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Michael Lin, MD PhD 🧬

@michaelzlin

May 6

Taiwan is the latest place to get an Omicron wave (maybe the last place on earth to do so?), and I have been watching the rising case numbers with some trepidation.

The reason for concern is clear, but may surprise you: Only ~70% of seniors over 75yo are 2x vaccinated.

Yes Taiwan has been a model in avoiding SARSCoV2 via quarantine, contact-tracing, testing, and isolation. It has been correctly praised alongside New Zealand and Korea for that.

But the previous success hid a problem in vaccination. This matters now that Omicron has taken root.

@cookiebandit

In Taiwan the Omicron surge has taken hold, but very few deaths have been seen yet. For example today it's 36000 cases and 10 deaths (below thx to the excellent @cookiebandit)

But there's nothing to celebrate in those numbers, yet. (@cookiebandit knows)

https://twitter.com/cookiebandit/status/1522458231620001792

Read 12 tweets

Michael Lin, MD PhD 🧬

@michaelzlin

May 2

Time for a new vax. Even for hospitalization, VE of 3x Pfizer stops to ~55% after 3 months against Omicron

thelancet.com/journals/lanre…

This BTW shows it was incorrect to claim that CD8 T cells, which can target more parts of the spike protein, will guarantee cross-strain protection against severe disease even in the absence of high antibody levels. Very often hopeful ideas get traction without proof.

I should mention T cell levels decay slowly which was why the optimists hoped they could maintain cross-strain protection from severe disease for a long time. The decay in hosp VE against Omicron being faster than T cell decays indicates that antibodies are still most important.

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Michael Lin, MD PhD 🧬

@michaelzlin

Apr 26

There's been some debate about whether annual SARSCoV2 deaths can be limited to flu-like numbers despite widespread immunity, if 1-2 new waves occur each year.

No need to debate, just look at numbers. NZ is a good model because it's 95% vaccinated (98% in elderly)

NZ death rates from Omicron have crested, so we can measure deaths from a SARSCOV2 variant wave when essentially everyone has immunity to an earlier variant.

We can look at both ascribed deaths and excess mortality, and we can compare a few countries

Death rates from flu are <10k per year in the US if you go by flu as the listed cause of death. But the way we ascribe deaths to flu actually count deaths from CV and respiratory problems soon after a flu infection, so it's really more like "with flu". This gets 20–60k per year.

Read 19 tweets

Michael Lin, MD PhD 🧬

@michaelzlin

Apr 25

3rd minithread from ECCMID: In the same session as S-217622/ensitrelvir and anti-S DARPin/ensovibep, Merck presented molnupiravir (MOV) Ph3 virological outcomes. Results were less impressive, and no virological benefit seen in seropositive patients.

Viral RNA reduction vs. placebo at day 4 or 5 has been measured for all drugs, so can be used for comparison: Ensitrelvir: 0.41 logs (10⁰'⁴¹=2.6x) in 84% vaxxed
Ensovibep: 0.44 in 50% sero+
Paxlovid: 0.99 in sero–, 0.36 in sero+
Molnupiravir: ~0.4 in sero–, 0 in sero+

Viral levels start higher in sero–, so one can expect bigger reductions in sero– than sero+ (e.g. Paxlovid 0.99 in sero–, 0.36 in sero+).

But MOV benefit to sero– (0.4) is similar to the effects of other drugs on sero+, and MOV has no discernable benefit on sero+.

Read 16 tweets

Michael Lin, MD PhD 🧬

@michaelzlin

Apr 25

At ECCMID, Molecular Partners and Novartis revealed Phase 2/3 results for ensovibep, a SARSCoV2 spike binder based on Pluckthun's synthetic DARPin domain. Ensovibep is smartly designed to mimic an antibody: 3 domains binding spike for avidity and 2 to HSA for half-life extension.

Ensovibep was given as a one-time IV injection within 7 days after symptom onset. Patients were both vaxxed and unvaxxed (although %'s not described). 50% had previous exposure to SARSCoV2.

Only primary endpoint was suppression of viral RNA titers. This was met. Ensovibep showed reductions in viral RNA of 0.34 to 0.61 logs, which makes it similar to Shionogi's drug.

Read 6 tweets

Michael Lin, MD PhD 🧬

@michaelzlin

Apr 24

At ECCMID, Shionogi presented Phase 1, 2a, and 2b data for their SARSCoV2 protease inhibitor S-217622/ensitrelvir. This drug is dosed once daily. Unlike the 2x daily Paxlovid it doesn't require ritonavir which has many drug-drug interactions. A quick thread.

As the structure shows this is not a peptidomimetic. S217622 was discovered by HTS followed by structure-guided optimization. It binds the active site and partially fills S1 and S1'.

Showing how slow peer review usually is, it's still in preprint status.
biorxiv.org/content/10.110…

Testing in mostly vaxxed, ensitrelvir looks good on virologic endpoints. Here are results from the largest study (phase 2b). Note subjects were 84-87% vaxxed and median time from diagnosis to dosing is 3-4 days.

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