Making Vaccine
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?
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
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.)
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.
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.)
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
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.
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.
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 :).
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.
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
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...
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 ...
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.
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.
Often, e.g. Stanford profs claiming that COVID is less deadly than the flu for a recent and related example.
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.
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
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, ...
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
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!
Neat! Will you also use try commercial antibody tests on your mucus, or is that known to not-work?
Two years later, I suppose we know more than we did when the article was written. I would like to read some postscript explaining how well this article has aged.
I asked Alex from RADVAC on reddit about antibody responses to the vaccine. He replied by saying 4 of the researchers saw a "positive antibody response."
https://www.reddit.com/r/radvac/comments/ig2b1q/related_news_open_for_suggestions/
"Some of our core group started performing ELISA assays to determine the presence of anti-Spike antibodies, beginning back in May/June. Since only a handful of us had at that point been collecting samples rigorously, the sample size available to us was small, so although we saw a positive antibody response, we didn't consider the (n=4) data credible as a data set."
I dare not interpret the implications of this finding on how much we should expect out of these vaccines, but I thought that this would be important to discuss.
From my reading it seems like people sneezing after applying nasal vaccines is one of the main error conditions. How about using a nose clamp after spraying the vaccine into the nose to prevent sneezing it out?
My jaw dropped at "~500 doses". At $2 per dose... that's significantly cheaper than it's costing the companies to produce the official vaccine. What am I missing here? I know you're making a different thing than Moderna, but if the thing your making exists and is this cheap then why is Pharma leaving the money on the floor and not mass producing this?
I think you're underselling the potential benefit here! Doing a batch of this and distributing it to 500 people may be unfeasible. I assume the FDA or something comes for you if you're trying to commercially distribute home-brewed vaccines.
But say, to 20 friends? Why not. Which brings the price down to $50 per/person, which seems like it'd be totally worth it to have immunity even a month earlier than the official vaccine is available to me. And it potentially gives immunity to your whole social scene.
I'll wait for your results, and then will strongly consider doing a batch of this myself.
Oh, it's far, far worse (better?) than $2 per dose. As a thought experiment, I price estimated buying enough peptide for a hundred thousand doses, and it only costs about ten thousand dollars. Ten cents a dose is closer to realistic if you buy in bulk.
Which also brings to mind a question of civilizational inadequacy: if we really cared and it really mattered, why not have every university with a lab in the country crank out a hundred thousand doses per week to their local populace?
I don't think this has ever been possible in previous epidemics, at least for at-home manufacture.
That being said, I would strongly support compiling a list of low-risk interventions like this, so next time we can publicize them at the outset and try mitigating the problem while waiting for the low-risk&high-success solution to be developed.
If the thing your making exists and is this cheap then why is Pharma leaving the money on the floor and not mass producing this?
There are a number of costs that Moderna/Pfizer/Astrazenica incur that a homebrew vaccine does not. Of the top of my head:
1. Salaries for the (presumably highly educated) lab techs that put this stuff together. I don't know johnswentwort background, but presumably he wouldn't exactly be asking minimum wage if he was doing this commercially.
2. Costs of running large scale trials and going through all the paperwork to get FDA approval. I think I'm generally more in favour of organisations like the FDA than a lot of people
here, but even I expect this to be a very non-insignificant number.
3. Various taxes and costs of shipping/storing the vaccine until it can get to customers.
4. Costs of liability and a desire for the company to make a profit on this (as well as to pay the salaries for the all of the people needed to keep a large company running).
Given all that I don't think the gap between this and the commercial vaccines is that insane.
why is Pharma leaving the money on the floor and not mass producing this?
Both the other comments here are on-point. The materials for large amounts of radvac would cost pennies per dose, because the cost-per-unit of the peptides drops very rapidly as you scale up (remember, we doubled our order for <10% extra cost).
However, in general, people and logistics are a bigger expense than materials for most products these days, and I certainly expect that to apply to vaccines.
A great example of taking the initiative and actually trying something that looks useful, even when it would be weird or frowned upon in normal society. I would like to see a post-review, but I'm not even sure if that matters. Going ahead and trying something that seems obviously useful, but weird and no one else is doing is already hard enough. This post was inspiring.
I did eventually get covid.
