Making Vaccine

Back in December, I asked how hard it would be to make a vaccine for oneself. Several people pointed to radvac. It was a best-case scenario: an open-source vaccine design, made for self-experimenters, dead simple to make with readily-available materials, well-explained reasoning about the design, and with the name of one of the world’s more competent biologists (who I already knew of beforehand) stamped on the whitepaper. My girlfriend and I made a batch a week ago and took our first booster yesterday.

This post talks a bit about the process, a bit about our plan, and a bit about motivations. Bear in mind that we may have made mistakes - if something seems off, leave a comment.

The Process

All of the materials and equipment to make the vaccine cost us about $1000. We did not need any special licenses or anything like that. I do have a little wetlab experience from my undergrad days, but the skills required were pretty minimal.

One vial of custom peptide - that little pile of white powder at the bottom.

The large majority of the cost (about $850) was the peptides. These are the main active ingredients of the vaccine: short segments of proteins from the COVID virus. They’re all <25 amino acids, so far too small to have any likely function as proteins (for comparison, COVID’s spike protein has 1273 amino acids). They’re just meant to be recognized by the immune system: the immune system learns to recognize these sequences, and that’s what provides immunity.

Each of six peptides came in two vials of 4.5 mg each. These are the half we haven't dissolved; we keep them in the freezer as backups. 

The peptides were custom synthesized. There are companies which synthesize any (short) peptide sequence you want - you can find dozens of them online. The cheapest options suffice for the vaccine - the peptides don’t need to be “purified” (this just means removing partial sequences), they don’t need any special modifications, and very small amounts suffice. The minimum order size from the company we used would have been sufficient for around 250 doses. We bought twice that much (9 mg of each peptide), because it only cost ~$50 extra to get 2x the peptides and extras are nice in case of mistakes.

The only unusual hiccup was an email about customs restrictions on COVID-related peptides. Apparently the company was not allowed to send us 9 mg in one vial, but could send us two vials of 4.5 mg each for each peptide. This didn’t require any effort on my part, other than saying “yes, two vials is fine, thankyou”. Kudos to their customer service for handling it.

Equipment - stir plate, beakers, microcentrifuge tubes, 10 and 50 mL vials, pipette (0.1-1 mL range), and pipette tips. It's all available on Amazon.
Other materials - these are sold as supplements. We also need such rare and costly ingredients as vinegar and deionized water. Also all available on Amazon.

Besides the peptides, all the other materials and equipment were on amazon, food grade, in quantities far larger than we are ever likely to use. Peptide synthesis and delivery was the slowest; everything else showed up within ~3 days of ordering (it’s amazon, after all).

The actual preparation process involves three main high-level steps:

  • Prepare solutions of each component - basically dissolve everything separately, then stick it in the freezer until it’s needed.
  • Circularize two of the peptides. Concretely, this means adding a few grains of activated charcoal to the tube and gently shaking it for three hours. Then, back in the freezer.
  • When it’s time for a batch, take everything out of the freezer and mix it together.

Prepping a batch mostly just involves pipetting things into a beaker on a stir plate, sometimes drop-by-drop.

Finally, a dose goes into a microcentrifuge tube. We stick the intake tube of a sprayer into the tube, and inhale.

That’s the process, at a high level. Multiple boosters are strongly recommended, so there’s a few iterations of this, though only the “take stuff out of the freezer and mix it together” step needs to be repeated. See the whitepaper for the full protocol details, as well more information about each of the peptides and what the other ingredients do (summary: chitosan nanoparticles).

The Plan

The key problem is how to check that the vaccine worked. If it were injected, that would be easy: just get a standard COVID antibody test. Inhaling makes it a lot harder to hurt yourself, but also complicates testing.

The whitepaper goes into more detail and half-a-dozen different types of immune response, but the basic issue is that immunity response in the mucus lining (i.e. nose, lung, airway surfaces) can occur independently of response in the bloodstream. Commercial COVID antibody tests generally check a blood draw. In principle one can run a similar antibody test on a mucus sample, but <reasons>, so the commercial tests check blood.

(Side note: in many ways immunity in the mucus lining is better than in the blood, since it blocks infection at the point where it’s introduced. This is an advantage of inhaled vaccines over injected. So why do most commercial vaccines inject? Turns out logistics are a major constraint on commercial vaccine design, and injections are surprisingly easier logistically. One of the major relative advantages of radvac is that it’s intended to be prepared on-site shortly before administration, so it can use techniques which work better but don’t scale as well. That largely balances out the constraints of readily-available materials and simple preparation. As usual, the whitepaper goes into much more detail on this, including several other logistics-related relative advantages - multiple boosters, custom peptides, frequent design updates, etc.)

The whitepaper claims that “over a hundred” researchers have self-administered the vaccine so far, but I have not been able to find any data on test results from any of them. The paper says that inhaled vaccine can induce immunity in the blood, but I don’t have a quantitative feel for how likely that is, other than the usual assumption that more dakka makes it more likely. Meanwhile, I don’t have a convenient way to test for immune response other than the commercial tests.

So, the current plan is to search under the streetlamp. We’ll just use the commercial tests. Both of us got an antibody test before starting the project, and both came back negative.

My current model is:

  • If the vaccine induces an immune response in the blood, then it almost certainly induces one in the mucus lining, but the reverse does not hold. So a positive blood antibody test means it definitely works, a negative antibody test is a weak update against.
  • There’s some chance that a few doses are more than enough to induce a blood response.
  • There’s some chance that more dakka will induce a blood response, even if the first few doses aren’t enough.

So, we’ll do (up to) two more blood tests. The first will be two weeks after our third (weekly) dose; that one is the “optimistic” test, in case three doses is more-than-enough already. That one is optimistic for another reason as well: synthesis/delivery of three of the nine peptides was delayed, so our first three doses will only use six of them. If the optimistic test comes back positive, great, we’re done.

If that test comes back negative, then the next test will be the “more dakka” test. We’ll add the other three peptides, take another few weeks of boosters, maybe adjust frequency and/or dosage - we’ll consider exactly what changes to make if and when the optimistic test comes back negative. Risks are very minimal (again, see the paper), so throwing more dakka at it makes sense.

Consider this a pre-registration. I intend to share my test results here.

Motivations

Why am I doing this?

I imagine, a year or two from now, looking back and grading my COVID response. When I imagine an A+ response, it’s something like “make my own fast tests, and my own vaccine, test that they actually work, and do all that in spring 2020”. We’ve all been complaining about how “we” (i.e. society) should do these things, yet to a large extent they’re things which we can do for ourselves unilaterally. Doing it for ourselves doesn’t capture all the benefits - lots of fun stuff is still closed/cancelled - but it’s enough to go out, socialize, and generally enjoy life without worrying about COVID.

I’ve written a blog post about Benjamin Jesty, the dairy farmer who successfully immunized his wife and kids against smallpox the same year that King Louis XV of France died of the disease. I explicitly use this as an example of what Rationalism should strive to consistently achieve. Yet when a near-perfect real world equivalent came along, on super-easy mode with most of the work already done by somebody else, it still took me until December to notice. The radvac vaccine showed up in my newsfeed back in July, and I apparently failed to double-click. That level of performance is embarrassing, and I doubt that I will grade my COVID response any higher than a D.

So I’m doing this, in part, to condition the mental motions. To build the habit of Doing This Sort Of Thing, so next time I hopefully do better than a D.

Of course, the concrete benefits are nice too. But at this point it’s only ~4 months until I’d get a vaccine anyway, so the price tag is only arguably worthwhile. It’s still a fun project in its own right, and it gets dramatically cheaper with more people (remember, $1000 bought enough supplies for ~500 doses). Concretely, the largest benefits are in risk reduction. If there’s big hiccups in commercial vaccine deployment, this becomes much more worthwhile. If the South Africa strain turns out to evade commercial vaccines, this becomes much more worthwhile - the radvac design is frequently updated based on the latest COVID research, so we hopefully wouldn’t need to wait around for approval of a new commercial vaccine.

