A new pandemic

When an avian influenza virus manages to infect a mammalian host, it begins to produce millions of copies of itself, but as a single-stranded RNA virus it lacks the `error-checking' skills of DNA viruses, and is prone to making errors.  

When a transcription error makes the virus better suited to a mammalian host, it is more likely to thrive, allowing it to make many more copies with this `host adaptation'. 

As a result of these `spontaneous mutations', at some point during an infection you may have multiple `variants' of the virus all circulating within a single host, each  battling for dominance. Most mutations offer no benefits - or are even detrimental to the virus - but a number are known to convey a significant advantage. 

An avian virus that acquires the PB2-E627K substitution, for instance, is able to replicate efficiently at the lower temperatures (roughly 33C) found in the upper respiratory tract of mammals, while the HA-Q226L mutation switches binding preferentially to human receptor cells.

Mutations that occur in an infected host, but are not transmitted onward, are of less concern than those found in the `wild'. A prime example, the H275Y mutation which occurs in roughly 1% of patients receiving oseltamivir was thought incapable of spreading efficiently as late as 2007.

That is, until several `permissive' mutations in the NA changed the rules (see Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance) unexpectantly sending a resistant H1N1 virus on a world tour in 2008.

Last night the CDC published a report on the genetic sequences from the first severe H5N1 infection in the United States, which was linked to backyard bird exposure in Louisiana. 

While `red flag' mutations (e.g. PB2-E627K, HA-Q226L, etc.) were absent, they did find some mutations in the HA that suggest potential mammalian adaptation. Mutations that were not found in the birds they tested, suggesting they were `in-host' spontaneous mutations. 

Both the Canadian and the U.S. severe cases were caused by the new D1.1 genotype, which is spreading rapidly in birds. They also share an E186D mutation, which has previously been linked to increased virulence and improved binding to a2,6 human receptor cells.

While many seem reassured by the relatively mild presentation (so far) of the `bovine' B3.13 genotype in humans, this D1.1 genotype has already produced 2 severe illnesses, and is very aggressive in both poultry and wild birds. 

The superpower of influenza A is its ability to continually reinvent itself, either through random mutations (antigenic drift), or via reassortment (antigenic shift).  

Genotype D1.1 may currently lack the ability to spread efficiently between humans, but it is truly a work in progress. Each new spillover, particularly into a mammalian host, provides the virus with another opportunity to evolve and adapt.  

And the D1.1 genotype isn't alone. 

More than 100 genotypes have been documented in North America since H5N1 arrived in 2021, and more are expected. Globally, the number is much higher. Most fail to thrive, but each represents another free spin for the virus on the genetic wheel of fortune. 

It is obviously not easy for nature to create a pandemic virus.  If it were, we'd be knee deep in pandemics all the time.  

But nature is nothing, if not persistent.  And we underestimate its ability to serve up curve balls at our considerable peril.