Thread by @Friesein

We are clearly in the midst of an anomalously severe flu season.

Although H5N1 has not been detected in high numbers among humans, there's a good chance that it's quietly playing a significant role without even infecting humans directly.

How, exactly? Let's lay it all out: 🧵

If you want the answer up front without having to read through a detailed explanation, you can skip to the summary and conclusion in the last few posts of the thread.

Otherwise, read on!

To understand how influenza evolves, you need to trace the progression of the virus from its source.

All mammalian influenza A viruses are thought to originate in birds. They then find their way to certain mammals, where the viruses mutate significantly.

https://x.com/Friesein/status/1888945041583866339

After finding and infecting a mammal host that scientists coldly describe as a "mixing vessel" for multiple influenza subtypes at once, viruses swap genetic material with one another. They meet each other in the same cell.

This is called reassortment.

en.wikipedia.org/wiki/Reassortm…

Some animals are more susceptible to different influenza subtypes than others.

Pigs, for example, can be infected by both avian and mammalian subtypes of influenza A.

This makes them a perfect mixing vessel for reassortment. Hence swine flu of 2009 and other similar epidemics.

What evidence do we have that characterizes the risk of reassortment between seasonal flu subtypes (e.g., H3N2) and avian flu (e.g., H5N1)?

How many reassortants turn out to be H5 vs H3?

Let's take a look at a study where ferrets were infected simultaneously with H3N2 and H5N1.

Several ferrets were co-infected with H3N2 and H5N1 to ascertain the extent of reassortment, with a focus on H5 instead of H3 genotypes.

Among 360 total viruses that were isolated from infected ferrets, 9% were found to be reassortants (32 viruses).

pmc.ncbi.nlm.nih.gov/articles/PMC27…

But to me, the most interesting part of this study was buried in a supplemental table.

Among the 32 reassortant viruses found, 16 unique genotypes emerged. 5 of those were H5, and 11 of them were H3.

66% of the reassortant viruses found were of H3N1 subtype instead of H5N1.

We shouldn't ascribe too much importance to this one study with a small sample size, but to me this illustrates that it's not just H5N1 itself that we need to be concerned about.

It's also the threat of existing human-transmissible subtypes acquiring genetic material from H5N1.

It stands to reason that H1/H3 influenza viruses with genes acquired from H5 viruses would face less evolutionary resistance than vice versa.

They're already optimized for transmission in humans, after all, by virtue of their hemagglutinin proteins.

I'd like to point to another example that we're all familiar with: the 1918 influenza pandemic.

What if it emerged similar to how we just described?

A human-compatible influenza H1 virus acquiring gene segments from an avian virus through reassortment?

pnas.org/doi/10.1073/pn…

What about the 1957 H2N2-derived pandemic and its counterpart a decade later? Reassortment with a human-compatible subtype.

The 2009 swine flu padnemic? Reassortment with a human-compatible subtype.

pubmed.ncbi.nlm.nih.gov/8817180/

The process of reassortment is not unusual for influenza.

The viral landscape is constantly shifting, given the many hosts providing a receptive environment for viral replication.

What's different now? A highly pathogenic H5N1 recently became more adept at infecting mammals.

To summarize the hypothesis:

Human-transmissible H1/H3 influenza A subtypes may have already acquired genetic material from H5N1 through reassortment, via mammals simultaneously infected with H1/H3 virus and H5N1.

This could explain why we're seeing increased clinical severity.

In conclusion:

If you're waiting for human-to-human transmission of H5N1 subtyped virus as the sign that the bird flu pandemic has begun, you might not need to wait any longer.

Evolution may have arrived at a simpler approach, and it's quite possible that we're already there.

Thanks to everyone sharing insight and continued coverage on this topic, including: @mrmickme2 @Nucleocapsoid @HNimanFC @RickABright @outbreakupdates @MLS_Dave @TRyanGregory

I'm probably missing a few other good accounts on this subject. Share in the replies who else to follow.

As always, please feel free to correct me if I missed anything.