UKHSA Reports A Case of Mpox Clade Ib Without Recent Travel or Known Exposure

 

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Three weeks ago the UKHSA announced that while  - `Mpox remains a serious infection for some individuals and remains a World Health Organization (WHO) public health emergency of international concern (PHEIC)' - the  Clade I Mpox No Longer Meets the Criteria of a High Consequence Infectious Disease (HCID) in the UK.

Today the UK announced their 11th confirmed mpox Clade Ib case (see below).

What sets this case apart is - all previously reported cases have had recent travel to endemic countries, or known exposure to someone who has - while this case has neither.   

Last updated 7 April 2025

Latest update

The UK Health Security Agency (UKHSA) has detected a single confirmed human case of Clade Ib mpox where the case had no reported travel history and no reported link with previously confirmed cases in the UK.

More work is ongoing to determine where the individual, who is resident in the North East of England, may have caught the infection.

The individual was diagnosed in March, all contacts have been followed up and no further cases identified. The risk to the UK population remains low. Clade Ia and Ib mpox are no longer classified as a high consequence infectious disease (HCID).

UKHSA has robust mechanisms in place to investigate suspected cases of mpox of all clade types, irrespective of travel history.

All previous cases in the UK to date have either travelled to an affected country or have a link to someone that has.

Common symptoms of mpox include a skin rash or pus-filled lesions which can last 2 to 4 weeks. It can also cause fever, headaches, muscle aches, back pain, low energy and swollen lymph nodes.

Further information about symptoms is available on the NHS website.

UKHSA Mpox Incident Director Dr Gillian Armstrong said:

The risk to the UK population from mpox remains low.

The majority of people who have presented with symptoms report close physical contact, including massages, or sex prior to developing symptoms.

Regardless of whether you have travelled or not, it is important to remain alert to the risks. Anyone who thinks they may have mpox should contact NHS 111 for advice on what to do.

While mpox infection is mild for many, it can be severe for some and UKHSA is committed to preventing its spread within the UK.

Whether this turns out to be  a one-off event, or an early indication of community transmission, remains to be seen.   

Stay tuned.

California: Mono County Reports 3rd Hantavirus Death

 

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A little over a month ago award winning actor Gene Hackman and his wife Betsy Arakawa were found dead in their Santa Fe home, and it was determined that his wife died from a rare Hantavirus infection.  Over the weekend, the Mono County (California) Health Department announced their 3rd recent death from the virus. 

Hantavirus is a collective term for a group of viruses in the Bunyaviridae family – hosted by various types of rodents - that vary in distribution, symptomology, and severity around the world.

Scientists have identified dozens of viruses within the genus Hantavirus (named after the Hantaan River of Korea) from all around the world, with mortality that varies from 1%-2% for some varieties (i.e. Seoul Virus, Puumala Virus) to more than 30% for the North American Sin Nombre and South American Andes Virus.

While relatively rare, every year the U.S. reports between 10 and 50 Hantavirus Pulmonary Syndrome (HPS) cases, of which, roughly 35% prove fatal. Nearly 900 cases have been reported across 40 states (see map below), with >90% of all cases reported west of the Mississippi River.

The following press release was posed on the Mono County Facebook page.  I'll have more on past outbreaks and prevention when you return.

MONO COUNTY HEALTH AND HUMAN SERVICES

Public Health Division

FOR IMMEDIATE RELEASE

Third Hantavirus-Related Death Confirmed in Mono County

MONO COUNTY, Calif. (April 3, 2025) - Mono County Public Health has confirmed a third death due to Hantavirus in the Town of Mammoth Lakes. Hantavirus is a serious and often fatal illness which people can get through contact with infected deer mouse droppings, urine, or saliva. Deer mice are widespread in the Eastern Sierra region.

"A third case of Hantavirus Pulmonary Syndrome (HPS), each of which has been fatal, is tragic and alarming, said Dr, Tom Boo, Mono County Public Health Officer.

"We don't have a clear sense of where this young adult may have contracted the virus. The home had no evidence of mouse activity We observed some mice in the workplace, which is not unusual for indoor spaces this time of year in Mammoth Lakes. We haven't identified any other activities in the weeks before illness that would have increased this person's exposure to mice or their droppings.

We 've been aware of this suspected case for some weeks, but it has taken time to obtain testing. The occurrence of three cases in a short period has me worried, especially this early in the year. Historically, we tend to see Hantavirus cases later in the spring and in the summer. We've now gone about a month without any additional suspect cases, but remain concerned about the increase in activity.

