Preprint: Enhanced Encephalitic Tropism of Bovine H5N1 Compared to the Vietnam H5N1 Isolate in Mice

 

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Although seasonal flu can occasionally cause neurological symptoms (see 2018's Neuroinfluenza: A Review Of Recently Published Studies) it is relatively rare phenomenon, and usually only results in mild, and transient symptoms. 

The exact mechanisms behind these neurological manifestations are largely unknown, as seasonal flu viruses are generally regarded as being non-neurotropic.

Some researchers have posited that neurological symptoms may be due to neuroinflammation induced by the host's immune response. Regardless of the mechanism, we've seen seen evidence that some influenza viruses - particularly novel flu types - can be more neuroaffective than others.

Fifteen years ago H5N1 was considered primarily a respiratory disease, but in 2009 a PNAS study (link below) found that the H5N1 virus was highly neurotropic in lab mice, and in the words of the authors `could initiate CNS disorders of protein aggregation including Parkinson's and Alzheimer's diseases’.

Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration

In early 2014 we saw Alberta Canada Report a Fatal (Imported) H5N1 Infection, in a nurse who'd traveled to China for the holidays and succumbed to the virus shortly after her return.  This was Canada's 1st H5N1 infection, and in the following year we saw a study which described her infection as `neurotropic'. 

CJ ID & MM: Case Study Of A Neurotropic H5N1 Infection - Canada

The patient presented with `. . . pleuritic chest and abdominal pain . . . , this was followed by headache, confusion and, ultimately, respiratory failure, coma and death.' After reviewing MRI imaging and histological analyses, the authors wrote: `These reports suggest the H5N1 virus is becoming more neurologically virulent and adapting to mammals'.

Also in 2015 a Scientific Reports study on the genetics of the H5N1 clade 2.3.2.1c virus - Highly Pathogenic Avian Influenza A(H5N1) Virus Struck Migratory Birds in China in 2015 – the authors warned of its neurotropic effects, and that it could pose a ` . . . significant threat to humans if these viruses develop the ability to bind human-type receptors more effectively.'

While clinical details of many H5Nx human infections go unpublished, in 2022, in Clinical Features of the First Critical Case of Acute Encephalitis Caused by Avian Influenza A (H5N6) Virus, we learned of the severe neurological impact of the virus on a 6 year-old girl in China.

While certainly not the typical presentation of H5Nx infection in humans, the authors wrote:

In view of the fact that the clinical manifestations of this novel H5N6 reassortant are acute encephalitis, rather than previous respiratory symptoms, once these reassortants obtained the ability of human-to-human transmission through reassortment or mutations, it will bring great health threat for human.

 Over the past few years we've seen numerous reports of mammals infected with the 2.3.4.4b subclade of H5Nx experiencing severe, and often fatal, neurological manifestations.  Often, cats and other small mammals were initially suspected being rabid, only to test positive for H5Nx.

Just over a year ago, in Cell: The Neuropathogenesis of HPAI H5Nx Viruses in Mammalian Species Including Humans, we looked at a review that looked at the history, and recent trends, of neuropathogenesis of avian H5 in mammals.

All of which brings us to a preprint, published yesterday by researchers at NIAID (NIH), which compares the neurotropism of a 20 year-old strain of H5N1 collected from Vietnam to a recent isolate of the `bovine' B3.13 genotype of H5N1. 

What they find is the `modern' version of H5N1 is far more neurotropic in lab animals (mice) than its ancestral strains.  

The authors do point out that `Importantly, the findings in this study appear to be mouse specific and likely not representative of what will occur in humans, as thus far there is no evidence of CNS infection in contemporary H5N1 patients.'

But it is further evidence that the H5N1 viruses circulating today are different from those that emerged two decades ago in Southeast Asia, and they continue to evolve in unpredictable ways.   

First the link and abstract from the 38-page preprint, then I'll return with a bit more.

Enhanced encephalitic tropism of bovine H5N1 compared to the Vietnam H5N1 isolate in mice

Kerry Goldin,  Sarah van Tol, Randall C Johnson, Reshma Koolaparambil Mukesh, Shane Gallogly, Jonathan E Schulz, Greg Saturday, Kwe Claude Yinda, Vincent J Munster, Emmie de Wit, Neeltje van Doremalen
doi: https://doi.org/10.1101/2024.11.19.624162

          PDF 

Abstract

In recent years, the landscape of highly pathogenic avian influenza (HPAI) virus infections has shifted, as evidenced by an increase in infections among mammals. This includes the recent circulation of H5N1 in dairy cattle herds in the USA and a rise in associated human cases.

