Saturday, April 20, 2024

Two Recent Papers On The Evolution of H7N9 in China

H7N9 Epidemic Waves - June 14th 2017 - Credit FAO


Seven years ago - long before COVID emerged and at a time when HPAI H5N1 had all but disappeared from the map - the world held its breath and watched as China's 5th, and largest, wave of H7N9 raised pandemic concerns around the globe.   

LPAI H7N9, which had emerged in the spring of 2013, was virtually asymptomatic in poultry, but could be deadly in humans, and over 5 years had infected at least 1,500 people in China, killing roughly 40% of them.  

In late 2016, an HPAI version emerged, which threatened China's poultry industry as well as public health. Fearing the worst, China embarked on a national emergency poultry vaccination campaign with a new H5+H7 vaccine (see EID Journal: China's H5+H7 Poultry Vaccination Program, Guangdong 2017-18).

Within months human infections fell dramatically, with the last one reported in 2019.  Poultry losses plummeted, and in a 2019 report (see OFID: Avian H5, H7 & H9 Contamination Before & After China's Massive Poultry Vaccination Campaign) the authors reported:

The vaccine was associated with a 92% reduction in H7 positivity rates among poultry and a 98% reduction in human H7N9 cases.

While previous poultry vaccination programs around the world have yielded varying levels of success, China's H5+H7 poultry vaccination campaign exceeded all expectations. It even reduced the number of H5N1 & H5N6 spillovers, although China saw a rebound in H5N6 starting in late 2020. 

H7N9 remains largely suppressed in China, but it has not been eradicated, and so we check in on its continued evolution from time to time:

EID Journal: Antigenic Variant of Highly Pathogenic Avian Influenza A(H7N9) Virus, China, 2019

EID Journal: Evolution and Antigenic Drift of Influenza A (H7N9) Viruses, China, 2017–2019

This week we've seen 2 new studies published in major journals (EID & Emerging Microbes & Inf.) by Chinese researchers on the recent evolution of H7N9.  Both credit China's H5+H7 vaccination program's success, but caution that the virus continues to evolve, and that the vaccine needs to keep up.

I've only post excerpts from both studies, so follow the links to read them in their entirety. I'll have a postscript after the break. 

Evolution and Antigenic Differentiation of Avian Influenza A(H7N9) Virus, China
Yang Liu1, Yuhua Chen1, Zhiyi Yang, Yaozhong Lin, Siyuan Fu, Junhong Chen, Lingyu Xu, Tengfei Liu, Beibei Niu, Qiuhong Huang, Haixia Liu, Chaofeng Zheng, Ming Liao , and Weixin Jia


We characterized the evolution and molecular characteristics of avian influenza A(H7N9) viruses isolated in China during 2021–2023. We systematically analyzed the 10-year evolution of the hemagglutinin gene to determine the evolutionary branch. Our results showed recent antigenic drift, providing crucial clues for updating the H7N9 vaccine and disease prevention and control.

From early 2013 through October 2017, a total of 5 outbreaks of avian influenza A(H7N9) virus infection occurred, resulting in 616 human deaths (1). In particular, the fifth wave of the epidemic saw a substantial increase in human fatalities. By late 2017, a total of 1,568 laboratory-confirmed cases of H7N9 virus infection in humans had been reported according to International Health Regulations guidelines (External Link). The rapid emergence, prevalence, and pandemic potential of H7N9 virus were suddenly of great concern. Since 2017, low-pathogenicity avian influenza H7N9 virus transformed into the highly pathogenic avian influenza (HPAI) A(H7N9) virus (25). 

In response, China initiated a large-scale vaccination program in the poultry industry, effectively limiting the H7N9 epidemic. Although no human H7N9 infections have been reported since February 2019, the virus is still circulating in poultry, particularly in laying hens, and remains a potential threat to poultry industry and public health (68).
Furthermore, since 2017, the H7N9 virus has undergone multiple instances of antigenic drift to evade immune pressure from vaccines (911). We investigated the genetic evolution and antigenic differentiation of the H7N9 virus in China to provide information to better control the epidemic, ensure the safety of the poultry industry, and protect public health.

This study explored the evolution and antigenic differentiation characteristics of H7N9 virus over the past decade through continuous monitoring and selection of representative sequences from all publicly available H7N9 virus sequences. However, our research still had certain limitations, and further investigation is needed to understand the relationship between the evolution of viruses under positive selection pressure and the underlying cause of antigenic variation.

