It seems clear that focusing on the vaccine pipeline will become critical in the coming months, and we need to get ahead of it ASAP. Currently, the plan is to wait for safety approvals, then start manufacturing. That will obviously change—when we have moderate confidence that a vaccine is effective, we will want to start manufacturing, but there are several candidates, and too little productive capacity to make large quantities of several different vaccines. In fact, there is too little productive capacity to make any one vaccine in global quantities without stopping manufacture of other vaccines.
Vaccine manufacturing is very complex, and needs specialized facilities with clean rooms, sterilization facilities, very specific types of HVAC, etc. Building these is capital intensive, and there has been too little capacity for quite a while, leading to occasional vaccine shortages. I think we should be pushing large companies and governments to figure out how to create greater production capacity for vaccines. This is a global public good anyways. There are a few economic concerns for companies doing this, but right now is the perfect time to get government subsidies for such capital intensive projects.
How specific are vaccine production facilities to individual vaccines? To what extend can we build them before knowing which of our vaccines will succeed in the clinical trials?
From what I understand, we use eggs to incubate and clean-rooms to produce the final product for all of them, and I understood that vaccine producers can switch between which ones they make, with a couple month delay for incubation and switching over.
That’s not quite right. I can’t get to that book right now, but measles and mumps for MMR are also done in Chicken eggs, IIRC, as are Herpes and Poxviruses, while cell lines and other media can be used to grow other viruses—but the remainder of the facilities are still similar, and can be repurposed.
But I agree that we do need new platform technologies.
Hmm, well that book chapter claims measles and mumps vaccines are produced in chick embryo cell culture, which is different from propagation on chicken eggs. My quick Googling revealed that we don’t have a licensed herpes vaccine, and that while there might be one or two smallpox vaccines that are produced in chicken eggs, many are done in cell culture.
You might be right about the broader (and more important) point about ease of facilities repurposing, however—I don’t know enough to say, although the table in the book chapter makes me doubtful, given that pretty much all steps in the manufacturing process (production, isolation, purification, formulation) seem unique to each vaccine.
yellow fever vaccine is one that springs to mind that also uses eggs in production
The yellow fever vaccine is made by growing yellow fever virus in mouse embryo cells and in chick embryo cells. The final preparation of the vaccine is made in eggs. Growing yellow fever virus in mouse and chick cells over and over again weakened it. Therefore, when this “live, weakened” virus is injected, a protective immune response develops without causing illness. SOURCE
I’ve heard that the eggs used are special, more sterile than usual (you don’t want the chicken to have other diseases now, do you?), and usually require ordering at least a year in advance.
(Came up when I was researching flu-vaccine development.)
Some other vaccine production methods involve cell cultures, but the output of different cell cultures is pretty wildly variable and the preferred cell culture is different depending on the specific virus. This is probably a more expensive means of production. You may be able to scale it up faster and with less early prep-work, however.
Fair warning: While there have been coronavirus vaccines that have just worked, there have also been a lot of them that seemed to make the course of infection worse, probably due to antibody-dependent enhancement or a similar phenomenon. The set that were somewhat challenging to develop vaccines for seemed to include SARS-1. The lengthy process of animal testing would probably spot this, but it may make getting a reliable vaccine slower and harder than it would be with viruses that don’t have this problem.
Why do you need the eggs in the first place? Couldn’t you just feed animo acids that you get when you electrolyse proteins instead of having the proteins from the eggs?
...I’m confused about what method you’re even trying to gesture at.
They’re viruses*, they need a full set of environmentally-provided cell machinery to replicate or produce proteins: ribosomes, transcription machinery (ex: t-RNAs), ATP, the works. They need cells, so you’d need need at least a cell culture. All of biology has heavily optimized protein assembly lines, you’re not going to beat it acellularly.
The cells near the outside of an egg are probably used because they’re an elegant and self-contained little solution to sterilization (against everything but your virus) and the quality-control problems you’d have to contend with otherwise. It’s not really about the protein content, mostly.
(Cell culture is probably more expensive than eggs because 1) bioreactors are kinda expensive, 2) bioreactors are a bit of a pain to maintain, and sterilization is hard, two problems that using an egg pretty neatly solves, and 3) which cell culture will work best is surprisingly hard to predict, you basically have to test it experimentally.)
