COVID-19 Bullets

•  AstraZeneca will miss its Q2 COVID-19 vaccine shipments by half, according to a Reuters report.
• Moderna and Pfizer both expect to double their current output, and possibly triple it. Pfizer will go from four million doses a week to 13 million doses by mid-March, and 100 million doses by the end of the first half. Moderna plans on doubling its output to 40 million doses per month by April.
  
• Johnson & Johnson expects to have 20 million doses of its single-shot vaccine available by the end of March, and 100 million doses at the end of Q2.
  
• The B.1.1.7 variant now constitutes 6.2% of all new COVID-19 cases in New York City, up from 2.7% in January.
• Michael Osterholm, et al., say that prioritizing elderly (65+) for vaccination (PDF) should minimize the healthcare system strain in the coming weeks with new variants gaining traction in the US. He also recommends
• Deferring second doses of mRNA vaccines until after the surge.
• Deferring the second dose of mRNA vaccines in people with confirmed COVID-19 infections.
• Authorizing and use of the half-dose regimen for the Moderna vaccine.
• Pfizer/BioNTech and AstraZeneca vaccines are slowing the pace of hospitalizations already in Scotland.
• Meanwhile in France, vaccination lags far behind shipments of vaccines, with 8 million delivered but only 3.5 million vaccinated.
• Derek Lowe's latest on mRNA vaccine manufacturing isn't exactly grim, but there are so many caveats you might swallow hard. A ton of interesting links there (and I especially recommend Jonas Neubert's look at supply chains), but the quote that really stuck with me was this:

  As you would imagine, everyone involved is having quite a time meeting demand. As the article says, though, it’s hard to get a clear picture of where the exact pinch points are, because the terms of the various contracts are not public, nor are even the identities of the raw material suppliers further up the chain. But anyone who’s had to source intermediates or starting materials in the drug business at any kind of scale will appreciate that the fastest way to find out what those weak points are is to place a Big Ol’ Order for something.

  Lowe is, as I am, "struck by how much we’ve been able to scale up these things" despite the many potential obstacles along the way. "I’d be willing to bet that if you’d called any of [the Acuitas Therapeutics people making lipid nanoparticles] up in (say) December 2019 and asked them if they could get to where they actually are by February 2021 they’d have been terrified."
  
  

EU Crowns mRNA The Winning COVID-19 Vaccine Technology

 Thursday, the EU contracted with Pfizer and Moderna to purchase 350 million more doses of their SARS-CoV-2 vaccines, making for 2.6 billion doses in the pipeline altogether. Between those two and CureVac, this means mRNA vaccines account for 1.465 billion doses:

Technology	Manufacturer(s)	Number of Doses (Millions)	% of total
mRNA	Pfizer/BioNTech, Moderna, CureVac	1,465	54%
Vectored Virus	AstraZeneca, Johnson & Johnson	800	29%
Protein Subunit	Sanofi GSK	300	11%

 Sanofi earlier this week reported they would not have a COVID-19 subunit vaccine ready this year, so this purchase looks like the plugging of a hole rather than an increase. More importantly, it seems to me that if Peter Hotez is right as to what types of vaccines are going to be the "the workhorse of this epidemic", it is getting awfully late for any technology other than mRNA.

Update: it's probably worth mentioning that once you subtract the 300M vaccines Sanofi can't deliver, suddenly mRNA has 61% of EU sales. That's quite a vote of confidence.

COVID-19 Vaccine News

 Most of this is from Biopharma-Reporter.com, which looks promising as a future source of news in this space:

• France will ramp up its vaccine manufacturing efforts, with
• "CDMO Recipharm will start production for Moderna at its Monts facility next month; while Delpharm will manufacture the Pfizer/BioNTech vaccine in Saint-Rémy-sur-Avre from April. In May, Fareva is set to follow suit for CureVac’s vaccine."
• Other vaccines in the pipeline include "Johnson & Johnson, CureVac, Sanofi/GSK, Novavax and Valneva: with CureVac, J&J and Novavax being the most advanced of these."
• New Zealand has approved the AstraZeneca, Moderna, and Janssen vaccines.
• AstraZeneca says it could take 6-9 months to make vaccines for variant SARS-CoV-2 viruses.
• AstraZeneca has a deal with German IDT Biologika to increase production of its COVID-19 vaccine.
• German contract manufacturing firm Rentschler is expanding its UK presence, to increase materials necessary for vectored virus vaccine manufacture.
• The Biden administration has announced there should be 200 million vaccine doses by July, which should be enough to get everyone who wants a shot.
• CureVac's COVID-19 vaccine has started the approval process with the European Medicines Agency, the third mRNA vaccine in the pipeline.
• CureVac is also plotting how it will react to novel SARS-CoV-2 strains, expanding research in the UK.