As was the general pattern with this whole RADVAC episode, it's ambiguous how much the vaccine helped. I caught covid in May 2022, about 15 months after the radvac doses, and about 13 months after my traditional vaccine (one shot J&J). In the intervening 15 months, my general mentality about covid was "I no longer need to give a shit"; I ate in restaurants multiple times per week, rode BART to and from the office daily, went to crowded places sometimes, traveled, and generally avoided wearing a mask insofar as that was socially acceptable.
This is a very interesting article and as long as the substances are very pure, it's probably low risk of any real health danger. However, I would really want to be very sure about that point before putting anything into my nasal passages.
As a scientist working in the pharmaceutical industry for many decades, I can say there are several big issues with this vaccine method. First, you will never know if it really works until you run blinded clinical trials against a placebo. This is the only way to tell and that is why it's required for any new drug/vaccine to be launched on the market. You can't just take a antibody test and see if it works. Even if there were the right antibody tests for these peptides, it might indicate some activity, but without using rigorous scientific method, there could be many other factors why you could see a response. Like you were exposed already to the virus and didn't know it.
Second immune response to peptides is significantly less effective generally. Whole viral proteins in the marketed vaccines are the best method to create an immune response. That is why almost all vaccines use some whole enzyme method or multiple proteins.
F...
Welcome, and thanks for making your first comment!
As a fellow scientist with decades of experience in the industry, I disagree with several of your claims.
First, you will never know if it really works until you run blinded clinical trials against a placebo. This is the only way to tell and that is why it's required for any new drug/vaccine to be launched on the market.
Clinical trials are helpful for understanding whether a drug/vaccine works on the population level. But on the individual level, clinical trials are not the only way to tell. For example, you can just take an antibody test and see if it works.
You can't just take a antibody test and see if it works.
Of course you can.
Even if there were the right antibody tests for these peptides
Anna Czarnota posted an initial protocol here. I haven't tried it, but it seems reasonable and likely to provide useful information about one's level of protection.
but without using rigorous scientific method, there could be many other factors why you could see a response. Like you were exposed already to the virus and didn't know it.
The "rigorous scientific method" is not the only way to generate knowledge that allows individuals to update...
From the white paper:
Antibody can be measured in nasal wash, however this is less quantitative and reliable than measurement in serum.
Hi,
It's quite interesting what you are doing. Have you thought about testing immune response yourself using peptides from the vaccine? Of course you can only run humoral responses, but it would give you far more accurate results then any commercially available test. You could bind peptides to the high-binding plates, use your mucosa samples and detect with universal anti-human IgM+IgG+IgG antibodies conjugated with HRP.
This may be true, I'm talking about ELISA test. In theory you only need high binding plates, secondary antibodies and some kind of detection (TMB + H2SO4 give colorimetric effect and you can try and skip plate reader). I understand that it can be quite complicated to perform, but I am wondering how you plan to chceck the immune response against Orf1 and Orf 8. You could check blood against Spike and nucleocapside (you need to check if antigen test is using full length Spike and Nuc), but due to the use of peptides, lenghth of the peptides and expected low IgG titer, detection (as you said) can get tricky. But congrats anyway.
I think that you can perform ELISA using unpurified nasal wash or diluted mucus. I often perform ELISA using sera/full blood or unpurified cell lysates. I would do a nasal or throat swab and put it in phosphate buffer (or PBS). You can further dilute samples if the viscosity is too high. ELISA is very sensitive and my guess is, you should be able to see positive signal without plate reader. It very much depends on both antigen used in ELISA and antibody concentration. For peptides such as yours (without tags) I use concentration of about 10-20 ug/mL, sera diluted 1:1000-1:10000 and higher and still get good, clear signal. Of course you don't want to dilute your nasal samples so much, but undiluted, 1:5 or 1:20 could give nice reading, hopefully without any background. EDIT: I know it may sound complicated, but I just wanted you to know that checking immune response against antigen used (in this case peptides) is a possibility.
Hi,
I wrote down this manual for anyone to follow - https://drive.google.com/file/d/1qtfyE42ECZAqSFpqGR9JawX3YoVAvVSg/view?usp=sharing
As it is a modified protocol I'm not sure It will work (especially when we do not have any positive and negative baseline).