* Well, technically it’s weakened viruses, or single-gene plasmids, or something similar. The need for cells still holds either way.
…I’m confused about what method you’re even trying to gesture at.
Eggs do have a lot of ovalbumin where it’s not really desireable for that to end up in your final vaccine but I don’t think this is a discussion to have at a point where our key issue is scaling up vaccine production.
If you have to order the steralized eggs a year in advance, and we want our COVID-19 vaccine before a year is over, that suggests to me that we also have other problems.
If I understand the work Moderna is doing for their COVID-19 vaccine and read the paper where they describe their framework, it seems to me that they use human cell lines:
The modified mRNA was synthesized enzymatically and packaged into lipid nanoparticles (LNPs). Incubation of LNPs containing IgE signal-prM-E mRNA (IgEsig-prM-E) with 293T or HeLa cells resulted in efficient expression and secretion of ∼30 nm SVPs
Just like Moderna, CureVac which is another of the companies that want to produce a COVID-19 vaccine also focuses on delievering mRNA and not viruses. I didn’t immediately find information about how CureVac gets their mRNA but it wouldn’t surprise me if they also don’t use eggs.
Whoah, lipid-coated mRNA vaccines, not as an intermediate step but as the actual delivery method? That’s actually new to me! Sounds like it’s mRNAs coding for some subset of the viral proteins, which probably get assembled into proteins in your cells and then get used as something for antibodies to respond against. mRNAs should then just degrade themselves with time.
I have no idea what the most efficient method for producing those is; I am very used to vaccines being protein-based. This probably is in the realm where it’s simple enough that modifying PCR-protocols to produce RNA instead might actually work reasonably well, although RNA is generally more fragile and error-prone and that could be a problem.
You’d be using nucleotides, not amino acids, but mRNA from DNA is a short-enough assembly line that you might not need cells to do it.
(Protein production has a lot of dependencies. mRNA transcription should basically just require your DNA of interest, nucleotides (x4), and a transcriptase protein. Maybe add a transcription factor or two.)
HeLa definitely is a human cell line (although that was for Ebola, they may end up using a different cell line). That’s good, that probably scales up easily.
“Disease X could emerge suddenly and have deadly consquences—we’ve seen this happen with Ebola, MERS coronavirus, Zika, and countless other diseases. That’s why we’re striving to develop rapid-response vaccine platforms—like CureVac’s mRNA technology—to defend against these unknown pathogens. CEPI has now established partnership agreements totaling more than $50 million in three such platforms”.
It seems that the third mRNA vaccine company is BioNTech.
Johnson & Johnson appears to be using a more traditional approach in which the virus is inactivated so it can’t replicate but can still express viral proteins. The approach takes a little longer for both the development and manufacturing scale-up steps. On the plus side, Johnson & Johnson’s slow-but-steady approach could create a vaccine with a better immune response.
There’s a forth company with Inovio Pharm that also develops a COVID-19 vaccine. It’s technology is based on delievering DNA based.
I have the impression that the mRNA/DNA ways of vaccine delievery allow for faster development of a vaccine then the old fashioned protein based way.
The peer-reviewed literature has several papers talking about GI symptoms of COVID19, and there are several GI cells that are ACE2+ that are plausible targets. What I am wondering is the following a potential vaccine strategy?
innoculate with live strain in GI tract to avoid respiratory infection
Related to that observation I have wondered, but never posted/asked, if how one gets infected might influence severity as well. If I touch a contaminated surface and then rub my eye or then eat a sandwich without washing my hand is that more likely to end up somewhere other than my upper and lower respiratory systems?
If the same type of facility works for almost every kind of vaccine, do we think there would be interest in constructing the facilities as a speculative venture? Consider:
1. The economy is in chaos and may remain so, which I expect to produce unusually affordable access to design firms, construction crews, raw materials, and land.
2. There will be a strong incentive for regulators/inspectors to move with best speed, and the current administration at least in the US has a track record of being friendly to shortcuts.
