Pleased to report, at long last, the publication of ML2006a4, our SARS-CoV-2 protease inhibitor for COVID-19, in @ScienceTM.

Compared to nirmatrelvir, the inhibitor in Paxlovid, ML2006a4 binds more tightly and has greater antiviral activity in vivo.

science.org/doi/10.1126/sc… @ScienceTM This paper tells the origin story of nirmatrelvir and ML2006a4 (they are brothers) and reveals why these two drugs work so well.

It also explains the chemical basis for ML2006a4's superior activity, which goes back to a deliberate decision we made back in 2000.

So much for viruses evolving to less pathogenicity.

As I've said before, we might expect viruses to become more transmissible, e.g. by replicating faster or suppressing immunity. That's not less pathogenic.

A new report shows recent variants suppress innate immunity more.

https://twitter.com/NaturePortfolio/status/1749188642449260549

There are a lot of plots, but the general gist is that BA.4/5 infection in cells generates less IFN and other innate immunity cytokines than earlier BA.1/2, and BA.4/5 shows less gain from innate immunity suppression by a drug (ruxolinitib) (because it suppressed it already)

Actually a person who could have sparked COVID19, accidentally or not, has been ID'ed in the open for a long time.

The name is Zhou Yusen. Evidence?
1. He filed a patent for SARS2 vax in 2/2020, when others only knew of SARS2 from 1/2020
2. He died from a rooftop fall in 5/2020

https://twitter.com/harishseshadri2/status/1685139352240914432

Those facts are not disputed, but somehow not widely discussed.

The theory isn't mine. It is described in detail by former Assistant Secretary for Preparedness and Response at the US Department of Health, Dr Robert Kadlec, above and more recently below

skynews.com.au/australia-news…

Just published: Another useful difference between Novavax over RNA vaccines has just been discovered.

3x RNA vaccines induce IgG4 antibodies, which clear antigens poorly and is associated with immunotolerance.

By contrast, 3x Novavax does not induce IgG4.

https://twitter.com/vipintukur/status/1748321694962315644

IgG3 antibodies bind Fc receptors on phagocytic cells like macrophages so that viral particles bound to them will be ingested and destroyed. This antibody-dependent phagocytosis (ADP) is a crucial part of the immune response to viruses...

The full DEFUSE proposal on gain-of-function experiments on bat coronaviruses is available, and I'd say it's quite shocking. It does not lay out a plan to create SARSCoV2, but does propose to identify and culture natural sarbecoviruses with the ability to infect human cells. A 🧵 There are threads interpreting the DEFUSE proposal as intending on making SARSCoV2. A careful read shows that is not the case. However the intention was to identify natural viruses with features that would help them infect cells. So it may be not much of a difference functionally

In 2023 about 70,000 Americans died of SARSCoV2, although >95% have some immunity. That's about 2x the usual annual deaths attributed to flu.

In people with immunity, SARSCoV2 has an infection fatality rate similar to flu, but it's much more contagious and widespread. We spent years of effort trying to eke out small decreases in flu fatality. COVID19 has undone that and more, with >1M deaths in 3 years and now a higher hospitalization and fatality burden than flu.

Moderna's RNA vaccine was a copy of BioNTech's, per the EU

That means Novavax was the *only* US company to create a COVID-19 vaccine with their own research

No, Pfizer didn't create a COVID-19 vaccine. They licensed from BioNTech, a German company

fiercepharma.com/pharma/covid-1… Even more impressively, Novavax did it as a company on the edge of bankruptcy. That means FDA staffers aren't going to treat its applications with kids gloves (they didn't), because they aren't sure there's a high-paying job at Novavax awaiting them

https://twitter.com/michaelzlin/status/1727120796337021259

"Anti-COVID drug accelerates viral evolution”

nature.com/articles/d4158…
Pretty much as I wrote here, the week molnupiravir was approved, in December 2021: "A new drug to treat covid could create a breeding ground for mutant viruses"

By understanding mechanism, you can predict these things, 2 year before data can prove it.

washingtonpost.com/outlook/2021/1…

24h after my Novavax COVID shot (and flu shot), and very happy. Much milder side effects than my 5 earlier COVID vaccines.

It's just my experience of course, but I'm hopeful we may finally have a sustainable and acceptable format for annual vaccinations.

A short 🧵 Earlier COVID19 vax were 4 Pfizer original and 1 Moderna bivalent, plus a BA.5 infection in 2022 summer 3 weeks after #4.

All RNA vax shots produced noticeable side effects of fatigue and/or headache within 24h.

This time no fatigue or headache after Novavax and flu.

Missed this excellent commentary calling for FDA to share all data on Paxlovid. FDA gave it full approval based on the one trial in nonimmune patients (now irrelevant) while another trial in immune patients (relevant) trended to but did not meet endpoints. medpagetoday.com/opinion/second… Meanwhile Pfizer had run more trials but didn't reveal the data.

