How is Transmissibility to Humans Evolving and How are we doing Managing the Pandemic Risk?
To answer these questions, I am going to review two recent articles with you: “Pathogenicity and Transmissibility of Bovine H5N1 Influenza Virus” Pathogenicity and transmissibility of bovine H5N1 influenza virus | Nature published in Nature in July of this year and “How Policy Makers Can Act Now To Prevent An Avian Influenza Pandemic” How Policy Makers Can Act Now To Prevent An Avian Influenza Pandemic | Health Affairs published in Health Affairs this month.
As I have written about previously, H5N1 is an avian influenza virus (“bird flu” as it is colloquially referred to) that normally infects waterfowl, who in turn infect domestic poultry and sometimes wild birds through contamination of their food and habitats with droppings as these waterfowl fly over or temporarily land in these habitats. The H5N1 influenza virus (a type A influenza virus, but not one of the human seasonal influenza viruses) infects birds by binding to α 2, 3 – sialic acid residues on cell surfaces that are abundant in birds. Fortunately, prior to 2022, this virus transmitted inefficiently to other mammals and humans, likely due to the fact that most mammals, and certainly it is the case for humans, do not have α 2, 3 – sialic acid attached to a sugar on the cell surfaces in the upper airways, but rather the sialic acid conformation in human upper airways is of the α 2, 6 type. While there have been infections in humans, until this year, these have generally occurred in persons with extensive contact with sick and diseased birds, such as poultry farm workers or those who worked at the culling facilities during outbreaks on poultry farms. Unfortunately, when avian influenza of the H5N1 type has infected humans, the infection mortality rate (# deaths/# recognized infections) has been exceedingly high varying anywhere from 40 – 80 percent, and seemingly posing the greatest threat to young children.
In March of this year, it was recognized for the first time that H5N1 was causing outbreaks among dairy farms in the U.S. Studies revealed that the virus infected the utters of dairy cows and the milk from these cows had extremely high levels of virus in it. It was latter reported that cows’ utters have both α 2, 3 – sialic acid receptors and α 2, 6 – sialic acid receptors raising concern that the infected utters could serve as “mixing bowls” in which the potential exists for cows infected with H5N1 influenza virus (a new revelation) could be co-infected with seasonal human influenza viruses (a long-recognized potential and growing concern as we approach our influenza season given the continued spread of H5N1 virus among dairy cattle). Influenza viruses are known for their “reassortment” proclivity, in which any one of eight gene segments can be swapped from one virus to another. The resultant virus could then potentially have the virulence (potential to cause severe illness or death) of avian influenza coupled with the increased transmissibility of human influenza viruses, significantly raising the potential for a pandemic, as has happened in the past when avian influenza and human influenza viruses infected swine.
The outbreak of H5N1 among dairy cattle has been concerning not only because natural infection of cattle was unknown prior to this year, but also because it is the first time we are seeing convincing evidence of forward transmission among mammals, increasing the concern that the virus is evolving in a manner that might allow the same to happen in humans, a requisite for the virus to be of pandemic potential.
[A note to readers to help avoid confusion. First, although the H5N1 is an avian influenza virus, now that it is spreading among dairy cattle and there is evidence that transmission between cattle is occurring (as opposed to each cow being infected directly from a bird), the virus obtained from cattle (generally in the milk of the infected cow) is referred to by some as “bovine H5N1 influenza virus.” Secondly, since there are limitations to the studies we can conduct on humans relative to infectious diseases, it is common to identify animal models of infection that tend to have similarities to human infections or modes of transmission to facilitate our study of the infectious agent and/or disease it causes. Ferrets are commonly used as an animal model for influenza virus due to the similarities of our respiratory systems. Mice are commonly used to examine the ability of the infectious agent to transmit to the unborn offspring during pregnancy or to their offspring through lactation.]
Mice can become infected with bovine H5N1 virus through ingestion of the infected cow’s milk, and the virus quickly spreads throughout the mouse organs. When the mouse ingests a high dose of virus in the milk, virus can be detected in the nasal passages, lungs and brain of the mouse by day 6. The study showed that mice can also be infected by intranasal inoculation of virus.