Finally, I'm curious whether it will work - or whether we'll be able to tell that it works. It's a data point as to just how often large bills are left sitting on sidewalks just a little ways off the beaten path.

Making Vaccine
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Do you have any thoughts on the risks/hazards involved here? To me that's a much more significant consideration than the price. Some thoughts / priors:

  • Snorting chemicals I got from the Internet / mixed up myself without really knowing what I was doing: Superficially, seems potentially pretty risky.
  • Snorting peptides (assuming that the stuff ordered online was what it claimed to be, was pure and not contaminated with anything hazardous, and that I didn't accidentally create anything hazardous in the process): Definitely not as risky as snorting arbitrary unknown substances. Seems unlikely to be directly poisonous (although that's without reading about the other contents of the vaccine.)
  • Snorting COVID-19 peptides, in particular: Should I be worried about things like antibody-dependent enhancement? Are there other possible hazards specific to experimental vaccine administration that I should worry about? I'm sure the paper talks about this stuff, but I'm not a biologist so I can't promise I'd understand it if I read it.
  • Is there a possibility that this vaccine is both ineffective, and interferes in some way with the effectiveness of subsequent administration of a different vaccine?
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The main answer here is "see the paper"; there's a lot of discussion about this stuff. I'll summarize a few points, as I understand them, relevant to your particular thoughts.

  • The "snorting chemicals" aspect is generally not much of an issue, since every ingredient other than the peptides is food-grade, and the quantity in a dose is tiny (one dose is <1 mL, and most of that volume is vinegar and water). If you were eating this stuff in your food and coughed on it, you'd probably get a higher dose than what's in the vaccine.
  • Peptide synthesis services generally provide various quality control checks on the product (some free, some upcharge). So at least you'll know what you're getting.
  • Antibody-dependent enhancement is one of the main things the paper discusses. It's pretty rare to begin with, and the cases where it's happened have some patterns to them which can be avoided; the peptides are chosen to avoid those pitfalls. Reading between the lines, it sounds to me like historical cases were largely a by-product of historical vaccine techniques (e.g. attaching pieces of one virus to the backbone of another in the case of Dengvaxia) which aren't used here.
  • As I understand it, interfer
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Regarding the final paragraph, "you need some level of expertise yourself before you can distinguish real experts from fake":  that has been the number one reason I didn't beat johnswentworth to the punch and post first with my experience.

I have learned more about biochemistry in the last three months than in my entire prior life combined.  It has taken me three months of research, asking questions, and conferring with experts to get sufficient confidence in my understanding to commit to the project.

I'm incredibly thankful to you (johnswentworth) for posting this article; it tracks almost perfectly with my understanding, and I have no significant model conflicts with any of your observations.  It raises my confidence in both my understanding, and the project, substantially.

I'd be very interested in a post on what you learned! I relied mostly on general bio background from undergrad, it sounds like you probably went into more depth in areas specifically relevant to this.

Thanks, I really appreciate you taking the time to respond.

I should probably have clarified my current views / epistemic status in my comment, since I think it sounded more skeptical than I actually am. I would say it's something like: "I expect this is quite possibly a good idea, and most probably at worst a neutral idea. I am interested in trying to elicit anything in the long tail of risks that could change that."

(I guess I did also want to encourage other people to at least briefly consider risks before trying this themselves -- although given the complexity and expense, perhaps I shouldn't worry that anybody might rush to try it.)

No worries, these are the right questions to ask and I'm glad someone brought them up.

3cistran
How many times do you snort adjuvants with your food? I bet the concentration of adjuvants in your homebrew is much higher than what a person could accidentally inhale. This is on purpose of course, so that you are much more likely to get an immune response. But your comparison with things that are not designed to elicit an immune response seems somewhat optimistic.

I think a lot of these questions are answered in the radvac paper. I sent a copy of it to a biologist I know, and asked if he thought it was crazy to do this, and he read it and said “geez this looks safer than doing drugs”. I don’t have enough expertise to add anything beyond that.

5gwillen
Thanks, that's helpful (and hilarious.) I am looking through the paper now, and it definitely at least purports to answer some of my questions/concerns. (I haven't had a chance to follow the references to see the details.) I would love to hear more takes from people expert enough to weigh in.

Well, this post was just crying out for some embedded predictions! So here we go: 

Thanks johnswentworth for help with some of the operationalisations!

I included many different ones, as I think it is often good try to triangulate high stakes questions via different operationalisations. This reduces some some "edge-case noise" stemming from answering vague questions in overly specific ways.

@Davidmanheim you're a pretty big outlier here, and this is also the kind of question where I'd trust your judgement a fair bit: 

So curious if you wanted to elaborate a bit on your model?

First, base rates are critical. Looking at potential drugs overall, the rate of approvals due to safety alone - i.e. "Investigational New Drugs" to phase-II efficacy trials, is very low. Phase 1 trials are typically 80-100 people, and most don't manage to make it past that stage. It would take much stronger evidence than I have seen to think that this vaccine is going to be outside of the norm.

Second, even if the process as done was safe, I can't imagine that greater than 99% of people manage to do this without screwing up in some serious way. That's less true of the LW crowd, but I don't think people are aware of how dumb the mistakes that get made are, or how much quality control matters, and how difficult it is with trying to enforce it for DIY projects.

Lastly, I'm well within the consensus for almost all the rest of the questions - I think it probably works in most cases, and I think it will have side effects in far fewer than 50% of cases.

(But another place I'm a bit outside the consensus is that I think it's unlikely to trigger standard antibody tests, since standard antibody tests are looking for antibodies against a specific part of the virus, and I'm unsure, reading the "Antibodies and B-cell immune response" section of the white paper, that standard tests would detect the elicited types of NABs.)