We believe that deer mouse numbers are high this year in Mammoth (and probably elsewhere in the Eastem Sierra). An increase in indoor mice elevates the risk of Hantavirus exposure. Therefore, it is crucial to take precautions and follow the prevention steps outlined below I want to emphasize that as far as we know, none of these deceased individuals engaged in activities typically associated with exposure, such as cleaning out poorly ventilated indoor areas or outbuildings with a lot of mouse waste. Instead, these folks may have been exposed during normal daily activities, either in the home or the workplace. Many of us encounter deer mice in our daily lives and there some risk. We should pay attention to the presence of mice and be careful around their waste "

Ongoing Investigation

Each Hantavirus case is investigated by local and state public health officials. Each of our recent cases lived and worked in Mammoth Lakes and experienced illness beginning in February_ When a person has died, we can only talk to people who knew them about the places they were and things that they did in the weeks before they got sick We know that one person had numerous mice in their home.

No evidence of mice was found in the other two homes. In all three cases there was some evidence of mice in places they had worked, but no major infestations were found. Investigators did note that one person did some vacuuming in one or more areas where investigators later found mouse droppings. Vacuuming can aerosolize the virus from mouse waste spreading the virus through the air and lead to infection.

Mono County has now recorded 27 cases since it was first reponed here in 1993, the most in the State of California. Twenty-one of these infections affected County residents, and six occurred in visitors who were infected in Mono_ Hantavirus more commonly occurs in the late spring or summer, so three cases this early in the year is strikingly unusual,

(Continue . . )

Over the summer of 2012 we followed a months-long outbreak among visitors to California's Yosemite National Park (see here, here, and here). In November of that year, in MMWR: Yosemite Hantavirus, the CDC's investigation cited 10 cases and 3 deaths linked to that outbreak. 

Ages ranged from 12 years to 56 years; four were female. Nine patients had typical symptoms of HPS, and one lacked respiratory symptoms; three died.

Most Hantavirus cases are sporadic, but occasionally we see clusters.  Eight years ago, Washington State Reported their 5th Hantavirus Case Of 2017.  Exposure is often linked to cleaning out sheds and garages in the late spring and summer, so the cluster in February in Mono County is a bit of an outlier. 

The CDC has a 20-page PDF guide on reducing exposure risks. 

While far less deadly, in 2017 we followed a multi-state outbreak of a milder `Seoul' Hantavirus linked to the sale and distribution of pet rats (see  CDC HAN Advisory: Seoul Virus Outbreak Associated with Home-based, Rat-breeding Facilities in Wisconsin and Illinois).

A year later, the CDC's MMWR reported,

In January 2017, CDC confirmed recent, acute Seoul virus infection in both patients. An investigation was conducted to identify additional human and rat infections and prevent further transmission. Ultimately, the investigation identified 31 facilities in 11 states with human and/or rat Seoul virus infections; six facilities also reported exchanging rats with Canadian ratteries.

Testing of serum samples from 183 persons in the United States and Canada identified 24 (13.1%) with Seoul virus antibodies; three (12.5%) were hospitalized and no deaths occurred. This investigation, including cases described in a previously published report from Tennessee (1), identified the first known transmission of Seoul virus from pet rats to humans in the United States and Canada. Pet rat owners should practice safe rodent handling to prevent Seoul virus infection (2).

The list of rodent-borne zoonotic diseases is long, and - based on recent reports with H5N1 (see here, here, and here) coronaviruses (see here and here) and Hepatitis (see here)  - only seems to be getting longer. 

Texas DHSH Announces 2nd Child Death From Measles In 2025

 

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Over the weekend the Texas DSHS announced a second unvaccinated child has now succumbed to measles infection (see press release below), in an outbreak which is rapidly approaching 500 cases (n=481).

Last month, in neighboring New Mexico, an adult (> 40) reportedly died while infected with measles, although the cause of death remains under investigation. So far, New Mexico has reported 54 cases. 

According to the CDC - prior to 2025 - the last known measles related death in the United States occurred in 2015. While measles deaths are rare (1-3 per 1,000 unvaccinated cases), serious complications - including, pneumonia, eyesight and hearing damage - are more common.

First, the DSHS announcement, after which I'll have a bit more.

Texas announces second death in measles outbreak

News Release
April 6, 2025

The Texas Department of State Health Services is reporting the second measles death of a Texas resident in the ongoing outbreak centered in the state's South Plains region. The school-aged child who tested positive for measles was hospitalized in Lubbock and passed away on Thursday from what the child’s doctors described as measles pulmonary failure. The child was not vaccinated and had no reported underlying conditions.