In short:
Antigen (peptide) binding to the plates:
- Prepare peptide solutions in PBS buffer in 1.5 mL tubes. The final concentration of the peptides should be around 10-20 µg/mL
- Prepare high-binding 96-well plates and a piece of tin foil for cover. Add a 100 µL of peptide solution to each experimental well. Cover the plate and incubate at 4oC over night (16h).
- Take the plate from the fridge and discard peptide solution
- Wash the plate by adding wash buffer (approx. 200 µL per well).
Blocking:
- Add approx. 200 µL of blocking solution to each well. Incubate for 2h at room temperature and discard.
- Wash the plate 3 times as described above.
Addition of the primary antibodies (from nasal swabs):
- Prepare the nasal swab/wash samples. Collected swabs should be stored in PBS. Nasal wash can be performed using PBS. The samples can be applied to the wells without dilution, but I would suggest further dilution
Props to you for taking action here, this is some impressive stuff.
That being said, I'm extremely skeptical that this will work, my belief is that there's a 1-2% chance here that you've effectively immunized yourself from COVID.
What do you believe is the probability of success?
Why are established pharmaceutical companies spending billions on research and using complex mRNA vaccines when simply creating some peptides and adding it to a solution works just as well?
My rough guess is that there's a 75% probability of effectively full immunity, and a 90% probability of severity reduction. This is a pretty well tested and understood vaccine mechanism, and the goal isn't "perfect immunity" as "prime the immune system so it doesn't spend a week guessing about what antibodies it needs to combat the virus effectively".
As to why established companies don't do it, I believe it's partially logistics, and largely red tape. Logisitics first (though it should be noted that at least some of these could likely be tackled with a bit of effort):
- Shots are well understood and easy; people are used to them, people know how to give them, etc. Nasal spray is irritating and makes you want to blow your nose, which washes out a lot of it and reduces effectiveness.
- You need multiple of these annoying doses in the nose, staggered a few days apart, to generate a 'good' response.
- This particular nanoparticle vaccine doesn't have a long shelf life due to peptide degradation. Peptides don't last forever, and while they're more stable than the RNA vaccines, you'd have to ship them frozen as well.
- Nanoparticle vaccines in general suffer from particle aggregati
This is a very in-depth explanation of some of the constraints affecting pharmaceutical companies that (mostly) don't apply to individuals, and is useful as an object-level explanation for those interested. I'm glad this comment was written, and I upvoted accordingly.
Having said that, I would also like to point out that a detailed explanation of the constraints shouldn't be needed to address the argument in the grandparent comment, which simply reads:
Why are established pharmaceutical companies spending billions on research and using complex mRNA vaccines when simply creating some peptides and adding it to a solution works just as well?
This question inherently assumes that the situation with commercial vaccine-makers is efficient with respect to easy, do-it-yourself interventions, and the key point I want to make is that this assumption is unjustified even if you don't happen to have access to a handy list of bullet points detailing the ways in which companies and individuals differ on this front. (Eliezer wrote a whole book on this at one point, from which I'll quote a relevant section:)
...My wife has a severe case of Seasonal Affective Disorder. As of 2014, she’d tried sitting
A simple Google search shows thousands of articles addressing this very solution.
The solution in the paper you link is literally the solution Eliezer described trying, and not working:
As of 2014, she’d tried sitting in front of a little lightbox for an hour per day, and it hadn’t worked.
(Note that the "little lightbox" in question was very likely one of these, which you may notice have mostly ratings of 10,000 lux rather than the 2,500 cited in the paper. So, significantly brighter, and despite that, didn't work.)
It does sound like you misunderstood, in other words. Knowing that light exposure is an effective treatment for SAD is indeed a known solution; this is why Eliezer tried light boxes to begin with. The point of that excerpt is that this "known solution" did not work for his wife, and the obvious next step of scaling up the amount of light used was not investigated in any of the clinical literature.
...But taking a step back, the "Chesterton’s Absence of a Fence" argument doesn't apply here because the circumstances are very different. The entire world is desperately looking for a way to stop COVID. If SAD suddenly occurred out of nowhere and affected the entire economy
I wouldn't take 50/50. I do think it's much more likely than that to induce mucus antibodies, but not blood antibodies. I would take 3:1 odds.