9Raemon
As someone considering taking it, I'd be interested in whether you have models of particular side effects or severities that might happen and why? Do you just have vague "accidents and harmful unknown unknowns aren't that unlikely here"? I have not currently read the paper or looked into anything very hard. But one question I'd have is "given the ingredients you're working with, is there are particularly obvious way to mix these on purpose that'd result in something harmful happening?" 
3Davidmanheim
Mostly vague "accidents and harmful unknown unknowns aren't that unlikely here" - because we have data on baseline success at "not have harmful side effects," and it is low. We also know that lots of important side effects are unusual, so the expected loss can be high even after a number of "successes," and this is doubly true because no-one is actually tracking side effects. We don't know much about efficacy either, but again, on base rates it is somewhat low. (Base rates for mRNA are less clear, and may be far higher - but these sequences are unfiltered, so I'm not sure even those bse rates would apply.)  Finally, getting the adjuvants to work is typically tricky for vaccines, and I'd be very concerned about making them useless, or inducing reactions to something other than the virus. But if you want to know about intentional misuse, it's relatively low. I would wonder about peanut protein to induce you to develop a new allergy because you primed your immune system to react to a new substance, but you'd need someone more expert than I. Overall, I'd be really happy taking bets that in 20 years, looking back with (hopefully) much greater understanding of mRNA vaccines, a majority of immunologists would respond to hearing details about this idea with a solid "that's idiotic, what the hell were those idiots thinking?" (If anyone wants to arrange details of this bet, let me know - it sounds like a great way to diversify and boost my expected retirement returns.)
8Ben Pace
This was great.
5eillasti
> The radvac vaccine will have serious side effects (i.e. besides stuffy nose for a day) for >50% of people who try it It should be well below 1%. Firstly, if it were that bad as to cause serious side effects for >50% of people who try it, would the RaDVaC team risk promoting it? Secondly, if it were that bad, wouldn’t we hear bad stories about side effects? Thirdly, getting serious side effects accidentally in >50% cases sounds pretty hard on its own. > The radvac vaccine induces antibodies detectable in a standard commercial blood test in most people, using the dosage in the paper with 2 booster shots <1%, because RaDVaC team has tried it and didn’t manage to get any positive result. > The radvac vaccine induces antibodies detectable in a standard commercial blood test in most people, using "more dakka", for some reasonable version of "more dakka" This greatly depends on what “more dakka” and “reasonable version” means. I assume that “reasonable version” implies "doesn't cause too much harm due to immune system overstimulation”. If “more dakka” means simply a higher dosage, then I think, that this is unlikely (5%), because 1) RaDVaC team experimented on themselves quite a bit, they received a lot of dakka, but no commercial blood test detection, 2) RaDVaC team seems reasonable enough to try this approach if it looked promising. If “more dakka“ includes stronger adjuvants (chitosan is considered a weak, but safe one), then it is much more likely (20%?), because RaDVaC team didn’t investigate those (for a reason) and it sounds plausible that you can get an immune response by irritating the immune system really, really strongly.
2jacobjacob
That's false, they got several positive anitbody results in ~June or so last year. See a comment elsewhere on this post. 
2johnswentworth
I think he might mean commercial blood antibody tests specifically?
1eillasti
Yes, exactly. "None of us has tested positive using insensitive commercial point-of-care tests"
2ChristianKl
I would prefer "immunizes against COVID-19" to be better defined when asking the question. Immunizing against becoming systomatic with COVID-19 is a different value then immunizing against not being infectious with COVID-19 and both of those matter. Preventing rate of hospitalization and rate of death would also be important. 
2Davidmanheim
In epidemiology / medicine, etc. "Immunizes" has a technical meaning - it means you cannot contract or carry the disease. (i.e. not that you don't get symptoms.)
4ChristianKl
By that definition Moderna and BionTech don't have vaccines that are proven to immunize people against COVID-19. That technical meaning might be used in some communities but I think if you would ask the median rationalist whether or not there was a clinical trial whether the Moderna or Pfizer vaccine immunizes people against COVID-19 they would say "yes, there was such a trial". If a journalist would ask someone at the FDA or CDC the question whether such a trial I doubt they would get the answer "technically there wasn't a trial that showed the those vaccines immunize anyone". The idea that the technical meaning of a scientific term is something that isn't operationalized seems to me also problematic. There might be people in epidemiology who believe that but it's ontologically problematic and causes a lot of harm.
2Davidmanheim
"Immunity" and "efficacy" seem like they should refer to the same thing, but they really don't. And if you talk to people at the FDA, or CDC, they should, and probably would, talk about efficacy, not immunity, when talking about these vaccines. And I understand that the technical terms and usage aren't the same as what people understand, and I was trying to  point out that for technical usage, the terms don't quite mean the things you were assuming.  And yes, the vaccines have not been proven to provide immunizing protection - which again, is different than efficacy. (But the vaccines do almost certainly provide immunizing protection for some people, just based on the obvious prior information and the current data - though it's unclear how well they do so, at how long after the vaccine.)  And, to make things worse, even efficacy is unclearly defined. It gets defined in each clinical trial  - differently for each drug/vaccine/etc. and I don't think it actually mean the same thing for the currently approved COVID-19 vaccines. It's pretty similar, stopping symptomatic cases, but even given the same endpoint, it's not necessarily identical, since the studies picked how to measure the endpoints independently, and differently.
2Pongo
I didn’t mean to predict on this; I was just trying to see number of predictions on first one. Turns out that causes prediction on mobile
4jp
You can un-predict by clicking on the prediction block again.

You have my admiration, and my hope that you are calculating the risks accurately!

I have not read the RaDVaC paper so I don't have a good object level model of safety and risks. From a distance it looks like heroism, because from a distance it looks like taking a risk in a way that could provide a role model for many if it works safely! It reminds me a bit of Seth Roberts who was a part of the extended tribe who did awesome stuff over and over again (seemingly safely) but who also may have eventually guessed wrong about safety. 

I guess I just want to say: "This is so freaking awesome, and PLEASE be very careful, and also please keep going if the risks seem worth the benefits."

If you get a positive antibody result, have you thought about a personal challenge trial?

The big benefits to be gained from vaccination seem to be to be behavioral: going out, doing life similarly to the Before Times... which is similar to a partial/random/natural sort of "challenge trial". 

I wonder if 1daysooner can or would be interested in keeping track of people who have tried the RaDVaC option, to build up knowledge (based on accidental exposures or intentional challenges) of some sort.

I double-cruxed this article because my "voice of caution" objected to it.

I eventually realized the issue was that part of my decision-making process when I do something weird, potentially risky, or expensive, is to consult with friends and family. Yet I feel that the feedback I would get from them would be so thoughtless, negative, frustrating, and potentially damaging, that it's not worthwhile. And I don't want to ignore this "consult someone first" rule, because it seems like a generally good rule that loses its force if ignored.

However, I do know some specific people who might be good to talk it over with. They're warm, open-minded, very smart, scientifically literate, unconventional, have my best interests in mind, trustworthy, and willing to discuss this kind of stuff at length. My next move is probably not to read the paper, but rather to discuss it with them.

I think what you have done here is re-invented the actual helpful version of a practice whose authoritarian bureaucratic cargo-culted version is called "anonymous peer review".

It is easy (and maybe dangerously wrong) to come to the straightforward conclusion that peer review in general is simply evil bullshit... until one finds the place from which a benevolent truth-oriented human (like oneself) finds a reason to consult with an actual "epistemic peer" as a prudent and socially-embedded response to one's own uncertainty about things one cares about.

I talked this out with a consultant friend who got his BS in biology. Here's what we came up with.

A conceptual solution would have the following variables, labeled for clarity.

Cost of vaccine = C

  • C = (Cost of manufacturing RacVac) ÷ (Doses you'll administer) + (Dollar value to represent cost of unconventionality of the project)

Probably that vaccine provides value = P

  • P = (Chance that RadVac works at all) x (Effectiveness if it does work) x (Chance you'll catch COVID before getting vaccinated) x (Chance you'll fail in your execution)

Value that could be provided per person = V

  • V = [ (Dollar value of your life) x (Chance you'll die if you catch COVID) + (Dollar value of avoiding a day on a ventilator) x (Chance of serious case of COVID) x (About 14 days on a ventilator) + (Dollar value of avoiding a day of fatigue/anosia) x (Chance of long-term fatigue/anosia) x (Expected length of long-term fatigue) + (Expected number of days out of work) x (Cost of lost work) + (Expected out-of-pocket cost of medical care if you caught COVID)]
  • P' = 1 - (Chance you'll transmit it to a particular other person if you catch it) x (Chance they'd have caught it anyway)
  • V' = Calculation of V but for anothe
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6kuudes
I made a little different, simplified take on the matter: For Radvac to be net useful, it needs that following is true: p(RV prevents Covid)*p(user gets Covid [is exposed to Covid such that it would lead to infection])*p(Covid causes long term harm) > p(RV causes long term harm) p(RV harm) is currently from the RV paper likely less than 1/10000, cited example is Pandemrix that caused long term harm of narcolepsy with 1/16000 if you had Swedish or Finnish genome. p(Covid harm) is high in old people, where you can die with up to 25% probability, but for most of young people around here long Covid would seem to dominate and that seems to be maybe 1%. Long Covid probability seems to be not well found, and this seems a likely direction for improving decision with better data. with these presets we get: p(RV prevents Covid)*p(user gets Covid) > p(RV harm)/p(Covid harm) <=> p(RV prevents Covid)*p(get Covid) > 0,0001/0,01 = 0,01 from this, we get 3 inequalities as boundary conditions: (presume scenario where getting Covid is max, that is 100% => prevention needs to be > 0,01; vice versa) * p(RV prevents Covid) > 0,01 * p(get Covid) > 0,01 * p(RV prevents Covid)*p(get Covid) > 0,01 so with current boundary conditions the key thing to find out with Radvac is how likely it is to cure Covid. This needs to be shown likely to be over 1% or it should not be used unless other boundary conditions can be shown to differ. An aside: this same calculation applies to all other vaccines, which is why the effort has been put into making sure p(harm from vaccine) is ascertained to be much less than 1/10000. This making sure the vaccine harms the least is about necessary condition for mass vaccinations to be net useful for the participants themselves. This is why we have used 1 year+ for safety testing, which gives us way better and lower prior for vaccine harm than 1/10000. If you get no long term harm from N trial persons, then per succession rule your naive prior is that p(harm)
7kuudes
A friend offered that page 7 of white paper could maybe be used to deduce that Radvac would prevent Covid with ~40%. This would mean the decision boundaries would get to p(Covid)*40% > 0.01 <=> p(Covid) > 0.01/0.40 <=> p(Covid) > 0.025 so then you would need your chance to get Covid to be over 2.5% for the use to be net beneficial. If we also presume a 80+ year old person who has 25% probability of death given Covid, then it becomes p(RV works)*p(get Covid)*p(Covid harm) > p(RV harm) <=> p(Covid)*40%25% > 1/10000 <=> p(Covid) > 0.0001/(0.40.25) = 0.001 so for them the chance to get Covid before official vaccination would need to be over 0.001 for it to be net beneficial with these boundary conditions.