As of April 4, 481 cases of measles have been confirmed in the outbreak since late January. Most of the cases are in children. Fifty-six people have been hospitalized over the course of the outbreak.

Measles is a highly contagious respiratory illness, which can cause life-threatening illness to anyone who is not protected against the virus. During a measles outbreak, about one in five children who get sick will need hospital care and one in 20 will develop pneumonia. Rarely, measles can lead to swelling of the brain and death. It can also cause pregnancy complications, such as premature birth and babies with low birth weight.

DSHS’s interactive dashboard and additional information about the outbreak can be found on the News & Alerts page that is updated on Tuesdays and Fridays.

Health care providers can find recommendations for infection control and diagnostic testing in DSHS health alerts. Providers should report any suspected cases to their local health department immediately, preferably while the patient is still with the provider.

Background:

Measles can be transmitted by direct contact with infectious droplets or by airborne spread when an infected person breathes, coughs, or sneezes. People who are infected will begin to have symptoms within a week or two after being exposed. Early symptoms include high fever, cough, runny nose, and red, watery eyes. A few days later, the telltale rash breaks out as flat, red spots on the face and then spreads down the neck and trunk to the rest of the body. A person is contagious about four days before the rash appears to four days after. People who could have measles should stay home during that period.

People who think they have measles or may have been exposed to measles should isolate themselves and call their health care provider before arriving to be tested. It is important to let the provider know that the patient may have measles and to get instructions on how to come to the office for diagnosis without exposing other people to the virus.

The best way to prevent getting sick is to be immunized with two doses of a measles-containing vaccine, which is primarily administered as the combination measles-mumps-rubella or MMR vaccine. Two doses of the MMR vaccine prevent more than 97 percent of measles infections. A small number of vaccinated people can occasionally develop measles. In these cases, the symptoms are generally milder, and they are less likely to spread the disease to other people. DSHS and the Centers for Disease Control and Prevention recommend children receive one dose of MMR at 12 to 15 months of age and another at 4 to 6 years. Children too young to be vaccinated are more likely to have severe complications if they get infected with the measles virus. However, each MMR dose lowers the risk of infection and the severity of illness if infected.

According to the CDC's latest update (Apr 3rd), more than 600 cases have been reported in 2025 across 22 jurisdictions: Alaska, California, Colorado, Florida, Georgia, Kansas, Kentucky, Maryland, Michigan, Minnesota, New Jersey, New Mexico, New York City, New York State, Ohio, Oklahoma, Pennsylvania, Rhode Island, Tennessee, Texas, Vermont, and Washington.

Prior to the introduction of a measles vaccine in the early 1960s, the United States saw hundreds of thousands of cases a year, and thousands of deaths (see chart below). The chart below (source: CDC) shows the remarkable effectiveness of that vaccination campaign.

Over the past 20 years we've seen a decline in uptake of the measles vaccine, due in large part to the growing anti-vaccination movement. This move away from proven vaccines is what has allowed old scourges - like Pertussis, Measles, Scarlet Fever, and even diphtheria - to make a comeback around the globe.

While many cling to the idea that `what doesn't kill you, makes you stronger' in recent years we've learned that measles infection can dramatically reduce your immune system's ability to fight other pathogens; even those to which you had previously developed antibodies against. 

It's been dubbed `Immune Amnesia' - where the patient's T cells and B cells are greatly reduced - a condition that may last for several years.  A few studies include:

Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens

Immune amnesia induced by measles and its effects on concurrent epidemics

Measles vaccination and reduced child mortality: Prevention of immune amnesia or beneficial non-specific effects of measles vaccine?

Which - in a world where emerging infectious diseases are on the rise - is far from ideal. 

Given measles' long incubation period (2-3 weeks), its extreme transmissibility, and the ability of an infected person to transmit the virus for several days before showing symptoms, this year's outbreak is going to be very difficult to contain. 

J. Virology: Synergistic Effects of PA (S184N) & PB2 (E627K) Mutations on the Increased Pathogenicity of H3N2 Canine Influenza Virus Infections in Mice and Dogs

Just one of many scenarios - Dogs as `mixing vessels' for Influenza

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The revelation - just over a year ago - that goats and dairy cattle were susceptible to HPAI H5 infection wasn't the first such `Aha!' moment with unexpected influenza hosts.  A little over 20 years ago, most researchers believed cats and dogs weren't susceptible to influenza A viruses. 

