I feel a little guilty about wasting the megaphone you granted me on RaDVaC, so instead of talking further about that, here are a few things I think are more important:
1. Do any of the emerging COVID variants evade existing vaccines?
A strain that evades existing vaccines could render all the effort we've put into vaccinating people moot and set us on track for a rerun of the whole pandemic (but worse because people are much less willing to lock down a second time). It's better to figure this out sooner rather than later, so that my household can decide what lengths to go to chasing vaccination this round, whether there's anything that we should scramble to do over the next few months when we'll likely be vaccinated against the dominant strains and benefitting from COVID's seasonality, and, of course, whether to surrender and take our chances instead of giving another year of our lives away to avoidance.
We know that we're probably safe from B.1.1.7, but it's not the only variant of concern now, and there will likely be more later.
I paged through your last couple months of posts, and it looks like you're already following new strains closely, so I guess just take this as positive reinforcement :-)
2. Related to above: how quickly can we expect vaccines against novel variants?
If we are facing a vaccine-evading strain (there might already be one propagating somewhere), we probably need to start tooling up factories by late summer (better yet: be doing it now) in order to get ahead of it, and that requires the pharmaceutical and regulatory apparatus to exhibit much faster turnaround than we saw for the first vaccines. What are the odds this speedup will actually happen?
3. No countries, even rich countries, are spending anywhere near enough money on vaccines. I think it might still make a big difference if this changed now, even if there are no vaccine-evading variants to contend with.
Great comment! Also, I don't think our conversation about RaDVaC was a waste at all. I think that was pretty important to discuss.
There are very few comments that I don't share with the whole group, by the way--I share all of these exchanges unless I feel the comment didn't add anything that wasn't already covered in the newsletter. Or if the poster asked me not to share it.
Anyway, to your questions:
1) really depends on what we mean by "evade." There is clear evidence that efficacy of several vaccines against the B.1.351 lineage is compromised somewhat, but that is efficacy against even mild disease. Efficacy against severe disease or against death does not appear to be compromised. Specifically, the mutations at position 501 and position 484 in the spike protein, both present in this variant as well as some other variants, have been identified as antibody-escape mutations. I believe the presence of these and other mutations in that lineage is responsible for the efficacy drop observed in several studies.
Complete evasion of existing vaccines is not something we have seen so far, and it's sort of a complicated question, in my opinion, as to whether we will ever see it. Coronaviruses mutate rather slowly, and a recent paper from the Bloom lab looked at drift over time of human seasonal coronaviruses: https://www.biorxiv.org/content/10.1101/2020.12.17.423313v1 This paper seems to demonstrate that it takes almost a decade for seasonal coronaviruses to drift substantially enough that archived antibodies are no longer able to neutralize them. It's actually kind of an incredible paper, and great work by the Bloom lab (as usual). This long period of drift is pretty interesting, because it would mean that repeated exposures to intermediate mutants along the way likely "update" our immune memory to where we never really see a coronavirus evade the immune response. This may--may--partly explain why human coronaviruses typically cause very mild disease, in that we generally have some kind of immune memory response to them that moderates the severity of infection.
If SARS-CoV-2 also drifts so slowly, then by the time it would evade vaccine-induced immunity, we may have been infected with so many intermediates, experiencing no or very mild disease each time, that our immune memory is meaningfully updated and no evasion effect is seen.
On the other hand, sarbecoviruses (the subgenus that contains the SARS-CoV species), are known to recombine readily with their relatives in cases where the host is infected with more than one variant (this is called "superinfection"). Other coronaviruses do this as well, but I understand the effect to be particularly common with sarbecoviruses (although I may be mistaken about this). It might then be possible for different lineages to combine with each other and produce a truly new strain that is immunologically distinct. Presumably this would then be designated SARS-CoV-3, and a new vaccine would need to be raised against it.
Thankfully, companies that have developed vaccines for SARS-CoV-2 have been thinking about this problem already. Moderna has already begun creating a new vaccine that targets mutations common in concerning variants. The mRNA platform makes it relatively easy to update the vaccine. I expect that if a really very concerning variant emerged, we would quickly manufacture a great many vaccine doses and everyone would go in for a booster shot against it. This is what we do each year with influenza viruses, and it could be plausible to do it with SARS-CoVs as well. I hope that isn't the scenario, though, because people are notoriously bad at adhering to annual influenza vaccination. This results in a boatload of influenza deaths in typical years, all of which can be contact-traced back to at least one person who decided getting the vaccine just wasn't worth their time. You can imagine how sad and frustrating I find that fact.
