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Feb 17 17 tweets 6 min read Read on X
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: 🧵 A graph of influenza specimens tested for influenza in California. 2024/2025 shows a trend peaking above previous 4 years at 27% vs ~22% and lower peaks.
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 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.
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.

Emergence and transmission of influenza A viruses from aquatic wild bird reservoirs and zoonotic and reverse zoonotic events involving veterinary species. Adapted from Frymus, T., Belák, S., Egberink, H., HofmannLehmann, R., Marsilio, F., Addie, D.D., Boucraut-Baralon, C., Hartmann, K., Lloret, A., Lutz, H., et al. 2021. Influenza Virus Infections in Cats. Viruses 13, 1435. https://doi.org/10.3390/v13081435. Used under the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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. Image
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. Reassortment between Avian H5N1 and Human H3N2 Influenza Viruses in Ferrets: a Public Health Risk Assessment  Sara Jackson, Neal Van Hoeven, Li-Mei Chen, Taronna R Maines, Nancy J Cox, Jacqueline M Katz, Ruben O Donis
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. Image
Image
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. Reassortment (in pigs) -> Current Transmission (in pigs and humans) -> Potential Pandemic (Unknown hosts to Humans)
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…The origin of the 1918 pandemic influenza A virus (IAV) and the reasons for its unusual severity are two of the foremost biomedical mysteries of the past century. We infer that the virus arose via reassortment between a preexisting human H1 IAV lineage and an avian virus. Phylogenetic, seroarcheological, and epidemiological evidence indicates those born earlier or later than ∼1880–1900 would have had some protection against the 1918 H1N1 virus, whereas many young adults born from ∼1880–1900 may have lacked such protection because of childhood exposure to an antigenically distinct H3N8 virus.
The source, timing, and geographical origin of the 1918–1920 pandemic influenza A virus have remained tenaciously obscure for nearly a century, as have the reasons for its unusual severity among young adults. Here, we reconstruct the origins of the pandemic virus and the classic swine influenza and (postpandemic) seasonal H1N1 lineages using a host-specific molecular clock approach that is demonstrably more accurate than previous methods. Our results suggest that the 1918 pandemic virus originated shortly before 1918 when a human H1 virus, which we infer emerged before ∼1907, acquired avian...
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 Hong Kong Flu was a flu pandemic caused by a strain of H3N2 descended from H2N2 by antigenic shift, in which genes from multiple subtypes reassorted to form a new virus. This pandemic of 1968 and 1969 killed an estimated one million people worldwide.[14][15][16] The pandemic infected an estimated 500,000 Hong Kong residents, 15% of the population, with a low death rate.[17] In the United States, about 100,000 people died.[18]  Both the H2N2 and H3N2 pandemic flu strains contained genes from avian influenza viruses. The new subtypes arose in pigs coinfected with avian and human viruses a...
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. https://nextstrain.org/avian-flu/h5n1/ha/2y?c=host  Phylogeny of H5N1, showing emergence of cattle and human infections of H5N1 starting predominately in 2024.
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.

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More from @Friesein

Jul 3
30 staff scientists at the FDA had signed off on approving Novavax for anyone 12 or older.

They had reviewed multiple clinical trials with 30-45K participants, showing no more than 3 total cases of myocarditis.

Then Vinay Prasad overruled them and limited access to 65+. 🧵
Anyone who has seriously followed the research on COVID will tell you that the risk of myocarditis (among numerous other conditions) from COVID is far greater than that of Novavax.

Yes, that includes Omicron and later variants.

Put aside spike protein for a minute.

The 3CL protease, a critical part of the viral machinery that allows SARS-CoV-2 to replicate, binds with hundreds of proteins in the liver and gut alone.

And that's just scratching the surface.

Read 13 tweets
Jun 12
Novavax Availability Update 📢

Costco in Little Rock, AR has reportedly confirmed that they'll have Novavax stock in place by September.

My gut feeling is that this is much closer to the timeline we'll end up seeing for most stores instead of July/August.

Here's why. 🧵
In 2024, the first CVS I heard of that had received their stock was in Pittsfield, MA on September 9.

For Costco, it was in Limerick/Sanatoga, PA on September 13.

Prior to that, the national Costco distribution center had received their stock on September 10, and they began shipping to stores shortly afterwards.

Read 7 tweets
Jun 11
Novavax Availability Update 📢

I've heard several reports that some Costco pharmacies are expecting Novavax supply between July and the end of August.

I recommend checking with Costco via their web app to find out when you'll be getting it in your area (instructions below). 🧵
Here's how to contact Costco corporate for pharmacy inquiries.

I recommend doing this over talking to your local pharmacy because stores are not always in the loop on shipping status.

Doing this also sends a demand signal to Costco for ordering stock.

Image
This will be the first time Novavax is available outside of Emergency Use Authorization.

Getting access to it this year may require a bit of extra effort, since the new license stipulates that most must have an underlying condition to access the vaccine.

Read 10 tweets
May 29
And some of the symptoms like intense throat pain and fatigue seem to kick in a week or so after the first appearance of symptoms.

Read 11 tweets
May 23
SARS-CoV-2 is known to bind with mitochondrial proteins in humans.

Mitochondrial dysfunction caused by COVID persists past the acute phase.

