I would summarize the leading thought in 2020 on vaccination on LessWrong and the review that’s now popular in the mainstream as:
New vaccination technology like mRNA-based vaccines and adenovirus-based vaccines allow faster development of vaccines. We still have the challenge of building enough vaccine factories. To build enough vaccine factories. This seems to be wrong and the better view is: Peptide-based vaccines are well understood and unsexy. We have existing adjuvants with well understood safety profile. They can be easily produced with equipment we already have. Given that they are unsexy nobody wants to run a clinical trial right and Western governments are interested in suing people for developing such technology then they are interested in vaccine development. According to it’s Moderna’s information, the first patient who got the Moderna vaccine got it on the March 16. Two weeks later Euroimmun founder and biotech billionaire Winfried Stöcker gave himself the first dose of a vaccine he developed himself. In contrast to Moderna he however was not focused on bringing a vaccine to market. He just wanted don’t wanted to get COVID-19 and vaccinated himself. His company rather focused on developing antibody tests that were in short supply at the time. Given past studies of the Coronavirus it was common knowledge that targeting the spike protein of COVID-19 was a good idea for developing a vaccine. Moderna announced that they designed a vaccine in one day by simply targeting the spike protein. Stöcker decided to also go for a domain of the spike protein and mixed it with an already well-understood adjuvant. Given that a lot of the risks from a vaccine come from bad adjuvants and he thought that being in his 70ths getting COVID-19 was undesirable the risk calculation clearly came out in favor of vaccinating himself with his mix. After everything went well with himself and he developed antibodies as predicted he blogged about it and gave it to his family as he didn’t want them to get COVID-19 either. It’s hard to get the timeline right here but Preston Estep, Don Wang, Alex Hoekstra, Ranjan Ahuja and George Church et al had a similar idea. They also didn’t want to get COVID-19 and knew plenty about biology. In contrast to Stöcker they cared a bit more about not being boring and thought about what they wanted out of a vaccine and coordinated with their friends instead of just making a vaccine alone for themselves. They wanted something that’s easy to brew together and that still works even if the spike protein mutates. Instead of just targeting a protein domain of the spike protein they focused on nanopeptides that are shorter sequences then individual protein domains. Short peptides also have the advantage that they are easy to order online instead of having to wait 1-2 weeks for a protein domain like the one targeted by Stöcker it’s a matter of days to get the sequences one orders for short peptides. They brew together RadVac and decided to make their whitepaper public in late July where the first public version of the whitepaper seems to be version 2-3-2 from the July 29, 2020. That’s the kind of version number one usually sees in software projects. While the FDA would never allow a product that’s developed as agile to be sold, publishing information is free and given that no scheduled substances are involved in RadVac people are free to brew RadVac together for themselves. Sometime in September Stöcker thinks (not his words): "It seems like the commercial vaccine trials don’t provide us a vaccine that allows us to vaccinate everyone in Germany this year. I could easily brew up enough vaccine doses so that we could vaccinate everybody in Germany this year and give them antibodies." Stöcker then writes the Paul-Ehrlich-Institut (PEI), which is the German institution responsible for vaccination, a letter proposing to vaccinate everybody in Germany who wants by the end of the year based on his experience of giving five probands (including himself) his vaccine nobody having side-effects and all developing antibodies. First giving it to a sizeable number of volunteers and then giving it to even more volunteers. A single 2000-liter-reactor is able to produce enough peptides for vaccines for 1 million people per day. From the perspective of the PEI this is heresy. They first ignore his letter and then contact another agency to sue Stöcker for making an unregistered clinical trial with his five probands. By German law as a doctor who’s allowed to practice medicine, Stöcker is allowed to give his patients a mix that he brew together medical trials require registration. In an actual trial with 64 patients Stöcker finds that the adverse reactions to his vaccine brew are a lot lower then that of the currently approved vaccines with their new technologies. It’s worth noting here that the side-effects of the existing vaccines are worth enduring to be protected against COVID-19. I just want a vaccine and if that means I’m ill for a day because of an adverse reaction that’s completely worth it to be protected against COVID-19. For this post I will leave the question of why companies pushed for getting the new technology to market here for the reader. Zvi wrote that the problem with the Gates Foundation was that they didn’t trust the new vaccination technologies enough. The problem seems to me the polar opposite. They fall for the mRNA researchers conning them when they funded them via CEPI. The mRNA technology seems to provide no benefit over simply giving the peptides directly but the mRNA researchers really wanted to do fancy research on mRNA. Gates had a model where he could simply give the mRNA people a few billions to build the necessary factories to produce the vaccines in a time of crisis like our pandemic. Zvi also seems to think this to be true. From basic EA principles we know that room for funding is central when it comes to effective charity interventions. As LessWrongers we understand programming and the principle of the Mythical Man-Month where adding more programmers to a project doesn’t always make it faster. Chief Financial Officer and Chief Operating Officer of BioNTech Sierk Poetting is on record (DER SPIEGEL Nr. 6 / 6. 2. 2021 Site 64) for saying that there was open room for funding for their vaccine effort in 2020. Given that Moderna’s vaccination effort got a similar amount of funding as that of BioNTech/Pfizer, I would expect them also to have no open room for funding. Mixing the mRNA with their lipid coating seems to require custom microfluid mixing technology that can’t be simply ordered and where scaling up the production needs more then just money. After hearing from Michael Vassar last year that we need a truth and reconciliation committee after this is over, I’m at the point where I want a truth and reconciliation committee.
