Potential animal pandemic pathogens
"On reading," by Simon Wain-Hobson, is a weekly discussion of scientific papers and news articles around gain of function research in virology.
Since January 2024, Dr. Wain-Hobson has written weekly essays for Biosafety Now discussing risky research in virology. You can read his entire series here.
On reading the United States Government Policy for Oversight of Dual Use Research of Concern and Pathogens with Enhanced Pandemic Potential and Implemental Guidance document from the animal virus perspective. And more.
This is the animal counterpart to the recent essay on plant viruses. Without animals, humans would never have gotten to 8 billion and rising. The economic numbers are even more vertiginous than for plants.
1) The global livestock and meat market size is calculated at $1.39 trillion in 2025.
• North America dominated the global market with the largest market share of 35% in 2024.
• By meat type, the poultry segment accounted for the biggest market share in 2024.
2) The poultry market is projected to grow from $384.95 billion in 2024. Consumers are increasingly demanding ethically sourced and sustainable poultry products.
3) The size of the global animal feed market is estimated to be $465.65 billion in 2024.
The two are intimately interconnected. Dangerous GOOFing around with plant pathogens could result in famine by a double whammy: loss of agricultural and animal products.
Animals pay a high price. They are preyed on by nematodes, parasites, protozoa, bacteria and viruses. And with livestock they are impacted by antibiotic resistant bacteria. When bird flu falls from heaven (Skyfall) and infects chickens on farms millions die with the rest being slaughtered. The same thing happens when foot and mouth disease virus breaks out among herds of cattle.
In addition, animals can catch infections from humans, notably the COVID virus that spread to deer, mink and many other members of the cat family. …great apes are highly susceptible to common human respiratory pathogens. Although most respiratory pathogens, such as human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV), rarely cause severe disease in healthy human adults, they are associated with considerable morbidity and mortality in wild great apes habituated to humans for research or tourism.
Animals also pay a high price due to invasive carnivores. In Australia, feral cats kill more than 1.5 billion native mammals, birds, reptiles and frogs and 1.1 billion invertebrates a year. They have contributed to the extinction of more than 20 Australian mammals and can spread diseases to native animals, livestock and humans.
Rinderpest was a nasty disease of cattle caused by a measles like virus (Rinderpest). Readers will know about the eradication of smallpox by vaccination but less so Rinderpest. It is only the second microbe that has been eradicated, and once again by vaccination.
Stepping back a little, in 1898 Loeffler and Frosch identified the first animal virus, foot and mouth disease virus. Today, with the power of modern detection methods we know there are scores of viruses for any species whether it be an elephant, shrew, duck or salmon.
Work on animal viruses has hugely advanced biology. By 1908 Peyton Rous showed that some bird viruses produced both leukemias and sarcomas. Sixty-eight years later a group in San Francisco showed that the sarcoma virus had stolen a gene from the bird genome and mutated it into an oncogene – a cancer-causing gene. It was through studying a lowly virus of mice, lymphochoriomeningitis virus, that immunologists finally worked out how the all-important T cells of the immune system recognized pathogens.
Insights from animal viruses can help understand human viruses, a notable case being HIV. In the early days nobody knew what fraction of those infected would develop AIDS. Some researchers speculated it could be as little as 10%. After having established the sequence of the HIV genome in 1984 On reading’s lab spotted some traits shared by visna virus of Icelandic sheep. Although slow, visna infection was known to progress remorselessly to neurological disease in 100% of animals over a decade.
Resolution of the sequence of the visna virus genome showed it to be a distant cousin of HIV. The shock was the realization that most HIV carriers would progress to AIDS.
Viruses have been exploited by Sapiens against animal pests. Myxomatosis virus is a poxvirus of rabbits and was used to cull the European rabbit that had been introduced to Australia starting 1950. Subsequently, a calicivirus was released in Australia in 1996, again to control wild rabbits. To complete the picture there is a licensed vaccine for pet rabbits.
Fortunately, caliciviruses don’t readily spill over to other species although a rhesus monkey calicivirus was shown to grow in human cells.
Perhaps the most well-known lab leak of an animal virus was that of foot and mouth virus from the UK top BSL-4 facility at Pirbright. Something prosaic like bunged up waste pipe. So prosaic which is a good reminder of the importance of black swan events.
A notable GOF precursor moment came from some Australian government funded work. A 2001 publication reported the unanticipated development of a novel highly lethal poxvirus for mice by the incorporation of a mouse IL4 gene into the virus genome. It sparked much discussion at the time but not enough to stop the deliberate US funded GOF 2.0 morphing of chicken flu viruses into novel human pathogens that sparked the gain of function controversy in late 2011.