I can't entirely predict the future in this respect, but right now I anticipate that as variants emerge, they will emerge slowly enough that our vaccine-induced immunity gives us at least partial protection from disease. Under this scenario, SARS-CoVs will become mild seasonal illnesses and exposure to them will update individuals' immunity without causing severe disease. This will leave us at an equilibrium with the virus where it can survive and become endemic, but where its impacts on the human population are quite minimal. That is a rosy but plausible scenario, and I hope it's what comes to pass.
On to 2: Well, I sort of answered this already. But to go more in-depth, this really depends on the FDA licensing pathway that is given for a new modification of a vaccine. For influenza vaccines, an annual licensing pathway is given by which a previously-approved influenza vaccine design can be approved on a fast-track. Minimal studies are required because we understand well how vaccines against influenza virus work, and the whole process of licensing an updated vaccine can take a month or two. The same might end up being true of COVID-19 vaccines, if we end up needing to routinely update them. For influenza vaccines, it can then take months for enough doses to be manufactured, but this has to do with influenza vaccine manufacturing techniques being somewhat slow. For SARS-CoV-2 vaccines, particularly the mRNA ones, retooling manufacturing capabilities to make a new variation on the vaccine should be a lot faster. It looks like we can get a new vaccine rolled out in a matter of months, and if we keep the manufacturing capacity in place, it might be faster than that. So if COVID-19 vaccines end up going through a similar licensing update process as influenza vaccines, it shouldn't take long at all to react to new variants.
On the other hand, the FDA may insist on more in-depth clinical studies. In that case, it could take 4-6 months to perform the trials and go through the regulatory process. I imagine the FDA will not opt for this approach in the face of an imminent threat from an escape variant, particularly now that these new vaccines have been demonstrated to have an excellent risk-benefit profile.
3) I agree. We don't spend enough on biodefense or biosecurity at all, particularly not against emerging threats like SARS-CoV-2. The problem is worse than that link envisions, however. Dr. Peter Hotez of Baylor, an absolute legend in this field, was working on a rapidly-deployable sarbecovirus vaccine candidate before 2020. He intended this candidate to be a cassette-type approach, where virus-specific sequences could be inserted into an engineered backbone that had already been demonstrated to be safe. Here, Dr. Hotez spins this as laying the groundwork to design the current vaccines (which is true): https://www.ama-assn.org/delivering-care/public-health/how-decade-coronavirus-research-paved-way-covid-19-vaccines However, as true as that is, he is glossing over the unfortunate fact that if he had been better funded by the government, he could have completed the backbone of a vaccine platform well in advance of the pandemic, complete with clinical testing to establish, at least, the safety of that platform. He would have been ready for Phase 2b trials in Q1 of 2020 and Phase 3 trials not long thereafter. We might have had the current vaccine-rollout situation that we have now in October or November of 2020--before the concerning variants started to really expand and spread globally.
All of this didn't happen because work like his was not funded. Our preparedness was abysmal, because we (I speak of the US here) spend less than $40 billion in total on all of the government-funded health research conducted in the US annually before the pandemic. That includes research on cancer, research on heart disease, research on toe fungus, etc. etc. That's the whole pot.
Meanwhile we are spending $1.5 trillion on the F-35, which was supposed to be a cheap next-generation fighter jet, as opposed to the expensive and finicky F-22, a plane which cost in total less than $100 billion. The F-35 has turned out to be more expensive and more weighted down with features than the F-22, and much of it doesn't actually work as intended. It is a complete quagmire. If we cut the program by even 10% and redirected those funds to biomedical research, we could double our investment in health sciences for at least three years.
I have been on this funding soapbox for a very long time, by the way. It all began with the following piece in Mashable, written when I was a very frustrated and bitter graduate student: https://mashable.com/2013/09/20/why-you-dont-love-science/
I've matured a bit since I wrote that and might not be so harsh today, but it's presented as evidence that this is an extremely longstanding problem that we continue to do a laughable amount to address.
The US and other countries in the developed world need to do a hell of a lot more to support basic science. There is clear evidence that it is a fantastic investment, but it doesn't happen. Hopefully COVID-19 will teach humanity a lesson in this regard, but...I am skeptical.
Wow, thanks for the spotlight!