In summary, influenza A viruses are highly prone to mutation and evolution, making the H7N9 virus epidemic more complex and challenging to control. This study offers vital insights into the genetic evolutionary branches and recent antigenic drift, providing crucial clues for updating the H7N9 vaccine seed virus and for disease prevention and control.     

         (Continue . . . )


While the first dispatch was more cautionary, this second report is more upbeat, describing a greatly attenuated threat from the H7N9 virus. 

Evolution of H7N9 highly pathogenic avian influenza virus in the context of vaccination

Yujie HouGuohua DengPengfei CuiXianying ZengBin LiDongxue Wang


Human infections with the H7N9 influenza virus have been eliminated in China through vaccination of poultry; however, the H7N9 virus has not yet been eradicated from poultry. Carefully analysis of H7N9 viruses in poultry that have sub-optimal immunity may provide a unique opportunity to witness the evolution of highly pathogenic avian influenza virus in the context of vaccination. Between January 2020 and June 2023, we isolated 16 H7N9 viruses from samples we collected during surveillance and samples that were sent to us for disease diagnosis.
Genetic analysis indicated that these viruses belonged to a single genotype previously detected in poultry. Antigenic analysis indicated that 12 of the 16 viruses were antigenically close to the H7-Re4 vaccine virus that has been used since January 2022, and the other four viruses showed reduced reactivity with the vaccine.
Animal studies indicated that all 16 viruses were nonlethal in mice, and four of six viruses showed reduced virulence in chickens upon intranasally inoculation. Importantly, the H7N9 viruses detected in this study exclusively bound to the avian-type receptors, having lost the capacity to bind to human-type receptors. Our study shows that vaccination slows the evolution of H7N9 virus by preventing its reassortment with other viruses and eliminates a harmful characteristic of H7N9 virus, namely its ability to bind to human-type receptors.

The early H7N9 viruses bound to human-type receptors with high affinity and to avian-type receptors with low affinity [5,47,48], which is a major reason why these viruses easily infected humans. However, since 2018, the receptor-binding preference of the H7N9 viruses we detected from poultry gradually changed: their affinity for avian-type receptors has gradually increased, and their affinity for human-type receptors has gradually declined [32].

The viruses detected in this study exclusively bound to avian-type receptors. Although the underlying mechanism that has driven this receptor-binding change remains to be investigated, the fact that the surviving H7N9 viruses in vaccinated poultry have lost a key harmful trait indicates that vaccination does not cause the highly pathogenic avian influenza virus to become more dangerous to humans.

In conclusion, our study reveals the genetic evolution and biological properties of the H7N9 highly pathogenic avian influenza virus detected in recent years in China. Although antigenic differences could be easily detected between the surviving viruses and the vaccine seed strain, the lack of reassortment with other viruses and the loss of human-type receptor binding ability of existing H7N9 viruses strongly suggest that although vaccination alone cannot eradicate highly pathogenic H7N9 influenza viruses from poultry in a short time, surviving H7N9 viruses are not evolving faster or becoming more dangerous to humans.

         (Continue . . . )

Although the evolutionary trend of H7N9 appears to be away from posing a public health threat, one lucky reassortment, or a handful of of the `right' amino acid changes, could change that trajectory overnight.  

All of which makes it important that researchers in China continue to study the virus, and update the poultry vaccine. 

While H7N9 isn't anywhere near the top of my pandemic concerns today, we've seen how swiftly things can change.  And with influenza viruses, it is wise never to say `never'.

Friday, April 19, 2024

Preprint: Rapid mortality in Captive Bush Dogs (Speothos venaticus) Caused by H5N1 At A Wildlife Center In the UK

 Credit Wikipedia


Just over 13 months ago the UK government announced (see below) the deaths of 10 captive bush dogs (in November of 2022) apparently due to HPAI H5N1.  At the time it wasn't clear why there had been a 5-month delay in detecting the virus. 

Research and analysis

Confirmed findings of influenza of avian origin in captive mammals

Published 17 March 2023

Applies to England, Scotland and Wales

Details of confirmed findings of influenza of avian origin in captive mammals in Great Britain (England, Scotland and Wales).

South American bush dogs, March 2023

Ten South American bush dogs (Speothos venaticus venaticus) have tested positive for highly pathogenic avian influenza (H5N1) in March 2023.