I think this might be (very slightly) unfair to mRNA vaccines, as the comparison between them and peptide vaccines is pretty situation dependent:
We have reason to believe that peptide vaccines will work particularly well here, because we’re targeting a respiratory infection, and the peptide vaccine delivery mechanism targets respiratory tissue instead of blood.
That said, mRNA vaccines are expected to elicit much stronger immune responses than peptide vaccines would.
I suspect that the low efficacy of mRNA vaccines (only 95% - low is relative) is likely because they’re only targeting the spike protein, which apparently has ‘high mutant escape potential’. We have a LOT more information about the virus now than we did when the mRNA designs were finalized. If companies had been allowed to make mRNA vaccine updates without resetting all the clinical trials, I believe we’d have a substantially better/stronger vaccine than just 95%, with a single shot instead of two.
mRNA vaccines are really just a technology demo at this point; sure, you can make vaccines with the tech, but that’s not the real superpower here. The superpower is that we have a platform we can use to generate arbitrary proteins in live cells, including proteins we know about but for which we have no reasonable delivery mechanism. Not all proteins/peptides are water soluble, and fewer are able to get through cell walls.
As a technology demo (and not a simple one at that), it’s surprising that companies have as much production capability as they do. I would expect that capacity to be ramped up substantially in the next few years as we start aggressively making use of mRNA treatments to address a host of issues. To sum up, my view is that mRNA technology is pretty great and I’m really, really glad someone was able to make use of the disaster that was 2021 to ram through safety and clinical trials. My issue is less with the technology and it’s large promise, and more with how vaccine testing and rollout has been botched or unnecessarily slowed down at every level. Peptide vaccines are easy and fast to both design and construct, while being safe unless you really screw up, and effective as long as designed correctly. However, they do have rather substantial limitations, and it’s just happenstance that they’re particularly well suited for the situation. I could see mRNA vaccines having a much wider berth.
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I should probably know this, but are any of the mass produced COVID vaccines peptide vaccines?
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The Novavax candidate is a recombinant protein.
I don’t believe so, only radvac and euroimmun are peptide based. My question is why none of the commercial vaccines are peptide based (?) given this is a very well established vaccine technology (and particularly well suited for sars-cov2.
The evidence that the adenovirus-based and mRNA-based vaccines are safe and effective is large-scale trials with tens of thousands of participants. The evidence that Stöcker’s peptide-based vaccine is safe and effective is Stöcker’s own testimony that he and a few other people used it, didn’t get sick, and have the relevant antibodies. [EDITED to add:] Sorry, "a few" isn’t fair because he claims to have done a further experiment with 64 people. ~70 people is definitely better evidence than ~5 people, but I don’t see any reason to trust Stöcker enough to be confident that what he says about those ~70 people is actually true. The evidence that RadVac is safe and effective is a general argument that it should be safe and might be effective, and so far as I can tell nothing else at all. It might be true that the peptide approach is better, but I’d want to see much better evidence before calling for a "Truth and Reconciliation Committee" to look into the alleged awful misdeeds of the people who promoted other approaches.
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The evidence that Stöcker’s peptide-based vaccine is safe and effective is Stöcker’s own testimony that he and a few other people used it, didn’t get sick, and have the relevant antibodies.
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What do you mean by "suppressing"? I know of one instance of attempted suppression: Stöcker gave his alleged vaccine to a bunch of people and someone brought a legal action against him for running an unregistered clinical trial. If that’s what you mean: it seems to me that if someone breaks the law, then taking the legal steps that are generally taken against people who break the law isn’t obviously properly described as "suppressing his efforts", even if he claims he did it for the Greater Good. (It sounds as if you reckon he didn’t break the law because he’s a doctor; maybe you’re right—I don’t know anything about German law—but it seems to me unlikely that anyone would bother making laws against unregistered clinical trials if you could work around them simply by having a doctor administer the drugs, since surely that happens in pretty much all clinical trials anyway, and I’ve got to assume that whoever brought the case against Stöcker has some idea what the law says.) If instead you mean that the German agencies didn’t actively work with Stöcker to bring his alleged vaccine to proper clinical trials, mass production, etc., then again it seems to me that this doesn’t deserve the name of "suppression". I bet there are thousands of people claiming to have better ways to deal with COVID-19, and I bet they’re all writing to institutions like the PEI demanding that things be done their way. What algorithm are you proposing they should have executed that would have told them to put time and effort into working with Stöcker but not with dozens of cranks? And how are you so sure that Stöcker isn’t a crank himself? Again, so far as I can tell we have only his word for it that his alleged vaccine is safe and effective, even on the small sample of people he allegedly tested it on.
