect species not previously known to carry the virus, not all of these variant forms can infect humans. H5N1 as an avian virus preferentially binds to a type of galactose receptors that populate the avian respiratory tract from the nose to the lungs and are virtually absent in humans, occurring only in and around the alveoli, structures deep in the lungs where oxygen is passed to the blood. Therefore, the virus is not easily expelled by coughing and sneezing, the usual route of transmission.[22][23][61]

H5N1 is mainly spread by domestic poultry, both through the movements of infected birds and poultry products and through the use of infected poultry manure as fertilizer or feed. Humans with H5N1 have typically caught it from chickens, which were in turn infected by other poultry or waterfowl. Migrating waterfowl (wild ducks, geese and swans) carry H5N1, often without becoming sick.[62][63] Many species of birds and mammals can be infected with HPAI A(H5N1), but the role of animals other than poultry and waterfowl as disease-spreading hosts is unknown.[64]

According to a report by the World Health Organization, H5N1 may be spread indirectly. The report stated the virus may sometimes stick to surfaces or get kicked up in fertilizer dust to infect people.[65]

Virulence[edit]

H5N1 has mutated into a variety of strains with differing pathogenic profiles, some pathogenic to one species but not others, some pathogenic to multiple species. Each specific known genetic variation is traceable to a virus isolate of a specific case of infection. Through antigenic drift, H5N1 has mutated into dozens of highly pathogenic varieties divided into genetic clades which are known from specific isolates, but all belong to genotype Z of avian influenza virus H5N1, now the dominant genotype.[42][41] H5N1 isolates found in Hong Kong in 1997 and 2001 were not consistently transmitted efficiently among birds and did not cause significant disease in these animals. In 2002, new isolates of H5N1 were appearing within the bird population of Hong Kong. These new isolates caused acute disease, including severe neurological dysfunction and death in ducks. This was the first reported case of lethal influenza virus infection in wild aquatic birds since 1961.[66]

Genotype Z emerged in 2002 through reassortment from earlier highly pathogenic genotypes of H5N1[67] that first infected birds in China in 1996, and first infected humans in Hong Kong in 1997.[41][42][68] Genotype Z is endemic in birds in Southeast Asia, has created at least two clades that can infect humans, and is spreading across the globe in bird populations. Mutations occurring within this genotype are increasing their pathogenicity.[69] Birds are also able to shed the virus for longer periods of time before their death, increasing the transmissibility of the virus.

Transmission and host range[edit]

Transmission electron micrograph (TEM) of negatively stained Influenza A virus particles (small and white) attached to host cells (large and irregular) (late passage). (Source: Dr. Erskine Palmer, Centers for Disease Control and Prevention Public Health Image Library)

Infected birds transmit H5N1 through their saliva, nasal secretions, feces and blood. Other animals may become infected with the virus through direct contact with these bodily fluids or through contact with surfaces contaminated with them. H5N1 remains infectious after over 30 days at 0 °C (32 °F) (over one month at freezing temperature) or 6 days at 37 °C (99 °F) (one week at human body temperature); at ordinary temperatures it lasts in the environment for weeks. In Arctic temperatures, it does not degrade at all.

Because migratory birds are among the carriers of the highly pathogenic H5N1 virus, it is spreading to all parts of the world. H5N1 is different from all previously known highly pathogenic avian flu viruses in its ability to be spread by animals other than poultry.

In October 2004, researchers discovered H5N1 is far more dangerous than was previously believed. Waterfowl were revealed to be directly spreading this highly pathogenic strain to chickens, crows, pigeons, and other birds, and the virus was increasing its ability to infect mammals, as well. From this point on, avian flu experts increasingly referred to containment as a strategy that can delay, but not ultimately prevent, a future avian flu pandemic.

