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55-668: HVRI was created in 1948 and is the first veterinary medicine research institute in China. In 2013 the HVRI has come to the public attention due to the controversies surrounding its research on H5N1 and H1N1 viruses. In 2018, the Institute put the country's second biosafety level-4 (BSL-4) lab, and the first for large animals, into operation. This China -related article is a stub . You can help Misplaced Pages by expanding it . H5N1 Influenza A virus subtype H5N1 ( A/H5N1 )

110-475: 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. The Global Influenza Surveillance and Response System (GISRS)

165-472: 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

220-468: 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 –

275-546: 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

330-406: 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

385-556: 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. Research Institute for Biological Safety Problems (RIBSP), Zhambyl Region, Republic of Kazakhstan. Hemagglutinin (influenza) Influenza hemagglutinin ( HA ) or haemagglutinin ( British English )

440-403: 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. Between 2003 and November 2024,

495-688: 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,

550-399: 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). H5N1

605-458: 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. Many more outbreaks are recorded, in almost every country in the world, affecting both wild birds and poultry, with occasional spillover events infecting humans. In October 2022 an outbreak of H5N1 on

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660-447: Is a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity . Hemagglutinin is a class I fusion protein , having multifunctional activity as both an attachment factor and membrane fusion protein . Therefore, HA is responsible for binding influenza viruses to sialic acid on the surface of target cells, such as cells in the upper respiratory tract or erythrocytes , resulting in

715-618: 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. Birds – Influenza A viruses of various subtypes have

770-419: Is a homotrimeric integral membrane glycoprotein . It has C3 molecular symmetry . It is shaped like a cylinder , and is approximately 13.5 nanometres long. HA trimer is made of three identical monomers . Each monomer is made of an intact HA0 single polypeptide chain with HA1 and HA2 regions that are linked by 2 disulfide bridges . Each HA2 region adopts alpha helical coiled coil structure and sits on top of

825-552: 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. 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

880-415: 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

935-417: 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

990-430: 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 –

1045-680: 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

1100-482: Is hidden in a hydrophobic pocket between the HA2 trimeric interface. The C-terminus of HA2, also known as the transmembrane domain , spans the viral membrane and anchors protein to the membrane. HA plays two key functions in viral entry. Firstly, it allows the recognition of target vertebrate cells, accomplished through the binding to these cells' sialic acid -containing receptors . Secondly, once bound it facilitates

1155-413: Is more stable at the lower pH), it "retracts the grappling hook" and pulls the endosomal membrane right up next to the virus particle's own membrane, causing the two to fuse together. Once this has happened, the contents of the virus such as viral RNA are released in the host cell's cytoplasm and then transported to the host cell nucleus for replication. Since hemagglutinin is the major surface protein of

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1210-632: 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

1265-415: Is released from the hydrophobic pocket and HA1 is dissociated from HA2 domain. HA2 domain then undergoes extensive conformation change that eventually bring the two membranes into close contact. This so-called " fusion peptide " that was released as pH is lowered, acts like a molecular grappling hook by inserting itself into the endosomal membrane and locking on. Then, HA2 refolds into a new structure (which

1320-488: 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

1375-427: Is shed in the saliva, mucus, 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 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

1430-491: 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. Between January and October 2023, at least 24,000 South American sea lions died from H5N1 flu, with

1485-420: The World Health Organization has recorded 948 cases of confirmed H5N1 influenza, leading to 464 deaths. The true fatality rate may be lower because some cases with mild symptoms may not have been identified as H5N1. 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,

1540-474: The internalization of the virus. Additionally, HA is responsible for the fusion of the viral envelope with the late endosomal membrane once exposed to low pH (5.0–5.5). The name "hemagglutinin" comes from the protein 's ability to cause red blood cells (i.e., erythrocytes) to clump together (i.e., agglutinate ) in vitro . Hemagglutinin (HA) in influenza A virus (IAV) has at least 18 different subtypes. These subtypes are named H1 through H18. H16

1595-503: The H5N1 subtype which is considered the biggest risk among subtypes. 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

1650-454: The HA head is present, the immune system does not generally make bNAbs (broadly neutralizing antibodies). Instead, it makes the head antibodies that only recognize a few subtypes. Since the head is responsible for holding the three HA units together, a stem-only HA needs its own way to hold itself together. One team designed self-assembling HA-stem nanoparticles, using a protein called ferritin to hold

1705-601: The HA1 region, which is a small globular domain that consists of a mix of α/β structures. The HA trimer is synthesized as inactive precursor protein HA0 to prevent any premature and unwanted fusion activity and must be cleaved by host proteases in order to be infectious. At neutral pH, the 23 residues near the N-terminus of HA2, also known as the fusion peptide that is eventually responsible for fusion between viral and host membrane,