In this study, we investigated differences in tissue tropism of two HPAI H5N1 strains, the isolate A/Vietnam/1203/2004 (VN1203) isolated from a fatal human case in 2004 and the bovine isolate A/Bovine/Ohio/B24osu-342/2024 (Bov342) isolated in 2024, in C57BL/6J mice.

Infection with either HPAI H5N1 isolate was uniformly lethal in mice. However, tissue tropism differed significantly: while VN1203 replication was largely restricted to the respiratory tract, Bov342 successfully replicated in the respiratory tract as well as various regions of the brain.

Bov342-challenged animals exhibited clinical signs consistent with central nervous system (CNS) infection, and infectious virus was detected in brain tissue.

Correspondingly, cytokine profiles in the brain differed significantly between the isolates. Notably, in addition to abundant evidence of CNS infection in Bov342-challenged mice via immunohistochemistry, sporadic intranuclear and intracytoplasmic immunoreactivity was observed in other tissues in the head, including the choroid plexus, retina, and inner ear.

This study demonstrates that while both HPAI H5N1 isolates are uniformly lethal in C57BL/6J mice upon aerosol exposure, significant differences exist in tissue tropism, with Bov342 resulting in respiratory disease as well as increased neurotropism and inflammation in the brain and nasal turbinates compared to VN1203, which predominantly induces respiratory disease.

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While there are still more questions than answers, over the years we've looked at numerous studies (some more compelling than others) linking severe and/or repeated viral infections (including flu) to a variety of neurological diagnoses later in life. 

In 2011 a study by Boise State biology professor Troy Rohn  appeared in PLOS ONE , which unexpectedly found immunohistochemical evidence of prior influenza A infection in the post-mortem brain tissues of 12 Parkinson’s patients they tested.

Immunolocalization of Influenza A Virus and Markers of Inflammation in the Human Parkinson's Disease Brain

Troy T. Rohn*, Lindsey W. Catlin

The following year, in Revisiting The Influenza-Parkinson’s Link, we looked at another study, conducted by the University of British Columbia, that found a linkage between a past history of severe bouts of influenza and the likelihood of developing Parkinson’s disease later in life.

According to their research, a severe bout of influenza doubled a person’s chances of developing the neurological condition (Severe flu increases risk of Parkinson's: UBC research).

None of this is conclusive, but it does raise serious questions. 

As did a study published last year in Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks, which found statistical linkage between viral illnesses and developing neurodegenerative diseases later in life. 

Whenever we talk about long-term sequelae from influenza, the mysterious decade-long epidemic of Encephalitis Lethargica (EL) that followed the 1918 pandemic always comes to mind.

It is estimated that between 1 and 5 million people were affected with severe Parkinson's-like symptoms.  While some scientists have suggested they may have been linked to the pandemic virus, others have pointed to a post-streptococcal immune response, or believe it was an aberrant autoimmune response, and dismiss the link with the 1918 pandemic.

The cause remains a mystery.

Throughout history, there have been reports of similar outbreaks, including febris comatosa which sparked a severe epidemic in London between 1673 and 1675, and in the wake of the 1889–1890 influenza pandemic, a severe wave of somnolent illnesses (nicknamed the "Nona") appeared.

And more recently, we've seen evidence that SARS-CoV-2 infection can produce persistent neurological manifestations (see CMAJ: Even Mild COVID-19 May Have Long-term Brain Impacts).

While the mild presentation of H5N1 in the United States thus far is reassuring, these viruses continue to mutate and evolve, and what we say about them today may not hold true tomorrow. 

Because with influenza viruses, the only constant is change. 

California Dept Public Health: Investigating Presumed Positive H5 Infection In A Child

 

Alameda County - Credit Wikipedia

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While it hasn't appeared on the California PHD website yet, that agency emailed the following statement out shortly before noon EST today.  It described a presumed positive H5 case in a child in Alameda County with mild respiratory symptoms. 

Samples have been sent to the CDC for confirmation. Thus far the CDC has not offered a statement.

Note: The subtype is not mentioned in this statement, but I'm assuming it is H5. 