These animals were part of a captive breeding programme at a zoological premises in England. They were tested as part of a routine investigation into an unusual mammal die-off in November 2022. Ten animals died or were euthanised in a group of 15 bush dogs, over a 9 day period.

The bush dogs had minimal clinical signs before death, and APHA cannot definitively state whether or not H5N1 caused the clinical signs. Influenza of avian origin was not suspected at the time; the virus has since been detected in postmortem samples.

There is no clear evidence suggesting mammal to mammal transmission. It is very likely all animals were exposed to the same source of infected wild birds.

Today we have a preprint from scientists at the UK's APHA and other agencies which presents a somewhat different narrative.  

  • Instead of blaming infection on exposure to `infected wild birds' we now learn these animals were most likely infected from being fed infected meat
  • Instead of exhibiting `minimal clinical signs before death' as reported above, we now learn that some of these animals exhibited neurological manifestations and histopathic examination revealed `severe acute systemic disease characterised by vasculitis, and widespread necrosis and inflammation in many organs, specifically the liver, brain, lung, and adrenal glands.'

We also learn from this preprint that - despite earlier reports of H5N1/H5N8 spillover into mammals in the UK and elsewhere in Europe (see here, here, and here) - that `Influenza A virus infection was not on the list of differentials for causative agent in this disease event'.

The preprint (excerpts below) is highly detailed, and very much worth reading in its entirety.  I'll have a bit more after the break. 

Rapid mortality in captive bush dogs (Speothos venaticus) caused by influenza A of avian origin (H5N1) at a wildlife collection in the United Kingdom

Marco Falchieri, Scott Reid, Akbar Dastderji, Jonathan Cracknell, Caroline Janet Warren, Benjamin Mollett, Jacob Peers-Dent, Audra-Lynne Schlachter, Natalie Mcginn, Richard Hepple, Saumya Thomas, Susan Ridout, Jen Quayle, Romain Pizzi, Alejandro Nunez, Alexander M P Byrne, Joe James, Ashley C Banyard


Europe has suffered unprecedented epizootics of high pathogenicity avian influenza (HPAI) clade H5N1 since Autumn 2021. As well as impacting upon commercial and wild avian species, the virus has also infected mammalian species more than ever observed previously.
Mammalian species involved in spill over events have primarily been scavenging terrestrial carnivores and farmed mammalian species although marine mammals have also been affected. Alongside reports of detections in mammalian species found dead through different surveillance schemes, several mass mortality events have been reported in farmed and wild animals.
During November 2022, an unusual mortality event was reported in captive bush dogs (Speothos venaticus) with clade H5N1 HPAIV of avian origin being the causative agent. The event involved an enclosure of fifteen bush dogs, ten of which succumbed during a nine-day period with some dogs exhibiting neurological disease. Ingestion of infected meat is proposed as the most likely infection route.
Here we report on the infection and severe mortality within a pack of bush dogs (Speothos  venaticus) in captivity with avian origin H5N1 clade HPAIV. Bush dogs are a near  threatened species of wild canids that are of conservation concern. Wild populations of these dogs   range from northern regions of Panama (Central America) to northeastern Argentina and Paraguay;  with populations also being present in Colombia, Venezuela, the Guianas, Brazil, and eastern Bolivia  and Peru. 

This species is characterized by its small size, elongated body, small eyes, short snout, short  tail, short legs, and small and rounded ears, in addition to gregarious and diurnal behaviour (35).  

In this disease event which occurred in November 2022, two thirds of the pack of bush dogs, held  captive in a wildlife collection the UK, became clinically unwell with a disease that had a short duration and led to death and/or the need for euthanasia on welfare grounds with a range of clinical  signs including neurological disease. 

Avian influenza was not suspected at first and several tests and analysis were performed at private laboratories to ascertain cause of death and to exclude the involvement of more common canine pathogens. Overall inconclusive results led bush dog samples to be submitted retrospectively to the Animal and Plant Health Agency (APHA), Virology Department for shotgun metagenomic assessment, which detected presence of influenza type A virus sequences in internal organs. We describe the disease event, timeline, virological and pathological impact of disease and sequence analysis of the causative agent.


The exposure route to influenza A virus of avian origin in this case is hard to conclusively define. The bush dogs had been fed a diet that included frozen shot wild birds and game. In the absence of local disease events that may have been transferred to the bush dogs in the enclosure, infection through ingestion of infected meat / offal would appear to be the most likely route of  infection.

