A couple of random thoughts. Mu and Delta were the first two variants that showed any significant change in the conformation of the spike protein that might cause problems for the "neutralizing" IgG created by the mRNA and adenovirus-vector rDNA vaccines. That was what raised the interest of the WMO. Although I should be paying more attention to international surveillance, I've got this odd limit on time, since i'm not embedded in a department or research group, so I've focused on the US, and for the most part, CONUS, looking at Alaska and Hawaii when needed...
Delta has shown us some nasty tricks. It produces more viral replication product (particles) per cycle than WHU-1 or Beta, for instance, and the minor changes in the S1 protein allow it to show more affinity for the ACE2 receptor. Mu shared some of these properties but not at the same level as Delta, hence, in my mind, its lower competitive advantage overall. Were we to solely look at the S1 conformation changes in Mu, we'd have expected its resistance to our antibodies to be a bigger advantage, but there are so many factors to consider here, sometimes the obvious fails to win.
The research I've read shows the current vaccines are adequately effective against Delta. Their efficacy against Mu would require more available virus, and clinical observation with adequate genomic testing would be simpler than an in vitro estimation of efficacy. That didn't work out.
As to whether we need a Delta-specific booster... I currently don't think so (but like so many other things in this pandemic, I might have to change my mind). At least in the US, and other countries where Delta's predominated, it's burned through the susceptible population virtually unimpeded, because so many who acquired this strain were unvaccinated, and didn't really believe in either the virus overall, or the use of NPIs for mitigation. The sharp upward trajectory, short time at peak and sharp downward trajectory are what I learned in school as the shape of a "normal" pandemic where nothing is, or can be done to mitigate its spread.
I've said earlier that I have little faith in immunity conferred by infection providing any longer, or better protection than immune response conferred by the vaccines. The "why" is that the infection-conferred immunity tends to be more specific to the variant you've contracted, and there's some serial evaluations of humeral immunity that suggest its duration is shorter than the vaccine-conferred humeral immunity. Activation and training of the cellular immune system is also interesting as there are a couple of papers suggesting that cellular immunity training and activation by naturally conferred response is much more variable than that initiated by the vaccines.
I propose this is because infection-conferred immunity has the entire spectrum of antigenic triggers from a particular strain and may in fact train IgG to look for a more complete component, where the vaccines provide triggers for fragments of proteins, which allow less-specific response, but a response more tailored to the spike and plasmid capsule of this species of coronavirus... so is likely more effective overall.
What this suggests to me, today, pending more research, and likely another wave of cases down the road, is that the current set of vaccines authorized or approved in the US today are effective as they are.
Most likely, we don't still have a lot of unvaccinated, Delta-susceptible individuals left. Part of the reason is, I'm convinced (again... as of today at 0715) that recent prior infection likely confers some protection for at least 90 and as long as 180 days against the general SARS-CoV-2 virus regardless of which variant lineage it claims. As a result, I think we're looking at 4-6 month of relative quiet, when, hopefully, all our holdouts will get vaccinated and Merck and others will get their COVID-specific antivirals out to clinical availability. And then, I expect we'll see anther wave, caused by a variant imported via air transport from a part of the world still serving as an incubator for new variants because they're inadequately vaccinated. And the public will have already told us that, to them, the pandemic's over.
My thoughts, so there's no one else to blame organizationally...
Why do you think we don’t have many delta susceptible people left?
I understand your infection conferred immunity thoughts; however, I have questions.
Would severity of a case correlate with the level of immunity?
Are those who had cases with very little symptoms more likely to be reinfected than those who were hospitalized?
I guess in my thoughts delta is behaving kinda like a low temperature fire: it has burned through a lot of the grasses quickly; and, left large swaths of grass and all the trees and shrubs unburned as it’s moved through the states.
It packed hospitals with dry patches of grass; but, didn’t come close to burning all of the dry grass, due to how quickly it moved.