Speak of the devil.  I literally just placed my peptide order a couple of hours ago.  My experience (finding supplies, test runs of mixing the solution, safety profile, analysis, etc.) basically matches up with this post.

 

Thanks a lot for posting it.

[-]RaemonModerator Comment400

Note: this post was frontpaged (despite a general policy of not frontpaging covid content) both because a) it seems pretty important, and b) the rationality life lessons seemed pretty timeless.

Hmm, important as in "important to discuss", or "important to hear about"?

My best guess based on talking to a smart open-minded biologist is that this vaccine probably doesn't work, and that the author understates the risks involved. I'm interpreting the decision to frontpage as saying that you think I'm wrong with reasonably high confidence, but I'm not sure if I should interpret it that way.

You should make a top-level comment about this. Chance that the vaccine works and the associated risks are object-level questions well-worth discussing.

In general, frontpage decisions are not endorsements (though I don't know Raemon's thoughts in this particular case), and this comment section is not the place for a debate about frontpaging norms. This is definitely the place to talk about chance the vaccine works and associated risks, though.

6jsteinhardt
I don't think I was debating the norms, but clarifying how they apply in this case. Most of my comment was a reaction to the "pretty important" and "timeless life lessons", which would apply to Raemon's comment whether or not he was a moderator.
4johnswentworth
Yeah, I don't mean to say your comment was bad as-written, just preemptively heading off a potential thread.
4jsteinhardt
Ah got it, thanks!

Have you run this by a trusted bio expert? When I did this test (picking a bio person who I know personally, who I think of as open-minded and fairly smart), they thought that this vaccine is pretty unlikely to be effective and that the risks in this article may be understated (e.g. food grade is lower-quality than lab grade, and it's not obvious that inhaling food is completely safe). I don't know enough biology to evaluate their argument, beyond my respect for them.

I'd be curious if the author, or others who are considering trying this, have applied this test.

My (fairly uninformed) estimates would be:
 - 10% chance that the vaccine works in the abstract
 - 4% chance that it works for a given LW user
 - 3% chance that a given LW user has an adverse reaction
  -12% chance at least 1 LW user has an adverse reaction

Of course, from a selfish perspective, I am happy for others to try this. In the 10% of cases where it works I will be glad to have that information. I'm more worried that some might substantially overestimate the benefit and underestimate the risks, however.

In my case, yes.  My bio expert indicated that it was likely to be effective (more than 50%, but less than 90%) and that the risks were effectively zero in terms of serious complications.

Regarding the food grade versus lab grade question, as well as inaccuracies or mistakes in construction of the vaccine, this was a question I spent a reasonable amount of time on.  The TL/DR is that the engineering tolerances are incredibly wide; the molecular weight of the chitosan isn't that important, the mixing rate isn't that important other than it be fast enough, the quantities aren't that important, exact peptide quantities aren't that important etc.  A lot of these can be off by not just percentage points, but integer factors, and the result will still be acceptable.

It's also worth pointing out that unless you make serious, significant mistakes that dramatically impair effectiveness, you can always just use "more dakka" to overpower the variations.  My plan is to mix each batch independently, such that at least some of the construction variations are expected to cancel.  (Also, freezing the final vaccine is likely to impair effectiveness, from what little I've found on the topic.)

I wasn't sure what you meant by more dakka, but do you mean just increasing the dose? I don't see why that would necessarily work--e.g. if the peptide just isn't effective.

I'm confused because we seem to be getting pretty different numbers. I asked another bio friend (who is into DIY stuff) and they also seemed pretty skeptical, and Sarah Constantin seems to be as well: https://twitter.com/s_r_constantin/status/1357652836079837189.

Not disbelieving your account, just noting that we seem to be getting pretty different outputs from the expert-checking process and it seems to be more than just small-sample noise. I'm also confused because I generally trust stuff from George Church's group, although I'm still near the 10% probability I gave above.

I am certainly curious to see whether this does develop measurable antibodies :).

2John_Maxwell
Fixed twitter link
6Davidmanheim
"the risks were effectively zero in terms of serious complications" Your expert said that the risk of putting unfiltered peptide strains into your body was negligible? This claim confuses me. Did you talk to someone who has a background in immunology, or an infectious disease specialist? (The former seems like the more important type of expertise.) And while this isn't my area of expertise, the claim seems wrong. Having your body develop immune reactions to sequences that aren't the full virus seems potentially really bad - because they could look like other things you don't want your body reacting to.
4johnswentworth
You actually put unfiltered peptides into your body all the time. Pretty much any biological material you breath in (e.g. ordinary indoor dust or smelling a flower) contains some.
3Davidmanheim
Yeah, putting it in your nose definitely has far fewer risks than putting it in your blood, and that greatly reduces my skepticism. But the set of peptide sequences you naturally encounter is a tiny subspace of the total space of possible proteins, and so I'm less convinced that you might not have side effects.

Also, having random peptides along with an adjuvant (which triggers an immune response) might be risky even in cases where those random peptides are otherwise completely safe.

6johnswentworth
I did not try this test. I had enough bio and physiology background to be confident in my own assessment, though I would not advise others to be similarly confident in my assessment - my background is not legible enough for that.

There is another Covid-19 peptide vaccine developed by a Dr. Winfried Stöcker. He injected it into ≥64 volunteers, and the results he published look promising. They show both a good level of IgA, IgG and IgM antibodies and ≥ 94% neutralization for the vast majority of the test subjects. According to him (last paragraph of his blog post), none of the test subjects have reported any relevant adverse symptoms.

He describes the manufacturing in his blog (see translation below):

Man nehme dreimal 15 Mikrogramm rekombinante RBD der S1-Untereinheit (Arg319-Phe541) für eine Person. Als Adiuvans habe ich Alhydrogel von InvivoGen verwendet: Ordentlich durchschütteln und davon 200 Mikroliter mit der Tuberkulinspritze aufziehen. In eine größere Spritze 10 Milliliter Kochsalz aufziehen und die 200 Mikroliter dazugeben, mischen. Davon 500 Mikroliter pro Schuss, mit denen man seine Portion Antigen vermischt. Alles hübsch steril.

