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Michael Lin, MD PhD 🧬 Profile picture
@michaelzlin
Jun 4, 2021 • 21 tweets • 8 min read • Read on X
Antibodies elicited by the Pfizer/BioNTech RNA vax are 6x less potent in neutralizing B.1.617 (delta variant that devastated India).

This lowers predicted efficacy for symptomatic COVID19 to ~70%.

This compares to 2x drop in neutralizing activity for Covaxin.

I discuss in 🧵
The advantage of the RNA vax is their simplicity. They encode only the spike protein because it's the viral protein targeted by most of the antibodies that prevent viral entry. Another way to put it is Abs to the right place on spike are sufficient to block entry. (image Siemens) Image
The adenovirus vax also encode only spike but express it from Ad. Both types elicit high levels of neutralizing antibodies (nAbs) after just one dose. RNA is better here; in fact 1 dose of RNA gives you similar nAb levels to natural infection.

But immunizing just to spike limits the nAb repertoire. There are only a few places where Abs tend to bind to spike, and it seems binding to a loop containing E484 actually accounts for much neutralizing activity, as E484K drops neutralizing activity 3x.

thelancet.com/journals/lanmi…
The delta variant has both E484K to give that 3x lower neutralization, and another mutation P681R that is believed to enhance membrane fusion and thus the rate of viral entry. Overall neutralization activity of antisera is down ~6x (today's Lancet paper) Image
A landmark paper in May related nAb levels to % efficacy in trials (in terms of % protection from symptomatic disease). Using their efficacy-vs-nAb curve, and with Ab levels at 3x of convalescent sera, the 6x drop in nAb potency predicts efficacy at ~70%.
doi.org/10.1038/s41591… Image
The Chile study I posted above measured nAb levels post-Pfizer/BioNTech at 10x convalescent sera, so it's not clear if 3x or 10x is more common. If 10x, then efficacy would be predicted to remain >85% even with a 6-fold loss of potency against the delta strain.
And now this is rather preliminary and verification is required, but an April preprint reported that nAbs elicited by Covaxin, the whole-killed/inactivated virus vaccine, showed only a 2x dropoff in potency against delta.

biorxiv.org/content/10.110… Image
That's potentially interesting because whole killed/inactivated virus vaccines present the entire virus. In addition to spike, there are two other surface proteins, E and M. Anti-spike is certainly sufficient for neutralization, but perhaps anti-E and anti-S can contribute too. Image
So, to wildly speculate: in whole-virus vaccines, maybe you get a mix of the anti-spike (predominantly anti-E484), anti-E, and anti-M. Then if you lose the spike binding with E484K, you still get some neutralizing activity through E and M. Requires more study to know for sure.
The other thing that whole-virus vaccines present are the intracellular viral antigens. Dendritic cells (DCs) route some phagocytosed antigens to MHC-I via cross-presentation, so they can activate CD8 T cells with TCRs that recognize those viral antigens.
en.wikipedia.org/wiki/Cross-pre…
Intracellular viral antigens presented on MHC-I by infected cells then induce killing by these activated cytotoxic CD8+ T cells (CTLs). Dogma is that DC cross-presentation is not reliable enough as a vaccine mechanism, but this is not always true.
journals.asm.org/doi/full/10.11…
Now whole-virus vaccines such as Coronavac, Sinovac, and Covaxin do seem to have very little activity after the first dose, in contrast to RNA and Ad vaccines. Immune activation is just not as strong with dead virus and adjuvant as RNA or Ad.
However after dose 2, the whole-virus vax appear similar to convalescent sera. If they can maintain 50% neutralizing potency on new variants, then after dose 2, they will still be able to prevent symptoms by >50% and severe cases by >80%. Image
Adding a correction to main thread: Delta/B.1.617.2 has T478K; Kappa/B.1.617.1 has E484K.

They are on the same loop and both resist neutralizaing antibodies elicited to wild-type spike, so analyses and implications are unchanged.

Thx @Multi__X

nature.com/articles/s4159…
Also the 2x hit on Covaxin-elicited neutralization mentioned above was with Kappa/B.1.617.1. So for comparison we should look at RNA vaccine-elicited nAbs to B.1.617.1. They are down 7x.

We don't know Covaxin result on B.1.617.2; will be important to get

biorxiv.org/content/10.110… Image
To add a little background, anti-M antibodies are seen after coronavirus infections. Anti-E antibodies have not been seen so far.
nature.com/articles/s4146…
Meant "perhaps anti-E and anti-M can contribute too." Some evidence for anti-M.
In trials the Pfizer/BioNTech vax was estimated to be 88% effective against Delta in UK. That's very good news, and suggests the vax elicits very high nAb levels and/or T cell responses so that the 6x drop in nAb potency is not hindering efficacy too much

deccanherald.com/national/vacci…
Reference for the 88% efficacy finding (also in Lancet paper): medrxiv.org/content/10.110…
3a is another coronavirus transmembrane protein that, in SARSCoV1, was found to be targeted by neutralizing antibodies. It appears nobody has published anything on 3a of SARSCoV2 yet (S is clearly the right protein to target if you have to pick one)

febs.onlinelibrary.wiley.com/doi/full/10.10…

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More from @michaelzlin

Michael Lin, MD PhD 🧬 Profile picture
Sep 3
New study in JAMA: azelastine antihistamine nasal spray reduced occurrence of COVID19 and common cold by 67% in a placebo-controlled (but small) study.