That is, until spillovers occurred in both species (equine H3N8 in dogs and avian H5N1 in cats) in 2003-2004 (see A Dog & Cat Flu Review).  A few years later (2007), an Avian H3N2 virus spilled over into dogs in Korea, and has since spread globally, arriving in the United States in 2015.

In 2017 the CDC added Canine H3N2 to their IRAT List of zoonotic influenza viruses with pandemic potential, albeit with relatively low (3.7) Emergence and Impact Scores. 

H3N2: [A/canine/Illinois/12191/2015]

The H3N2 canine influenza virus is an avian flu virus that adapted to infect dogs. This virus is different from human seasonal H3N2 viruses. Canine influenza A H3N2 virus was first detected in dogs in South Korea in 2007 and has since been reported in China and Thailand. It was first detected in dogs in the United States in April 2015. H3N2 canine influenza has reportedly infected some cats as well as dogs. There have been no reports of human cases.

But Canine H3N2 continues to evolve (along with both Canine H3N8 and a recently discovered Canine H3N6 virus). Of the three, however, canine H3N2 appears to be making the most progress (see here, here, and here). 

Just over a month ago, we looked at Frontiers Vet. Sci: Genetic Characterization of an H3N2 Canine Influenza Virus Strain in China in 2023—Acquisition of Novel Human-like Amino Acid Substitutions, which warned of additional evolutionary changes:

CIV-CC23 has acquired 3 novel human-like amino acid substitutions compared to the preceding H3N2 CIV strains. This findings suggest that H3N2 CIV evolves over time, and if it accumulates a sufficient number of human-like amino acid substitutions, it may acquire the ability to efficiently propagate in humans.

Chinese scientists over the past decade have visibly increased their scrutiny of novel H3 viruses, as they are commonly observed in wild birds and poultry, and are increasingly spilling over into mammals (see EID Journal: Evolution of Avian Influenza Virus (H3) with Spillover into Humans, China).

All of which brings us to a new study from researchers at the Guangdong Provincial Pet Engineering Technology Research Center, which used serial passaging experiments (in murine lungs), to generate a more pathogenic and mammalian adapted virus. 

We've looked at serial passage experiments many times. The concept (see graphic below) is simple.

First, you inoculate a naive host with a strain of a virus, let it replicate a while, then take the virus from the first host and inoculate a second, and then repeat the process five, ten, fifteen times or more.  Often, assuming there are no insurmountable species barriers, adaptive mutations will appear.  

This is the laboratory approximation of what can happen when a novel virus is introduced to a high density population of (often farmed) animals (e.g. mink, swine, poultry, etc.). 

In today's study, researchers report significant mutations appeared in the Canine H3N2 virus after only 18 passages through laboratory mice, including the emergence of PB2-627K, which is associated in enhanced replication and pathogenicity in mammals. 

First the link, Abstract, and some excerpts from the study.  Follow the link to read it in its entirety.  I'll have a bit more after the break. 

Synergistic effects of PA (S184N) and PB2 (E627K) mutations on the increased pathogenicity of H3N2 canine influenza virus infections in mice and dogs

Authors: Xiangyu Xiao , Xinrui Wang, Fengpei Xu, Yanting Liang, Yi Luo, Shoujun Li , Pei Zhou 

https://doi.org/10.1128/jvi.01984-24

ABSTRACT

As companion animals, dogs are susceptible to various subtypes of influenza A virus (IAV), with the H3N2 and H3N8 subtypes of canine influenza virus (CIV) stably circulating among canines. Compared to the H3N8 CIV, the H3N2 CIV is more widely prevalent in canine populations and demonstrates increased adaptability to mammals, potentially facilitating cross-species transmission. Therefore, a comprehensive elucidation of the mechanisms underlying H3N2 CIV adaptation to mammals is imperative.

In this study, we serially passaged the GD14-WT strain in murine lungs, successfully establishing a lethal H3N2 CIV infection model. From this model, we isolated the lethal strain GD14-MA and identified the key lethal mutations PA(S184N) and PB2(E627K). 

Moreover, the GD14-ma[PA(S184N)+PB2(E627K)] strain exhibited markedly enhanced pathogenicity in dogs. Viral titers in lung tissues from infected dogs and mice showed that GD14-ma[PA(S184N)+PB2(E627K)] does not increase its pathogenicity to mice and dogs by upregulating viral titers compared to the GD14-WT strain. 