New article on Paxlovid rebound in @nytimes shows that people are finally accepting what I always proposed: Early Paxlovid suppresses virus levels before the immune system can mount an effective response, until the drug ends and the virus pops up again.
nytimes.com/2023/09/26/wel… "The theory behind Paxlovid rebound is that the treatment is so effective at suppressing the virus that the immune system does not ramp up its cellular and antibody defense"

There are now several studies looking at how neutralizing sera from XBB breakthrough infection is on EG.5 (an XBB derivative now dominant) and BA.2.86 (the new kid on the block).

First here's a nice map of immunogenic distance based on mouse work

Ref: biorxiv.org/content/10.110…
As you can see, BA.2-5 were as immunoevasive from D614G (ancestral SARSCoV2) as SARS1, hence the new boosters last year (although they shouldn't have been bivalent)

EG.5.1 covers the same distance, requiring another booster, which this time will be pure XBB as it should be

In case you weren't sure what to think of peer review:

Reviewers and editors demanded the Proximal Origin paper make their preferred conclusion

Every scientist complains about papers being held hostage by reviewers. The PO case shows the problem has implications beyond science.

https://twitter.com/BallouxFrancois/status/1684672499953332224

Remember how some authorities would dismiss preprint results they disliked (e.g. breakthrough infections, lower VE of J&J, higher VE of Moderna) by saying they weren't reviewed?

Reviews are meant as a QC step, but when reviewers impose their views, they can make articles worse

Important results from the Com-CoV blinded trial of COVID19 vaccines:

After a Pfizer/BioNTech primary (original strain), boosting with Novavax (also original) worked better than a 2nd dose of Pfizer.

The best part? It was esp effective on Omicron!

journalofinfection.com/article/S0163-… A summary of the work is below. Com-COVs are a set of robust vax comparison studies — prospective, randomized, blinded.

Talking about original strains now sounds like a bit of a throwback, but nicely it allows us to compare breadth of different regimens.
ox.ac.uk/news/2023-07-0…

Today, for the second time this year, clinical trial results were announced that proved the amyloid hypothesis of Alzheimer's disease is correct.

As a result of following this hypothesis for 40 years, we now have treatments that slow disease progression

npr.org/sections/healt… Pathologists have known for nearly a century that Alzheimer disease (AD) brains contain a gummy protein material, amyloid. The amyloid hypothesis is that amyloid accumulation is a driver of AD pathogenesis, so that inhibiting it would slow progression.
onlinelibrary.wiley.com/doi/full/10.10…

New study: Paxlovid rebound is much more likely if you initiate it within the first 2 days:

29% if started on day 1
17% on day 2
0% on day 3 or later

I had predicted such based on basic principles of immunity alone

medrxiv.org/content/10.110… My first prediction on this, April 2022, in response to @PaulSaxMD when the first rebound cases were reported:

"We could consider waiting 48h from symptoms to start Paxlovid"

Read the entire thread below for the immune hypothesis

https://twitter.com/michaelzlin/status/1516803882500112388

Just out: comparison of Novavax to Moderna as boosters following 2x Moderna (all ancestral) in primates. NVX BA.1 booster also studied.

Result: All boosters produce similar humoral and cellular responses. NVX might block early disease a little better.

science.org/doi/10.1126/sc… This is a much more comprehensive than the usual antibody study. There was a very long list of assays:
• Abs (IgG)
• neutralizing Abs (nAbs)
• non-nAb activities such as Ab-dependent neutrophil phagocytosis (ADNP)
• CD4 and CD8 T cell fxn

Some tests were done on variants too

Biden's approval dropped after announcing he's running. 58% of Dems prefer him not to. I'm one of them.

Biden must know the idea of a President Harris is widely unpopular. By running, he shows he cares more for himself than his party or country.

politi.co/42ztQzg The chance of him dying in a second term are much higher than him dying in the first. Harris was an unknown the first time but she has not grown into the VP position, unfortunately. This changes the calculus for swing voters. Biden certainly knows this.

Online today at Nature "Surveillance of SARS-CoV-2 at the Huanan Seafood Market"

"The origin of the virus cannot be determined… potential introduction of the virus to the market through infected humans, or cold chain products, cannot be ruled out yet"
nature.com/articles/s4158…… "We should note that the selection of shops for sampling was biased because shops selling wildlife as well as shops linked to early cases were prioritized for sampling"

A short history of scientific debate (beware, Groundhog Day vibes)

A: How do we know it originated at the market?
B: Because it's not engineered
A: It could be natural and come via a lab collection right?
B: Well we have proven it's not from a lab in any way
A: How? B: Read the paper. It's in a prestigious journal by expert scientists. If you were a scientist you wouldn't question the point.
A: I've read the paper, and I am a scientist, and you only said it's not engineered, but a natural virus could still come through lab collection right?

Peer review is becoming anachronistic due to increasing peer competition. Recently it appears more likely to handicap a good paper than improve a bad one. If you have a good paper and submit to a competitive journal, it's hard to avoid a reviewer who is competing against you and motivated to slow you down.

If you have a bad paper, you just submit to a less competitive journal happy to collect your publication fees.