I have been travelling a lot and taking some vacations with various family members, so I haven’t provided any recent updates on this topic. Now that I am back, let’s see where things are.
First, a quick refresh in case you have not read any of my prior blog pieces on this subject. “Bird flu” is the colloquial name for avian influenza.
Influenza viruses (whether human pandemic or seasonal viruses, or whether avian or swine viruses) are identified by their type. Type A viruses are further designated by the identification of two of their main proteins – the hemagglutinin (H or HA) and the neuraminidase (N or NA).
There are four types of influenza viruses – A, B, C, and D. Seasonal influenza outbreaks in humans occur primarily in the winter (they often start in late fall and extend into the spring) in both hemispheres (but recall that the southern hemisphere will be having its winter during our summer. Seasonal influenza epidemics are caused by influenza A and B viruses.
Influenza C causes very mild disease in humans and is not thought to contribute to our annual seasonal outbreaks.
Influenza D viruses are not known to infect humans, and primarily infect cattle.
All of the influenza pandemics of the 20th and 21st centuries have been caused by influenza A viruses, with origins that can be traced back to avian influenza viruses, which are influenza A viruses. The 2009 pandemic, originated from an avian influenza virus that infected a pig (swine) and then ultimately spilled over to humans to cause a pandemic.
As I stated above, influenza viruses are further identified by the identification of their hemagglutinin and neuraminidase proteins, designated as H_ where the blank is filled in by a number corresponding to the type of hemagglutinin protein followed by N_ where the blank is filled in by a number corresponding to the type of neuraminidase protein. For example, the avian influenza virus that is the concern addressed by this update is the H5N1 virus. There are 18 different hemagglutinin proteins that have been identified and 11 different neuraminidase proteins, but not all possible combinations have been identified in nature.
Our seasonal influenza A viruses have generally been H1N1 and/or H3N2 viruses. Influenza viruses are RNA viruses, and if you have followed my blog through COVID-19, you likely recall that RNA viruses mutate much faster than DNA viruses. So, while currently circulating influenza A(H1N1) viruses are derived from the H1N1 virus that caused the 2009 pandemic 15 years ago, that virus type has developed many mutations since then, so like we saw with the SARS-CoV-2 virus, these recent viruses are different from those of prior years.
Unlike our seasonal human influenza viruses, when we discuss avian influenza viruses, they may further be lumped into one of two groups – highly pathogenic avian influenza (HPAI) viruses or low pathogenic avian influenza viruses (LPAI) – and this designation is based upon the mortality rate of infections in domestic birds (particularly poultry).
The avian influenza virus of concern in this update is an HPAI, and while the H5N1 virus was first identified more than two decades ago in Asia (1996 from a goose in Guangdong, China), clade 2.3.4.4b (this is the designation for the specific genetic code of the strain of virus similar to the variant designations you likely have heard of for the SARS-CoV-2 virus, such as the currently circulating KP.2 and KP.3 variants) has been circulating in wild and domestic birds in the U.S. since 2022. We have seen many spillovers of infection from birds to other mammal species, which is concerning because this raises the potential for adaptation of the virus to mammalian infection and transmission, and therefore, increases its pandemic potential, and because we have seen transmission to numerous species that we have never identified infections in before. This is of particular concern when dealing with influenza viruses, because they not only develop mutations to their genetic codes, as we have seen with coronaviruses, but influenza viruses have 8 segments and they can swap segments with other influenza viruses that may be coinfecting the same host in a process called reassortment. Unlike mutations that generally result in what we call antigenic drift, where the mutations accumulate and cause incremental changes to the virus, but generally not marked changes in virulence and transmission, reassortments can result in antigenic shift, which can result in a new virus with very different characteristics, including potentially a greater efficiency in infecting humans and forward transmission (in other words, the infected human infects another human).
In March of this year, we identified a single spill-over event between birds and dairy cattle in Texas. While we knew that cows could theoretically and experimentally be infected with the H5N1 virus, we had never identified a natural infection before. Since March, the virus has been spreading on dairy farms, to nearby poultry farms from the cattle farms, and to other states after cattle have been moved resulting in a growing number of states with a growing number of dairy farms with infections in cattle confirmed.
