The mRNA technology seems to provide no benefit over simply giving the peptides directly but the mRNA researchers really wanted to do fancy research on mRNA.
I think you’re giving mRNA vaccines too little credit and peptide-based vaccines too much.* I haven’t looked into peptide vaccines much at all but my general impression is that they don’t work that well as a class. Hundreds of peptide vaccines have entered the clinic with no approvals (albeit, not all against infectious diseases, many against cancer which is more difficult) — without looking into the details, I couldn’t tell you exactly why, but my guess would be lack of efficacy. When you present something to the immune system, it’s important that it be in the right shape so that it trains the immune system properly. Peptides, removed from the context of the protein scaffold that they are normally a part of, are very floppy, and there’s no guarantee that the conformation a peptide takes will be the same as the conformation it takes in the native protein (more precisely, probably some of the conformations the peptide takes will be similar to the conformations in the native protein, but how many other conformations will the peptide be taking that are dissimilar, and will steer the immune system the wrong way?). A good heuristic is that to have an effective vaccine, you want to present something to the immune system that’s “as close to the real thing” as possible. mRNA vaccines, by being compatible with presentation of a full viral protein, allow you to do that. Peptide-based vaccines, less so.
*It’s worth noting that mRNA vs. peptide is a bit of a weird distinction, since mRNA is just a delivery mechanism, and so is also compatible with delivering peptides if that’s the way you wanted to go.
Proteins are peptides. When you give whole-proteins, protein domains or nanopeptides (short peptides). With peptide vaccine I mean a vaccine that contains peptides opposed to one that contains mRNA.
A good heuristic is that to have an effective vaccine, you want to present something to the immune system that’s “as close to the real thing” as possible.
That leaves the question of what “as close to the real thing” means. We have multiple usecases like an universal flu vaccine where the goal is to get the body to develop antibodies precisely against those sections of proteins of the flu virus that are conserved and don’t change year to year.
Peptides, removed from the context of the protein scaffold that they are normally a part of, are very floppy, and there’s no guarantee that the conformation a peptide takes will be the same as the conformation it takes in the native protein
MHC proteins don’t take native proteins. They take short peptides. If the short peptide doesn’t naturally fold in the same way as it folds in the native protein I don’t see how the human immune system would manage to build effective antibodies.
There are peptides in the RaDVaC vaccine where they created short peptides that fold into the shape of that the native protein has but that’s a different shape then you get if you just take the subsequence of the native protein and let it fold.
I think this leaves a lot of room for ambitious projects like a universal flu vaccine or a HIV vaccine that achieves better results then our bodies to naturally that then can fail their goals in clinical trials.
mRNA is just a delivery mechanism
Yes, the thing that’s making the effect is the synthesized peptide. I wrote the above with the assumption that you can generally give that protein directly. Just synthesise it and inject it.
Proteins are peptides. When you give whole-proteins, protein domains or nanopeptides (short peptides). With peptide vaccine I mean a vaccine that contains peptides opposed to one that contains mRNA.
It’s worth noting that calling proteins peptides is not standard terminology. If you say “peptide-based vaccines,” it’s generally understood that you’re not including protein-based vaccines (also known as subunit vaccines). And in your original post, it does sound like you are making this distinction. If you aren’t making this distinction, then it doesn’t quite make sense to decry the lack of focus on “peptide-based vaccines” (including protein-based ones) as opposed to mRNA when there are plenty of protein-based candidates (most notably Novavax) in advanced clinical development.
ETA: Read more about Stöcker’s vaccine; it’s not a peptide-based vaccine, it’s a protein subunit vaccine, using the whole RBD (peptides are usually <50 amino acids, the RBD is a couple hundred). So a different approach than RadVac. Just on priors I’d expect this to be more likely to work.
That leaves the question of what “as close to the real thing” means. We have multiple usecases like an universal flu vaccine where the goal is to get the body to develop antibodies precisely against those sections of proteins of the flu virus that are conserved and don’t change year to year.
Yeah, that’s fair — “as close to the real thing” isn’t always the best (e.g., see inactivated or live attenuated vaccines, which have plenty of problems). But when comparing vaccines where a whole protein is presented (so subunit and mRNA) to peptide-based vaccines, I think the fact that the whole protein has a more native-like conformation is a huge advantage in favor of the former. In the example of universal flu vaccines, the most advanced candidates are all presenting whole protein domains, not peptides.