I feel a little guilty about wasting the megaphone you granted me on RaDVaC, so instead of talking further about that, here are a few things I think are more important:
1. Do any of the emerging COVID variants evade existing vaccines?
A strain that evades existing vaccines could render all the effort we've put into vaccinating people moot and set us on track for a rerun of the whole pandemic (but worse because people are much less willing to lock down a second time). It's better to figure this out sooner rather than later, so that my household can decide what lengths to go to chasing vaccination this round, whether there's anything that we should scramble to do over the next few months when we'll likely be vaccinated against the dominant strains and benefitting from COVID's seasonality, and, of course, whether to surrender and take our chances instead of giving another year of our lives away to avoidance.
We know that we're probably safe from B.1.1.7, but it's not the only variant of concern now, and there will likely be more later.
I paged through your last couple months of posts, and it looks like you're already following new strains closely, so I guess just take this as positive reinforcement :-)
2. Related to above: how quickly can we expect vaccines against novel variants?
If we are facing a vaccine-evading strain (there might already be one propagating somewhere), we probably need to start tooling up factories by late summer (better yet: be doing it now) in order to get ahead of it, and that requires the pharmaceutical and regulatory apparatus to exhibit much faster turnaround than we saw for the first vaccines. What are the odds this speedup will actually happen?
3. No countries, even rich countries, are spending anywhere near enough money on vaccines. I think it might still make a big difference if this changed now, even if there are no vaccine-evading variants to contend with.
https://marginalrevolution.com/marginalrevolution/2021/01/preparing-for-a-pandemic-accelerating-vaccine-availability.html (don't read the post comments - they're terrible)
Great comment! Also, I don't think our conversation about RaDVaC was a waste at all. I think that was pretty important to discuss.
There are very few comments that I don't share with the whole group, by the way--I share all of these exchanges unless I feel the comment didn't add anything that wasn't already covered in the newsletter. Or if the poster asked me not to share it.
Anyway, to your questions:
1) really depends on what we mean by "evade." There is clear evidence that efficacy of several vaccines against the B.1.351 lineage is compromised somewhat, but that is efficacy against even mild disease. Efficacy against severe disease or against death does not appear to be compromised. Specifically, the mutations at position 501 and position 484 in the spike protein, both present in this variant as well as some other variants, have been identified as antibody-escape mutations. I believe the presence of these and other mutations in that lineage is responsible for the efficacy drop observed in several studies.
Complete evasion of existing vaccines is not something we have seen so far, and it's sort of a complicated question, in my opinion, as to whether we will ever see it. Coronaviruses mutate rather slowly, and a recent paper from the Bloom lab looked at drift over time of human seasonal coronaviruses: https://www.biorxiv.org/content/10.1101/2020.12.17.423313v1 This paper seems to demonstrate that it takes almost a decade for seasonal coronaviruses to drift substantially enough that archived antibodies are no longer able to neutralize them. It's actually kind of an incredible paper, and great work by the Bloom lab (as usual). This long period of drift is pretty interesting, because it would mean that repeated exposures to intermediate mutants along the way likely "update" our immune memory to where we never really see a coronavirus evade the immune response. This may--may--partly explain why human coronaviruses typically cause very mild disease, in that we generally have some kind of immune memory response to them that moderates the severity of infection.
If SARS-CoV-2 also drifts so slowly, then by the time it would evade vaccine-induced immunity, we may have been infected with so many intermediates, experiencing no or very mild disease each time, that our immune memory is meaningfully updated and no evasion effect is seen.
On the other hand, sarbecoviruses (the subgenus that contains the SARS-CoV species), are known to recombine readily with their relatives in cases where the host is infected with more than one variant (this is called "superinfection"). Other coronaviruses do this as well, but I understand the effect to be particularly common with sarbecoviruses (although I may be mistaken about this). It might then be possible for different lineages to combine with each other and produce a truly new strain that is immunologically distinct. Presumably this would then be designated SARS-CoV-3, and a new vaccine would need to be raised against it.
Thankfully, companies that have developed vaccines for SARS-CoV-2 have been thinking about this problem already. Moderna has already begun creating a new vaccine that targets mutations common in concerning variants. The mRNA platform makes it relatively easy to update the vaccine. I expect that if a really very concerning variant emerged, we would quickly manufacture a great many vaccine doses and everyone would go in for a booster shot against it. This is what we do each year with influenza viruses, and it could be plausible to do it with SARS-CoVs as well. I hope that isn't the scenario, though, because people are notoriously bad at adhering to annual influenza vaccination. This results in a boatload of influenza deaths in typical years, all of which can be contact-traced back to at least one person who decided getting the vaccine just wasn't worth their time. You can imagine how sad and frustrating I find that fact.