Another potential infection route is through scavenging of any wild bird carcases/any sick  wild birds landing in the un-netted pen. Other routes of infection including indirect contact (e.g., wild bird faeces) are possible but less likely and would not fit with the rapid onset of infection across a  number of dogs within a short time frame.


From the perspective of zoonotic risk, the well-established marker of mammalian adaptation (E627K) was detected in all but one of the bush dog sequences generated. This mutation alone is  insufficient to drive an increase in zoonotic risk and so the risk to human populations must be considered very low.  

          (Continue . . . )

The suspected route of infection - from being fed raw infected birds - is one we've seen repeatedly in Asia with captive big cats, going back to 2004.  The neurological manifestations reported in these bush dogs are quite similar to reports in other mammals (both in North America & Europe), including several widely reported prior to the bush dog outbreak:

CDC EID Journal: Encephalitis and Death in Wild Mammals at An Animal Rehab Center From HPAI H5N8 - UK

EID Journal: HPAI A(H5N1) Virus in Wild Red Foxes, the Netherlands, 2021

Netherlands DWHC Reports another Mammal (Polecat) Infected With H5N1

While hindsight is admittedly 20-20, it does seem as if there might have been enough clues here to at least merit testing for influenza A.  But apparently, it wasn't on the list . . . . 

Just like it wasn't on the list to test cattle, which started falling ill with a `mystery illness' last  January in Texas. 

While previously experiments (and outbreaks) had shown that cattle could be infected with influenza A (see A Brief History Of Influenza A In Cattle/Ruminants), it took weeks before anyone thought to test for it.

For years, we've watched as novel flu viruses have repeatedly `broken the rules', yet we continue to be surprised each time it happens. 

If we ever hope to get ahead of this growing threat, we need to start thinking outside of the check boxes. 

WHO Report: Proposed Terminology For Pathogens That Transmit Through The Air


Although we've seen similar debates with other outbreaks, during the opening months of the COVID pandemic there was much disagreement (see COVID-19: The Airborne Division) over whether SARS-CoV-2 was an `airborne' virus, and what levels of personal protections (masks/gowns/gloves/eye protection) were appropriate for medical workers and for the public. 

Six months into the crisis, 200+ scientists from around the world signed an open letter to the WHO, urging them to reconsider their stance on the airborne spread of the virus.

It is Time to Address Airborne Transmission of COVID-19

Lidia Morawska, Donald K Milton
Clinical Infectious Diseases, ciaa939,

While the CDC had recommended `airborne precautions' for health care workers (when possible) since the beginning of this epidemic (see J. Infect. Dis.: Airborne or Droplet Precautions For COVID-19?), their guidance on how the virus spread in the community focused more on large droplet (short-range and short-lived) spread of the virus and contaminated fomites, rather than on aerosols.

Hence early messaging discouraging the use of face masks for the public (partially reversed on Apr. 4th, 2000).

Even as late as August of 2020, the debate raged on (see BMJ Editorial: Airborne Transmission of Covid-19) and the following month the CDC posted - then retracted 72 hours later - Updated Guidance On Airborne & Asymptomatic Spread Of COVID-19

A large part of the problem was semantics.  Scientists and policy makers couldn't agree on what constituted `airborne' transmission, resulting in mixed and confused messaging. 

While today it is widely accepted that COVID is highly transmissible via the respiratory route (see EID Journal: Probable Aerosol Transmission of SARS-CoV-2 through Floors and Walls of Quarantine Hotel, Taiwan, 2021), we can't afford to go through this same protracted debate with every new pathogen. 

Although it has taken 4 years and countless committee meetings, yesterday WHO released a 52-page report on redefining the terminology that describes pathogens that transmit through the air

First the press release from the WHO, followed by a link and a few brief excerpts from the document.  

Leading health agencies outline updated terminology for pathogens that transmit through the air
18 April 2024
News release
Reading time: 3 min (692 words)
Following consultation with public health agencies and experts, the World Health Organization (WHO) publishes a global technical consultation report introducing updated terminology for pathogens that transmit through the air. The pathogens covered include those that cause respiratory infections, e.g. COVID-19, influenza, measles, Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), and tuberculosis, among others.