Affected cattle have displayed signs of disease that have included decreased feed intake, altered stool consistency, difficulty breathing, decreased milk production, and abnormal appearing milk (discoloration, thickened consistency). Caserta, L.C., Frye, E.A., Butt, S.L. et al. Spillover of highly pathogenic avian influenza H5N1 virus to dairy cattle. Nature (2024). https://doi.org/10.1038/s41586-024-07849-4.
It soon became evident that the utters of infected cows were a site of infection and virus replication in that we saw extremely high levels of virus in the milk of infected cows. While pasteurization effectively kills the virus, concern exists for those who drink raw milk as to whether this might be a potential route of infection, as it clearly is in some other mammals (e.g., cats, racoons, and mice).
Of particular concern is that we now have evidence of efficient cow-to-cow transmission. This is one of the first times we have identified efficient and sustained mammal-to-mammal transmission of HPAI H5N1.
We now have 14 confirmed cases of H5N1 infection in humans in the U.S. (1st case in 2022; 13 cases in 2024), the majority of which have occurred in Colorado. Thus far, the identified infections have only affected dairy and poultry farm workers and workers involved in culling infected poultry.
While the CDC has not raised its risk assessment for pandemic potential from low, the UK’s Health Security Agency increased its situational assessment from level 3 (in May of this year – limited or facilitated mammalian transmission) to level 4 (out of 6 – sustained and/or multispecies mammalian outbreaks; increasing human zoonotic cases or limited person to person spread, linked to zoonotic exposures) Influenza A(H5N1) 2.3.4.4b B3.13: US cattle outbreak: human health risk assessment (publishing.service.gov.uk) as of 7/17/24. The factors that contributed to this heightened level of concern include:
- The “ongoing transmission of influenza A(H5N1) in the US, primarily through dairy cattle but with multispecies involvement including poultry, wild birds, other mammals (cats, rodents, wild mammals) and humans … [with] no apparent reduction in transmission in response to the biosecurity measures that have been introduced to date.
- While there was not unanimous agreement that the evidence supports sustained transmission, the majority opinion was that this represents sustained transmission.
- “There is evidence of zoonotic transmission (human cases acquired from animals). There is likely to be under-ascertainment of mild zoonotic cases.”
- There is evidence to suggest that bovine cells can be infected by both avian influenza viruses and human influenza viruses. This could result in increased risk for reassortments among these viruses, as had been noted in swine.
Factors mitigating the concern include:
- There is no convincing evidence to date that the virus has evolved from its affinity and preference for binding receptors with α 2,3 sialic acids, which do not line the human respiratory tract to receptors with α 2,6 sialic acids, which do line the human respiratory tract.
I think that this report from the UKHSA is well done, and frankly, I wish we got this level of detailed analysis from the CDC. None of this means that we are going to have a H5N1 pandemic, and I pray we won’t, but unfortunately, if you were going to create a movie that created the circumstances under which a pandemic would evolve, this would be exactly what I would envision.
While it is unclear just how much risk there is for H5N1 to become a pandemic virus, there is no lack of clarity that we are ill prepared for a potential avian influenza pandemic, and that it appears we have failed to learn the lessons of the COVID-19 pandemic. Fearing that we would fail to learn those lessons was the reason that my co-author and I decided to write our book that was published in April of last year https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak.
A recent article Déjà Vu All Over Again — Refusing to Learn the Lessons of Covid-19 | New England Journal of Medicine (nejm.org) makes the case about our failure to learn the lessons of the COVID-19 pandemic:
- There is no widely available testing available at this time.
- We are under-testing and have no accurate idea of the amount of transmission among cows, to other animals, and to farm-workers and their families.
- Lack of full cooperation and coordination among federal and state agencies.
- The federal government and some states have enacted legislation that will make control of a pandemic virus much more difficult (and Idaho is trying).
I would add to this list:
- Supply chain vulnerabilities.
- Lack of transparency in reporting data from epidemiological studies.
- Inadequate vaccine policies and supplies.
- Inadequate supply of antivirals.
- Inadequate supplies in the National Strategic Stockpile.
- Health care staff shortages.
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