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.
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.