[ Question ]

What other peptide vaccines might it be useful to make?

by jacobjacob1 min read3rd Mar 202114 comments



Related: Making Vaccine

In my limited understanding of the workings of the open-source radvac vaccine, it is surprisingly basic. In particular, if the peptide design works, then simply ordering and snorting it is sufficient. Most of the rest of the process, which is about creating nanoparticles to which the peptides can attach, just serves to boost effectiveness. 

When I say this is "basic", I still want to commend the radvac team and johnswentworth for the combined ingenuity and agency required for making it happen. Sometimes it takes true skill to find a simple solution.

Especially when most people aren't even looking. 

I spent most of last year not even considering the hypothesis that it might be possible to make safe, cheap and effective vaccines at home. For a year I allowed my life to be governed by a constraint that a more competent version of me could have relaxed in a few months. 

It feels a bit like going to Hogwarts and seeing someone do transfiguration for the first time. The thoughts that should be racing through my mind are: how do I learn such magic? And: if I could master such magic... what else could I use it for? 

I'm curious for others' input as I think through that. 

What else could the general method of peptides, administered intranasally, be used for? 

Other diseases, things other than vaccinations, or even enhancement rather than prevention? 

My knowledge of this domain is very limited, and these questions might not have interesting answers. But they certainly seems worth at least posing, and I am curious about the result. 

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Broad-spectrum vaccines might be one useful place to look. Just last year, there was this paper on a universal flu vaccine. The numbers aren't super-impressive, but they're significant, and the study itself used a peptide vaccine. (See also this paper, or this page on a broad-spectrum vaccine against bacteria, which I didn't even know was a thing.)

A more speculative category might be therapeutic cancer vaccines. Some of these are tailored to one person's existing cancer, so they only make sense for someone with the disease. But my understanding is that some of them target common cancer antigens, so in-principle they could be used preventatively. (Seems like the magic word to search for here is "neoantigens".)

On the ultra-speculative and potentially-dangerous end of the spectrum, I have wondered before if a vaccine could make the immune system attack cells with transposon activity. Note that both this and cancer vaccines involve getting the immune system to attack one's own cells, which makes them both difficult and dangerous. But the rewards could potentially be quite large: transposons are top-of-list of likely root causes of the major age-related diseases (including cancer itself). For instance, this page mentions a current project to develop "transposon-derived neoantigens" for cancer vaccines, and that's exactly the sort of thing which would potentially be effective against other diseases of aging as well.

Also, I've heard there are reasons to ingest peptides other than just vaccines. I don't know much about other applications, though.

I went down the neoantigen rabbithole, and it was quite interesting. 

I liked this talk on "Developing Personalized Neoantigen-Based Cancer Vaccines".

It seems a core part of their methodology is using machine learning to predict which peptides will elicit a T-cell response, based on sequencing the patient's tumour. (Discussed starting from around 11 minutes in.)

They use this algorithm, which seems to be a neural network with a single hidden layer just ~60 neurons wide, and some amount of handcrafting of input features (based on papers from 2003 and 200... (read more)

2ChristianKl1moTo me the website looks like the published in 2020 a paper [https://academic.oup.com/nar/article/48/W1/W449/5837056]with the newest version. I would expect that you can solve any problems with that algorithm underperforming by simply taking more plausible neoantigens. If you want 20 one's that actually work and you have a successrate of 50% you can just take 40 different peptides. That makes it a bit more expensive but still doable. I would expect that in the span of this decade AlphaFold gets the capability to model those interactions nearly perfectly but without large resources I don't think you will easily improve on the existing bioinformatics models.

But my understanding is that some of them target common cancer antigens, so in-principle they could be used preventatively. (Seems like the magic word to search for here is "neoantigens".)

Common cancer antigens aren't neoantigens. The common cancer antigens are proteins that normally only get produced in fetal development or in other specific circumstances. As far as I understand the vaccines based on them also didn't produce good results. 

Neoantigens is when you use the feature of the tumor to produce a lot of random mutations.

For instance, this page

... (read more)

There are other coronavirus types that cause the common cold. If this type of peptide vaccine is effective in protecting against the novel coronavirus, it might work for the older types as well, if made with the appropriate peptides, of course.

