The EU Campaign To Shame Vaccines Out Of The US

 The ongoing fracas over AstraZeneca's ChAdOx1 vaccine and its sketchy trial data has not stopped its use in most countries. Indeed, as I learned today from Marginal Revolution, the New York Times writes that there's plenty of that vaccine in the US, whose manufacturing was started long ago (emboldening mine as usual):

About 30 million doses are currently bottled at AstraZeneca’s facility in West Chester, Ohio, which handles “fill-finish,” the final phase of the manufacturing process during which the vaccine is placed in vials, one official with knowledge of the stockpile said.

Emergent BioSolutions, a company in Maryland that AstraZeneca has contracted to manufacture its vaccine in the United States, has also produced enough vaccine in Baltimore for tens of millions more doses once it is filled into vials and packaged, the official said.

…But although AstraZeneca’s vaccine is already authorized in more than 70 countries, according to a company spokesman, its U.S. clinical trial has not yet reported results, and the company has not applied to the Food and Drug Administration for emergency use authorization. AstraZeneca has asked the Biden administration to let it loan American doses to the European Union, where it has fallen short of its original supply commitments and where the vaccination campaign has stumbled badly.

 Given that the US has no apparent interest in using those doses, at least in the short run, this would seem like a reasonable request. However, there's an interesting detail in the Times story that merits further comment:

The European Council president, Charles Michel, said the United States, along with Britain, “have imposed an outright ban on the export of vaccines or vaccine components produced on their territory.” Asked on Thursday about the American supply of the AstraZeneca vaccine, Jen Psaki, the White House press secretary, told reporters that vaccine manufacturers were free to export their products made in the United States while also fulfilling the terms of their contracts with the government.

The link in that graf points to a remarkably self-serving and frankly nonsensical press release, claiming there would be 

1. No vaccines without Europe. This is demonstrably false, because outside of AstraZeneca, the three other approved vaccines were all (first) manufactured in the US. (Germany's BioNTech developed the Pfizer vaccine, but Pfizer manufactured it.) This is even more ridiculous when you realize that mRNA vaccines now constitute a majority of the EU's vaccine buy.
   
2. Without Europe, many countries would not yet have received their first doses. On the other hand, the Netherlands, Italy, Germany, and France might have had their doses sooner. And in any case, "first doses" are mainly symbolic judging by overall vaccinations:
   
   
   
3. Europe is the most inclusive world power. This is mainly about funding COVAX, the effort to get vaccines to the rest of the world, but this is happening mainly symbolically while the EU waits for more vaccine.
   
4. Europe is an exporter. Here he expounds on what I can only believe is the purest of ignorance of his audience, raising the "outright ban" charge. Yet Our World In Data shows Pfizer and Moderna vaccines being deployed in many nations in and outside the EU, and if the recent, belated efforts at starting up mRNA manufacturing in Europe are any indication, production at scale wasn't possible there (and won't be for many months). Edit: the claim is made that "Most of the doses with which Israel embarked on its mass vaccination programme were sent from Belgium", but "most" is not "all", and this is important.
   
5. Europe is set to become the leading vaccine producing continent before the end of the year. This might be true, but only because they're producing vaccines licensed from US companies — including Johnson & Johnson. 

It's the third point that causes me to raise my eyebrows: if anything, the US is exporting vaccine to Europe. What else do they want? One expects this is a bid to shame additional doses contracted and paid for under Operation Warp Speed out of the US — at a bargain price. But as the EU itself shows with this point, doses go first to member nations — and only after local demand is satisfied will the rest of the world see any.

No, Israel Is Not Over 90% Vaccinated

 If, like me, you had accepted at face value the marvelous gift of 91-DIVOC.com, you probably assumed all the figures there were taken directly from the underlying data sources, and that any errors were due to their sources. This led me to the conclusion that Israel has already vaccinated over 90% of their population.

Unfortunately, it does not appear this is true. The Our World In Data repository at GitHub in their README.md file for country vaccination data says that the total_vaccinations field is 8,975,914 for 2021-03-09 — which is also the figure being shown on the graph above. Unfortunately, this field only tells us how many shots have been given, so a two-dose regime double-counts such individuals. When we use the people_fully_vaccinated and people_vaccinated fields, the graph looks like this:

I've fired off an email to Prof. Fagen-Ulmschneider, and we'll see if he responds.

Update 2021-03-22: Much overdue, but the good professor back on March 11 acknowledged my contribution on his main page, and has made appropriate corrections.

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.