Azelastine in the US is sold OTC as Astepro, just $10 at CVS (with coupon). Note it's not the more common steroid nasal spray Image
Azelastine is generic now, and this was an academic study. Little interest by companies to test off-patent drugs. It was done in Germany (zero interest by US to do COVID-19 research now)

Trial was n=450 split into azelastine and placebo groups. That's large by academic standards
Subjects took azelastine 3x/day for 8 weeks. SARS2 antigen testing was done 2x weekly by study personnel, so not self-reported which is good. Those with symptoms but SARS2 negativity were tested for other viruses. Solid study.

SARS2 rate 2.2% treatment v 6.7% placebo, p = 0.02 Image
Read 20 tweets
Michael Lin, MD PhD 🧬 Profile picture
Aug 19
People have been asking about the SARSCoV2 (COVID19) vaccine outlook so I'll summarize as best as I can. But overall, the current situation is chaotic and in constant flux, and if FDA is trying to apply consistent criteria then they haven't shown it yet
Right now there are 4 vaccines from 3 companies covering 2 technologies with FDA approval in some form or other. The approvals are for different age ranges and risk categories. In addition each August or September new formulations have to be reapproved, kind of like influenza.
The vax are Comirnaty (Pfizer), Spikevax (Moderna), mNEXSPIKE (Moderna), and Novaxovid (Novavax). The first 3 are RNA, the last is protein. HHS.gov shows who qualifies for each, but hasn't been updated with mNEXSPIKE. Must be the DOGE cuts hhs.gov/coronavirus/co… Image
Read 22 tweets
Michael Lin, MD PhD 🧬 Profile picture
Jul 6
In case you think cameras can detect cars or people ahead of them through the glare of the sun, or that AI has learned to react to ambiguous situations with the, well, intelligence of humans, read this Image
It's a frightening and sad story (a grandmother was killed) and I'm surprised to find out about it only now.

There's clear evidence from the Tesla's own cameras that no kind of image processing can beat glare (and that FSD lacks all sense of caution)
bloomberg.com/features/2025-…
Glare happens when light rays from the sun get scattered by water or dust in the air at every lit location to new directions. That means air between an object and the camera can scatter sunlight toward the eye or camera.
Read 7 tweets
Michael Lin, MD PhD 🧬 Profile picture
May 18
FDA has granted regular approval to the Novavax vaccine. What does this mean? A lot of things, all good.

1- It proves Novavax has met efficacy and safety criteria to merit approval outside of the emergency use situation.
Novavax is safer than the RNA vaccines, but ironically the RNA vaccines received full approval earlier than Novavax. That meant Novavax was the only COVID vaccine which vaccine skeptics could incorrectly claim was not safe enough to receive regular approval.
2- Novavax will get to participate in annual booster updates on the same terms as the RNA vaccines. This year's advisory committee for booster strain selection has already been scheduled.

3- All health insurers should now cover Novavax.
Read 14 tweets
Michael Lin, MD PhD 🧬 Profile picture
Apr 18
"Novavax had 1.7 systemic symptoms compared with 2.8 in Pfizer recipients. In total, 43.8% of Pfizer vaccinees reported at least one symptom of moderate or higher grade, compared with 24.2% of Novavax"

@RobertKennedyJr in case you didn't know. It's also more broadly protective. Image
This is the 2nd controlled study to show about half the side effects rate for Novavax vs Pfizer.

Of the 3 covid vaccines, Novavax is the only one still on EUA. Happens it's the smallest of the 3 companies and hasn't hired ex-FDA staffers.

Article below.
cidrap.umn.edu/covid-19/novav…
FDA had a deadline of April 2 (this month) to decide on regular approval for Novavax, and reportedly was going to, except Peter Marks resigned the day before. Sadly he didn't sign the approval before he left. Was different for Pfizer and Moderna, who got early review and approval
Read 9 tweets
Michael Lin, MD PhD 🧬 Profile picture
Mar 25
Our NIH grant to discover coronavirus antiviral meds was terminated today.

With this grant, we had developed a better SARSCoV2 inhibitor than Paxlovid, and we recently discovered an improved drug that looks better than Pfizer's own second-generation inhibitor. Image
This is part of a complete elimination of COVID19-related research, including on long COVID.

The rationale given is that the pandemic is over.

In reality, people are dying of COVID at several times the rate of flu, and still getting long COVID.

arstechnica.com/health/2025/03…
This goes against RFK Jr's stated intention to concentrate on chronic disease.

Long COVID is a bad chronic disease to get, and there are reports of long COVID cases getting better immediately after treatment by protease inhibitors such as the ones we are improving.
Read 9 tweets

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