Until we have better data on the immune response to this type of vaccine, I wouldn't want to quit conventional vaccinations or try to fully replace them with radvac. I'd consider diy vaccines a likely improvement for supplementing traditional vaccines in the cases of respiratory infections that mutate too fast for commercial vaccines and respiratory infections that are too rare or localized for big manufacturers to bother making vaccines against them, though.

I would want to see more data on the safety of the process before using nasal peptides against non-respiratory infections, because my mental model of the immune system explains some of its malfunctions as the system freaking out over seeing something it's acquainted with in an unusual context. These examples include the way that beekeepers can suddenly develop.an anaphylactic reaction to being stung after years of being stung with no problems, and a model of childhood food allergy in which children exposed to an allergen by skin contact before they eat it are more likely to have a reaction when eating it.

It's 2020 hindsight to suggest that it would have made sense to snort covid peptides as soon as its genome was sequenced, though. I recall a lot of early confusion about whether it would be possible to develop safe and effective vaccines for it, because some people were seeing patterns in the data that looked like the more severe symptoms might be caused by an immune response developed by earlier and milder exposure to the virus. I don't think that possibility was truly ruled out until data from commercial vaccine trials became available. Given what was known at this time last year, for instance, I don't think the expected benefits of snorting covid peptides would have necessarily outweighed the likely-looking drawbacks. Once the other vaccine data was out, though, there were far fewer reasons not to try to self-vaccinate.

I've always wondered if it could be used for organic fungal toxins and other common airborne hazards

It only has any chance of working against things your immune system can attack effectively. So "fungal toxins" are probably a nonstarter, but if you've got fungal spores in the air and are worried about having mould grow in your lungs or something it might maybe be able to do something.

Except that if you're already exposed to whatever-it-is, that exposure is probably more effective in training your immune system than a vaccine would be. So it would only be useful for things you're not usually exposed to much but anticipate being exposed to in the not-too-d... (read more)

1RedMan1moThank you for educating me. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979841/ [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979841/] Existing approaches to toxoids like aflatoxin and ricin use specially built molecules where something immunoreactive is modified to be bonded to an antigen. A peptide vaccine that doesn't require the chemistry would be pretty cool. The vaccine for morphine works the same way. The immune system recognizes the opiate pharmacophore and binds to it, so that opiates don't bind to their receptors and therefore, heroin rats don't get high. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558830/ [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558830/]

Gum disease. While oral pathogens are mostly bacteria, they're also excellent at evading and even subverting the natural immune response. Considering the likelihood that human diets will continue to contain large amounts of carbohydrates for the foreseeable future, gum disease represents a very large and growing cause of both morbidity and economic burden for people in all economic situations. Targeting key bacterial species or even maladaptive human immune activity could save everyone money, pain, and increase the day-to-day well-being of a majority of humans in perpetuity.

gum disease represents a very large and growing cause of both morbidity and economic burden for people in all economic situations.

Curious if you have some links for data/calculations on the disease burden?

Also, do we have a reason to believe this is an area where peptide vaccines would be especially helpful?

Choosing peptides for targeting bacteria that are good at evading the natural immune response is hard. A combination of phage therapy for the bacteria that you don't want in your mouth along with probiotics to fill your mouth with desirable bacteria would likely be a better intervention.

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It sounds as if you're assuming it does actually work, which so far as I can tell is still in considerable doubt.

(I agree that "supposing it turns out that it works; what else might it be good to use this approach for?" is a reasonable question and am not suggesting you shouldn't be asking it. But e.g. it is very far from clear that "a more competent version of me could have [stopped having to worry about getting Covid-19] in a month".)

I'm updating fairly hard on the four radvac team members who found antibodies using custom-built ELISA assays (rather than commercial tests). I wasn't super compelled by arguments that those might be false positives, but I do find it important that we don't know the denominator off how many of them took that test.

It maybe moved my probability from 17% to 45% that it would work for me (so still less optimistic than Wentworth!)

Though I think even a 5% chance of it working would make the original question worth asking. As they say: huge if true :)

(Also, the more competent version of me who solved it in a month would need to be competent on many other dimensions as well, not just knowing about peptide vaccines. Thinking about it, just the peptide delivery time could be longer than a month, as could the vaccine booster schedule. I do think there are worlds where it's actually a month, but I'll update the question to say "a few")