Notably, sequence alignments across all H3N2 IAVs showed an increasing prevalence of the PA (S184N) and PB2 (E627K) mutations from avian to human hosts. Finally, single-cell RNA sequencing of infected mouse lung tissues showed that GD14-ma[PA(S184N)+PB2(E627K)] effectively evaded host antiviral responses, inducing a robust inflammatory reaction. Considering the recognized role of the PB2 (E627K) mutation in the mammalian adaptation of IAVs, our findings underscore the importance of ongoing surveillance for the PA (S184N) mutation in H3N2 IAVs.

IMPORTANCE

Since the 21st century, zoonotic viruses have frequently crossed species barriers, posing significant global public health challenges. Dogs are susceptible to various influenza A viruses (IAVs), particularly the H3N2 canine influenza virus (CIV), which has stably circulated and evolved to enhance its adaptability to mammals, including an increased affinity for the human-like SAα2,6-Gal receptor, posing a potential public health threat. Here, we simulated H3N2 CIV adaptation in mice, revealed that the synergistic PA(S184N) and PB2(E627K) mutations augment H3N2 CIV pathogenicity in dogs and mice, and elucidated the underlying mechanisms at the single-cell level. Our study provides molecular evidence for adapting the H3N2 CIV to mammals and underscores the importance of vigilant monitoring of genetic variations in H3N2 CIV.

(SNIP)

DISCUSSION

In this study, we successfully established a lethal mouse model for H3N2 CIV and isolated a lethal mouse strain, designated as GD14-MA. Employing reverse genetics, we identified the PA (S184N) and PB2 (E627K) mutations as critical factors contributing to lethality in mice. Pathogenicity studies in dogs revealed that the GD14-ma[PA(S184N)+PB2(E627K)] strain exhibited significantly enhanced virulence compared to the GD14-WT strain. Single-cell RNA sequencing of infected mouse lung tissues showed that GD14-ma[PA(S184N)+PB2(E627K)] effectively evaded host antiviral responses, inducing a robust inflammatory reaction.

         (Continue . . . )

In April of 2020,  China's MOA reclassified dogs as `companion animals' rather than `livestock', although it is estimated that somewhere between 10 and 20 million dogs are farmed/abducted in China each year for fur and/or meat. 

But even in countries where such practices uncommon, animal shelters have proven excellent venues for extended chains of infection (e.g. Canine parvovirus, feline panleukopenia, canine and feline viral respiratory pathogens, etc. )

The avian H7N2 outbreak in cats across several NYC animals shelters over Christmas of 2016 spread to hundreds of felines, and spilled over into several workers (see J Infect Dis: Serological Evidence Of H7N2 Infection Among Animal Shelter Workers, NYC 2016).

Admittedly, the emergence of a human-adapted H3N2 virus is probably a long-shot. But the more opportunities we give it, the greater the chances of it eventually getting lucky. 

And since it isn't just canine H3N2 - but rather a large (and growing) array of novel flu viruses all with varying degrees of zoonotic potential (e.g. H5N1, H5N5, H5N6, H9N2, H10Nx, etc.) -  the smart money is on preparing now for what could be a very bumpy road ahead.   

Mexico MOH Reports 1st Human H5N1 Case

 
Location of Durango State (pop 1.8 million)

Credit Wikipedia

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Last yesterday Mexico's MOH announced that country's first human HPAI H5N1 infection, in a 3-year old girl from (largely agricultural) Durango State, who is currently hospitalized in serious condition and who tested positive on April 1st.  

How the girl was infected is not known, although authorities are monitoring wild and synanthropic birds around the girl's home. SENASICA (MOA) reports no commercial outbreaks anywhere in the country.

Details on the genotype, and sequences, have not yet been published.   Hopefully they will provide some clue as to the source of this infection.  The Mexican Government Joint Communications press release follows, after which I'll have a bit more.  

Ministry of Health reports detection of the first human case of avian influenza A (H5N1)

Ministry of Health | April 04, 2025 | National
www.gob.mx/salud

The Ministry of Health reports the detection of the first human case of avian influenza A (H5N1) in Mexico.

The case occurred in a three-year-old girl, resident in Durango state. On April 1, the Institute of Epidemiological Diagnosis and Reference (InDRE) confirmed the result to Influenza A (H5N1). The patient initially received treatment with oseltamivir and is currently hospitalized in a third-level unit in the city of Torreón and her condition is reported serious.

