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Michael Lin, MD PhD 🧬 Profile picture
@michaelzlin
Jun 10, 2021 • 12 tweets • 4 min read • Read on X
The J&J vaccine is <10% of vaccinations in the US, and ~0% outside, so it isn't studied as much as other vax. In particular how well J&J works against Delta (b.1.617.2) hasn't been discussed, whereas we know a lot about Pfizer/Moderna/AZ. So I've decided to take a stab at it.
🧵
2) I was motivated by this CNN article which revealed recent findings that the Pfizer/BioNTech vaccine (and likely the similar Moderna) are 88% protective against symptomatic Delta infection after dose 2 (good), but only 33% after dose 1 (not so good)
cnn.com/2021/06/10/opi…
3) The article says "Of note, this variant appears to be extremely transmissible, and the first dose of a two-dose vaccine regimen is much less effective than is the first dose against other variants." What about J&J which only has 1 dose?
4) Will 1-dose J&J act more like the first dose of a two-dose RNA vaccine regimen against Delta (33% protection) or more like the second dose (88% protection)?

My best guess is that it will be 64%. Why?
5) The J&J vax is 64% effective against Beta (501Y.V2 from South Africa) when looking ≥1mo after vaccination (vs 66% for original). Beta has a E484K mutation that reduces potency of neutralizing antibodies (nAbs) elicited by the J&J vax by ~5x.
rupress.org/jem/article/21…
6) The Delta variant has a nearby mutation T478K that reduces nAb potency by 6x. So escape from nAbs by Beta and Delta are very similar. Image
7) So because Delta and Beta resists nAbs similarly, we might expect J&J efficacy against symptomatic Delta might be similar to that against Beta: 64%. Protection against severe disease would be predicted to be similar, at 82%.
9) It's not known why J&J didn't show much efficacy drop from original to Beta with the 5x drop in nAb potency. This contrasts with the drop in 1-dose RNA vax efficacy from 80% on original to 33% on Delta being predicted by nAb potency drop alone.
nature.com/articles/s4159…
10) It could indicate that J&J elicits better cellular immunity than the RNA vax, but this is just speculation. It would be nice if studies can be performed on the post-J&J T-cell and nAbs responses against original and B.1.617.2 so we can tell.
@michaelmina_lab @florian_krammer
p.s. J&J efficacy numbers taken from below article
nejm.org/doi/full/10.10…
There's an assumption in the analysis that if J&J is remaining effective against variants due to cellular immunity, then Delta won't resist that any more than Beta. Many mysteries with this vaccine.
Dr. Barouch (ex-classmate, running studies of J&J vax at Harvard) also concludes the robust T cell immunity may account for J&J maintaining efficacy against Alpha and Beta variants. If so, then likely will be true for Delta as well. bostonglobe.com/2021/06/09/nat…

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More from @michaelzlin

Michael Lin, MD PhD 🧬 Profile picture
Mar 13
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.
The story began in March 2020 when, entering COVID shutdown, I asked if the hepatitis C virus protease inhibitor boceprevir (BPV, an oral pill) could be adapted for COVID (the viruses are distantly related).

Manually docking BPV into SARSCoV protease suggested yes (Fig. 1A). Image
Read 38 tweets
Michael Lin, MD PhD 🧬 Profile picture
Jan 23
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.
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)
Long-time followers recall I had postulated that SARSCoV2 was milder for children was because their innate immunity was better at suppressing viral replication until antibodies were generated.

I first proposed this in July 2020.

Read 7 tweets
Michael Lin, MD PhD 🧬 Profile picture
Jan 21
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
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…
If he was the one, it goes to explaining other things.

Zhou was not in Shi's group, so he could have been doing experiments without telling her.

However, he was at the WIV, so he could have learned her techniques for sarbecovirus full-genome synthesis and culture.
Read 17 tweets
Michael Lin, MD PhD 🧬 Profile picture
Jan 19
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.
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...
because just one bound IgG3 molecule on a virion lead to its destruction, whereas multiple bound IgG molecules would be needed to block entry (due to multiple S proteins per virion). Also you need to clear circulating viruses to stop spread; killing infected cells is too slow.
Read 10 tweets
Michael Lin, MD PhD 🧬 Profile picture
Jan 18
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
The draft proposal and related documents can be downloaded at the link below. We know DARPA rejected the final submitted proposal for being too risky. This draft proposal certainly matches that description. Were the experiments attempted? We don't know.

archive.org/details/2021-0…
Read 26 tweets
Michael Lin, MD PhD 🧬 Profile picture
Jan 4
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. Image
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. Image
Widespread annual boosting is more important for reducing death for SARSCoV2 than flu, because of its high contagiousness.

Unfortunately SARS2 booster uptake is even lower than flu or RSV.

"More US adults roll up sleeves for flu than COVID, RSV vaccines"
cidrap.umn.edu/covid-19/studi…
Read 7 tweets

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