COVID-19 Bullets

•  New York Gov. Andrew Cuomo is in hot water now that the state "has reported 8,600 nursing home deaths tied to the coronavirus since the pandemic began. Overall COVID-19 deaths in the Empire State exceed 40,000. ... New York only counted residents who died on nursing home property, rather than any who were transferred to hospitals. But according to the report, most of the deaths occurred in hospitals.
•  The vaccination situation in Canada is even worse than that in the US. "The Canadian deficit is mostly because they don’t have enough vaccine. Canada bought doses but they didn’t invest in capacity and a deal with China fell through. As a result, Canada won’t be getting lots of vaccine until March or April."
• I mentioned mRNA scaling as an update to my roundup of recent Derek Lowe blog posts, and also in the comments there. Someone was kind enough to give an extended reply, which I repost here in its entirety:

  It is possible BUT there are several hurdles to overcome.

  1) Raw materials. You need recombinant *GMP quality* (as in, NOT lab quality) enzymes. These can certainly be made, the technology existed even when I was an undergrad back in the Clinton/Kurt Cobain era. Bacterial fermentation at smallish scale and relatively easy to do. Since they’re being used for industrial processing and not put into humans, you can do convenient things to improve the process like stick 6his tags on the end and tether them to IMAC resin to better control the reaction rate and set yourself up for continuous methods.

  2) Liposome/LNP formulation needs to be done by process engineers who actually know a little something about liposome manufacturing. Sanofi has these, or should have, or can afford to hire them and keep them.

  3) Different kinds of lipids and a wider variety need to be at least tried out, instead of this whole getting married to just one other startup’s lipid and then having a patent pissing contest with them. Never restrict yourself to a single source of anything, there is far too much risk that one source will go out of business and you’ll be screwed, unless you plan for vertical integration and make the lipids yourself at a small molecules site within your company. Which Sanofi also has the resources to do if they choose.

  4) The medicinal chemists need to choose targets appropriate for the PK of intracellular transient expression. Alnylam did an excellent job of thoroughly understanding the PK of their modality, and Sanofi should follow their example.

  Hope That Helps!
  

The Zero COVID Brigade

The "lockdowns forever" crowd won't stop once we get the population vaccinated.  Israel now has just over 60% of its people inoculated with at least one Pfizer shot, and here come the "vaccines aren't enough" brigade (emboldening mine):

Naftali Bennett, the former defense minister who coordinated much of the nation’s initial virus response and is now running to replace Netanyahu, accused the government of adopting a strategy that, in his words, can be summed up as, “We’re not going to manage the crisis in this country, we’re going to put all our eggs in the one basket: vaccines,” he told Intelligencer.

“Israel’s entire strategy relies on the hope that no variant will escape the vaccine,” he continued. “If a mutation that can bypass the vaccine appears tomorrow, we’re in trouble.”

On Thursday, at a cabinet meeting convened to debate the future of a partial, fraying lockdown, which is scheduled to end on Sunday, Netanyahu acknowledged that “the British mutation is running amok in Israel,” driving 80 percent of Israel’s recent COVID-19 fatalities.

That public health officials, driven by a messiah complex, might not want to surrender emergency powers is scarcely a new thing, but the idea turns up again and again. Freddie Sayers in Unherd did a good writeup on the subject of Zero COVID, a movement he claims is "crucially distinct from people who support ongoing lockdown measures to suppress the virus to a level where it is safe to reopen — for ZeroCovid believers, we cannot rest until that level is zero."

This distinction does not actually matter. The reason for this is that the main response to outbreaks has in fact been more stringent and longer lockdowns. Essentially, whether you want to call it Zero COVID or not, what it means is putting the US in a state of permanent emergency should the virus become another of the endemic respiratory viruses. The Biden administration is waffling on whether it wants to actually do this:

So far, the Biden administration has tried to have it both ways—coddling those who appear to welcome a perpetual pandemic while assuring those who don’t that deliverance is near at hand. In a pre-Super Bowl interview with CBS News, President Biden said that it was necessary and possible for schools to reopen safely in accordance with CDC guidelines, which will be forthcoming shortly (never mind that the CDC produced just such a set of guidelines as far back as last August). But a sprawling White House COVID-19 strategy memo released by the Biden White House last month also provides for the possibility that “new coronavirus variants that may have a higher transmission rate” might forestall the resumption of full-day, in-person education. And, in a late January call with teachers’ unions’ representatives, Fauci said that those variants, which “may” be more resistant to vaccines, are likely to scuttle the president’s desire to see K-8 classrooms reopen nationally.

