[url]https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2023.28.7.2300085[/url] or https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2023.28.7.2300085 - https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2023.28.7.2300085  

Letter to the editor: Highly pathogenic influenza A(H5N1) viruses in farmed mink outbreak contain a disrupted second sialic acid binding site in neuraminidase, similar to human influenza A viruses.

To the editor: We read with much interest the article by Agüero et al. [ https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2023.28.7.2300085#r1" style="box-sizing: border-box; background-color: transparent; color: rgb(200, 22, 68); text-decoration: none; outline: none; - 1 ], reporting a highly pathogenic influenza A(H5N1) virus outbreak in farmed minks in northwest Spain in October 2022. Genetic characterisation of the viruses showed that they resembled the A/gull/France/22P015977/2022-like genotype within clade 2.3.4.4b. Considering efficient airborne transmission of human viruses among ferrets (reviewed in [ https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2023.28.7.2300085#r2" style="box-sizing: border-box; background-color: transparent; color: rgb(200, 22, 68); text-decoration: none; outline: none; - 2 ]), the concern is raised that adaptation of avian viruses to mink may provide a first step towards potential human-to-human transmission.

The authors focused on the amino acid substitution T271A in polymerase subunit PB2, which is known to enhance polymerase activity of influenza A virus (IAV) in mammalian host cells similar to the seminal PB2 E627K mutation. They also show that the only substitution in haemagglutinin (HA) in comparison with closely related avian strains is I390M. This mutation is in the stem region of HA and might be associated with altered HA stability and transmissibility but as of yet has no known biological relevance. Mutations previously associated with increased human-type alpha 2,6-linked sialic acid receptor binding and/or airborne transmission in ferrets [ https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2023.28.7.2300085#r2" style="box-sizing: border-box; background-color: transparent; color: rgb(200, 22, 68); text-decoration: none; outline: none; - 2 ] were still limited to the lack of a glycosylation site at position 158. Substitutions F74S and V163L in neuraminidase (NA), which are located at sites of unknown functional importance, also distinguished the viruses in minks from closely related avian viruses. Remarkably, all four viruses from minks contained a methionine at position 396 located in the second sialic acid binding site (2SBS) in NA (for a review on the 2SBS, see [ https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2023.28.7.2300085#r3" style="box-sizing: border-box; background-color: transparent; color: rgb(200, 22, 68); text-decoration: none; outline: none; - 3 ]). Influenza A(H5N1) viruses predominantly carry an isoleucine at this position, which is critical for efficient binding of sialic acid to the 2SBS [ https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2023.28.7.2300085#r3" style="box-sizing: border-box; background-color: transparent; color: rgb(200, 22, 68); text-decoration: none; outline: none; - 3 , https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2023.28.7.2300085#r4" style="box-sizing: border-box; background-color: transparent; color: rgb(200, 22, 68); text-decoration: none; outline: none; - 4 ].

DJ...I am NOT an expert but H5N1 in investigated Spanish minks showed mutations that "brings" H5N1 in minks closer to the way A-type flu spreads...

That is my (again non expert) view on it...

DJ, With more H5N1 in more birds in more countries over a much longer time it only makes sense to expect more mammals showing H5N1 infection. 

So far most of the spread in mammals was bird-mammal. A carnivore did eat an infected bird...contact with bird droppings-with H5N1 virus- also meant further spread. 

From "statistics" point of view it was only expected to see more mammals showing H5N1...

From "statistics" point of view further spread in mammals should be expected...

Spanish minks showed "mammal-to-mammal/mink-to-mink" spread...the above study points to further mutations in that process... Another study did find H5N1 in carnivore brains...even when the respitory system still may be not showing it in limited cases...

DJ-In my view these studies may only show the tip of a H5N1 spread "mountain"...ferrets, rats, mice, foxes, otters etc. cat-like animals may show H5N1 could be much wider spread...we miss a lot of cases...Waste water sampling may detect H5N1 from rats in urban areas (if there is H5N1 in those rats etc.). 

If there is not yet already "limited mammal-to-mammal" H5N1 spread in wild animals it is only a matter of time...

So...Lots of indications pointing towards a growing risk of H5N1 also for humans...

Another discussion could be on the danger of H5N1 for humans...(there are "sub groups" of H5N1)...Case Fatality Ratio so far is believed to be high...but we may have missed mild/a symptomatic human H5N1 cases...

Also so far H5N1 human-to-human spread in the last decades was "very limited/isolated"...H5N1 still could evolve to "very hard spread" outside birds...with mink-likes, maybe cat-like animals more at risk ? 

DJ You have the disease; H5N1

spread...via birds, mammals (rats, mice spreading the virus ?) H5N1 in dry urine/droppings aerosol spread ???

ending up in a host...

The major problem starts when H5N1 virus becomes able to act like flu/cold virusses...It is not yet on that point...but it may be moving in that direction...

For humans so far it is still limited cases...some animals may be in the "cluster phase" ...the "boom" H5N1 pandemic phase could be around the corner...but we should expect more cases then...

-------

Another discussion is did CoViD damage human immunity protection. My non-expert view; YES...but looking at the almost over flu-season (most H3N2 as far as I followed it...) decrease of human-species immunity may NOT mean less protection against flu...

DJ, I find it sad to see even wikipedia did see some information "made fit to political causes"...Politics should not be a poison destroying democracy....