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The question here is whether general arguments that experts make based on inference are reliable, or do you need specific evidence. What is the track record for expert inferences about vaccines?
From a quick search, it seems that the clinical trial success rate for vaccines is about 33%, which is significantly higher than for medical trials in general, but still not all that high? Perhaps there is a better estimate for this.
Estimation of clinical trial success rates and related parameters https://academic.oup.com/biostatistics/article/20/2/273/4817524
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Proteins are peptides. When you give whole-proteins, protein domains or nanopeptides (short peptides). With peptide vaccine I mean a vaccine that contains peptides opposed to one that contains mRNA.
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(Side note: You wouldn’t use CRISPR nor HeLa cells, but rather traditional cloning techniques + any of a number of other cell lines traditionally used for recombinant protein production. But that’s tangential to your question.) I’m far from an expert here, but anything involving cell culture is generally thought to be pretty expensive. The media is expensive, other culture conditions can add to the cost as well (e.g. continuous supply of CO2 for mammalian cells), transfection reagents are expensive, and you have to expend a lot of effort keeping out bacterial/fungal/viral contamination. The inherent variability in biological processes means that you have to deal with batch-to-batch variability in your recombinant protein product, which might mean added expenses in monitoring and analysis (and headaches dealing with regulatory agencies). Basically, cells are fickle and require a lot of babysitting and care. mRNA vaccines don’t have any of these issues, because cell culture isn’t involved for the most part. Most everything is done in vitro — in that sense, mRNA vaccine production is more like chemistry than biology. And, therefore, it’s more similar to peptide-based vaccine production (chemical synthesis) than protein-based vaccine production is — which, again, is why it’s weird to contrast peptide- and protein-based vaccines together against mRNA vaccines.
Peptide vaccines aren’t old and boring, they are new and unproven. From a 2014 review
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I don’t know about subtle difference between proteins and peptides, but I would say the relevant category is "recombinant vaccines" and I believe that the first such was the Hepatitis B vaccine approved in 1986. This used genetically engineered yeast to produce a protein from the virus that was harvested and injected into people.
Novavax (non-mRNA) may be more effective on new variants. https://www.biospace.com/article/comparing-covid-19-vaccines-pfizer-biontech-moderna-astrazeneca-oxford-j-and-j-russia-s-sputnik-v/
Here is a specific proposal about the role of sexiness, ie, newness. I don’t mean to put a lot of weight on this hypothesis as opposed to the general class, but it is useful to spell out details. Also, I’m not sure what you’re saying and I suspect this is about a somewhat different irrationality than you were proposing. Perhaps governments will not allow drug companies to profit in cash from selling vaccines. But they can still profit in intangible experience. This is most obvious with Moderna and BioNTech, whose existence is predicated on mRNA vaccines working in general and the companies being able to make them in particular. After this is over, they may not have any more net cash, but they will find it easier to raise money and convince regulators, not to mention that they will be more competent. Similarly, AZ and J&J will learn about vector vaccines.
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I think a vaccine strategy that would have resulted in enough vaccines to vaccinate everyone at the end of 2020 would have been benefitial to a vaccine strategy that helps Moderna and BioNTech gather more experience with their technology platforms. I’m not arguing that giving Moderna experience with their technology platform isn’t useful but it’s not worth the delay in vaccination over using technology that can be more easily scalled up.
Another technique would be to remove a vial of blood, add covid, keep the blood alive, and wait till it beats the covid. Then reinject blood full of trained immune cells. Is this a thing? Why not?
The vaccine by Stoecker is a protein subunit produced by cell culture. It uses cell machinery like ribosomes, and, more importantly, chaperones, which fold the polypeptide correctly, to make it a functional protein (or protein subunit in this case).
Unlike Radvac, which is a mix of peptide strings synthetised chemicaly.
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Both share the feature that they are easily produced in large quantities while mRNA vaccines aren’t.
Christian, I don’t usually post here anymore, but I am going to reiterate a point I made recently: advocating for a vaccine that isn’t adequately tested is coming close to health fraud.Testing requirements are fairly onerous, but that is for a good reason.
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https://www.statista.com/statistics/1040079/life-expectancy-united-states-all-time/ is the chart for the US lifespan. For the timeframe from 1880 to 1960 it looks like a straight line with the expection for the First World War / Spanish flu. Our medical system is now so broken that lifespan dropped from 2015 to 2020.
I just read Christian’s post and I don’t see what ‘comes close to health fraud.’ Please explain?