A flu virus designated H3N8 has been circulating in dogs since 2004 and was probably picked up by greyhounds from horses at a US racecourse they shared. As there has been only a single recorded infection of a child with canine H3N8 flu virus in China in 2022 it is not considered to be a threat to humans.
Another bird flu virus, H3N2, crossed over an took hold in dogs as of 2006. There may be a few others at very low levels, reflecting poor surveillance for human influenza viruses can be transmitted to dogs. It is important to keep track of this dog H3N2 virus for it can infect multiple mammalian animals, including ferrets, guinea pigs, mice, and cats.
A splendid paper on dog H3N2 flu virus was published by a Chinese group in 2024 representing a colossal amount of work. They analyzed isolates of the virus from 2012 to 2019 and showed that by 2015 they had acquired a 100% transmission rate via respiratory droplets in a ferret model, while earlier isolates had not. Readers will know from previous essays that this is considered to be synonymous with human-to-human transmission. Not only that, infection with these 2015 viruses resulted in more severe clinical symptoms such as pyrexia, sneezing, wheezing, and coughing,… and a higher mean body temperature ranging from 39.9 to 40.2°C. They could pinpoint ferret transmission to three mutations, two in the all important hemagglutinin that recognizes the target cell and one in the neuraminidase both or which are on the outside of the virus.
It should be mentioned that canine influenza virus (CIV) can be transmitted by close contact, essentially licking which explains how the virus spread up to 2015. From then on transmission appears by the respiratory route seems to have been more efficient.
In parallel to acquisition of aerosol transmission, they found replication ability in human cells increased stepwise during their circulation in the dog population. In A549 cells, levels of later viruses were significantly higher (up to nearly 100-fold higher). The A549 cell line is of human origin and widely used in influenza research.
For good measure they performed serological studies showing that human populations lack immunity to H3N2 CIVs, and even preexisting immunity derived from the present human seasonal influenza viruses cannot provide protection against H3N2 CIVs.
Combining this with the acquisition of aerosol transmission their conclusion was, to lower the prevalence of novel influenza viruses that are a potential public health threat, controlling the prevailing H3N2 CIVs in dogs and continuous monitoring of their biological characteristics should be implemented.
Its makes sense, although you’d have expected more spillovers to humans especially as immunity to the current H3N2 seasonal flu virus being of no help. Maybe there are with the resulting infections being much milder. We saw that the H5N1 bird flu infection in cattle is much milder than in humans. Once again, it shows that extraordinary vagaries around viruses, transmission and disease. And with all these findings nobody can predict whether this virus could pick up further mutations and burgeon into a human pandemic. Certainly, H3N2 is a virus to track.
This paper shows how to investigate the potential inherent in animal flu viruses.
There is a but, however. All experiments with live viruses were performed in animal biosafety level 2 (ABSL-2) environments. For a respiratory transmissible virus for which humans have no immunity On reading finds this insufficient. We know the reasons why – the fixation with it being a dog virus at the outset fixes the biosafety level. This is odd when the literature had already shown that it can infect a wide range of mammals and grow in human cells. This is the only negative, albeit a big one, in what is a superb paper of use to public health authorities.
This paper makes for a test case for public health. The H3N2 flu virus is clearly transmissible by respiratory droplets, grows well in human cells and present in homes the world over. As there is a risk of crossing over to humans this brings us to pandemic preparedness. What should be done?
Fortunately, there is a vaccine for dogs made by Merck and licensed in 2024 while Zoetis make a combined H3N2/N3N8 vaccine recommended for use in healthy dogs 7 weeks of age or older.
Someone should try it out on humans in a phase I study. Companies will balk as the risk is there but unquantified. It’s a classic situation where the national authorities could sponsor a human trial.
Of course, this brings us ultimately to the very difficult problem of developing an efficient flu vaccine, but let’s concentrate on canine H3N8 for the moment, as the world’s population is immunologically naïve.
What are the obvious no-nos in animal virology? Resurrecting rinderpest virus or working with it which could result in a lab leak. Given their huge economic value, making novel animal viruses that could prey on economically important livestock like cattle, pigs or chickens ‘to see if it was possible.’ We know it is possible for many, nut not necessarily viruses. We also know there are no benefits to the dangerous GOF work on avian flu viruses performed 14 years ago. Over time all the claims made back then of have disappeared – dixit Drs. Fouchier and Kawaoka. Another no-no would be to increase deliberately the virulence of an existing animal virus, ‘to see if it was possible.’
There needs to be better recognition from a regulatory standpoint of virus capable of infecting multiple species. Work on a dog virus doesn’t sound dangerous but when you know that recent isolates grow well on human cells and can be transmitted by the respiratory route, then, if only to protect the lab workers, biosafety level 3 is appropriate.