[url]https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1[/url] or https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1 - https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1 ;

Overview[ https://en.wikipedia.org/w/index.php?title=Influenza_A_virus_subtype_H5N1&action=edit§ion=1" style="text-decoration: none; color: rgb(51, 102, 204); background: none; white-space: nowrap;" title="Edit section: Overview - edit ]

HPAI A(H5N1) is considered an avian disease, although there is some evidence of limited human-to-human transmission of the virus. ^{https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1#cite_note-10" style="text-decoration: none; color: rgb(51, 102, 204); background: none; - [10]} A risk factor for contracting the virus is handling of infected poultry, but transmission of the virus from infected birds to humans has been characterized as inefficient. ^{https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1#cite_note-11" style="text-decoration: none; color: rgb(51, 102, 204); background: none; - [11]} Still, around 60% of humans known to have been infected with the Asian strain of HPAI A(H5N1) have died from it, and H5N1 may  https://en.wikipedia.org/wiki/Mutation" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Mutation - mutate or  https://en.wikipedia.org/wiki/Reassortment" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Reassortment - reassort into a strain capable of efficient human-to-human transmission. In 2003, world-renowned virologist  https://en.wikipedia.org/wiki/Robert_G._Webster" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Robert G. Webster - Robert G. Webster published an article titled "The world is teetering on the edge of a pandemic that could kill a large fraction of the human population" in  https://en.wikipedia.org/wiki/American_Scientist" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="American Scientist - American Scientist . He called for adequate resources to fight what he sees as a major world threat to possibly billions of lives. ^{https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1#cite_note-webster-12" style="text-decoration: none; color: rgb(51, 102, 204); background: none; - [12]} On September 29, 2005,  https://en.wikipedia.org/wiki/David_Nabarro" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="David Nabarro - David Nabarro , the newly appointed Senior United Nations System Coordinator for Avian and Human Influenza, warned the world that an outbreak of avian influenza could kill anywhere between 5 million and 150 million people. ^{https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1#cite_note-UN-13" style="text-decoration: none; color: rgb(51, 102, 204); background: none; - [13]} Experts have identified key events (creating new  https://en.wikipedia.org/wiki/Clade" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Clade - clades , infecting new species, spreading to new areas) marking the progression of an avian flu virus towards becoming pandemic, and many of those key events have occurred more rapidly than expected.^{[ https://en.wikipedia.org/wiki/Wikipedia:Citation_needed" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Wikipedia:Citation needed - Due to the high lethality and  https://en.wikipedia.org/wiki/Virulence" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Virulence - virulence of HPAI A(H5N1), its endemic presence, its increasingly large  https://en.wikipedia.org/wiki/Host_(biology)" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Host (biology) - host reservoir, and its significant ongoing mutations, in 2006, the H5N1 virus has been regarded to be the world's largest pandemic threat, and billions of dollars are being spent researching H5N1 and preparing for a potential  https://en.wikipedia.org/wiki/Influenza_pandemic" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Influenza pandemic - influenza pandemic . https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1#cite_note-Rosenthal-14" style="text-decoration: none; color: rgb(51, 102, 204); background: none; - [14] At least 12 companies and 17 governments are developing prepandemic  https://en.wikipedia.org/wiki/Influenza_vaccine" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Influenza vaccine - influenza vaccines in 28 different clinical trials that, if successful, could turn a deadly pandemic infection into a nondeadly one. Full-scale production of a  https://en.wikipedia.org/wiki/Vaccine" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Vaccine - vaccine that could prevent any illness at all from the strain would require at least three months after the virus's emergence to begin, but it is hoped that vaccine production could increase until one billion doses were produced by one year after the initial identification of the virus. https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1#cite_note-15" style="text-decoration: none; color: rgb(51, 102, 204); background: none; - [15]}

H5N1 may cause more than one  https://en.wikipedia.org/wiki/Influenza_pandemic" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Influenza pandemic - influenza pandemic , as it is expected to continue mutating in birds regardless of whether humans develop  https://en.wikipedia.org/wiki/Herd_immunity" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Herd immunity - herd immunity to a future pandemic strain. ^{https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1#cite_note-content.nejm.org-16" style="text-decoration: none; color: rgb(51, 102, 204); background: none; - [16]} Influenza pandemics from its genetic offspring may include  https://en.wikipedia.org/wiki/Influenzavirus_A" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Influenzavirus A - influenza A virus subtypes other than H5N1. ^{https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1#cite_note-17" style="text-decoration: none; color: rgb(51, 102, 204); background: none; - [17]} While genetic analysis of the H5N1 virus shows that influenza pandemics from its genetic offspring can easily be far more lethal than the  https://en.wikipedia.org/wiki/Spanish_flu" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Spanish flu - Spanish flu pandemic, ^{https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1#cite_note-preparation-18" style="text-decoration: none; color: rgb(51, 102, 204); background: none; - [18]} planning for a future influenza pandemic is based on what can be done and there is no higher  https://en.wikipedia.org/wiki/Pandemic_Severity_Index" style="text-decoration: none; color: rgb(51, 102, 204); background: none;" title="Pandemic Severity Index - Pandemic Severity Index level than a Category 5 pandemic which, roughly speaking, is any pandemic as bad as the Spanish flu or worse; and for which all intervention measures are to be used. ^{https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1#cite_note-19" style="text-decoration: none; color: rgb(51, 102, 204); background: none; - [19]}

DJ, There are limits to what humans-even with a much larger budget- can do....

Non Pharma Intervention rules limiting CoViD spread also would limit H5N1...

Less air travel, less meat consumption does decrease people spreading the virus over the globe, number of animals catching a virus...

We HAVE TO CHANGE the way we live...we are destroying our planet...with that killing ourselves...