The publication, entitled “Global technical consultation report on proposed terminology for pathogens that transmit through the air, is the result of an extensive, multi-year, collaborative effort and reflects shared agreement on terminology between WHO, experts and four major public health agencies: Africa Centres for Disease Control and Prevention; Chinese Center for Disease Control and Prevention; European Centre for Disease Prevention and Control; and United States Centers for Disease Control and Prevention. This agreement underlines the collective commitment of public health agencies to move forward together on this matter.

The wide-ranging consultation was conducted in multiple steps in 2021-2023 and addressed a lack of common terminology to describe the transmission of pathogens through the air across scientific disciplines. The challenge became particularly evident during the COVID-19 pandemic as experts from various sectors were required to provide scientific and policy guidance. Varying terminologies highlighted gaps in common understanding and contributed to challenges in public communication and efforts to curb the transmission of the pathogen.

“Together with a very diverse range of leading public health agencies and experts across multiple disciplines, we are pleased to have been able to address this complex and timely issue and reach a consensus,” said Dr Jeremy Farrar, WHO Chief Scientist. “The agreed terminology for pathogens that transmit through the air will help set a new path for research agendas and implementation of public health interventions to identify, communicate and respond to existing and new pathogens.”

The extensive consultation resulted in the introduction of the following common descriptors to characterize the transmission of pathogens through the air (under typical circumstances):

Individuals infected with a respiratory pathogen can generate and expel infectious particles containing the pathogen, through their mouth or nose by breathing, talking, singing, spitting, coughing or sneezing. These particles should be described with the term ‘infectious respiratory particles’ or IRPs.
IRPs exist on a continuous spectrum of sizes, and no single cut off points should be applied to distinguish smaller from larger particles. This facilitates moving away from the dichotomy of previously used terms: ‘aerosols’ (generally smaller particles) and ‘droplets’ (generally larger particles).

The descriptor ‘through the air’ can be used in a general way to characterize an infectious disease where the main mode of transmission involves the pathogen travelling through the air or being suspended in the air. Under the umbrella of ‘through the air transmission’, two descriptors can be used:

1. Airborne transmission or inhalation, for cases when IRPs are expelled into the air and inhaled by another person. Airborne transmission or inhalation can occur at a short or long distance from the infectious person and distance depends on various factors (airflow, humidity, temperature, ventilation etc). IRPs can theoretically enter the body at any point along the human respiratory tract, but preferred sites of entry may be pathogen-specific.

2. Direct deposition, for cases when IRPs are expelled into the air from an infectious person, and are then directly deposited on the exposed mouth, nose or eyes of another person nearby, then entering the human respiratory system and potentially causing infection.

“This global technical consultation process was a concerted effort of many influential and experienced experts,” said Dr Gagandeep Kang, Christian Medical College, Vellore, India who is a Co-Chair of the WHO Technical Working Group. “Reaching consensus on these terminologies bringing stakeholders in an unprecedented way was no small feat.
Completing this consultation gives us a new opportunity and starting point to move forward with a better understanding and agreed principles for diseases that transmit through the air,” added Dr Yuguo Li from the University of Hong Kong, Hong Kong SAR (China), who also co-chaired the Technical Working Group.

This consultation was the first phase of global scientific discussions led by WHO. Next steps include further technical and multidisciplinary research and exploration of the wider implementation implications of the updated descriptors.

The WHO overview, and a link to the PDF follows:


Terminology used to describe the transmission of pathogens through the air varies across scientific disciplines, organizations and the general public. While this has been the case for decades, during the coronavirus disease (COVID-19) pandemic, the terms ‘airborne’, ‘airborne transmission’ and ‘aerosol transmission’ were used in different ways by stakeholders in different scientific disciplines, which may have contributed to misleading information and confusion about how pathogens are transmitted in human populations.

This global technical consultation report brings together viewpoints from experts spanning a range of disciplines with the key objective of seeking consensus regarding the terminology used to describe the transmission of pathogens through the air that can potentially cause infection in humans.

This consultation aimed to identify terminology that could be understood and accepted by different technical disciplines. The agreed process was to develop a consensus document that could be endorsed by global agencies and entities. Despite the complex discussions and challenges, significant progress was made during the consultation process, particularly the consensus on a set of descriptors to describe how pathogens are transmitted through the air and the related modes of transmission. WHO recognizes the important areas where consensus was not achieved and will continue to address these areas in follow-up consultations.