FOR IMMEDIATE RELEASE 

November 19, 2024 

NR24-037 

Contact: media@cdph.ca.gov 

State Reports Single, Possible Case of Bird Flu Virus in Child with Mild Symptoms

No person-to-person spread of the virus has been detected or is suspected; Risk to public remains low

What You Need to Know: California has identified a possible bird flu case in a child who has had mild respiratory symptoms and is recovering at home. Human infections with bird flu viruses are rare, and no person-to-person spread has been detected in California or the United States. 

SACRAMENTO – California has identified a possible bird flu case in a child in Alameda County who was tested for mild upper respiratory symptoms. The child, who has been treated, is recovering at home. They had no known contact with an infected animal, but public health experts are investigating a possible exposure to wild birds.

The California Department of Public Health (CDPH) is working with local public health officials and the Centers for Disease Control and Prevention (CDC) to investigate the cause of the initial positive test in the child. The positive test showed a low-level detection of the virus, indicating the child was not likely infectious to others. Repeat bird flu testing on the child four days later was negative, and additional testing shows the child was also positive for respiratory viruses that could be the cause of their cold and flu symptoms.

The test specimens are being sent to CDC for confirmatory testing.

Family Members Tested Negative

No person-to-person spread of the virus has been detected or is suspected. Due to mild respiratory symptoms, all close family members of the child were tested – and all are negative for bird flu and not suspected of having the virus at all. Family members were also confirmed to have the same, more common respiratory viruses as the child. They are also being treated with preventive medication.

Additional Contacts Involved, No Indication of Larger Outbreak 

Out of an abundance of caution, other individuals who had contact with the child are being notified and offered preventive treatment and testing. Public health officials are aware that the child attended daycare with mild symptoms before the child’s test was reported as a possible bird flu infection. Local public health officials have reached out to potentially exposed caregivers and families to conduct health checks for symptoms and offer connections to preventive treatment and testing if they develop symptoms.

“It’s natural for people to be concerned, and we want to reinforce for parents, caregivers and families that based on the information and data we have, we don’t think the child was infectious – and no human-to-human spread of bird flu has been documented in any country for more than 15 years,” said CDPH Director and State Public Health Officer Dr. Tomás Aragón.

Bird Flu in Humans is Rare

Human infections with bird flu viruses are rare, and no person-to-person spread has been detected in California or the United States. In the rare cases where bird flu has spread from one person to another, it has never spread beyond a few close contacts.

Limited and sporadic human infections with bird flu where there is not clear route of exposure or infection are expected and have occurred in the past and during the outbreak public health officials have been monitoring since 2022. Regardless, public health surveillance and investigations of such cases will continue at the local, state and federal levels to monitor for any concerning changes.

People Working with Infected Animals are at Higher Risk 

People who have contact with infected dairy cows, poultry, or wildlife have a greater chance of getting bird flu, which can happen if the virus gets into a person’s eyes, nose, mouth, or is inhaled. As a general precaution, whenever possible people should avoid direct contact with sick or dead wild birds, poultry, and other animals and observe them only from a distance.

Since early October, California has reported 26 confirmed human cases of bird flu, all following direct contact with infected dairy cows. To date, all have reported mild symptoms (primarily eye infections), and none have been hospitalized. Because bird flu viruses can change and gain the ability to spread more easily between people, public health officials have provided preventive measures and are monitoring animal and human infections carefully.

CDPH has been closely monitoring the bird flu situation in both animals and humans since the state's first detection in poultry in 2022. To protect public health, and especially workers who may be exposed to infected animals, CDPH encourages those who work with infected dairy cows, raw milk, or infected poultry to use protective gear. Individuals who have symptoms or a significant exposure (such as raw milk splashing into the eye) should get tested quickly and treatment. In humans, bird flu symptoms include eye redness or discharge, cough, sore throat, runny or stuffy nose, diarrhea, vomiting, muscle or body aches, headaches, fatigue, trouble breathing, and fever.

Public health experts also encourage farm workers to get a flu shot this year. While a seasonal flu shot doesn’t stop bird flu, it protects against severe illness from seasonal flu and reduces the chance of human and bird flu viruses mixing and turning into new viruses that can spread more easily or be more severe.