I've attempted a translation and added some of my own understanding in [square brackets]. Though I'm a German native speaker, I have zero domain knowledge in this field, so please correct me if anything is wrong:

Take three times 15 μg [three doses of 15 μg per person, spaced

... (read more)
9ChristianKl
You need to work a lot more sterile when injecting then when you spray something in your nose. I'd rather have a few additional steps with less problems if I mess up some of the steps.

Good point! I've attempted to expand on this a bit, and list the advantages that each vaccine currently seems to have over the other:

For RaDVaC:

  • Extensive Documentation, Whitepaper and reasoning about its development available
  • Manufacturing does not require a sterile environment
  • Simpler administration
  • Has a small community, might be easier to exchange questions and results
  • Regularly updated (possibly double-edged - seems very useful to keep up with any variant capable of immune escape, but may (?) make it more difficult to estimate efficacy across vaccine generations)
  • Designed to prevent immune escape, may still work when commercial vaccines become less effective (uses 9 - 13 peptides instead of just targeting the spike protein like other vaccines)
  • Cheaper ingredients, because the peptides required are shorter

For Dr. Stöcker's Vaccine:

  • Test results released so far show very good efficacy and safety (for n=64)
  • Known-good dosing regimen available
  • Efficacy can be verified using commercial blood antibody tests
  • Requires only one peptide (which might be orderable as-is, without custom synthesis) and two passive ingredients

One way to achieve sterility might be to use a self-made glovebox (example tu... (read more)

Has a small community, might be easier to exchange questions and results

Given that this community exists it's likely that they somehow privately share results. It would be really interesting to know more about what's going on in that community.

as long as we knew what kind of Arg319-Phe541 peptide we need for it.

I understand Arg319-Phe541 to mean the subsection of the spike protein that begins with arginine at position 319 and ends with phenylalanin at position 541. At the moment I don't immediately find the sequence with googling but it's worth checking whether 319 is indeed arginine and  541 phenylalanin to check whether this interpretation makes sense. 

The problem is that this is 222 amino acids longs which is longer then what the peptide sequencing company sell you so you can't get them the same way you get the peptide you need for the RaDVaC vaccine.

Active-Bioscience seems to sell 100 µg of SARS-CoV-2 Spike Glycoprotein-S1 RBD (319-541, biotinylated) recombinant Protein for 1.150 € which gives you enough doses for two people.

I think RaDVaC has another advantage. It's designed to be difficult for the virus to mutate to get immune to it. Having to change ... (read more)

3fluffyclouds
Thank you, this is helpful - I've edited the parent post to include some of your feedback. About the community: the only other place I've found so far is /r/radvac - though pretty dead, it may be useful to find people connected to the community. This page also mentions a Boston RaDVaC group. This seems right - the RaDVaC white paper has a nicely formatted copy of the S protein on page 40, and it begins with R / arginine at 319 and ends with F / phenylalanine at 541. I found 230-01102-1000-RB by RayBiotech as a cheaper option. If you buy 100 µg of it at 308 € (includes 19 % VAT) you end up at 52 € per dose / 154 € per person. Or you buy 1000 µg at 1129 €, which is enough for 22 people, it's 18 € per dose / 52 € per person. Again, I have no clue about what you have to look out for when buying this peptide (e.g. format, purity, formulation, ...?) for an injected vaccine, any info on this would be highly appreciated! Apart from that, the data released on the Stöcker vaccine shows that shots 1, 2 and 3 were on average 10 and 32 days apart. Storing the peptides for this amount of time does not seem to be trivial, see e.g. the storage requirements from RayBiotech for their Arg319-Phe541: Maintaining 4 °C sounds doable with a good fridge and a data logging thermometer. -20 °C is more tricky - maybe use a home freezer (*** is specced at ≤ -18 °C) and add a data logger. If it then turns out that it can't reach -20 °C, it might be possible to fix that by modding its internal thermostat somehow. Or have access to a lab freezer, or shell out the big bucks (four figures) to buy one. I am curious about the storage requirements for RaDVaC and couldn't find out anything specific on the webpage or in the whitepaper. Though the latter does mention some steps that were taken to improve peptide stability, it would be nice to have some info on this.
8kjz
As someone who has worked in the labs a long time, I wouldn't worry about having to hit exactly -20 °C; that basically just means "freezer temperature". Lab freezers don't work any differently than home freezers as far as I can tell, although they do have certain safety features that a home freezer wouldn't. But the temperature can still vary a few degrees up or down, and it shouldn't affect your storage much. The (very) general rule of thumb is a difference of +/- 10 °C makes chemical reactions (such as peptide degradation) go 2x faster/slower. So even having to store in a fridge temporarily would only be ~4x faster than a freezer, still maybe good enough for one's purposes. The big difference comes for -20 °C vs -80 °C, since there you have a 2^6 or 64-fold rate difference. So something that can last for a month at -80 °C might degrade in half a day in a freezer. Hence the complex supply chains needed for such vaccines.
9Juno
Lab freezers have no defrost cycle. Home freezers often do, which prevents ice buildup but also means they don’t maintain temperature.
4johnswentworth
So that's why those damn things were always so full of ice! Thankyou, I did not know this before.
2johnswentworth
This thread was excellent, strong upvotes for both of you.
8caffemacchiavelli
Thanks for posting this, this looks excellent. It's my impression that you can indeed just buy the antigen needed - the lowest price for 1mg I found was around 900€. Allowing for 10% waste, this would cover 20 individuals at 45µg each. I looked at the antigen test results first and was worried that the vaccine wouldn't perform as well in live tests, but the neutralization results Stöcker posted are quite promising and a Nature study suggests that using 319–545 of the RBD is effective in providing immunity to live virus in primates. I don't expect the remaining amino acids will affect the results in a major way, so this looks quite promising indeed. I've asked a few people with more domain knowledge to comment on this and depending on their judgment (and access to sterile lab space) I might fund vaccines for myself and friends, given that Germany's vaccine rollout seems to be taking its time.
4ChristianKl
Not legal advise: It's my understanding that German law allows you to take things you brew up yourself but only doctors or Heilpraktikers are allowed to give brews like this to other people. If you have a friend who's a doctors or Heilpraktikers who could take the role might be helpful (and that person should have a better idea about the exact conditions under which he can give out brews).
2caffemacchiavelli
From what preliminary legal advice I've received, I'm allowed to hand it out as a research chemical but anything beyond that might get me into trouble. That sadly limits me to offering it to other nerds who I can reasonably expect to use it for research purposes, but I also highly doubt that anyone outside that cluster would even be interested.

I was banned from r/neoliberal for sharing this. 

"Spreading dangerous medical information"

I think deleting it was a fair response (though perhaps banning is a little over the top). assuming the moderator has no way of checking for himself whether this makes sense and he knows he doesn't, he's left with a bet about whether this is the real thing or just bullshit. he expects more bullshit than real things, and he expects the bullshit to be dangerous. so he removes everything that fits this class of things, knowing he might end up also removing something real.