Once the case was confirmed, the following actions were implemented immediately:

• Notification to the World Health Organization, in accordance with the protocol established for it in the International Health Regulations.

Health

• Health personnel from the Durango and Coahuila Health Services were trained in relation to the National guide for the preparation, prevention and response to an outbreak or event by zoonotic influenza in the animal-human interface.
• Intentional search of cases with suspected viral respiratory disease began.

Semarnat - Conanp

• Biological tours and samplings of wild and synanthropic birds were carried out in the area of influence surrounding the home of the positive case of avian influenza A (H5N1), and a permanent monitoring system was established for the timely detection of other similar cases in wildlife that inhabits the place.

Agriculture - Senasica

• The Ministry of Agriculture and Rural Development, through the National Service of Health, Safety and Agri-Food Quality (Senasica), reported that so far no commercial production units affected by avian influenza A (H5N1) have been reported in any area of the country ; however, Senasica continues with active epidemiological surveillance actions, in order to timely identify any case that may arise, and if so, the corresponding national and international protocols will be implemented.

The Ministry of Health informs the population:

The WHO considers that the public health risk of this virus for the general population is low, so the consumption of well-cooked chicken or egg meat does not represent a danger to human health. Zoonotic influenza is a disease that can be transmitted from birds or other animals to humans. So far there is no evidence of sustained person-to-person transmission.

The Ministry of Health has a strategic reserve of 40 thousand oseltamivir treatments.

The population is recommended:

• Wash hands frequently with soap and water or 70 percent alcohol-based solutions.
• Use mouth covers in case of respiratory symptoms and ventilate spaces.
• Cover your mouth and nose when coughing or sneezing.
• Wash hands before handling cooked food and after handling raw food.
• Properly cook chicken and egg meat (greater than 70 ° C)
• Do not use the same utensils to handle raw and cooked food.
• Avoid touching or approaching wild animals.
• Do not handle or collect dead animals.
• Do not touch sick or dead poultry or poultry for unknown reasons.
• Wear gloves, mouth covers and protective clothing if you work on farms or slaughterhouses and have contact with birds or other animals, their products and waste.
• Monitor possible data of disease or abnormal death in farm or backyard animals and notify the authorities immediately.

The Ministry of Health recommends requesting medical attention in case of fever, conjunctivitis (burning, itching, red eyes), cough, sore throat, runny nose, shortness of breath, headache, vomiting, diarrhea, bleeding or disturbances of consciousness, after contact with birds or other sick or dead animals.

X: @SSalud_mx

Facebook: facebook.com/SecretaryadeSaludMX

Instagram: ssalud_mx

YouTube: Mexico Health Secretariat

 As we've discussed (ad nauseum) over the years, detecting sporadic cases of H5 infection often involves a bit of luck, and it is likely that some (perhaps many) go unreported; even in countries with well-equipped and functioning public health systems.

First, an infected person must become sick enough to seek medical care, which - depending on the flu strain - may exclude > 90% of infections. They then must have access to modern medical care, an option not available to > 40% of the world's population, and then be lucky enough to be properly tested for novel influenza. 

In this case, no details are provided on the onset of the patient's illness, how many hospitals or clinics were visited, or how long it took to establish HPAI H5 as the cause. 

As we saw last June, when  Mexico announced the death of a 58-year-old man (who also suffered from serious comorbidities) who tested positive for the HPAI H5N2 virus, it can sometimes be a circuitous route.

The patient died in the hospital on April 24th, but H5N2 wasn't identified until two weeks later (May 8th). Notification of WHO/PAHO occurred on May 23rd, after another 2 week delay. No source of the virus was ever determined. 

A demonstration of how difficult picking up novel flu infections can be; even in a big city hospital, and during a time of increased awareness (see CDC HAN: Accelerated Subtyping of Influenza A in Hospitalized Patients).

Two years ago, in UK Novel Flu Surveillance: Quantifying TTD, UK health authorities released  HPAI H5 Technical Briefing #3, which modeled the TTD (Time to Detect) community spread of HPAI H5 under 3 different scenarios (in the UK). 

Assuming a relatively low R0 of 1.2, it could take 2 to 3 months before community spread would become apparent.  In rural, or resource scarce regions of the world, presumably even longer. 

A reminder that no news isn't necessarily a sign that nothing is happening, and that anything we say about the threat from H5N1 must carry an implied asterisk. 

A disclaimer that says, ` * based on available, and likely incomplete, information. . .  '. 

