Time for another look at the coronavirus vaccine front, since we have several recent news items. Word has come from GSK and Sanofi that they are going to collaborate on vaccine development, which brings together two of the more experienced large organizations in the field. It looks like Sanofi is bringing the spike protein and GSK is bringing the adjuvant (more on what that means below). Their press release says that they plan to go into human patients late this year and to have everything ready for regulatory filing in the second half of 2021. For its part, Pfizer has announced that they’re pushing up their schedule with BioNTech and possibly starting human trials in August, which probably puts them on a similar timeline for eventual filing.
“But that’s next year!” will be the reaction of many who are hoping for a vaccine ASAP, and I can understand why. The thing is, that would be absolutely unprecedented speed, way past the current record set by the Ebola vaccine, which took about five years. More typical development times are ten years or more. But hold that thought while you peruse another news item today from J&J. They have an even more aggressive timeline proposed for their own vaccine work: they have already announced that they have a candidate, and they say that they plan first-in-human trials in September. Data will be available from those in December, and in January 2021 they say that they will have the first batches of vaccine ready for an FDA Emergency Use Authorization. Now that is shooting for the world record on both the scientific and regulatory fronts.
So let’s talk vaccine development, because everything is going to have to work perfectly for any such timetable to be realized. Here’s a good overview of the coronavirus vaccine world in Nature Reviews Drug Discovery. The official WHO list is here, and at BioCentury they have constantly updated open-access summaries of the vaccines and other therapies that are in the clinic and the ones that are still preclinical. They have also just published this excellent overview of the vaccine issues; I recommend reading that one after you’ve picked up some background from this post.
NRDD counts 115 (!) vaccine programs, of which 37 are unconfirmed (no further information available on them) and 78 are definitely real. Of those 78, five of them are in the clinic, although that number will be climbing rapidly. You have Moderna’s mRNA1273, which as the name tells you is an mRNA candidate, and Inovio’s INO4800, which is a DNA plasmid, There are two cellular candidates from Shenzhen Geno-Immune Medical Institute: LV-SMENP-DC, a dendritic cell vaccine that’s been modified with lentivirus vectors to express viral proteins, and an artificial antigen-presenting cell (aAPC) vaccine along the same lines. And finally there’s a more traditional protein-fragment vaccine, Ad5-nCoV from CanSino.
Let’s go into what all those mean. You will note the diversity of approaches in that list, and that’s not even the whole spread. When you go back into the preclinical candidates, you have in addition “virus-like particles”, viral vectors, both replicating and non-replicating, live attenuated viruses, inactivated viruses, and more. From this you may deduce correctly that there are a lot of ways to set off the immune response. What are the differences between them?
Types of Vaccines (...)
Adjuvants (...)
Developing a Covid-19 Vaccine: Efficacy (...)
“But that’s next year!” will be the reaction of many who are hoping for a vaccine ASAP, and I can understand why. The thing is, that would be absolutely unprecedented speed, way past the current record set by the Ebola vaccine, which took about five years. More typical development times are ten years or more. But hold that thought while you peruse another news item today from J&J. They have an even more aggressive timeline proposed for their own vaccine work: they have already announced that they have a candidate, and they say that they plan first-in-human trials in September. Data will be available from those in December, and in January 2021 they say that they will have the first batches of vaccine ready for an FDA Emergency Use Authorization. Now that is shooting for the world record on both the scientific and regulatory fronts.So let’s talk vaccine development, because everything is going to have to work perfectly for any such timetable to be realized. Here’s a good overview of the coronavirus vaccine world in Nature Reviews Drug Discovery. The official WHO list is here, and at BioCentury they have constantly updated open-access summaries of the vaccines and other therapies that are in the clinic and the ones that are still preclinical. They have also just published this excellent overview of the vaccine issues; I recommend reading that one after you’ve picked up some background from this post.