"Since 1997, studies of influenza A (H5N1) indicate that these viruses continue to evolve, with changes in antigenicity and internal gene constellations; an expanded host range in avian species and the ability to infect felids; enhanced pathogenicity in experimentally infected mice and ferrets, in which they cause systemic infections; and increased environmental stability."[70]

The New York Times, in an article on transmission of H5N1 through smuggled birds, reports Wade Hagemeijer of Wetlands International stating, "We believe it is spread by both bird migration and trade, but that trade, particularly illegal trade, is more important".[71]

On September 29, 2007, researchers reported the H5N1 bird flu virus can also pass through a pregnant woman's placenta to infect the fetus. They also found evidence of what doctors had long suspected—the virus not only affects the lungs, but also passes throughout the body into the gastrointestinal tract, the brain, liver, and blood cells.[72]

In May 2013, North Korea confirmed a H5N1 bird flu outbreak that forced authorities to kill over 160,000 ducks in Pyongyang.[73]


Confirmed human cases and mortality rate of avian influenza (H5N1) 2003–2024
Country
 Australia
 Azerbaijan
 Bangladesh
 Cambodia
 Canada
 Chile
 China
 Djibouti
 Ecuador
 Egypt
 India
 Indonesia
 Iraq
 Laos
 Myanmar
 Nepal
 Nigeria
 Pakistan
 Spain
 Thailand
 Turkey
 United Kingdom
 United States
 Vietnam
Total
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 Total
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
1 0 0% 1 0 0%
8 5 62.5% 8 5 62.5%
1 0 0% 2 0 0% 3 0 0% 1 1 100% 1 0 0% 8 1 12.5%
4 4 100% 2 2 100% 1 1 100% 1 0 0% 1 0 0% 1 1 100% 8 8 100% 3 3 100% 26 14 53.8% 9 4 44.4% 6 4 66.7% 5 1 20.0% 67 42 62.7%
1 1 100% 1 1 100%
1[74] 0 0% 1 0 0%
1 1 100% 8 5 62.5% 13 8 61.5% 5 3 60.0% 4 4 100% 7 4 57.1% 2 1 50.0% 1 1 100% 2 1 50.0% 2 2 100% 2 0 0% 6 1 16.7% 1 1 100% 1 0 0% 55 32 58.2%
1 0 0% 1 0 0%
1 0 0% 1 0 0%
18 10 55.6% 25 9 36.0% 8 4 50.0% 39 4 10.3% 29 13 44.8% 39 15 38.5% 11 5 45.5% 4 3 75.0% 37 14 37.8% 136 39 28.7% 10 3 30.0% 3 1 33.3% 359 120 33.4%
1 1 100% 1 1 100%
20 13 65.0% 55 45 81.8% 42 37 88.1% 24 20 83.3% 21 19 90.5% 9 7 77.8% 12 10 83.3% 9 9 100% 3 3 100% 2 2 100% 2 2 100% 1 1 100% 200 168 84.0%
3 2 66.6% 3 2 66.6%
2 2 100% 1 0 0% 3 2 66.7%
1 0 0% 1 0 0%
1 1 100% 1 1 100%
1 1 100% 1 1 100%
3 1 33.3% 3 1 33.3%
2 0 0% 2 0 0%
17 12 70.6% 5 2 40.0% 3 3 100% 25 17 68.0%
12 4 33.3% 12 4 33.3%
1 0 0% 4 0 0% 5 0 0%
1 0 0% 3 0 0% 4 0 0%
3 3 100% 29 20 69.0% 61 19 31.1% 8 5 62.5% 6 5 83.3% 5 5 100% 7 2 28.6% 4 2 50.0% 2 1 50.0% 2 2 100% 1 0 0% 1 1 100% 129 65 50.0%
4 4 100% 46 32 69.6% 98 43 43.9% 115 79 68.7% 88 59 67.0% 44 33 75.0% 73 32 43.8% 48 24 50.0% 62 34 54.8% 32 20 62.5% 39 25 64.1% 52 22 42.3% 145 42 29.0% 10 3 30.0% 4 2 50.0% 0 0 0% 1 1 100% 1 0 0% 2 1 50.0% 6 1 16.7% 12 4 33.3% 10 2 20.0% 892 463 51.9%
Source: World Health Organization Human Animal Interface · edit this table


2020–2024 global H5N1 outbreak[edit]

Main article: 2020–2024 H5N1 outbreak

Europe[edit]

A major outbreak of a new strain of H5N1 in wild birds and poultry appeared in Russia in August 2020 and quickly spread to other parts of Europe by October.[75]