MHC proteins don’t take native proteins. They take short peptides. If the short peptide doesn’t naturally fold in the same way as it folds in the native protein I don’t see how the human immune system would manage to build effective antibodies.
Fair enough for MHC’s, but this only holds for T cell-based immunity. B cells, on the other hand, absolutely care about the conformation of the protein as it exists. To build effective antibodies to whole proteins, the immune system selects for B cells that display antibodies that bind well to those whole protein targets (MHC’s, and therefore peptides, are involved in this process as well, but that doesn’t change the fact that the antibody displayed by the B cell still has to bind well to the whole protein in order for that B cell to be selected for).
There are peptides in the RaDVaC vaccine where they created short peptides that fold into the shape of that the native protein has but that’s a different shape then you get if you just take the subsequence of the native protein and let it fold.
It’s good that they’re doing this (I skimmed the white paper and saw an example where they introduced a non-native disulfide bond), it’s probably better than just using the native sequence for all their peptides. But I’d say our tools for this are pretty limited, and you’re still going to end up with a crude approximation of the native fold rather than exactly the native fold, which is just better.
It’s worth noting that calling proteins peptides is not standard terminology.
It’s the terminology that you get when you read the dictionary whether cambridge or webster. I had my molecular biology lectures in German and more then a decade ago, and the German Wikipedia still sees the German word Peptide as having the dictionary definition it has in English.
I can see how it’s can be confusing when peptide is usually meant for shorter strings.
It seems like we have problem in Wikidata with diverging German and English definitions for https://www.wikidata.org/wiki/Q172847 . What name would you use to talk about a chain of two or more amino acids?
But I’d say our tools for this are pretty limited, and you’re still going to end up with a crude approximation of the native fold rather than exactly the native fold, which is just better.
I would expect that we have experimentally determined the structure of the native fold. I would expect that our computer models might be good enough to predict how an amino acid chain of <20 amino acids folds.
there are plenty of protein-based candidates (most notably Novavax) in advanced clinical development.
It seems good that CEPI funded them. I think the issue here is that Novavax doesn’t have a vaccine on the market and has their own property adjuvant so it’s not an “existing adjuvants with well understood safety profile” that you would want when skipping phase 3 trials. It also means there likely hasn’t been large scale manufacturing of the adjuvants before which is also problematic.
What name would you use to talk about a chain of two or more amino acids?
Yeah I don’t know if there is a term that’s not super clunky like “amino acid-based polymer.” But I think the more fundamental issue is that it’s weird to group peptide-based and protein-based vaccines together for the claims that you’re making. You can’t both fend off the claim that “whole protein domains are better immunogens than peptides because they have more native-like folds” by saying that “proteins ARE peptides, and are included in my category” AND say that “it’s irresponsible for us as a society not to have invested more in peptide-based vaccines because they’re so cheap and easy to synthesize”, when “cheap and easy to synthesize” don’t apply to protein-based vaccines.
I would expect that we have experimentally determined the structure of the native fold. I would expect that our computer models might be good enough to predict how an amino acid chain of <20 amino acids folds.
Yes, I would agree with both of those (although less sure about the second one, given that I’d expect a peptide of <20 amino acids to have an ensemble of conformations; it’s one thing to be able to predict the lowest energy conformation, another to predict exactly what percentage of the population is in each of 20 possible conformations). But more importantly, it’s difficult to bridge from one to the other. If you’re starting with the original peptide sequence, the best you can do is probably introduce a disulfide bond or cyclize it to introduce some conformational constraint, but that’s not going to constrain it the same way that the native scaffold would’ve. You could maybe do de novo computational design of the peptide (not starting with the native sequence) to have the desired fold, but that’s more cutting-edge stuff and not what RadVac did, and I’m not sure how well that would work anyway.
when “cheap and easy to synthesize” don’t apply to protein-based vaccines.
Why aren’t proteins cheap to produce? You do CISPR on some hela cells and they will produce the proteins for you. I would expect that’s what behinds Winfried Stöcker claim to be able to produce a lot of vaccine very cheaply very fast.
(Side note: You wouldn’t use CRISPR nor HeLa cells, but rather traditional cloning techniques + any of a number of other cell lines traditionally used for recombinant protein production. But that’s tangential to your question.)