EID Journal: Influenza A(H1N1)pdm09 Virus with Reduced Susceptibility to Baloxavir, Japan, 2024

Credit NIAID

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Although we spend a good deal of time looking at the risks from novel influenza viruses, seasonal flu kills hundreds of thousands every year around the globe.  Even with somewhere near a billion people getting the flu vaccine every year (which is only moderately effective), that leaves a lot of people at risk of serious illness or death. 

Influenza antivirals have been around for nearly 50 years (Amantadine was approved in the US in 1976), while oseltamivir (aka Tamiflu) was approved in 1999, and Baloxavir in 2018.  

But very much like we see with antibiotics and bacteria, antivirals are susceptible to resistance developing over time in targeted viruses. By the end of 2005 our oldest class of flu antivirals - M2 ion channel blockers (e.g. Amantadine, Rimantadine) - had become largely ineffective against seasonal H3N2, and in early 2006 were no longer recommended for use. 

Luckily we had oseltamivir -- an NAI (neuraminidase inhibitor) - to fall back on. It was, however, far more expensive and difficult to produce in quantity. While occasional instances of Oseltamivir resistance (1%) were reported prior to 2007, in nearly every case, it developed after a person was placed on the drug (i.e. `spontaneous mutations’).

Studies suggested that these resistant strains suffered a `fitness penalty', and were therefore unlikely to spread from human-to-human.

An optimistic view that lasted just over 2 years, as by 2008 seasonal H1N1 picked up `permissive mutations' (Cite) that enabled resistant seasonal H1N1 viruses to spread  rapidly around the globe. By the end of 2008, the CDC was forced to issue major new guidance for the use of antivirals (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).

This resistance was due primarily to the acquisition of an H275Y mutation, and had seasonal H1N1 not been supplanted by a (still NAI susceptible) pandemic swine H1N1 virus in the spring of 2009, oseltamivir might still be off the table. 

We've been watching ever since 2009 for any signs that the replacement pH1N1 virus has been gaining resistance to oseltamivir, but for the most part, the news has been pretty good.  And in 2018 a new (albeit more expensive) class of antivirals (Baloxavir) was added to our armamentarium. 

But recently we've seen some cracks in the veneer.  While 99% of wild-type seasonal flu viruses remain susceptible to Oseltamivir/Baloxavir, we follow reports of resistant strains with considerable interest. A few of many include:

Eurosurveillance: An outbreak of A(H1N1)pdm09 Exhibiting Cross-resistance to Oseltamivir & Peramivir in an Elementary School in Japan, Sept 2024

Viruses: Increase of Synergistic Secondary Antiviral Mutations in the Evolution of A(H1N1)pdm09 Influenza Virus Neuraminidases

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

Eurosurveillance: A community Cluster of Influenza A(H3N2) Virus infection with Reduced Susceptibility to Baloxavir - Japan 2023

EID Journal: H-2-H Transmission Of A(H3N2) with Reduced Susceptibility to Baloxavir, Japan

This week we have a new dispatch, published in the CDC's EID Journal, that describes another instance of Baloxavir resistance in Japan (where the drug is mostly widely used).  While only one case is reported, it was in a child who had not been treated with the antiviral, and it was due to a previously unassociated mutation. 

I've posted the link, abstract, and some excerpts, but many will want to read the full dispatch.  I'll have a bit more after the break. 

Dispatch

Influenza A(H1N1)pdm09 Virus with Reduced Susceptibility to Baloxavir, Japan, 2024

Emi Takashita, Hiroko Morita, Shiho Nagata, Seiichiro Fujisaki, Hideka Miura, Tatsuya Ikeda, Kenichi Komabayashi, Mika Sasaki, Yohei Matoba, Tomoko Takahashi, Naomi Ogawa, Katsumi Mizuta, Sueshi Ito, Noriko Kishida, Kazuya Nakamura, Masayuki Shirakura, Shinji Watanabe, and Hideki Hasegawa

Abstract

Influenza A(H1N1)pdm09 virus carrying an I38N substitution was detected in an untreated teenager in Japan. The I38N mutant virus exhibited reduced susceptibility to baloxavir but remained susceptible to neuraminidase inhibitors and showed reduced growth capability. Monitoring antiviral drug susceptibility of influenza viruses is necessary to aid public health planning and clinical recommendations.

(SNIP)

The PA I38T substitution is the most frequent substitution and has the greatest effect on baloxavir susceptibility (5). Influenza A(H1N1)pdm09 (pH1N1) and A(H3N2) viruses with the PA I38T substitution isolated from baloxavir-treated patients show similar replication fitness and pathogenicity to wild-type isolates tested in hamsters and efficiently transmit between ferrets by respiratory droplets (6). 