Over the winter of 2021 and 2022 avian flu spread among the population of barnacle geese on the Solway Firth, UK, with estimates of up to a third of the Svalbard population being lost;[76][77] pink-footed geese were also affected there and it seems carried the virus to new sites in northern Scotland. The disease was confirmed in sandwich terns in South Africa in April 2022.[78] In late spring 2022 avian flu outbreaks affected many species of wild bird in the United Kingdom, with heavy losses reported among seabirds returning to breed at colonies in the Northern Isles and Outer Hebrides,[79] including great skuas (bonxie) for which outbreaks had initially been reported in 2021[80] (Scotland hosts c. 60% of the world's breeding population) – the 2022 census on St Kilda showed a 64% decline on 2019 with 106 dead birds recorded so far (to 6 June),[81] gannets (1000+ birds reported dead at the Shetlands' Hermaness colony alone,[79] where there are around 26,000 breeding pairs), with many more gannets being reported dead at other colonies (Troup Head, Bass Rock, and St Kilda);[82] the range of species also seems to be expanding, with reports for many species of wildfowl, seabirds (auks, terns and gulls) and scavenging species (corvids and raptors).[83][84]

Elsewhere in Europe the virus killed hundreds (574+) of Dalmatian pelicans in Greece,[85][86] and in Israel around 6000 common cranes were found dead at Hula in December 2021.[87] A report by Scientific Task Force on Avian Influenza and Wild Birds on: "H5N1 Highly Pathogenic Avian Influenza in poultry and wild birds: Winter of 2021/2022 with focus on mass mortality of wild birds in UK and Israel" summarises the situation up to 24 January 2022 and mentions that "H5N8 HPAI is still responsible for poultry and wild bird cases mainly in Asia, H5N1 has now in effect replaced this subtype in Africa and Eurasia in both poultry and wild birds".[88]

The 2022–2023 season was also the worst recorded outbreak in the United Kingdom, with the British government requiring a so-called "poultry lockdown" which required that farmers keep their birds indoors.[89] Meanwhile, an outbreak of H5N1 on a Spanish mink farm led researchers to believe that they had observed the first case of mammal-to-mammal transmission of H5N1.[90] Human cases were reported in Spain in November 2022, and in the UK in May 2023.[75]

Asia[edit]

By November 2020, large outbreaks of the new strain of H5N1 had started to spread into wild birds and farmed poultry across Asia. In February 2023, human cases were reported in Cambodia.[75]

Africa[edit]

Large losses of poultry and wild birds to H5N1 started to occur in Africa in November 2021 and continued through 2022.[75]

Americas[edit]

Similar to 2021 reports, outbreaks were noted from gannet colonies in Canada, with thousands of birds dead in June 2022,[91] as well as common eiders and great black-backed gulls.[92] Prior to that there were reports of spread in wild birds in over 30 states in the US, including major mortalities in a double-crested cormorant colony in Barrington, Illinois,[93][94] the virus also spreading to scavengers including three bald eagles in Georgia.[95] Mass die-offs of both birds and mammals were noted in Peru during the 2022–2023 season.[96] In particular, the Peruvian government reported the deaths of approximately 63,000 birds as well as 716 sea lions, with the WHO noting that mammalian spillovers needed to be "monitored closely".[89][97] In the United States, the 2022–2023 avian outbreak was the worst since H5N1 was first detected.[89]

Ecuador entered into a three-month "animal-health emergency" on 29 November 2022, just days after its first case was reported, whereas Argentina and Uruguay both declared "national sanitary emergencies" on 15 February 2023, after their respective first cases were discovered.[98] On 22 May 2023, Brazil, as the world's largest exporter of chicken meat, declared a 180-day emergency following several cases detected in wild birds and created an emergency operations center to plan for and mitigate potential further spread of H5N1.[99] Human cases were reported in Ecuador and Chile.[75]

In March 2024, H5N1 infections were recorded for the first time in deceased and sick livestock located in the United States. Goats and cows in three states became ill after exposure to wild birds and culled poultry.[100] In early April, H5N1 was reported to have spread amongst dairy cow herds in multiple states of the USA, indicating cow-to-cow spread. A dairy worker in Texas also became infected, with conjunctivitis being the main symptom.[101]

On 22 May 2024, a farm worker in Michigan was infected with the H5N1 virus due to their regular exposure to infected dairy cows. The person had mild symptoms and recovered.[102] On 30 May, it was announced that a second Michigan farm worker from a different dairy farm had been diagnosed with H5N1 after exhibiting respiratory symptoms.[103][104]

Antarctica[edit]

H5N1 was detected in dead birds on the Antarctic mainland for the first time in February 2024.[105]

Arctic[edit]

In December 2023, conservation officials confirmed that a polar bear had died of H5N1 near Alaska's northernmost city, Utqiagvik.[106]

Australia[edit]