The study also revealed that ferrets could be infected by intranasal inoculation of virus and that ferrets can become ill. Virus in the ill ferrets could be detected in respiratory and non-respiratory tissues, including the eyes, brain, colon, liver, spleen, kidney and/or heart.
The investigators showed that infected mice could transmit the bovine H5N1 influenza virus to their pups likely through the milk of the mother. However, it did not appear that the mice could transmit the virus to other adult mice (through respiratory droplets or aerosols).
The investigators tested the potential for infected ferrets to transmit the bovine H5N1 virus by respiratory droplets by infecting some with this influenza virus and others with an H1N1 virus, for which respiratory droplet transmission among ferrets has already been demonstrated, by placing uninfected ferrets in cages in proximity to cages with infected ferrets. The ferrets were tested with nasal swabs every other day. The infected ferrets developed positive tests with high viral titers (suggesting that they should be infectious to the uninfected ferrets if respiratory droplets are a mode of transmission). None of the ferrets exposed to ferrets infected with the bovine H5N1 showed any signs of infection, nor developed positive nasal swab tests. However, one of four exposed ferrets did have low-level antibodies to the H5 virus, which suggests that there is only inefficient transmission of the virus by respiratory droplets in ferrets.
Of concern, the investigators showed that, at least in the laboratory, the bovine H5N1 virus showed the ability to bind both α 2, 3 – sialic acid and α 2, 6 -sialic acids, raising the potential that the virus has already adapted in cows’ utters to be able to infect the upper airways of humans.
The authors of the Health Affairs article argue that this latter finding is concerning, but does not necessarily mean that this virus will spark a pandemic. However, they caution that this situation demands a more vigorous public health response to ensure that it doesn’t. The authors point out that the true assessment of the extent of the H5N1 outbreaks among poultry and dairy farms is severely hampered by the voluntary nature of testing of these farms and the relatively low level of engagement by farmers. Even more lacking is testing of farm workers, which is essential to identifying the extent of spillover transmission to humans and for serial genetic sequencing to detect whether the virus has picked up genetic mutations known to enhance mammalian spread.
I quote the following paragraph from the article that precisely mirrors my thoughts on our response thus far:
Any effective pre-pandemic strategy must be based on sound and timely data. Waiting for H5N1 to declare its presence among humans would be to waste precious time and risk converting preventative measures into futile exercises in rescue and recovery. The COVID-19 pandemic taught the danger of getting caught flat-footed, yet policy makers do not seem to have learned the lesson.
The authors make another suggestion with which I whole-heartedly agree and was a lesson that should have been learned from the COVID-19 pandemic. That is to set up multiple testing centers across the U.S. to screen for H5 influenza cases and to allow for more prompt sequencing and reporting of positive specimens. They also point out the need for rapid tests for providers, and ideally even for home use, especially by those workers and their families that are currently identified at highest risk of infection.
Adding my own personal thoughts is that this will be increasingly important as we enter into our seasonal flu season in which positive cases of influenza A will likely be assumed to be the seasonal human virus, missing potential cases of H5 infection.
The authors point out the need for rapid initiation of antiviral therapy, the need to avoid delayed antiviral treatment to reduce the risk of antiviral-resistance, and the need for more research and development into more effective antivirals that are effective against all strains of influenza.
The authors point out the very real limitation of our monitoring for infections and investigations of outbreaks among dairy farms in that farmers are reluctant to have virus detected due to the financial harm that could follow and farm workers are reluctant to seek medical attention for illness due to financial limitations, lack of health insurance, and fear of loss of their jobs if they are sick. An adequate public health response will have to address these concerns.
Finally, the authors rightly point out that our current influenza vaccine technology is too slow to allow for a prompt pandemic threat response. Further, given that the avian influenza H5N1 virus is highly pathogenic in poultry and results in a high mortality rate and the need to cull large numbers of poultry to contain outbreaks, it may not make as much sense to rely on an egg-based vaccine method. We must develop new vaccine strategies.
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