I’m far from an expert here, but anything involving cell culture is generally thought to be pretty expensive. The media is expensive, other culture conditions can add to the cost as well (e.g. continuous supply of CO2 for mammalian cells), transfection reagents are expensive, and you have to expend a lot of effort keeping out bacterial/fungal/viral contamination. The inherent variability in biological processes means that you have to deal with batch-to-batch variability in your recombinant protein product, which might mean added expenses in monitoring and analysis (and headaches dealing with regulatory agencies). Basically, cells are fickle and require a lot of babysitting and care.
mRNA vaccines don’t have any of these issues, because cell culture isn’t involved for the most part. Most everything is done in vitro — in that sense, mRNA vaccine production is more like chemistry than biology. And, therefore, it’s more similar to peptide-based vaccine production (chemical synthesis) than protein-based vaccine production is — which, again, is why it’s weird to contrast peptide- and protein-based vaccines together against mRNA vaccines.
I think you’re giving mRNA vaccines too little credit and peptide-based vaccines too much.* I haven’t looked into peptide vaccines much at all but my general impression is that they don’t work that well as a class. Hundreds of peptide vaccines have entered the clinic with no approvals (albeit, not all against infectious diseases, many against cancer which is more difficult) — without looking into the details, I couldn’t tell you exactly why, but my guess would be lack of efficacy. When you present something to the immune system, it’s important that it be in the right shape so that it trains the immune system properly. Peptides, removed from the context of the protein scaffold that they are normally a part of, are very floppy, and there’s no guarantee that the conformation a peptide takes will be the same as the conformation it takes in the native protein (more precisely, probably some of the conformations the peptide takes will be similar to the conformations in the native protein, but how many other conformations will the peptide be taking that are dissimilar, and will steer the immune system the wrong way?). A good heuristic is that to have an effective vaccine, you want to present something to the immune system that’s “as close to the real thing” as possible. mRNA vaccines, by being compatible with presentation of a full viral protein, allow you to do that. Peptide-based vaccines, less so.
*It’s worth noting that mRNA vs. peptide is a bit of a weird distinction, since mRNA is just a delivery mechanism, and so is also compatible with delivering peptides if that’s the way you wanted to go.
Proteins are peptides. When you give whole-proteins, protein domains or nanopeptides (short peptides). With peptide vaccine I mean a vaccine that contains peptides opposed to one that contains mRNA.
That leaves the question of what “as close to the real thing” means. We have multiple usecases like an universal flu vaccine where the goal is to get the body to develop antibodies precisely against those sections of proteins of the flu virus that are conserved and don’t change year to year.
MHC proteins don’t take native proteins. They take short peptides. If the short peptide doesn’t naturally fold in the same way as it folds in the native protein I don’t see how the human immune system would manage to build effective antibodies.
There are peptides in the RaDVaC vaccine where they created short peptides that fold into the shape of that the native protein has but that’s a different shape then you get if you just take the subsequence of the native protein and let it fold.
I think this leaves a lot of room for ambitious projects like a universal flu vaccine or a HIV vaccine that achieves better results then our bodies to naturally that then can fail their goals in clinical trials.
Yes, the thing that’s making the effect is the synthesized peptide. I wrote the above with the assumption that you can generally give that protein directly. Just synthesise it and inject it.
It’s worth noting that calling proteins peptides is not standard terminology. If you say “peptide-based vaccines,” it’s generally understood that you’re not including protein-based vaccines (also known as subunit vaccines). And in your original post, it does sound like you are making this distinction. If you aren’t making this distinction, then it doesn’t quite make sense to decry the lack of focus on “peptide-based vaccines” (including protein-based ones) as opposed to mRNA when there are plenty of protein-based candidates (most notably Novavax) in advanced clinical development.
ETA: Read more about Stöcker’s vaccine; it’s not a peptide-based vaccine, it’s a protein subunit vaccine, using the whole RBD (peptides are usually <50 amino acids, the RBD is a couple hundred). So a different approach than RadVac. Just on priors I’d expect this to be more likely to work.
Yeah, that’s fair — “as close to the real thing” isn’t always the best (e.g., see inactivated or live attenuated vaccines, which have plenty of problems). But when comparing vaccines where a whole protein is presented (so subunit and mRNA) to peptide-based vaccines, I think the fact that the whole protein has a more native-like conformation is a huge advantage in favor of the former. In the example of universal flu vaccines, the most advanced candidates are all presenting whole protein domains, not peptides.