My estimate for whether or not I would test positive on a blood test was only about 50%, since blood isn't the primary place that the response is generated. I'm already betting a substantial amount of money (peptide purchases and equipment) that this will be helpful, and I see no reason to throw an additional $50 on a break-even bet here.
I would, however, be happy to commit to sharing results, whether they be positive or negative.
... and now it occurs to me that if Lesswrong had a 'public precommitments' feature, I would totally use it.
Amazing initiative John - you might give yourself a D but I am giving you an A+ no doubt.
Trying to decide if I should recommend this to my family.
In Spain, we have 18000 confirmed COVID cases in January 2021. I assume real cases are at least 20000. Some projections estimate that laypeople might not get vaccinated in 10 months, so the potential benefit of a widespread DIY vaccine is avoiding 200k cases of COVID19 (optimistically assuming linear growth of cases).
Spain pop is 47 million, so the naïve chance of COVID for an individual before vaccines are...
How were you able to find someone who would give you an antibody test?
I made some effort to get an antibody test a few weeks ago but multiple sources refused to order or run one, even after I had an appointment that I showed up for in person.
FYI, there's a map of people working on this that you can add yourself to for coordination:
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.
Seems like partial sequences could contribute to the autoimmune disease risk since they would be much more likely to match to normal cellular proteins. Has this been considered?
Alright, so the thing that antibodies are "trained" to detect is called an epitope. On page 23 of the white paper, it says:
- VED might arise through vaccine design-induced distortion of viral epitopes, as has been proposed to occur by formalin treatment of RSV. a. Our preferred epitope type is synthetic peptides. Such peptides are chemically well defined and have a high degree of structural integrity.
So distortions of the epitope can cause an autoimmune reaction, and synthetic peptides are good because they're stable and you know exactly what you are getting. But if you have a bunch of partial peptides mixed in, then it substantially weakens this point.
Re: 3. It does seem to be true that "damage" is required. Substances which provoke an immune response are called adjuvants, and the adjuvants in this vaccine are the Chitosan and the Tripolyphosphate.
Reading the paper more closely, it says that the truncated peptides are fine because the peptides get chopped up by proteases anyway. This does make me feel a bit less worried about this, but it also implies that this would be a potential issue for purified peptides as well.
ETA: I also did a spot-check to see at which point this woul...
Are there other nasal vaccines that are based on nanopeptides currently on the market and FDA-approved?
The whitepaper is a good source, but like johnswentworth, I also contacted a medical professional to evaluate it. The response came back quickly and confidently, and was along these lines:
"Oh, yeah, this is safe. Nasal vaccines are safe. The biggest worry is that it might not work, so make sure you get the commercial vaccine too. I'd be interested in doing this with you as a joint project and giving it to my family, and I also have a colleague who might be interested in doing it."
The biggest point of disbelief on their part was that it's possible to order all the equipment and peptides online and have them shipped to your door.
Thank you for both conducting this experiment as well as for writing it up in great detail.
How much study do you estimate someone would have to invest into biology (or biohacking) to at least understand what's going on here? What are some "genres" of biology someone could start looking into to understand this work?
This looks like a really interesting area to probe, but my current level of knowledge in biology ("1 year of high school biology classes") makes it difficult to even formulate questions or google queries about it.
Very impressed by this, I really hope it works. These are the kind of audacious efforts that I love to see in this community
If anyone knows of anybody planning to do this in the Maryland/DC/Virginia area, please let me know
Any updates on how well you think this worked, especially as compared with other vaccines now available?
Edit: never mind, I see the followup post now :D
Quote: “But at this point it’s only ~4 months until I’d get a vaccine anyway, so the price tag is only arguably worthwhile.”
I’d question this assumption, due to the new mutations such as E484K. It’s looking probable that “v1” vaccines will be significantly less effective against it - and v2 vaccines may not be out until end of 2021.
Theoretically, assuming RadVac is effective, once they update for new mutations, you may be able to do a new batch and self-vaccinate quicker than waiting for your turn at v2.
Thank you for this. I would like to also thank everyone would has commented for the rational and calm manner you have added to the discussion. I’d about given up on humanity with how people have been treating each other on other posts.
Have you tried making at home rapid covid tests? I have often wondered if it is possible to make an at home version of the spit paper rapid tests. No clue what this would take but would be great since the government hasn’t allowed them yet.