Pasteurized Milk Products are Safe to Consume

Pasteurized milk and dairy products are safe to consume.  Drinking raw milk or eating raw milk products could be dangerous. Reduce your risk by choosing pasteurized milk and dairy foods like cheese and yogurt. Pasteurization, the process of heating milk to specific temperatures for certain times, inactivates the bird flu virus and harmful germs that can be found in raw milk.

For the latest information on the national bird flu response, see CDC's Bird Flu Response Update.

Hawaii: Duck Sanctuary Identified As Infected With HPAI H5N1

Hawaii lies beneath the West Pacific Flyway

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On Friday the Hawaii Dept of Agriculture Reported the 1st Detection of HPAI H5 in the state in what they described as `. . . a backyard flock of various birds in Central O‘ahu'.  Yesterday the USDA released the following statement:

USDA Confirms Highly Pathogenic Avian Influenza in Backyard Non-Poultry Flock in Hawaii

WASHINGTON, [November 18, 2024] – The United States Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service (APHIS) has confirmed the presence of highly pathogenic avian influenza (HPAI) in a non-commercial backyard flock (non-poultry) in Honolulu County, Hawaii. This is the first case of HPAI in domestic birds in Hawaii during this outbreak, which began in February 2022.

Samples from the flock were tested at the Hawaii State Laboratories Division, part of the National Animal Health Laboratory Network, and confirmed at the APHIS National Veterinary Services Laboratories in Ames, Iowa.

APHIS is working closely with state animal health officials in Hawaii on a joint incident response and will provide appropriate support as requested.

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We get further details from KITV Island News 4 in a report published overnight, which interviews Susan Wilkinson - the owner/operator of the duck rescue service Susies Duck -who reports the first ducks began dying on Nov. 5th, and that initially poisoning was suspected. 

Wahiawa duck sanctuary loses birds to first confirmed avian flu cases in Hawaii

The spread of HPAI H5 to local wildlife in Hawaii is another testament to the aggressiveness of clade 2.3.4.4b of HPAI H5, and is why Australia - despite being the only continent free of the virus - is increasingly concerned (see Australia : Biodiversity Council Webinar on HPAI H5 Avian Flu Threat) that they may be next. 

USDA Adds 14 More H5 Outbreaks In Poultry

 

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Much like we're seeing in British Columbia, and in Europe, reports of HPAI outbreaks in commercial poultry operations have increased steadily since the summer (see chart below), as migratory birds once again begin their southbound journeys. 

(Note: November numbers only thru the 15th)

The latest update adds 14 outbreaks since last week, with California being the hardest hit with 10. Utah, Arizona, Oregon, and Colorado each reported one new outbreak.  The number of birds affected/culled during the month of November has increased by roughly 750,000 since last week's update. 

Since `bird flu season' typically starts in October or November, and runs through the spring, poultry interests could have a long and challenging winter ahead.

CDC HAN #00519 - First Case of Clade I Mpox Diagnosed in the United States

 

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Over the weekend California announced the first known detection of clade Ib Mpox in the United States, making the U.S. the 6th non-African nation to report an imported case since this emerging virus was declared a PHEIC by the WHO in August. 

This is not an unexpected development, as nearly two months ago the CDC released HAN #00516 - Prevention Strategies for Mpox, in response to the PHEIC declaration. 

While geared primarily for clinicians and public health officials, late yesterday the CDC published an updated HAN (excerpts below).  I've only reproduced the summary, so follow the link to read it in its entirety. 

First Case of Clade I Mpox Diagnosed in the United States

 

Distributed via the CDC Health Alert Network
November 18, 2024, 5:30 PM ET
CDCHAN-00519

Summary

The Centers for Disease Control and Prevention (CDC) is issuing this Health Alert Network (HAN) Health Advisory to provide information about the first case of clade I mpox diagnosed in the United States and recommendations to clinicians about preventing, diagnosing, treating, and reporting mpox cases. On November 15, 2024, the California Department of Public Health (CDPH) confirmed the first reported case of clade I mpox in the United States.

This individual had recently traveled to areas experiencing clade I monkeypox virus (MPXV) transmission and sought medical care for mpox symptoms in the United States. Consistent with other recent clade I mpox cases, the patient has relatively mild illness and is recovering. CDC and the local and state health departments are investigating potential contacts; no additional cases in the United States have been detected as of November 18, 2024. The risk of clade I mpox to the public in the United States remains low.