8Dentin
I agree as well.  It takes a non-trivial amount of knowledge and research to evaluate the the whitepaper and its claims, and I wouldn't expect the moderator of a "neoliberal" group to have that expertise.  We have options with a known risk profile (the commercial vaccines), and there's a spot of fraudulent "cures" out there.  The safe thing for a moderator to do is blackhole potentially dangerous claims they don't have the time and/or experience to evaluate.
5jimmy
I think this is inaccurately charitable. It's never the case that a moderator has "no way" to know whether it checks out or not. If "Hey, this sounds like it could be dangerous misinfo, how can I know it's not so that I can approve your post?" is too much work and they can't tell the good from bad within the amount of work they're willing to put in, then they are a bad moderator -- at least, with respect to this kind of post. Even if you can't solve all or even most cases, leaving a "I could be wrong, and I'm open to being surprised" line on all decisions is trivial and can catch the most egregious moderation failures. Maybe that's acceptable from a neoliberal moderator since it's not the core topic, but the test is "When confronted with evidence that they can correctly evaluate as showing them to have been wrong, do they say 'oops!' and update accordingly, or do they double down and make excuses for doing the wrong thing and not update". I don't know the mod in question, but the former answer is the exception and the latter is the rule. If the rejection note was "Medical stuff isn't allowed because I'm not qualified to sort the good from the bad", then I'd say "fair enough". But actively claiming "Spreading dangerous misinfo!" is rarely done with epistemic humility out of necessity and almost always done out of the kind of epistemic hubris that has gotten us into this mess by denying that there's an upcoming pandemic, denying that masks work and are important, and now denying that we can and should dare to vaccinate in ways that deviate from the phase 3 clinical trials. This kind of behavior is hugely destructive and is largely the result of enabled laziness, so it's really not something we ought to be making excuses for.
6Yoav Ravid
I agree i was being charitable. and yes, i was talking specifically about my expectations from a neoliberal forum moderator (if this was a biology or medicine forum i would have higher standards). my point wasn't necessarily that the mod did that out of good epistemics, just that the decision is justifiable, whatever method he actually used to take it. (i don't know the moderator in question either). actually I'd bet the moderator didn't do it with good epistemics, since he overreacted and outright banned him rather than just deleting it.
6jimmy
Being as charitable as the facts allow is great. Starting to shy away from some of the facts so that one can be more charitable than they allow isn't. The whole point is that this moderators actions aren't justifiable. If they have a "/r/neoliberal isn't the place for medicine, period" stance, that would be justifiable. If the mod deleted the post and said "I don't know how to judge these well so I'm deleting it to be safe, but it's important if true so please let me know why I should approve it", then that would be justifiable as well, even if he ultimately made the wrong call there too.  What that mod actually did, if I'm reading correctly, is to make an active claim that the link is "misinformation" and then ban the person who posted it without giving any avenue to be proven wrong.  Playing doctor by asserting truths about medical statements, when one is not competent or qualified to do so, getting it wrong when getting it wrong is harmful, and then shutting down avenues where your mistakes can be shown, is not justifiable behavior. It's shameful behavior, and that mod ought to feel very bad about his or herself until they correct their mistakes and stop harming people out of their own hubris. The charity that there is room for is along the lines of "Maybe the line about misinformation was an uncharitable paraphrase rather than a direct quote" and "Hey, everyone makes mistakes, and even mistakes of hubris can be atoned for" -- not justifying the [if the story is what it seems to be] clearly and very bad behavior itself.
5benjaminikuta
>The charity that there is room for is along the lines of "Maybe the line about misinformation was an uncharitable paraphrase rather than a direct quote" For what it's worth, it was a direct quote, and the entirety of the ban message, other than a link to the comment. 
4benjaminikuta
Even with a Harvard professor as an author? 

It depends more on the ignorance of the moderator and on how much time he's willing to spend than on the quality of the evidence. there definitely are cases of of PHDs and maybe even professors advancing pseudoscience. so this doesn't guarantee trustworthiness.

the moderator has to make a decision in a state where he can't trust himself to distinguish real stuff from bullshit. he goes for minimizing harm at the cost of deleting novel good ideas. seems like a sensible decision to me.

7benjaminikuta
How often do scholars of such prominence promote dangerous pseudoscience? 

Often, e.g. Stanford profs claiming that COVID is less deadly than the flu for a recent and related example.

7waveBidder
John Ioannidis, of all people, who should know better.
-1cistran
For children, it is as far as we know.
1Yoav Ravid
Interesting question, i don't know. but it also doesn't matter here. if the moderator is ignorant he's also ignorant of this fact, and thus cannot take it into account or will have to spend effort finding a good answer for it - so we're back at square one.
5Dentin
Again, I have to disagree - misinformation is much more likely than information by default, and the moderator need only have a reasonable low-probability prior in order to reject unusual/uncommon claims without evidence.
7Yoav Ravid
I agree with that. not sure what you think i meant that you disagree with it.. (or was it directed at the comment above me?)
2Dentin
Sorry about that; I believe I misread your comment as implying that if the moderator is ignorant, he won't have enough information to form a reasonable prior.  My disagreement was along that line, as it seems that misinformation, especially about medical things, is so prevalent that everyone's default prior should be 'fraud unless lots of evidence points the other way'.
5ChristianKl
I think there's a difference here between sharing a link to RadVac and sharing a link to a LessWrong post by someone without credentials doing something on their own.
6AI_WAIFU
I wouldn't look too deeply into that. The selection process for moderators on reddit is essentially first come first serve + how good are you at convincing existing moderators you should join the team. As far as I can tell this process doesn't usually select for "good" moderation, especially once a sub gets big enough that network effects make a subreddit grow despite "bad" moderation. This applies for most values of "good" and "bad". 

Via Sarah Constantin's Twitter:

I looked into this, because yay citizen science. I could not find one research study using any of the peptides in the RADVAC white paper that found they inhibited SARS-CoV-2 infection in cells, let alone animals or humans.

and

“Take a random peptide that has never been tested on any living thing” is not at all the same thing as “take a well-known, well-studied recreational drug”, as far as risk goes.

She doesn't explicitly state that this has never been tested on any living thing. Possibly because she wasn't confident enough in her research survey to claim that, possibly because she was drawing a starker contrast than applies to this instance. But all the COVID testing for RADVAC is purely in silico, so while the chemicals involved may be studied for safety in vivo, efficacy is completely untested even at the (much simpler than organism) cell level.

So the EV of the benefits are low, and the risks are unclear.

4kjz
This article from July 2020 claims that George Church and many of his colleagues had already self administered their vaccine at that point. It's almost certainly true that there hasn't been a clinical trial, because nobody has ever had an incentive to run a clinical trial. I don't think their intent was to publicize this widely or profit commercially from it. Rather, they realized they could just do it, went ahead and did it, and wrote up their findings publicly but under the radar, so other like-minded individuals could duplicate their procedure at their own risk. Remember that they are an academic research group and they face very different incentives than the drug companies trying to vaccinate the general public. In any case, it seems clear that these vaccines have been tested on many living things, just not in an official study.
5Czynski
No one said anything about a clinical trial. Emphasis added: Researching the effects in cells requires no IRB approval and publishing the results of that research as a publicly-accessible preprint is not hard. This should be fairly easy to do, for someone with access to a good lab, personal-scale funding, and motivation. I have to assume that Church et. al. have the first two, so either they don't care enough to bother, or they did but the results weren't encouraging (and either kept quiet or just unnoticed). Neither is what I'd call a 'good sign'.
2kjz
Agree neither Sarah or you had explicitly mentioned a clinical trial. I was pushing back more against Sarah's statement “Take a random peptide that has never been tested on any living thing” and your statement "She doesn't explicitly state that this has never been tested on any living thing", which I interpreted as endorsing the claim that this vaccine has never been tested on any living thing. My point is that there is evidence this vaccine has been tested in living things, namely the humans who claim to have self administered it. I have no strong reason to doubt they have done so, and I haven't seen any reports of harm coming to these individuals as a result (although admittedly I have no idea if such reports would be publicly available). When I mentioned clinical trials, I was trying to think of what evidence might convince Sarah this approach is not as risky as she fears, and a clinical trial was the first thing that came to mind. Agree they almost certainly have the first two, but I don't see why they would have had motivation to perform the kind of cell-based studies you are looking for. Here is how I imagine their motivation and incentives throughout the last year, mostly drawn from the article I linked above and info from the radvac website: * They see Covid is becoming a pandemic, estimate that a commercial vaccine is >1 year away, and wonder if they can develop an open source vaccine that will provide some level of protection more quickly. At this point, their strongest motivation is to develop a vaccine for their own personal use. * They design the radvac vaccine, and based on their personal and collective understanding of vaccines, biochemistry, immunology, etc., each individual decides it is in their personal best interest to self administer the vaccine. * They are torn between competing desires to make their protocol and the underlying research public, and to avoid unnecessary attention from regulatory authorities. From the article: * Therefore

Related: This was discussed on LW in August 2020, someone claims to have done it in December: https://www.lesswrong.com/posts/62WuBbQpSwAbctGDP/what-price-would-you-pay-for-the-radvac-vaccine-and-why

I'm afraid I'm not flexible enough to kick myself that hard.