3. If the facilities are already built, this allows a limit to the risk the companies producing the vaccines need to absorb in order to increase supply.
4. We could squeeze out unscrupulous opportunists.
Build new vaccine production facilities.
It seems clear that focusing on the vaccine pipeline will become critical in the coming months, and we need to get ahead of it ASAP. Currently, the plan is to wait for safety approvals, then start manufacturing. That will obviously change—when we have moderate confidence that a vaccine is effective, we will want to start manufacturing, but there are several candidates, and too little productive capacity to make large quantities of several different vaccines. In fact, there is too little productive capacity to make any one vaccine in global quantities without stopping manufacture of other vaccines.
Vaccine manufacturing is very complex, and needs specialized facilities with clean rooms, sterilization facilities, very specific types of HVAC, etc. Building these is capital intensive, and there has been too little capacity for quite a while, leading to occasional vaccine shortages. I think we should be pushing large companies and governments to figure out how to create greater production capacity for vaccines. This is a global public good anyways. There are a few economic concerns for companies doing this, but right now is the perfect time to get government subsidies for such capital intensive projects.
How specific are vaccine production facilities to individual vaccines? To what extend can we build them before knowing which of our vaccines will succeed in the clinical trials?
From what I understand, we use eggs to incubate and clean-rooms to produce the final product for all of them, and I understood that vaccine producers can switch between which ones they make, with a couple month delay for incubation and switching over.
FWIW, eggs are actually specific to influenza vaccine manufacturing. Page 3 of this book chapter ( https://reader.elsevier.com/reader/sd/pii/B9780128021743000059?token=F492A74B3C4545B108379536769CF93D7F1DB89321DADE859256496F5D85CB6259372D34376809219BBBE2FFFDEF25FB ) has a really nice table showing the production process of a number of different vaccines—they are all very different from one another. This is why we need new vaccine platform technologies—i.e., tech that can be used to produce multiple different vaccines. mRNA vaccines would fall into this category and is a reason why Moderna’s mRNA vaccine candidate for COVID-19 would be so exciting if it works.
That’s not quite right. I can’t get to that book right now, but measles and mumps for MMR are also done in Chicken eggs, IIRC, as are Herpes and Poxviruses, while cell lines and other media can be used to grow other viruses—but the remainder of the facilities are still similar, and can be repurposed.
But I agree that we do need new platform technologies.
Hmm, well that book chapter claims measles and mumps vaccines are produced in chick embryo cell culture, which is different from propagation on chicken eggs. My quick Googling revealed that we don’t have a licensed herpes vaccine, and that while there might be one or two smallpox vaccines that are produced in chicken eggs, many are done in cell culture.
You might be right about the broader (and more important) point about ease of facilities repurposing, however—I don’t know enough to say, although the table in the book chapter makes me doubtful, given that pretty much all steps in the manufacturing process (production, isolation, purification, formulation) seem unique to each vaccine.
yellow fever vaccine is one that springs to mind that also uses eggs in production
Good to know, thanks!
I’ve heard that the eggs used are special, more sterile than usual (you don’t want the chicken to have other diseases now, do you?), and usually require ordering at least a year in advance.
(Came up when I was researching flu-vaccine development.)
Some other vaccine production methods involve cell cultures, but the output of different cell cultures is pretty wildly variable and the preferred cell culture is different depending on the specific virus. This is probably a more expensive means of production. You may be able to scale it up faster and with less early prep-work, however.
Fair warning: While there have been coronavirus vaccines that have just worked, there have also been a lot of them that seemed to make the course of infection worse, probably due to antibody-dependent enhancement or a similar phenomenon. The set that were somewhat challenging to develop vaccines for seemed to include SARS-1. The lengthy process of animal testing would probably spot this, but it may make getting a reliable vaccine slower and harder than it would be with viruses that don’t have this problem.
Why do you need the eggs in the first place? Couldn’t you just feed animo acids that you get when you electrolyse proteins instead of having the proteins from the eggs?
...I’m confused about what method you’re even trying to gesture at.