I can't entirely predict the future in this respect, but right now I anticipate that as variants emerge, they will emerge slowly enough that our vaccine-induced immunity gives us at least partial protection from disease. Under this scenario, SARS-CoVs will become mild seasonal illnesses and exposure to them will update individuals' immunity without causing severe disease. This will leave us at an equilibrium with the virus where it can survive and become endemic, but where its impacts on the human population are quite minimal. That is a rosy but plausible scenario, and I hope it's what comes to pass.
On to 2: Well, I sort of answered this already. But to go more in-depth, this really depends on the FDA licensing pathway that is given for a new modification of a vaccine. For influenza vaccines, an annual licensing pathway is given by which a previously-approved influenza vaccine design can be approved on a fast-track. Minimal studies are required because we understand well how vaccines against influenza virus work, and the whole process of licensing an updated vaccine can take a month or two. The same might end up being true of COVID-19 vaccines, if we end up needing to routinely update them. For influenza vaccines, it can then take months for enough doses to be manufactured, but this has to do with influenza vaccine manufacturing techniques being somewhat slow. For SARS-CoV-2 vaccines, particularly the mRNA ones, retooling manufacturing capabilities to make a new variation on the vaccine should be a lot faster. It looks like we can get a new vaccine rolled out in a matter of months, and if we keep the manufacturing capacity in place, it might be faster than that. So if COVID-19 vaccines end up going through a similar licensing update process as influenza vaccines, it shouldn't take long at all to react to new variants.
On the other hand, the FDA may insist on more in-depth clinical studies. In that case, it could take 4-6 months to perform the trials and go through the regulatory process. I imagine the FDA will not opt for this approach in the face of an imminent threat from an escape variant, particularly now that these new vaccines have been demonstrated to have an excellent risk-benefit profile.
3) I agree. We don't spend enough on biodefense or biosecurity at all, particularly not against emerging threats like SARS-CoV-2. The problem is worse than that link envisions, however. Dr. Peter Hotez of Baylor, an absolute legend in this field, was working on a rapidly-deployable sarbecovirus vaccine candidate before 2020. He intended this candidate to be a cassette-type approach, where virus-specific sequences could be inserted into an engineered backbone that had already been demonstrated to be safe. Here, Dr. Hotez spins this as laying the groundwork to design the current vaccines (which is true): https://www.ama-assn.org/delivering-care/public-health/how-decade-coronavirus-research-paved-way-covid-19-vaccines However, as true as that is, he is glossing over the unfortunate fact that if he had been better funded by the government, he could have completed the backbone of a vaccine platform well in advance of the pandemic, complete with clinical testing to establish, at least, the safety of that platform. He would have been ready for Phase 2b trials in Q1 of 2020 and Phase 3 trials not long thereafter. We might have had the current vaccine-rollout situation that we have now in October or November of 2020--before the concerning variants started to really expand and spread globally.
All of this didn't happen because work like his was not funded. Our preparedness was abysmal, because we (I speak of the US here) spend less than $40 billion in total on all of the government-funded health research conducted in the US annually before the pandemic. That includes research on cancer, research on heart disease, research on toe fungus, etc. etc. That's the whole pot.
Meanwhile we are spending $1.5 trillion on the F-35, which was supposed to be a cheap next-generation fighter jet, as opposed to the expensive and finicky F-22, a plane which cost in total less than $100 billion. The F-35 has turned out to be more expensive and more weighted down with features than the F-22, and much of it doesn't actually work as intended. It is a complete quagmire. If we cut the program by even 10% and redirected those funds to biomedical research, we could double our investment in health sciences for at least three years.
I have been on this funding soapbox for a very long time, by the way. It all began with the following piece in Mashable, written when I was a very frustrated and bitter graduate student: https://mashable.com/2013/09/20/why-you-dont-love-science/
I've matured a bit since I wrote that and might not be so harsh today, but it's presented as evidence that this is an extremely longstanding problem that we continue to do a laughable amount to address.
The US and other countries in the developed world need to do a hell of a lot more to support basic science. There is clear evidence that it is a fantastic investment, but it doesn't happen. Hopefully COVID-19 will teach humanity a lesson in this regard, but...I am skeptical.