Consider the following. The human virus H2N2 sparked the Asian flu pandemic in 1957. It was replaced by H3N2 Hong Kong flu in 1968 after which it went extinct. 47 years later the majority of Sapiens is immunologically naïve for this virus – just as it is for canine H3N2 flu virus.
Experiments with influenza viruses containing genes or segments from… human H2N2 (1957-1968)… and highly pathogenic avian influenza H5N1 strains within the Goose/Guangdong/96-like H5 lineage (HPAI H5N1), including, but not limited to, strains of HPAI H5N1 virus that are transmissible among mammals by respiratory droplets, as demonstrated in an appropriate animal model or clinically in humans (hereinafter referred to as mammalian-transmissible HPAI H5N1 virus), shall be conducted at BL3 enhanced containment. Page 22 - NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (April 2024).
Here we find a biosafety parallel between H2N2 flu virus and the mammalian transmissible dangerous GOF research on flu viruses made Drs. Fouchier and Kawaoka. Just a touch away from contemporary H3N2 dog flu viruses.
A reader of these essays, Jeff Bell, made a good comment at the end of an essay which is worth sharing. It anticipated uncannily the present essay: “We are one experiment away from devastation”. This summation is alien if you will, because it is ‘too big’. If instead it were true that “we are one experiment away from the devastation of cats and dogs” that might be an easily adopted, common concern. There’s an insanity of not being able to accept that there is something so terrible which needs attention.
Fortunately, the new NIH Director knows where he’s going: But the main thing for me is we have to restore gold-standard science to this agency. We have to restore the focus on making America healthy, and we have to make sure that we don't ever use this agency to conduct research that puts the American people in danger, the way that the research on gain-of-function that the previous sort of leadership of the agency sponsored. We have to make sure that that never happens again. And with this executive order by the President, that gives me the tools to do that for sure.
Conclusion
Change is coming and not a moment too soon. Hopefully, it will cover GOOFing around with animal and plant pathogens. The last thing we can handle is yet more disease anywhere.
Aside 1
This wonderful Afghan hound turned up in the form of a birthday card from my sister who ever so discretely wished to remind him who was the older sibling. Many thanks to Lucy Ledger of the The Great British Card Company for permission to reproduce this photo by Christian Vieler.
Aside 2
With bird H5N1 currently wreaking havoc among chicken farms, the US has resorted to importing eggs from South Korea and Turkey. Novel bird flu viruses will enter the US with these eggs. A particularly reliable email correspondent wrote this was a REALLLY REALLY REALLY BAD IDEA.
Aside 3
A very recent Congressional report documents the problems of bird flu in the US. An HPAI outbreak occurred in the United States in 2014-2015 when two HPAI strains, H5N2 and H5N8, infected 211 commercial flocks and 21 backyard flocks in 15 states. More than 50 million birds, primarily egg-laying hens and turkeys, died directly from the disease or were euthanized to help control the spread of the disease, resulting in direct economic losses reaching $1.6 billion.
Aside 4
In the US the Plum Island research facility on the upper end of Long Island was used for years to study some of the most virulent animal viruses, supposedly to limit collateral damage if ever there was a lab leak. It was eventually closed and removed to a new installation in Kansas. Initially estimated to cost $451 million, the price tag more than doubled after the National Research Council published a report in 2010 that questioned putting the facility in the heart of cattle country with a history of large, destructive tornadoes.
Aside 5
ALSO, our astute lay science observer, spotted the $ numbers associated with global plant and animal economies in these two essays yet noted that for COVID only the economic losses and the support programs were decorated by $$$. Loss of 20+ million lives went uncosted. This is a variant of the Jeff Bell perspective.
Loss of life due to pathogens has always dwarfed death through wars and stupidity, a pleonasm if ever there was one.
Aside 6
With mention of papers on dog flu viruses and licensed dog flu vaccines, a conspiracy theorist could quickly come up with 2+2=5. First, the H3N8 flu virus came from horses. The H3N2 dog flu virus was first isolated in 2006 from Guangdong Province in China, and was found to be genetically most closely related to the H3N2 avian influenza viruses prevalent in aquatic birds in South Korea for all eight gene segments. This is a far cry from US pharma’s home base. Second, it doesn’t take 18 years (2006 to 2024) to make a licensed vaccine for animals. If it was part of a money-making endeavor, they would have cashed in before. Yet, as readers know only too well, arguments are no bulwark against fiction. This is merely for the record.
Aside 7
Sapiens can be afflicted by foot-in-your-mouth disease. As the pathogen has not been identified, therapeutics are lacking.
Abundant research material, thank you.