From the report, we get the following graphical summary. 

The WHO also adds the following caveat about the immediate practical implications of these changes. 

There is NO suggestion from this consultative process that to mitigate the risk of short range airborne transmission full ‘airborne precautions’1 (as they are currently known) should be used in all settings, for all pathogens, and by persons with any infection and disease risk levels where this mode of transmission is known or suspected (126).

But conversely, some situations will require ‘airborne precautions’. This would clearly be inappropriate within a riskbased infection prevention approach where the balance of risks, including disease incidence, severity, individual and population immunity and many other factors, need to be considered, inclusive of legal, logistic, operational and financial consequences that have global implications regarding equity and access. 

While these changes should help streamline the conversation, we'll have to wait to see what practical effect they will have on the issuance of guidance on infection protection against novel disease threats going forward.  

Thursday, April 18, 2024

CDC Protection Advice & PPE Recommendations For Working With Farm Animals



Yesterday we looked at recommendations for protective gear to be worn by veterinarians handling potentially infected cats (see CDC Guidance for Veterinarians: Evaluating & Handling Cats Potentially Exposed to HPAI H5N1),and today we have recommendations from the CDC for PPEs for farm workers who may be in contact with infected animals, or their environment. 

I'm no farmer, but I have to wonder how practical donning & doffing PPE, and trying to work with farm animals in the summer heat while wearing this kind of attire, really is.  

But practicalities aside, it is important that people understand there are heightened risks right now.

Hopefully guidance like this will convince people it is worth taking extra precautions when working in potentially contaminated environments. 

Preprint: Highly Pathogenic Avian Influenza A (H5N1) clade Virus detected in dairy cattle



Yesterday researchers from the Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, at Iowa State University published a preprint with additional detailed information the HPAI H5N1 virus that spilled over from birds into cows - and a human and several cats - in Texas earlier this year (see graphic above)

While the exact route of introduction of the virus to cattle remains unknown, based on the available evidence, the authors hypothesize:

. . .  wild birds may spread the virus through direct contact or contamination of water sources or feed staffs utilized by dairy cattle or other animals such as skunks. Consequently, other cattle in the herd, workers and domestic felids on dairy farms may contract the virus through direct contact with infected cattle or after consuming raw colostrum and milk from infected cattle. The detection of the same strain of HPAI viruses in various wild bird species, such as blackbirds and common grackles in Texas and Canada geese in  Wyoming (Central Flyway), provides further support for this hypothesis. 

Another potential transmission scenario involves bovine-to-bovine spread. Recently, the USDA has verified the presence of this HPAI virus strain in dairy herds located in Idaho, Michigan, Ohio, North Carolina, and South Dakota (Link). In these cases, a documented history exists of cattle introduction from farms in the initial outbreak area, further supporting the  hypothesis that lateral transmission can occur among cattle.

Although human infections with this relatively new HPAI H5N1 clade virus remain rare, the authors write:

. . .  37 new mammal species have been afflicted since  2021. The majority of these cases involve wild terrestrial mammals such as foxes, skunks, bears,  bobcats, and raccoons (9, 23, 24). Intriguingly, there have been sporadic infections among  domestic pets like domestic cats and dogs (25), as well as marine mammals, including dolphins and sea lions (26). 

Moreover, from January 2022 to April 2023, eight documented human cases  of H5N1 influenza from clade have been recorded, several of which were severe or fatal  (, underlining the gravity of this situation.

I've reproduced the link, and some excerpts from this 19-page public domain summary below, but you'll want to follow the link to read it in its entirety.

Highly Pathogenic Avian Influenza A (H5N1) clade Virus detected in dairy cattle
Xiao Hu, Anugrah Saxena, Drew R. Magstadt, Phillip C. Gauger, Eric Burrough, Jianqiang Zhang, Chris Siepker, Marta Mainenti, Patrick Gorden, Paul Plummer, Ganwu Li
This article is a preprint and has not been certified by peer review 

Preview PDF


The global emergence of highly pathogenic avian influenza (HPAI) A (H5N1) clade viruses poses a significant global public health threat. Until March 2024, no outbreaks of this virus clade had occurred in domestic cattle. We genetically characterize HPAI viruses from dairy cattle showing an abrupt drop in milk production. They share nearly identical genome sequences, forming a new genotype B3.13 within the clade.