They’re viruses*, they need a full set of environmentally-provided cell machinery to replicate or produce proteins: ribosomes, transcription machinery (ex: t-RNAs), ATP, the works. They need cells, so you’d need need at least a cell culture. All of biology has heavily optimized protein assembly lines, you’re not going to beat it acellularly.
The cells near the outside of an egg are probably used because they’re an elegant and self-contained little solution to sterilization (against everything but your virus) and the quality-control problems you’d have to contend with otherwise. It’s not really about the protein content, mostly.
(Cell culture is probably more expensive than eggs because 1) bioreactors are kinda expensive, 2) bioreactors are a bit of a pain to maintain, and sterilization is hard, two problems that using an egg pretty neatly solves, and 3) which cell culture will work best is surprisingly hard to predict, you basically have to test it experimentally.)
* Well, technically it’s weakened viruses, or single-gene plasmids, or something similar. The need for cells still holds either way.
Eggs do have a lot of ovalbumin where it’s not really desireable for that to end up in your final vaccine but I don’t think this is a discussion to have at a point where our key issue is scaling up vaccine production.
If you have to order the steralized eggs a year in advance, and we want our COVID-19 vaccine before a year is over, that suggests to me that we also have other problems.
If I understand the work Moderna is doing for their COVID-19 vaccine and read the paper where they describe their framework, it seems to me that they use human cell lines:
Just like Moderna, CureVac which is another of the companies that want to produce a COVID-19 vaccine also focuses on delievering mRNA and not viruses. I didn’t immediately find information about how CureVac gets their mRNA but it wouldn’t surprise me if they also don’t use eggs.
Whoah, lipid-coated mRNA vaccines, not as an intermediate step but as the actual delivery method? That’s actually new to me! Sounds like it’s mRNAs coding for some subset of the viral proteins, which probably get assembled into proteins in your cells and then get used as something for antibodies to respond against. mRNAs should then just degrade themselves with time.
I have no idea what the most efficient method for producing those is; I am very used to vaccines being protein-based. This probably is in the realm where it’s simple enough that modifying PCR-protocols to produce RNA instead might actually work reasonably well, although RNA is generally more fragile and error-prone and that could be a problem.
You’d be using nucleotides, not amino acids, but mRNA from DNA is a short-enough assembly line that you might not need cells to do it.
(Protein production has a lot of dependencies. mRNA transcription should basically just require your DNA of interest, nucleotides (x4), and a transcriptase protein. Maybe add a transcription factor or two.)
HeLa definitely is a human cell line (although that was for Ebola, they may end up using a different cell line). That’s good, that probably scales up easily.
From last year: From CEPI awards US$ 34M contract to CureVac to advance The RNA Printer™
It seems that the third mRNA vaccine company is BioNTech.
It seems that Johnson & Johnson is still developing a vaccine the traditional way:
There’s a forth company with Inovio Pharm that also develops a COVID-19 vaccine. It’s technology is based on delievering DNA based.
I have the impression that the mRNA/DNA ways of vaccine delievery allow for faster development of a vaccine then the old fashioned protein based way.
At scale? Not easily—eggs are cheaper, more effective, and easier to deal with.
The peer-reviewed literature has several papers talking about GI symptoms of COVID19, and there are several GI cells that are ACE2+ that are plausible targets. What I am wondering is the following a potential vaccine strategy?
innoculate with live strain in GI tract to avoid respiratory infection
Interesting—I’d ask Robin Hanson if that fits with his variolation suggestion.
Related to that observation I have wondered, but never posted/asked, if how one gets infected might influence severity as well. If I touch a contaminated surface and then rub my eye or then eat a sandwich without washing my hand is that more likely to end up somewhere other than my upper and lower respiratory systems?
If the same type of facility works for almost every kind of vaccine, do we think there would be interest in constructing the facilities as a speculative venture? Consider:
1. The economy is in chaos and may remain so, which I expect to produce unusually affordable access to design firms, construction crews, raw materials, and land.
2. There will be a strong incentive for regulators/inspectors to move with best speed, and the current administration at least in the US has a track record of being friendly to shortcuts.
3. If the facilities are already built, this allows a limit to the risk the companies producing the vaccines need to absorb in order to increase supply.
4. We could squeeze out unscrupulous opportunists.