NRDD counts 115 (!) vaccine programs, of which 37 are unconfirmed (no further information available on them) and 78 are definitely real. Of those 78, five of them are in the clinic, although that number will be climbing rapidly. You have Moderna’s mRNA1273, which as the name tells you is an mRNA candidate, and Inovio’s INO4800, which is a DNA plasmid, There are two cellular candidates from Shenzhen Geno-Immune Medical Institute: LV-SMENP-DC, a dendritic cell vaccine that’s been modified with lentivirus vectors to express viral proteins, and an artificial antigen-presenting cell (aAPC) vaccine along the same lines. And finally there’s a more traditional protein-fragment vaccine, Ad5-nCoV from CanSino.
Let’s go into what all those mean. You will note the diversity of approaches in that list, and that’s not even the whole spread. When you go back into the preclinical candidates, you have in addition “virus-like particles”, viral vectors, both replicating and non-replicating, live attenuated viruses, inactivated viruses, and more. From this you may deduce correctly that there are a lot of ways to set off the immune response. What are the differences between them?
Types of Vaccines (...)
Adjuvants (...)
Developing a Covid-19 Vaccine: Efficacy (...)
Developing a Covid-19 Vaccine: Safety (...)
Developing a Covid-19 Vaccine: Logistics
Another big problem is going to be manufacturing and distribution. Many readers will have heard about the difficulties that sometimes occur during the flu-vaccine production process, leading to shortages. Depending on what vaccine technology comes out on top, manufacturing enough doses in a reproducible fashion could be quite challenging – space and finger fatigue don’t permit going into all the details, but they are many and complex. Keep in mind as well that many vaccines need “cold chain” distribution and storage, which is always a layer of complexity. What if an eventual vaccine needs more than one round of administration, as many of the adjuvant-formulated ones do? Keeping track of that and following up on it is yet another issue.
My guess is that scale-up and manufacturing could well be the biggest chance for the timelines mentioned earlier to blow up, so there is going to be a massive effort to front-load the work on these problems – this is why, for example, Bill Gates has already indicated willingness to fund factories for up to seven vaccines up front. The live-virus, attenuated virus, recombinant protein, and nucleic acid vaccines will all involve completely different production methods and formulations, and since we don’t know which way we’ll be going, this would seem the only way to address the issue. Pfizer and others have already said that they’re going to be working on production even before the efficacy data come in, which needless to say is not the usual business practice. I think we’ll get vaccine efficacy, one way or another, although it sure won’t be characterized as thoroughly as it normally would. And I think we’re already agreeing to cut corners on safety, whether anyone says so in as many words or not. But producing the vaccine on scale could be a bigger issue yet, and as the process goes on, that’s where I would keep an eye out for trouble.
Developing a Covid-19 Vaccine: Logistics
Another big problem is going to be manufacturing and distribution. Many readers will have heard about the difficulties that sometimes occur during the flu-vaccine production process, leading to shortages. Depending on what vaccine technology comes out on top, manufacturing enough doses in a reproducible fashion could be quite challenging – space and finger fatigue don’t permit going into all the details, but they are many and complex. Keep in mind as well that many vaccines need “cold chain” distribution and storage, which is always a layer of complexity. What if an eventual vaccine needs more than one round of administration, as many of the adjuvant-formulated ones do? Keeping track of that and following up on it is yet another issue.
My guess is that scale-up and manufacturing could well be the biggest chance for the timelines mentioned earlier to blow up, so there is going to be a massive effort to front-load the work on these problems – this is why, for example, Bill Gates has already indicated willingness to fund factories for up to seven vaccines up front. The live-virus, attenuated virus, recombinant protein, and nucleic acid vaccines will all involve completely different production methods and formulations, and since we don’t know which way we’ll be going, this would seem the only way to address the issue. Pfizer and others have already said that they’re going to be working on production even before the efficacy data come in, which needless to say is not the usual business practice. I think we’ll get vaccine efficacy, one way or another, although it sure won’t be characterized as thoroughly as it normally would. And I think we’re already agreeing to cut corners on safety, whether anyone says so in as many words or not. But producing the vaccine on scale could be a bigger issue yet, and as the process goes on, that’s where I would keep an eye out for trouble.
by Derek Lowe, Science Translational Medicine | Read more:
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