- “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.
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.
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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. - 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.
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.
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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.
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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. - 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.
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