6Dentin
I believe that initial post is what got me going down the rabbit hole of peptides and proteins and dna and rna and transcription factors oh my!  It's been a long ride.

Vaccines that are brought to clinical trials have a 33.4% approval rate, which seems like a reasonable estimate of the chances that this vaccine works if executed correctly. Note that this is from trials conducted from 2000-2015.

I probably have a roughly 5% chance of catching COVID before I'm vaccinated. Given my age, COVID would put me at a 0.2% risk of death. Let's double that to account for suffering and the risk of long-term disability.

If I value my life at $10,000,000, then an intervention that gives me a 33.4% chance of avoiding a 5% chance of a 0.4% chance of death is worth $668. So it seems like I'd want to be vaccinating at least one other person in order for this to be worthwhile.

I welcome any further thoughts on this expected value calculation. In particular, I think it's possible that I'm dramatically underestimating the risk and potential severity of long-term symptoms. It doesn't take much additional risk to make this project worthwhile for a single person.

Regarding the 33.4% approval rate:  based on what I've learned about traditional vaccine development and production in the last few months, I am not at all surprised.  Both peptide and RNA vaccines are effectively "state of the art" technologies compared to traditional vaccine techniques.  It's like comparing modern non-invasive out-patient surgery to the 1970's equivalent.

You need look no further than the russian and chinese vaccines - those use the rather crude technology of "throw big chunks of inactivated virus particles at the immune system and hope that the immune system guesses the right antibodies to deal with the live version."

Both peptide and RNA vaccines are instead, "we have identified very specific antibodies which we know are effective both from the serum of recovered patients and from computational modeling, then use exactly the minimal protein sequences needed to generate those antibodies."

Both the russian and chinese vaccines use chunks of proteins that are thousands (and likely tens of thousands) of amino acids long, in a mostly inactivated form.  The immune system has no idea what to latch onto, what will be effective at stopping replication, ... (read more)

5ChristianKl
That seems to me like a strange statement. In what way are amino acids sequences in the peptides "from antibodies"? 
3TheSimplestExplanation
It's my impression that the peptides in question are the antigens to those particular antibodies.
4Dentin
Yes; sorry I was unclear.  Those peptides generate the antibodies we care about, that are known to be effective against the full virus.
2ChristianKl
It's unclear to me to what extend we know this and your description looks to me like it asserts that we know things that are very hard to know.

A lot of people have been working really hard for the last year to discover, understand, and know these things.  It's the foundation for how the mRNA vaccines work.

Perhaps take a look through this:

https://www.sciencedirect.com/science/article/pii/S2319417020301530

-1ChristianKl
I seems my intuition is well-founded here. According to Sarah Constantin the peptide here are selected in silico and not based on antibodies developed by infected people. 
8Dentin
Sarah Constantin is confused, and likely has not spent significant time reviewing the vaccine design.  From page 32 of the whitepaper: "Empirical evidence should dominate selection criteria. Here are some best types of evidence: * Mapping of epitopes in blood and other samples collected from convalescent patients (ideally stratified by severity of illness). This can be accomplished by a few primary means: * 3D structural studies and modeling of neutralizing antibody binding to a viral antigen (e.g. Spike protein) * Mapping of linear B-cell epitopes by binding antibodies in convalescent sera to a library of peptides representing viral antigens. A strong signal in a linear epitope mapping study does not guarantee that the epitope peptide in the context of a vaccine will trigger the production of an antibody that binds to this epitope within the context of the virus. However, it is a good indicator that this is at least possible. Peptides can be constrained to approximate native conformation, making it more likely to bind the native epitope. * Mapping of T-cell epitopes by stimulating convalescent T-cells with epitope peptides, and measuring their response (e.g. cytokine secretion; ELISpot) * Epitope peptides from a peptide vaccine that has shown protection against infection * Successful use of epitope peptides in vaccines that elicit antibodies (or serum) effective in virus neutralization assays. B-cell epitopes that allow antibody binding to the virus but don’t block viral function might increase risk of antibody-dependent enhancement. * Mapped epitopes that are effective in virus neutralization assays (e.g. peptides compete with viral sequences in cellular infection assays). * Successful use of epitope peptides in vaccines that elicit T-cell responses, or peptides shown to stimulate T-cells or cytokine production in ELISpot or other T-cell assay in cells from convalescents."
5ChristianKl
Speaking about what are the best types of evidence is different from demostrating that this evidence exists for individual sequences. If we start with the list the first is Spike 802-823cir. They provide no citations to papers for this and changed the structure in a way the believe to be benefitial (likely based on in silico modelling). 
1jmh
Doesn't this speak to your concern: They perform the substitution to keep the shape that our immune system is looking for by recreating a disulfide bond that to form a loop with the same sequence the B-cells are targeting in the  virus. While I agree their expression was "potentially beneficial" (or close) it seems clear to me the point was our B-cells are bonding to that loop and if there are not other aspect in the larger peptide that lead the cell to that site for bonding, construction the loop via the disulfide bond they introduce logically should result in triggering an immune response. I'm not sure why they would need to provide some type of citation for this, much less that they would even have a source for this specific application.
3ChristianKl
The argument about the substition of the amino acids looks to me like it rests completely on in silicio modeling.  That's theory-based reasoning and not empirical evidence based. Sarah Constantin says that everything is theory-based reasoning (supported by computer modeling) and Dentin argues that they not only do theory-based reasoning but also have empiric evidence for individual peptides. 
1FireStormOOO
While it does seem there was a certain amount of shotgun aproach following a few different lines of reasoning, that critism is difficult to square with actually reading the paper.  It looks like the peptide selection was largely empirical and cited.  The decisions about how to actually package that info into a vacine is largely educated guesswork (as you say theory, supported by computer modeling). "Mapping of linear B-cell epitopes by binding antibodies in convalescent sera to a library of peptides representing viral antigens. A strong signal in a linear epitope mapping study does not guarantee that the epitope peptide in the context of a vaccine will trigger the production of an antibody that binds to this epitope within the context of the virus. However, it is a good indicator that this is at least possible." Or as I understood from elsewhere: present antibodies from recovered people to every possible short peptide sequence and see which ones they actually attacked.  Make the inference that people with less severe infection had better antibodies than those with more severe symptoms in the event antibodies differed.  Package a selection of promising looking pepties into a vacine; choose enough that there's likely multiple effective peptides even if 2/3rds of the choices are duds.
4henryaj
I also don't understand her comments about the peptide 'not neutralising COVID in cell [culture]' - why would it? The peptide is just an antigen to get the body to raise an immune response; on its own it doesn't kill COVID.
3Juno
I interpreted this to mean antibody against the peptide.
2johnswentworth
I was also confused about that. I'm sure some kind of cell-culture method is useful for testing vaccines, but I don't know exactly what's involved. Just culturing immune cells, maybe?
1TheSimplestExplanation
Do you have doubts? It seems plausible to me?
4Creutzer
The Russian vaccine, unlike the Chinese one, is not an inactivated virus. It uses an adenovirus vector for delivery of genetic material that makes the body's cells synthesise antigen material, much like the AstraZeneca/Oxford vaccine.
6Czynski
This is an inappropriate reference class. This has no in vitro testing conducted; it's entirely a computational model. "“Peptide” just means “sequence of amino acids.” Would you conclude that, because some lines of code can navigate a rocket to the moon, that your code is pretty likely to navigate a rocket to Mars?". A vaccine brought to clinical trials has already overcome many more hurdles than this has. Generally in vitro testing (I think both for safety and efficacy), in vivo safety testing (in rats!), and some scaled-up testing in other animal models. This isn't a vaccine candidate. This is a promising research lead for a vaccine candidate.
5johnswentworth
I'm not sure what your level of background knowledge is, but I heard that the Moderna vaccine was designed in two days. Clearly they did not do any significant in vitro or in vivo testing in that timespan. Maybe they did some in-vitro before human trials, I don't know; that would support an argument against using "vaccine brought to clinical trials" as a reference class. But the deeper point which this is trying to operationalize is "vaccine design just isn't that hard", in the sense that we don't need to test many designs to find one which works. People basically-know-how-to-design-vaccines, maybe not to quite the same extent as people basically-know-how-to-design-bridges, but to enough of an extent that experimental verification just isn't necessary in order to get a >50% chance that the design works, especially for relatively-mechanical designs like mRNA or peptides. Under this view, the reasons we don't see nearly-every vaccine trial succeed are (1) commercial vaccines are harder than lab (especially if you want no boosters, easy logistics, etc), and (2) diseases which are harder-than-average will naturally end up with disproportionately many trials, and (3) out-of-date companies take time to die off.
3Czynski
The in vitro testing had already been done before those two days; they had the basic structure of the vaccine known, so once they had a virus sample they could fill in the blank (the spike protein of this particular virus rather than another in its 'family') with high confidence that it would work. One of the two days, IIUC, was spent synthesizing a sample vaccine and running some very-short-term tests. This, again, has only simulation to support that it's hitting the correct target at all. There is no indication that any of that has been done, by the authors or anyone else; IIUC there is not a clear path for doing short-term tests for this type of vaccine. Also, it's not my background knowledge that you should be comparing to, it's Sarah's. And I literally believe there is no one in the world who can be more trusted to reason clearly, well-informedly, correctly, and with humility and arrogance in their respective correct places than Sarah Constantin. Evaluating biomedical research has been her job for many years, with some gaps, and she's really good at rationality, Aumann-level good. The bare fact that Sarah C thinks this is very unlikely to work is conclusive on its own.
1CharlieMarr@protonmail.com
How does the "vaccine design just isn't that hard" align with these points? a) Average time to develop a vaccine for a new virus is many years b) There is still no HIV vaccine after 35 years of well-funded research c) Until a few months ago, there were no approved coronavirus vaccines for humans I'm prepared to accept that "bureaucracy" is the main cause for the delays in standard big company vaccine development and approval.   But if it's easy to develop vaccines, why has there been no coronavirus vaccine previously?  Why is there still no vaccine for SARS 1 or MERS or the common cold?  Why was this Radvac idea or something similar not rolled out pre-Covid?  (or was it?  maybe nasal vaccines are easier?) Anyway, I'm just stuck on the logical conflict between "it's easy to develop a coronavirus vaccine" and "we've never had one (approved) before."  Any thoughts? 
4johnswentworth
Good questions. First, I expect a disproportionate number of vaccine trials are for "unusually difficult" viruses, like HIV. After all, if it's an "easy" virus to make a vaccine for, then the first or second trial should work. It's only the "hard" viruses which require a large number of trials. I expect this is still mainly a result of regulatory hurdles. Clinical trials are slow and expensive, so there has to be a pretty big pot of gold at the end of the rainbow to make it happen. Also, companies tend to do what they already know how to do, so newer methods like mRNA or peptide vaccines usually require a big shock (like COVID) in order to see rapid adoption.
4DirectedEvolution
I agree with the point of your comment, that vaccines brought to clinical trials is a suboptimal reference class. However, I think that this is a locally invalid argument: A computational model plus grounding in theory, if done right, should increase our confidence in the the efficacy of a sequence of peptides taken from the virus above the efficacy we'd assume for a random sequence of peptides. How much? Can't say. As others have pointed out here, we on the other hand are comparing a new and perhaps much more effective means of designing a vaccine to the methods that were used from 2000-2015, which may be less effective. Hence, perhaps the reference class is suboptimal in the opposite direction as well. I have no way to know how to weigh these competing factors. So I think the best thing to do is to start with the basic formula I concocted above, then modify it based on our intuitions about these other factors. Alternatively, you could very justifiably stick with the rule "I don't take untested medications." Although as someone else pointed out, if you have that rule then perhaps you should also make sure to not use any drugs? I don't have the answer, but wanted to try and provide some clarity for people who are considering breaking the "take no untested medications" rule.
5waveBidder
You're missing the very real possibility of long-term negative side-effects from the vaccine, such as triggering an auto-immune disease or actually increasing your susceptibility, both mentioned in the whitepaper (whose risk-assessment I would be pretty sceptical of). I would think of this as more a trade-off between risks of side effects and COVID risks, rather than whether or not you can afford it.
5Dentin
Yes.  The differential tradeoff is how one should evaluate this.  The only reason my evaluation came out in favor of trying the radvac vaccine is because I have a high-risk event coming up in the next few months, and I am extremely unlikely to be able to acquire a commercial vaccine before then.
5cursed
  I don't follow. Don't vaccines have trials on cells, mice, primates, before clinical? So unless radvac has also done similar testing, this 33.4% isn't comparable.
5[anonymous]
Do you value your life at ten million? As in, would you take a 50% chance of death for five million? If so, why are you not smuggling drugs or whatever?
8DirectedEvolution
Well, a couple of researchers estimated that drug mules made a median of $1313 back in 2014, so I'd need to smuggle a lot of cocaine to earn that much. Seems like it would take a while...
3Bucky
Say my life expectancy from now is 50 years and I work at an hourly salary of $30 (~$60k yearly salary) then I implicitly value the remaining 310,250 hours of my waking life at something like $9.3m total. This breaks down if offered larger probabilities of death and larger amounts of money (e.g. opportunity cost) but $10m seems like a sensible place to start for a Fermi calculation. In this case we don't even have to worry about larger probabilities of death - the calculation here is essentially an expected gain of 1.2 days of life for $1000 which comes to about $50 per hour of waking life. Instead of making a vaccine only for myself I would be better just to take half a week unpaid leave and gain the same amount of time for a cost of only $600. Obviously this has some assumptions baked in (like that I don't value my job) but If It’s Worth Doing, It’s Worth Doing With Made-Up Statistics.
1cistran
That's is an easy calculation. Life value can change later and there might be a more attractive bet you will be forgoing by taking this one, say 10 million for 50% chance of dying.

Wow!

I guess a thing that still bugs me after reading the rest of the comments is, if it turns out that this vaccine only offers protection against inhaling the virus though the nose, how much does that help when one considers that one could also inhale it through the mouth? Like, I worry that after taking this I'd still need to avoiding indoor spaces with other people, etc, which would defeat a lot of the benefit of it.

But, if it turns out that it does yield antibodies in the blood, then... this sounds very much worth trying!

8Dentin
My understanding is that it helps a lot. The biggest benefit seems to be that the immune system is primed in at least some fashion; it knows what to look for, and it has readily available tools that should be effective.  It doesn't have to take a day or a week to try random things before it finally discovers a particularly effective antibody and gets the production chain ramped up to start a proper immune response. Instead, your immune system will very quickly get a signal it understands as bad and can immediately start ramping up when it does detect the virus. Keep in mind that the commercial vaccines don't have 100% success rate in that some people still get sick, but the 'priming' of the immune response is still there.  I believe this is why the death rate / severe complications rate is effectively zero for immunized patients, even though it's possible to get sick. (Again, my understanding.  I would very much appreciate correction/clarifications here.)