 But once we get vaccines that, at least, will prevent hospitalization and death, there has to be some level of disease burden we're willing to tolerate rather than stay hunkered down indefinitely. The most recent bad influenza season, 2017-18, saw over 800,000 hospitalizations and 61,000 deaths (estimated). Meanwhile, in Israel, over 90% of the 60+ population has been vaccinated, and the results are quite striking:

 Yes, younger cohorts now make up a larger fraction of new cases (per the New Yorker article, 44% under 19 years old and an increasing number from the under 50 crowd). But given what we know about outcomes, these groups are unlikely to get severe disease. At some point, we'll have to ramp up vaccine production and learn to live with this disease. We don't really have a choice.

Three Four From Derek Lowe On Vaccine Efficacy, Manufacturing

Some great stuff, as always, from Derek Lowe’s In The Pipeline blog at Science magazine. I’ve been a little behind in following him, and he’s been quite prolific lately (as befits the circumstances).

• “Vaccination Against The New Variants: Real-World Data” tackles the thorny problems posed by the B.1.1.7 (UK) and B.1.351 (South African) variants. Excerpt:

  Now to the vaccinated-patient plasma samples, because that’s what a lot of people are really wondering about: how well does being vaccinated with the current agents provide you with protection against the new variants? The authors studied serum from 12 patients that had been given both doses of the Moderna vaccine and 10 patients who had had both doses of the Pfizer/BioNTech one. The activity drop against the B.1.1.7 variant was only about 2-fold in both groups, whereas the overall activity drop against the B.1.351 variant was 6.5-fold in Pfizer vaccinnees and 8.6-fold in Moderna ones.
  
  ...
  
  What about those activity drops, especially the larger ones against the B.1.351 variant? Does that still leave room for protection? Here’s the good news: it very much does.

  This is why, frankly, I find South Africa's halting of its AstraZeneca vaccination campaign to be utterly insane: what is the point? Even if the vaccine only confers protection from severe disease, that is still worthwhile. Of course, Lowe doesn't mention that in this post, but small-scale data (n=2,000) thus far points in that direction.
• In “Myths of Vaccine Manufacturing”, Lowe tackles a subject that has been on many a mind lately: how do we increase production? There are a lot of potential bottlenecks, but the biggest single one is mRNA encapsulation. As usual, emboldening is all on me:

  Turning a mixture of mRNA and a set of lipids into a well-defined mix of solid nanoparticles with consistent mRNA encapsulation, well, that’s the hard part. Moderna appears to be doing this step in-house, although details are scarce, and Pfizer/BioNTech seems to be doing this in Kalamazoo, MI and probably in Europe as well. Everyone is almost certainly having to use some sort of specially-built microfluidics device to get this to happen – I would be extremely surprised to find that it would be feasible without such technology.
  
  ...
  
  These will be special-purpose bespoke machines, and if you ask other drug companies if they have one sitting around, the answer will be “Of course not”. This is not anything close to a traditional drug manufacturing process. And this is the single biggest reason why you cannot simply call up those “dozens” of other companies and ask them to shift their existing production over to making the mRNA vaccines.
  
  ...
  
  And let’s not forget: the rest of the drug industry is already mobilizing. Sanofi, one of the big vaccine players already (and one with their own interest in mRNA) has already announced that they’re going to help out Pfizer and BioNTech. But look at the timelines: here’s one of the largest, most well-prepared companies that could join in on a vaccine production effort, and they won’t have an impact until August. It’s not clear what stages Sanofi will be involved in, but bottling and packaging are definitely involved (and there are no details about whether LNP production is). And Novartis has announced a contract to use one of its Swiss location for fill-and-finish as well, with production by mid-year. Bayer is pitching in with CureVac’s candidate.

  Bottom line is that, once again, calls for the use of the Defense Production Act on the grounds that other pharma companies are twiddling their thumbs are delusional.
• A post summarizing the Gamelaya Institute's Sputnik V vaccine, which uses an adenovirus-26 and adenovirus-5 vector for the first and second doses respectively. Two-dose efficacy is 91.6% on a test population of 15,000.