Thanks for posting this, I didn't know about radvac before and now I am excited. I will read the white paper and probably make some myself. If your results are good which I really hope they are, I will try to help my family members get some as well. I don't mind paying $1000+ for family safety, and with the delayed vaccine rollout I would feel better even getting the vaccine to them one month earlier. So thanks again! I hope all goes well.
Thanks for the write up! I started to do this myself but quickly found I was a bit confused on how to even order the peptides. I was expecting to be able to search product lines but.... Not really possible. So...is the process to simply identify some suppliers (not hard to find with Google) give them the amino acid sequences in the instructions and ask for a quote? (Hit that initial speed bump and have not gotten back to looking for phone numbers or customer support chat windows.)
Just a thought. So this doesn't scale well for storage and shipping it sounds...
How about sharing the link?
I don't want people giving the company crap if this post ends up very widely read. If anyone would like a link, PM me.
Absolutely obviously yes. I have some level of concern that this post will go viral (ha ha), get a lot of attention outside of lesswrong, and the company I'm working with will cancel my order because it's "covid misinformation" related.
The FDA might be slow and take months to approve safe things while thousands of people die per day, but they're perfectly capable of announcing an immediate and indefinite peptide ban in under a day because a news article crossed the wrong person's desk.
About the "viral" part. This post is currently at the top of HN: https://news.ycombinator.com/item?id=26022750
Is this blog post potentially a source of X-risk? Popularizing the idea of "mix together chemicals you got in the mail" sounds like an attack vector for an AGI wanting to escape its box.
At the risk of arguing from fictional evidence, Eliezer writes in That Alien Message of an AGI coming up with a cover story to convince someone outside the box to construct nanomachines (amino acids!) to do its bidding.
...We sent messages [...] to labs that did their equivalent of DNA sequencing and protein synthesis. We found some unsuspecting schmuck, and gave it a pla
I think another John Wentworth post is applicable here. It's not hard to invent reasons why any given post might increase existential risk by some amount. (What if your comment encourages pro-censorship attitudes that hamper the collective intellectual competence we need to reduce existential risk?) In order to not function as trolling, you need to present a case for the risk being plausible, not just possible.
I ran this by an epidemiologist friend and they pointed out that SARS-CoV-2 is mutating fairly quickly, so wide deployment of low-effectiveness vaccines (possibly including this one) would encourage the emergence and spread of vaccine-resistant strains of the virus.
This might become a big problem because vaccines are being rolled out whilst there is a lot of the virus circulating in the community.
If it's so cheap and easy to make vaccines, why aren't commercial ones made this way? In particular, the Novavax vaccine sounds similar, so why wasn't that the first vaccine to market?
Added: Specifically, the ultimate purpose of a vaccine is to get protein into the body. Traditional vaccines grow the virus using its own reproductive apparatus. Fancy new vaccines, like the adenovirus and mRNA vaccines inject instructions and induce the subject to manufacture proteins. But if it's so easy to just print proteins, why don't we do that? That's what Novavax does...
Crazy thought, and I doubt this is likely on large scale or it would have been in the news, but any chance this could explain the higher than expected percentage of nurses who have rejected getting the vaccine? Perhaps some have already vaccinated themselves under the radar! And therefore have no need to take the "real" one.
My personal estimate is that the the percentage of nurses who have done this is effectively zero (less than one in a thousand with high probability, less than one in ten thousand with moderate probability.)
Further, those who did do it are likely to have read through the whitepaper, and therefore are also likely to get the commercial vaccine, as it covers different epitopes than the radvac vaccine.
This seems like a cool and interesting experiment, and it seems rational from a "zoomed-in" perspective. i.e. "if I'm going to get vaccinated, I might as well do it myself, nasally, with fewer ingredients....the potential benefits are greater than the costs. Especially when considering adjacent benefits like learning, being a trailblazer, potentially advancing knowledge, etc."
But if you "zoom out" and take a broader view of the whole Covid phenomenon, it seems like you may be (irrationally?) accepting a number of big assumptions before b...
If nasal application doesn't provide a blood immune response it might be worth testing whether anal application will lead to a blood immune response.
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.
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.
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.
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:
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:
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.