Fair enough for MHC’s, but this only holds for T cell-based immunity. B cells, on the other hand, absolutely care about the conformation of the protein as it exists. To build effective antibodies to whole proteins, the immune system selects for B cells that display antibodies that bind well to those whole protein targets (MHC’s, and therefore peptides, are involved in this process as well, but that doesn’t change the fact that the antibody displayed by the B cell still has to bind well to the whole protein in order for that B cell to be selected for).
It’s good that they’re doing this (I skimmed the white paper and saw an example where they introduced a non-native disulfide bond), it’s probably better than just using the native sequence for all their peptides. But I’d say our tools for this are pretty limited, and you’re still going to end up with a crude approximation of the native fold rather than exactly the native fold, which is just better.
It’s the terminology that you get when you read the dictionary whether cambridge or webster. I had my molecular biology lectures in German and more then a decade ago, and the German Wikipedia still sees the German word Peptide as having the dictionary definition it has in English.
I can see how it’s can be confusing when peptide is usually meant for shorter strings.
It seems like we have problem in Wikidata with diverging German and English definitions for https://www.wikidata.org/wiki/Q172847 . What name would you use to talk about a chain of two or more amino acids?
I would expect that we have experimentally determined the structure of the native fold. I would expect that our computer models might be good enough to predict how an amino acid chain of <20 amino acids folds.
It seems good that CEPI funded them. I think the issue here is that Novavax doesn’t have a vaccine on the market and has their own property adjuvant so it’s not an “existing adjuvants with well understood safety profile” that you would want when skipping phase 3 trials. It also means there likely hasn’t been large scale manufacturing of the adjuvants before which is also problematic.
Yeah I don’t know if there is a term that’s not super clunky like “amino acid-based polymer.” But I think the more fundamental issue is that it’s weird to group peptide-based and protein-based vaccines together for the claims that you’re making. You can’t both fend off the claim that “whole protein domains are better immunogens than peptides because they have more native-like folds” by saying that “proteins ARE peptides, and are included in my category” AND say that “it’s irresponsible for us as a society not to have invested more in peptide-based vaccines because they’re so cheap and easy to synthesize”, when “cheap and easy to synthesize” don’t apply to protein-based vaccines.
Yes, I would agree with both of those (although less sure about the second one, given that I’d expect a peptide of <20 amino acids to have an ensemble of conformations; it’s one thing to be able to predict the lowest energy conformation, another to predict exactly what percentage of the population is in each of 20 possible conformations). But more importantly, it’s difficult to bridge from one to the other. If you’re starting with the original peptide sequence, the best you can do is probably introduce a disulfide bond or cyclize it to introduce some conformational constraint, but that’s not going to constrain it the same way that the native scaffold would’ve. You could maybe do de novo computational design of the peptide (not starting with the native sequence) to have the desired fold, but that’s more cutting-edge stuff and not what RadVac did, and I’m not sure how well that would work anyway.
Why aren’t proteins cheap to produce? You do CISPR on some hela cells and they will produce the proteins for you. I would expect that’s what behinds Winfried Stöcker claim to be able to produce a lot of vaccine very cheaply very fast.
(Side note: You wouldn’t use CRISPR nor HeLa cells, but rather traditional cloning techniques + any of a number of other cell lines traditionally used for recombinant protein production. But that’s tangential to your question.)
I’m far from an expert here, but anything involving cell culture is generally thought to be pretty expensive. The media is expensive, other culture conditions can add to the cost as well (e.g. continuous supply of CO2 for mammalian cells), transfection reagents are expensive, and you have to expend a lot of effort keeping out bacterial/fungal/viral contamination. The inherent variability in biological processes means that you have to deal with batch-to-batch variability in your recombinant protein product, which might mean added expenses in monitoring and analysis (and headaches dealing with regulatory agencies). Basically, cells are fickle and require a lot of babysitting and care.
mRNA vaccines don’t have any of these issues, because cell culture isn’t involved for the most part. Most everything is done in vitro — in that sense, mRNA vaccine production is more like chemistry than biology. And, therefore, it’s more similar to peptide-based vaccine production (chemical synthesis) than protein-based vaccine production is — which, again, is why it’s weird to contrast peptide- and protein-based vaccines together against mRNA vaccines.