B3.13 viruses underwent two reassortment events since 2023 and exhibit critical mutations in HA, M1, and NS genes but lack critical mutations in PB2 and PB1 genes, which enhance virulence or adaptation to mammals. The PB2 E627K mutation in a human case underscores the potential for rapid evolution post-infection, highlighting the need for continued surveillance to monitor public health threats.


In addition to being the first documented occurrence of HPAI A (H5N1) clade virus infection in domestic dairy cattle, early pathology observations in this outbreak revealed an apparent tissue tropism for mammary gland in lactating domestic dairy cattle (personnel communication).

Prior to this incident, the clade IAV has typically caused systemic and respiratory diseases in wild mammals (9). Gross and microscopic lesions in wild mammals were frequently observed in organs such as the lung, heart, liver, spleen, and kidney, with some cases resulting in lesions in the brain leading to neurological signs.

Furthermore, while it is widely  recognized that certain strains of HPAI H5N1 clade virus can breach the blood-brain barrier (9, 23, 25, 27), this is the first instance where the virus may penetrate the blood-milk barrier and be present in milk, raising potential public health concerns.  


Notably, all HPAI  viruses originating from dairy cattle and cats exhibit consistent amino acid residues in the HA gene, including 137A, 158N, and 160A, which have been documented to enhance the affinity of avian influenza viruses for human-type receptors (15, 16). Additionally, these dairy cattle derived and cat-derived HPAI viruses harbor key virulence-increasing amino acid residues, such  as 30D, 43M, and 215A in M1 (17-19), as well as 42S, 103F, and 106M in NS1(20). 

The  presence of these amino acid mutations raises legitimate concerns regarding the potential for  cross-species transmission to humans and other mammalian species. It is noteworthy that crucial mutations associated with mammalian host adaptation and enhanced transmission, specifically residues 591K, 627K/V/A, 701N, in PB2 (18, 21, 22), and 228S, along with the virulence increasing residue 66S in PB1-F2(30), were conspicuously absent in all HPAI virus strains derived from dairy cattle and cats

This observation suggests that the current overall risk to  human health is relatively low. However, it is imperative to recognize that influenza viruses have  the capacity for rapid evolution within their host environments post-infection. A recent human case with direct contact with infected dairy cattle revealed a genetic change (PB2 E627K) (LINK), indicating the potential for adaptation or transmission events. This underscores the dynamic nature of influenza viruses and the importance of continued surveillance and vigilance in monitoring potential  threats to human health. 

          (Continue . . . )


While the genetic analysis still shows a virus not quite ready for prime-time, we are seeing only a tiny slice of what is going on in the wild.  Officially, Texas has only reported a single spillover into mammalian wildlife (a striped skunk in 2023 - see map below) but is a pretty safe assumption that many others have gone unreported. 

Over the past two years nearly half the states in the country haven't reported a single spillover - and while infected animals may die in remote and difficult to access places where their carcasses are quickly scavenged -  this probably speaks more to our reluctance to aggressively look for cases than how often they actually occur. 

While the USDA cites logistical problems and concerns over laboratory capacity, we appear embarked on a similar path with livestock testing, which remains both limited and voluntary. 

As long as the virus remains poorly adapted to humans, it is possible what we don't know won't hurt us. But given the enormous strides HPAI H5 has made over the past 3 years, any purported `bliss from  ignorance' may prove short-lived. 

Wednesday, April 17, 2024

APHIS/USDA Updated FAQ On Detection of HPAI (H5N1) in Dairy Herds


A little over two weeks after their first FAQ (Frequently Asked Questions) on HPAI H5N1 in dairy cattle we have new update, dated April 16th.  I've selected some excerpts to highlight, but you'll want to follow the link to read the full 5-page document.

I'll have a brief comment after there break.

What is the appropriate nomenclature for this virus, now that it has appeared in dairy cows? 

From USDA’s perspective, highly pathogenic avian influenza or H5N1 are the most scientifically accurate terms to describe this virus. This is also consistent with what the scientific community has continued to call the virus after it has affected other mammals. As a reminder, genomic sequencing of viruses isolated from cattle indicates there is no change to this virus that would make it more transmissible to or between humans, and the CDC considers risk to the public to be low at this time. However, people with more exposure to infected animals do have a greater risk of infection. Since the virus is not highly pathogenic in mammals, H5N1 is the most fitting of the two scientifically correct options. It is important to note that “highly pathogenic” refers to severe impact in birds, not necessarily in humans or cattle.