Since March 2024, CDC has been working with local, tribal, state, and territorial public health authorities to prepare for potential cases of clade I mpox in the United States by enhancing surveillance, detection, and reporting capacities of existing domestic public health systems and structures. This reported case demonstrates that these systems are working as intended. There is no change to CDC clinical or travel guidance on clade I mpox since HAN Health Update 516.

Clinicians should be aware of mpox symptoms, ask patients with comparable signs and symptoms about recent travel history and other risk factors for mpox, and consider MPXV testing. Given the widespread outbreaks in Central and Eastern Africa, additional travel-associated cases may be reported in the future in the United States. Suspected and confirmed cases of clade I mpox should be reported to local, territorial, and state public health authorities as soon as possible. State, local, and territorial public health authorities should report cases to CDC promptly. This includes orthopoxvirus generic (i.e., non-variola orthopoxvirus) positive and clade II negative test results from a patient with travel history to country affected by clade I mpox. CDC recommends vaccination to people who are eligible for mpox vaccine, including those who may have a recent MPXV exposure.

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CDC H5 Bird Flu Update (Nov 18th)

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It's been a busy week, with HPAI reported for the first time in Hawaii, the first human infection in Oregon, another huge jump in infected dairy herds in California, and the addition of 7 human cases to the CDC's list.

Late yesterday the CDC published a lengthy update on HPAI H5, including a summary of the latest laboratory findings (see below).  

Of particular interest, they report finding the NA-S247N mutation in 3 poultry workers from Washington state, which has been previously linked to modestly reduced susceptibility to the antiviral oseltamivir (aka Tamiflu).  

Regular readers will recognize this as one of two mutations (I223V/S247N) which have increasingly turned up in A(H1N1)pdm09 viruses in recent yeas, which have sparked a number of studies, including:

EID Journal: Multicountry Spread of Influenza A(H1N1)pdm09 Viruses with Reduced Oseltamivir Inhibition, May 2023–February 2024

The Lancet Correspondence: Global Emergence of Neuraminidase Inhibitor-Resistant Influenza A(H1N1)pdm09 Viruses with I223V and S247N Mutations

Compared to the more common H275Y mutation- which can produce a 900-fold reduction in oseltamivir effectiveness - the impact of the NA-S247N mutation alone is relatively small, but in combination with other known resistance mutations, it can have a much more serious impact. 

Due to its length, I've only posted some excerpts, so follow the link to read it in its entirety. 

Situation Update

November 18, 2024 – CDC continues to respond to the public health challenge posed by a multistate outbreak of avian influenza A(H5N1) virus, or "H5N1 bird flu," in dairy cows, poultry and other animals in the United States. CDC is working in collaboration with the U.S. Department of Agriculture (USDA), the Food and Drug Administration (FDA), Administration for Strategic Preparedness and Response (ASPR), state public health and animal health officials, and other partners using a One Health approach.

Since April 2024, CDC, working with state public health departments, has confirmed avian influenza A(H5) virus infections in 52 people in the United States. Twenty-one of these cases were associated with exposure to avian influenza A(H5N1) virus -infected poultry and 30 were associated with exposure to infected dairy cows [A][B]. The source of the exposure in one case, which was reported by Missouri on September 6, could not be determined.

The 52 cases include 26 cases among dairy farm workers in California, five of which were confirmed by CDC on November 13 and 14, and one additional case in a poultry farm worker in Oregon. This is the first human case of H5N1 bird flu reported in Oregon. All recent cases have occurred in workers on affected farms. All available data so far suggest sporadic instances of animal-to-human spread. These farm workers all described mild symptoms, many with eye redness or discharge (conjunctivitis). Some workers who tested positive in Washington reported some mild upper respiratory symptoms. None of the workers were hospitalized.

CDC is aware of the human case of H5N1 bird flu reported in Canada and is in communication with the Public Health Agency of Canada (PHAC), which has confirmed that the case was caused by an H5N1 virus that is different than those causing outbreaks in dairy cows and other animals in the United States. More information about the case in Canada and ongoing epidemiological investigation is available in a statement from PHAC. Updated case counts for the United States, including by state and source of exposure, are recorded in a table on CDC's website. To date, person-to-person spread of H5 bird flu has not been identified in the United States. CDC believes the immediate risk to the general public from H5 bird flu remains low, but people with exposure to infected animals are at higher risk of infection.