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1760-480: The entry of the viral genome into the target cells by causing the fusion of host endosomal membrane with the viral membrane. Specifically, the HA1 domain of the protein binds to the monosaccharide sialic acid which is present on the surface of its target cells, allowing attachment of viral particle to the host cell surface. HA17 and HA18 have been described to bind MHC class II molecules as a receptor for entry rather than sialic acid. The host cell membrane then engulfs

1815-489: 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

1870-413: 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 in addition to humans that have been recorded with H5N1 infection include cows, seals, goats, and skunks. Due to

1925-585: 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 . Between 2003 and November 2024, the World Health Organization has recorded 948 cases of confirmed H5N1 influenza, leading to 464 deaths. The true fatality rate may be lower because some cases with mild symptoms may not have been identified as H5N1. To unambiguously describe

1980-437: 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,

2035-449: The influenza A virus and is essential to the entry process, it is the primary target of neutralizing antibodies . These antibodies against flu have been found to act by two different mechanisms, mirroring the dual functions of hemagglutinin: Some antibodies against hemagglutinin act by inhibiting attachment. This is because these antibodies bind near the top of the hemagglutinin "head" (blue region in figure above) and physically block

2090-831: The interaction with sialic acid receptors on target cells. This group of antibodies acts by preventing membrane fusion (only in vitro ; the efficacy of these antibodies in vivo is believed to be a result of antibody-dependent cell-mediated cytotoxicity and the complement system ). The stem or stalk region of HA (HA2), is highly conserved across different strains of influenza viruses. The conservation makes it an attractive target for broadly neutralizing antibodies that target all flu subtypes, and for developing universal vaccines that let humans produce these antibodies naturally. Its structural changes from prefusion to postfusion conformation drives fusion between viral membrane and host membrane. Therefore, antibodies targeting this region can block key structural changes that eventually drive

2145-736: 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

2200-442: The membrane fusion process, and therefore are able to achieve antiviral activity against several influenza virus subtypes. At least one fusion-inhibiting antibody was found to bind closer to the top of hemagglutinin, and is thought to work by cross-linking the heads together, the opening of which is thought to be the first step in the membrane fusion process. Examples are human antibodies F10, FI6, CR6261 . They recognize sites in

2255-618: 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. 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

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2310-573: The outbreak starting on the Pacific coast of Peru, moving down the coast to Chile and then up the Atlantic coast of Argentina. 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

2365-490: The outbreak; however, it could take several months to ramp up mass production. 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

2420-558: 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

2475-500: The rest in group 2. The serotype of IAV is determined by the HA and neuraminidase (NA) proteins expressed on its surface. Neuraminidase has 11 known subtypes; hence, influenza viruses are named according to the combinations of HA and NA proteins expressed (e.g., H1N1 and H5N2 ). A highly pathogenic avian influenza A virus, A( H5N1 ), is known to infect humans as well as its original avian hosts , albeit quite infrequently. It has been reported that single amino acid changes in

2530-557: The risk of infection. 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

2585-522: 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. 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. Some governments have prepared strategic stockpiles of vaccines against

2640-404: The stem/stalk region (orange region in figure at right), far away from the receptor binding site. In 2015 researchers designed an immunogen mimicking the HA stem, specifically the area where the antibody ties to the virus of the antibody CR9114. Rodent and nonhuman primate models given the immunogen produced antibodies that could bind with HAs in many influenza subtypes, including H5N1 . When

2695-414: 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

2750-427: 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. Influenza viruses have a relatively high mutation rate that

2805-475: 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

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2860-556: The virus's H5 hemagglutinin have been found in human patients that "can significantly alter receptor specificity of avian H5N1 viruses, providing them with an ability to bind to receptors optimal for human influenza viruses." This finding seems to explain how an H5N1 virus that normally does not infect humans can mutate and become able to efficiently infect human cells. The hemagglutinin of the H5N1 virus has been associated with its high degree of pathogenicity , apparently due to its ease of conversion to an active form by proteolysis . HA

2915-422: The virus, a process known as endocytosis , and pinches off to form a new membrane-bound compartment within the cell called an endosome . The cell then attempts to begin digesting the contents of the endosome by acidifying its interior and transforming it into a lysosome . Once the pH within the endosome drops to about 5.0 to 6.0, a series of conformational rearrangement occurs to the protein. First, fusion peptide

2970-434: The zoonotic strain, and then authorised and distributed to vaccine manufacturers. 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. In many countries, it is routine to vaccinate poultry against H5N1. In China, the world's biggest poultry producer, there has been

3025-460: Was discovered in 2004 on IAVs isolated from black-headed gulls from Sweden and Norway . H17 was discovered in 2012 in fruit bats . Most recently, H18 was discovered in a Peruvian bat in 2013. The first three hemagglutinins, H1, H2, and H3, are found in influenza viruses that infect humans. By phylogenetic similarity , the HA proteins are divided into 2 groups, with H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18 belonging to group 1 and

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