Evidence of ongoing mitochondrial and metabolic dysfunction has been found in the heart, kidneys, liver, and lymph nodes, for example. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis.
These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.
In the case of SARS-CoV-2, it was shown that mitochondria appear swollen and damaged in skin biopsies from patients, and that depletion of mtDNA in endothelial cells significantly reduced the type I IFN response62. In SARS-Cov-2 infected cells, viral RNA was found to be associated with mitochondria using fluorescence and electron microscopy31. Several reports have suggested the colocalization of mitochondrial-SARS-CoV-2 RNA in infected human tissue.
According to recent studies, SARS-CoV-2 infection causes prolonged disruptions in mitochondrial function, significantly altering cellular energy metabolism. Our research employed transmission electron microscopy to reveal distinct mitochondrial structural abnormalities in Long COVID patients, notably including significant swelling, disrupted cristae, and an overall irregular morphology, which collectively indicates severe mitochondrial distress.
There seems to be an inverse relationship between viral load and the expression of mitochondrial genes during the acute phase.

Could the same be true of the chronic phase? Could persistent virus be causing ongoing mitochondrial dysfunction? Mitochondrial gene expression was reduced in autopsy tissues from patients admitted to the hospital with high compared with low viral loads, which confirmed that the extent of altered mitochondrial gene expression may be regulated by viral load (fig. S5). Down-regulation of mitochondrial pathways in response to virus in human autopsy samples was most extensive in hearts followed in decreasing order by the kidneys, livers, and lymph nodes (fig. S5). This inhibition of mitochondrial gene expression in visceral autopsy tissues parallels that seen in the nasopharyngeal samples with high viral t...
Overall, autopsy heart tissue from patients with SARS-CoV-2 infection showed a systematic down-regulation of genes involved in multiple mitochondrial functions; this was also found, to a lesser extent, in kidneys and livers and, to the least extent, in nasopharyngeal samples and lymph node autopsy samples. The lung autopsy samples showed down-regulation of CoQ synthesis and mtFASII but up-regulation of genes involved in the TCA cycle and cytosolic protein import (Fig. 3A).
It is clear is that SARS-CoV-2 is capable of causing mitochondrial damage that persists for months or even years.

And we independently know the virus persists in some form, chronically.

For patients, this means that new symptoms can appear after acute COVID infections. Image
We have observed an interesting phenomenon in the mitochondria, the swollen and vacuolated mitochondria, distorted and broken cristae, all indicated severe damage to this important cellular organelle. This damage is highly likely caused by the SARS-CoV-2 Infection, as we have found an almost identical mitochondria disorganization in the mice that were infected with SARS-CoV-2. Our findings are consistent with a recent study in which mitochondrial gene expression was analyzed in autopsy tissues from patients with COVID-19, and core mitochondrial gene expression were suppressed in the hearts,...
Image
Highlights: - SARS-CoV-2 spike protein persists in the skull- meninges-brain axis in COVID-19 patients.  - Spike protein is sufficient to induce brain pathological and behavioral changes in mice.  - Spike protein enhances brain vulnerability and exacerbates neurological damage in mice.  - mRNA vaccines reduce, but do not eliminate, the spike burden
Read 6 tweets
May 21
I can appreciate skepticism of long COVID as a concept. After all, it may instinctually seem like an epistemological overreach to assign a singular cause to such a heterogeneous disease presentation.

On the other hand, consider the localization of ACE2 throughout your body. Consider the reach of your blood vessels. Couple that with imaging studies that demonstrate spike persistence in areas such as the brain and skull. Consider also that viral persistence has been identified in the gut with replication competent virus.

In the last few years, I've interacted with tons of people on this platform, both vaccinated and unvaccinated, who have lost a significant amount of mobility after having had COVID infections. Healthy and unhealthy, comorbidities or not. People in their 40s are also dying of rare cancers. Athletes and soldiers are having a decrease in functional performance after a single COVID infection, let alone reinfections.

The deeper you look into viral persistence (look at the work Polybio and Erturk Lab are doing on imaging, for example), the more you'll find yourself willing to consider that COVID might play a role in it.

The key is in recognizing that the microvascular changes COVID causes are difficult to detect with off-the-shelf diagnostics. Once research develops more readily commoditized diagnostics, perhaps the condition will gain wider recognition. In the meantime we have a large segment of young, middle-aged, and previously healthy athletes succumbing to unusually debilitating chronic illness after COVID infections. That illness is real despite misgivings some may have. And so too is the underlying damage COVID causes, even if it's not straightforward to detect in all instances. Whatever you want to call the disease, those patients deserve medical treatment despite limitations in the diagnostic tools conventionally available.Image
Where in the body is it found? ACE2 is present in many cell types and tissues including the lungs, heart, blood vessels, kidneys, liver and gastrointestinal tract. It is present in epithelial cells, which line certain tissues and create protective barriers.  The exchange of oxygen and carbon dioxide between the lungs and blood vessels occurs across this epithelial lining in the lung. ACE2 is present in epithelium in the nose, mouth and lungs. In the lungs, ACE2 is highly abundant on type 2 pneumocytes, an important cell type present in chambers within the lung called alveoli, where oxygen i...
Image
Image
Long COVID in young Marines.

thelancet.com/journals/lanam…
Evidence of viral persistence from COVID.

ucsf.edu/news/2024/03/4…
Read 6 tweets

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