On the animal health side, since March 2024, USDA has confirmed infected cattle in 505 dairy herds in 15 U.S. states. The number of affected herds continues to grow nationally, with almost all new infections identified in herds in California. USDA reports that, since April 2024, there have been H5 detections in 50 commercial poultry flocks and 38 backyard flocks, for a total of 25.61 million birds affected.

Among other activities reported in previous spotlights and ongoing, recent highlights of CDC's response to this include:

Laboratory Update

To date, CDC has confirmed 11 human cases of H5 bird flu in poultry farm workers in Washington. Genetic sequencing of influenza virus from clinical specimens from these cases showed no changes in the hemagglutinin (HA) associated with increased infectivity or transmissibility among people. However, in influenza specimens from three of these H5 cases, CDC identified a change, NA-S247N, that may slightly reduce susceptibility to the neuraminidase inhibitor oseltamivir in laboratory tests.

NA-S247N has been detected sporadically in seasonal influenza viruses and has rarely been found in A(H5N1) viruses. Historically, two H5N1 viruses with the NA-S247N change have been tested for susceptibility to oseltamivir: an A(H5N1) virus collected from a chicken in Laos in 2008 (A/chicken/Laos/13/2008; PMID: 20016036) and a clade 2.3.4.4b H5N1 virus collected from a dolphin in Florida in 2022 (A/dolphin/Florida/2022; PMID: 37494978 and PMID: 38637646). These laboratory studies found either mildly reduced or reduced inhibition by oseltamivir, with results well below what has been reported for oseltamivir resistance of other influenza viruses.

It is important to note that this change is not spreading in H5 viruses. Additionally, this change is not expected to have an impact on the ability of influenza viruses to replicate or spread more easily. While NA-S247N may slightly reduce antiviral susceptibility in laboratory testing, that is NOT the same as resistance. Results of laboratory studies demonstrating mildly reduced or reduced inhibition by oseltamivir may not indicate reduced effectiveness of antiviral treatment of a patient with H5N1 virus infection. NA-S247N is unlikely to have a meaningful impact on the clinical benefit of oseltamivir, which is the currently recommended antiviral for treatment for H5 bird flu. CDC continues to recommend oseltamivir for treatment of patients with H5N1 and for post-exposure prophylaxis of close contacts of confirmed H5N1 patients and those with higher risk exposures to animals infected with H5N1 viruses.

Due to low viral RNA concentrations in clinical specimens from these three cases and unsuccessful attempts to isolate virus in culture, multiple sequencing attempts were required to generate data sufficient to meet CDC quality thresholds for posting of partial NA sequences.

CDC also identified a different change in the polymerase acidic (PA) protein of a virus collected from a recently confirmed human case of H5N1 bird flu in California (A/California/150/2024). This change, PA-I38M, is associated with decreased susceptibility to the influenza antiviral medication baloxavir marboxil and has been sporadically detected in a small number of avian influenza viruses.

Baloxavir is not currently recommended for treatment or post-exposure prophylaxis of H5N1 virus infection. As indicated above, oseltamivir is the recommended antiviral treatment for H5N1 bird flu. No H5N1 patients in the U.S. have received baloxavir treatment for H5N1. There are no available data on baloxavir treatment of H5N1 patients worldwide. And the optimal dosing and duration of baloxavir for treatment or post-exposure prophylaxis of H5N1 virus infection in humans are unknown.

Influenza genetic sequence data from these and other recently confirmed cases of H5 bird flu in humans have been posted in GISAID and GenBank. Additional laboratory investigations are ongoing and planned at CDC to better understand the implications of these changes in the context of the currently spreading H5 viruses. In summary, although these particular changes have not been detected widely and are not spreading among dairy cattle or birds, these findings underscore the importance of ongoing surveillance and testing to analyze H5 viruses for any changes that could potentially impact their susceptibility to flu antiviral medications.

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By itself, NA-S247N is unlikely to cause antiviral treatment failures, but in concert with other specific mutations (e.g. H275Y, I223V, etc.) it could become more of a factor.  

Continued monitoring for this, and other resistance mutations, remains critically important. 

For more on antiviral resistance in HPAI H5 viruses, you may wish to revisit:

Antiviral Research: Antiviral susceptibility of clade 2.3.4.4b HPAI H5N1 Viruses Isolated From Birds & Mammals in the United States, 2022