We have monitored baloxavir susceptibility of seasonal influenza viruses in Japan since the 2017–18 season and reported human-to-human transmission of PA I38T mutant H3N2 viruses in children <10 years of age (7,8).

Researchers detected a PA I38N substitution in a pH1N1 virus isolated from a patient during a phase 3 clinical trial of baloxavir. That substitution conferred a 24-fold reduction in baloxavir susceptibility in recombinant A/WSN/33(H1N1) and a 10-fold reduction in recombinant A/Victoria/3/75(H3N2) and reduced growth capability in both viruses (3,9). However, its effect on pH1N1 virus has not been reported. 

During our 2023–24 surveillance, we detected a PA I38N mutant pH1N1 virus in a 14-year-old patient not treated with baloxavir. Here, we report the in vitro characterization of the PA I38N mutant pH1N1 virus.

Conclusions

In this study, we showed that the PA I38N mutant pH1N1 virus had reduced susceptibility to baloxavir but remained susceptible to NA inhibitors. Our results indicate that the PA I38N substitution in the pH1N1 virus contributed to a reduction in baloxavir susceptibility, but the reduction in susceptibility was less than that caused by the PA I38T substitution (3,9).

PA I38 is highly conserved in influenza A and B viruses (1). During October 2023–March 2024, medical institutions that serve ≈3.7 million persons in Japan received baloxavir to use for antiviral treatment. The PA I38N substitution may negatively affect the growth capability of the virus in vitro; however, our findings suggest possible transmission of the PA I38N mutant pH1N1 virus from another host harboring the mutant virus, which may have emerged under the selective pressure of baloxavir or as a result of a rare spontaneous mutation.

In Japan, influenza activity was low throughout the COVID-19 pandemic; the first influenza outbreak occurred in the 2022–23 season (13). The influenza outbreak in the 2023–24 season was larger than that of 2022–23 (Figure 1). Influenza pH1N1 virus activity peaked in November 2023 and then declined.

The PA I38N mutant pH1N1 virus in this study was detected in March 2024. By March, the pH1N1 outbreak was almost over, and no regional spread of the PA I38N mutant pH1N1 virus was observed.

We reported a community cluster of influenza A(H3N2) viruses with reduced susceptibility to baloxavir caused by a PA E199G substitution in Japan in February–March 2023 (13). In addition, researchers reported widespread community clusters of pH1N1 viruses with cross-resistance to oseltamivir and peramivir in Australia and Japan (14,15). Monitoring of antiviral drug susceptibility of influenza viruses is necessary to aid public health planning and clinical recommendations for antiviral drug use.

Dr. Takashita is a virologist with the National Institute of Infectious Diseases, Tokyo, Japan. Her research interests include antiviral drug susceptibilities of influenza viruses. 

 

While a loss of one (or both) of our main classes of antivirals would be a disaster for seasonal flu, it could have even greater impact during a pandemic.  For most people, a novel flu vaccine would only be available 6 months or more into an outbreak (see Referral: SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1).

Just over 2 weeks ago, St. Jude Researchers warned Current Antivirals Likely Less Effective Against Severe Infection Caused by Bird Flu in Cows’ Milk, and 6 weeks ago we learned from Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms.

Although we've not seen any reports of H275Y in D1.1 samples collected in the United States, last November the CDC did report finding a far-less impactful mutation (NA-S247N) in 3 poultry workers from Washington State, which they stated may slightly reduce the virus's susceptibility to antivirals.

While other studies (conducted 2022-2024) have reported relatively little resistance in HPAI H5 viruses tested in the United States (see here, and here), the one thing you can count on with influenza viruses is they are always changing. 

Although I remain hopeful our antiviral stockpiles (mostly oseltamivir) can help `take the edge off' the opening months of the next pandemic, it is by no means assured.

To be most effective, antivirals ideally need to be given early (< 48 hours) into an infection. Stockpiles are finite, and even during moderately severe seasonal flu epidemics we've seen difficulties in rapidly dispensing these drugs (see 2022's CDC HAN #0482: Prioritizing Antiviral Treatment of Influenza in the Setting of Reduced Availability of Oseltamivir).

Any way you cut it, our first line of defense will - once again - rely heavily on NPIs (non-pharmaceutical interventions), like face masks, hand washing, ventilation, staying home while sick, and avoiding crowds.