In May 2024, H5N1 was detected for the first time in Australia after a human child who had returned to the country from India tested positive. The child had a severe infection but recovered.[107]

Mammalian infections[edit]

Main article: List of mammals that can get H5N1

H5N1 transmission studies in ferrets (2011)[edit]

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.[108] 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.[109] 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.[note 1] After much controversy surrounding the publishing of his research, Fouchier complied (under formal protest) with Dutch government demands to obtain a special permit[110] for submitting his manuscript, and his research appeared in a special issue of the journal Science devoted to H5N1.[111][112][113] 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.[114]

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.[115]

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.[116][117]

Mammal-to-mammal transmission (2022–2024)[edit]

Although mammals, including humans, had become infected with H5N1 bird flu strains in the past, these cases had ostensibly been caused by direct exposure to infected birds, such as through consumption of birds by wildlife or exposure to infected poultry by farmers. In contrast, the October 2022 mammalian 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.[90][118] The mink respiratory tract is particularly well suited to act as a pathway of viral transmission into humans, which has concerned public health professionals due to the production of all but one approved human vaccine requiring the eggs of chickens, which H5N1 kills at a 90–100 percent fatality rate.[119] Infected mink in Spain were also found to have exhibited the "PB2" viral mutation found when H5N1 jumped into pigs over a decade prior, adding to fears that farms could be acting as incubators and/or reservoirs of the virus, similar to the role of minks in SARS-CoV-2.[90]

As of January 2023, fifteen species of wild and captive mammals had become infected with H5N1 throughout the United States.[120] 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.[121] 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.[122]

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.[123] Although mortality in bovines infected with H5N1 is rare, abundant virus shedding in the milk is evident. 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.[124]

Human infections[edit]

As of April 2024, the WHO reported a total of 889 confirmed human cases which resulted in the deaths of 463 people since 2003.[125]

Human-to-human transmission[edit]

Cambodia (2023)[edit]

Following the February 2023 H5N1 death of an 11-year-old girl from Cambodia's Prey Veng province, her father was confirmed positive for the virus and several close contacts also began showing signs of infection. On 24 February 2023, the WHO expressed concern that the virus had potentially begun to spread among humans and ordered the production of a new human vaccine for H5N1.[126] Following the confirmed infections, the WHO began working with the Cambodian government to determine whether both individuals had gotten the virus directly from infected poultry or if it had indeed been a case of human-to-human transmission.[127] Further sequencing determined that at least one of the two cases was from an older H5N1 clade, 2.3.2.1c, which had circulated as a common H5N1 strain in Cambodia for many years, rather than the more recent clade 2.3.4.4b, which had caused mass poultry deaths since 2020. This older clade had jumped to humans in the past yet hadn't previously resulted in any known human-to-human transmission.[128]

On March 1, 2023, as Taiwan raised its travel alert for Cambodia, the WHO and the U.S. CDC, in concert with Cambodian authorities, determined that both of the individuals had been infected through direct contact with poultry.[129][130]

Society and culture[edit]

Main article: Social impact of H5N1

H5N1 has had a significant effect on human society, especially the financial, political, social, and personal responses to both actual and predicted deaths in birds, humans, and other animals. Billions of dollars are being raised and spent to research H5N1 and prepare for a potential avian influenza pandemic. Over $10 billion have been spent and over 200 million birds have been killed to try to contain H5N1.[131][132][133][134][135][136][137][138][139]

People have reacted by buying less chicken, causing poultry sales and prices to fall.[140] Many individuals have stockpiled supplies for a possible flu pandemic. International health officials and other experts have pointed out that many unknown questions still hover around the disease.[141]

Dr. David Nabarro, Chief Avian Flu Coordinator for the United Nations, and former Chief of Crisis Response for the World Health Organization has described himself as "quite scared" about H5N1's potential impact on humans. Nabarro has been accused of being alarmist before, and on his first day in his role for the United Nations, he proclaimed the avian flu could kill 150 million people. In an interview with the International Herald Tribune, Nabarro compares avian flu to AIDS in Africa, warning that underestimations led to inappropriate focus for research and intervention.[142]

See also[edit]

Notes[edit]

  1. ^ The World Intellectual Property Organization (WIPO) lists strategic goods with prohibited goods or goods that require a special permit for import and export without which the carrier faces pecuniary punishment or up to 5 years' imprisonment.

References[edit]

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Sources[edit]

  • 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[edit]

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