How did these cattle contract H5N1? 

Wild migratory birds are believed to be the original source of the virus. However, the investigation to date also includes some cases where the virus spread was associated with cattle movements between herds. Additionally, we have similar evidence that the virus also spread from dairy cattle premises back into nearby poultry premises through an unknown route. 

As a reminder, analysis sequences of viruses found in cattle thus far have not found changes to the virus that would make it more transmissible to humans and between people. While cases among humans in direct contact with infected animals are possible, CDC believes that the current risk to the public remains low. 

Is this the same virus that has been in circulation among wild and commercial flocks in recent months, or is this a different virus? 

Tests so far indicate that the virus detected in dairy cows is H5N1, Eurasian lineage goose/Guangdong clade This is the same clade that has been affecting wild birds and commercial poultry flocks and has caused sporadic infections in several species of wild mammals, and neonatal goats in one herd in the United States. A full list can be found here. 

How is a case of H5N1 in cattle confirmed by USDA? 

USDA encourages producers to work with their veterinarians to report cases of sick cattle to State Animal Health Officials and their APHIS Veterinary Services Area Veterinarian in Charge. Veterinarians should submit samples to a National Animal Health Laboratory Network (NAHLN) laboratory for initial testing. Samples with non-negative test results are then submitted to the National Veterinary Service Laboratories in Ames, Iowa for confirmatory testing. USDA considers a positive test result from testing performed by the NVSL as confirmation, and NVSL carries out viral genome sequencing.

Combined with the recent detections of H5N1 in baby goats in Minnesota, is there reason to be concerned H5N1 may spread to mammals more commonly than previously believed? 

H5N1 has been found in wild birds, poultry flocks, several species of wild mammals, farm cats, and neonatal goats in one herd in the United States. A full list can be found here. Many species are susceptible to influenza viruses, including wildlife that often come into direct contact with wild birds. Many of these animals were likely infected after consuming or coming into contact with birds that were infected with H5N1. In the case of the neonatal goats in Minnesota, they were exposed to domestic birds (ducks and chickens) infected with H5N1 through shared pasture and a sole water source. However, recent testing indicates the virus has also been spread by cattle movements between herds. 

Has USDA confirmed at this point that cow-to-cow transmission is a factor? 

Yes, although it is unclear exactly how virus is being moved around. We know that the virus is shed in milk at high concentrations; therefore, anything that comes in contact with unpasteurized milk, spilled milk, etc. may spread the virus. Biosecurity is always extremely important, including movement of humans, other animals, vehicles, and other objects (like milking equipment) or materials that may physically carry virus. USDA APHIS is continuing to examine herds that have diagnosed cows to better understand the mode of transmission. To date, we have not found significant concentration of virus in respiratory related samples, which indicates to us that respiratory transmission is not a primary means of transmission.

Why is APHIS taking a voluntary, rather than mandatory, approach to testing dairy herds? 

It is important to keep in mind that while H5N1 is highly pathogenic in birds, that is not the case in cattle. At this time, APHIS does not think it would be practical, feasible or necessarily informative to require mandatory testing, for several reasons ranging from laboratory capacity to testing turnaround times. We are working actively to learn more about the emergence of H5N1 in cattle, but right now we are seeing that a small portion of the affected herds are becoming ill, and that the number of herds exhibiting symptoms is relatively small. For context, there are more than 26,000 dairy herds nationwide. We are strongly recommending testing before herds are moved between states, which should both give us more testing information, and should mitigate further state-to-state spread between herds.

I greatly appreciate the APHIS/USDA refusal to re-brand HPAI H5N1 as the industry promoted kinder-and-gentler BIAV (Bovine Influenza A Virus), but we are now a full three weeks since the first positive tests for HPAI in cattle (which took far too long to be performed), and still we have disappointingly little in the way of solid information on exactly how this virus is spreading, or how wide-spread it really is.

If this is truly the best we can do, then we need to greatly improve our capacity for laboratory testing and investigating outbreaks before the next `unprecedented' event occurs.  

The beef/dairy industry and government agencies are understandably keen to reassure the public of the safety of the food supply, and the very low risk to human health from infected cattle.  

But bland reassurances, repeated without accompanying evidence, soon loses its powers of persuasion.