  My expectation is that it will deal with the B.1.1.7 [variant] at nearly the same efficacy and drop down to the 50-60% efficacy range against the B.1.351 strain, as has been seen with the other vaccines where we have such data. Based on the numbers we have, I see no reason why this vaccine can’t make a solid contribution to fighting the pandemic, and I’m very glad to have another efficacious one out there for use. Update: a skeptical take on the publication here!

  The article in that final link suggests the trial involved some possibly shady dealing in terms of patient samples, using mainly young people for the Phase II trial, and unexplained dropouts of trial subjects during the test. More worrying, serological testing was done by "convenience sample", which speaks to possible monkeyshines on immunogenicity.
  

• Back to manufacturing, next Lowe writes about vectored virus vaccines. As mentioned by others, this is a pretty complicated process, and there are many places where it can go wrong. Ignoring the political baggage arising from the use of aborted fetus kidney cells as a feedstock (the cell lines were originally created in the 1970s, but have been cloned for decades), the big technical hangup is the fact that
  

  Human cell culture – any cell culture – is simultaneously a scientific process and an art form. Ask anyone, literally anyone who’s done it, and if you can find someone who’s worked on it at an industrial scale, they’ll confirm that all the more vigorously. This is (or can be) the weak point of the entire viral-vector production process. When everything is working, this method for infecting living cells and turning them into virus factories is hard to beat. But it doesn’t aways work the way it’s supposed to. It appears that AstraZeneca has been having problems because one of their largest production facilities has been experiencing problems with low yields of virus, even though everything should be the same (same viral DNA, same cell line, etc.)
  

Some food for thought as we slowly improve on our vaccination efforts in the US.

Update: I wanted to come back to the Yahoo News story about using the Defense Production Act, but mainly for this quote from Peter Hotez about mRNA vaccines:

Baylor College of Medicine’s Dr. Peter Hotez, another top vaccine expert, said the current demand is pushing the limits of manufacturing a brand new technology, messenger RNA, at scale.

“We knew the mRNA vaccines were not going to be the workhorse of this epidemic. It’s a new technology, it doesn’t have that capacity for scale like other technologies do,” Hotez said.

Hotez is the Dean of the National School for Tropical Medicine, so presumably should know a little whereof he speaks. He repeats that sentiment in the Houston Chronicle, saying

This gets to the problem of the mRNA vaccines. We were never supposed to rely solely on the mRNA vaccines. It’s not a mature technology. It doesn’t have the capacity to do the job. We’ve known that for the whole year of 2020.

That was the whole rationale behind Operation Warp Speed: The mRNAs would be the first to get up, but then we would have later vaccines come along that are more robust in terms of production and the ability to vaccinate large numbers of people. That’s why you have the two adenovirus-based vaccines and the particle vaccines: They were they were supposed to be the worker bees on this. The mRNA was to get started, and then the others would follow it.

The multiple failures of both AstraZeneca and Janssen to scale (with the Sputnik V vaccine not even launching at scale yet) strongly suggests that Hotez — who is working on a protein subunit vaccine with Indian pharma company Biological E — is at odds with Sanofi CEO Paul Hudson's recent remarks to Barron's:

During a single-antigen pandemic, where speed is a key consideration, "I think we have to accept that ... mRNA is probably the first go-to," Hudson told the publication. But in disease areas where there are established vaccines, mRNA candidates will have to “compete with the standard of care” shots that feature a “well-characterized safety profile.” There, the “bar is high,” he added.

In other words, if you have a moving target (check) and/or a new disease (check), mRNA is the way to go. The price of a recombinant protein subunit vaccine might be cheaper once you get all the problems nailed down, but it's pretty clear that there are some very big problems with vectored virus vaccines versus mRNA.

Belated: Scott Greenfield's Recent History Of The ACLU's Decline

This needs to be cast in amber, to the extent anything is on the Interwebz. (Note that the link image at the bottom is not one of the top three links.)

It's almost as if I hadn't explained what happened to the ACLU in detail over the past few years. It's all there to be read.https://t.co/pFpbixxpvohttps://t.co/01AOQuQ1kchttps://t.co/aDPJgY6FRDhttps://t.co/ZEk49IQGKP

— Scott Greenfield (@ScottGreenfield) October 24, 2019