Do you think the fires could be relit, or did delta act like a “natural” controlled burn: essentially isolating the susceptible populations enough to “protect” them?
I’m not sure if I was clear in my questions; but, I’ll give it a go anyway. ;)
1. Delta primarily affected unvaccinated persons. It also affected vaccinated people at a level well above what we expected, but.. the absolute, and relative number of affected vaccinated people remained small. Those who are unvaccinated, and who had no prior exposure, or at least did not contract COVID were the primary players in the pool of susceptible individuals. Without interventions, and as I generalized earlier, unvaccinated individuals, by and large, were also the ones who didn't bother with masks, and attended crowded venues. There are, of course, exceptions, but considering the stories friends and former colleagues told me about denial in the ERs and ICUs (and, it's similar to what you've seen on the news), too many declared the pandemic a hoax. We'll see pockets of unvaccinated, susceptible people pop up, get sick and create a small spike, but consider that reports indicate that typically over 94% of the COVID patients in-hospital were unvaccinated. That's a LOT of people and while I've not run the estimate yet, I suspect it tops out around 30-35% of the total US population.
2. CDC continues to maintain that severity of illness is often associated with high levels of circulating antibody. However, that's not bee borne in practice either anecdotally nor by observational studies. the relationship's all over the place. Anecdotally, I had a case so mild I thought I needed antihistamines: I thought it was allergies but antihistamines didn't have any effect. When I lost my sense of smell and everything started tasting odd, I was tested and came out positive, but it was so long since exposure and subsequent symptom onset, such as it was, that I was released from home isolation immediately.
3. We don't know if severity of illness correlates with level of immunity. I had a mild case, but had high measured titers (I was part of the convalescent plasma study as a plasma donor, and the local principal investigator and I became friends; he shared my titers sequentially with me. My wife had a more severe case, but her last assay reported levels too low to determine if she retained immunity.
4. Again, an unknown. anecdotally, a patient I know has been infected 3 times, with genotyping each time confirming a different variant each time. She's never been hospitalized, although she came close on rounds 2 and 3. When she was finally cleared for vaccination, she had a profound reaction, not quite textbook anaphyllaxis but close enough, that she's now on the "don't get that vaccine again" list. Young, healthy otherwise, no chronic medical conditions.
5. Delta caught a lot of the unvaccinated population. Its actions were similar to a wildfire but it didn't leave too many easy targets around. The case curve normalized to 100k people and the transmission rate curve are rather classic (is there a classic pandemic?) rapid-rise/rapid-decay for an outbreak with lots of susceptible people and little intervention. In fact, it did pack the hospitals, but it didn't leave a lot of the real population centers with big pockets of unvaccinated unscathed. I guess I'm not sure what you mean by a controlled burn... SInce we've learned a lot about caring for COVID-19 cases and getting people to eventually recover, outcomes were different than last spring, or even this past winter.
So, if the vax works better against Delta than Mu, you might expect Mu to have a fitness advantage in vaxxed folk. But, with so many people being vaxxed, the prevalence of Mu hasn't increased. Am I thinking about this correctly?
yes... and no. Some of the substitutions in the Mu variant were thought to, perhaps, change the shape of the spike protein sufficiently to make IgG binding onto the binding difficult. We can hypothesize and model thing all day long but in the long run, in a biological system, we also need to look at the real data. In the real world, the antibody binding doesn't appear to have been as impacted on Mu as originally thought, so it didn't compete well with Delta.
As for it competing better in vaccinated persons, the vaccines still provide a degree of immunity that is non-trivial. The chance of evading all the different immune processes encoded in the new vaccines is low.
We know the flu vaccine gets updated every year to account for new variants. Does the flu vaccine repeatedly go through efficacy studies & a whole new approval process every single year (as you described above in #3 would be needed for a vaccine for the Delta variant)?
Hi, Dr. Jetelina. Would you be able to address boosters for children 12+? I haven't heard a thing about whether it's anticipated or recommended. It's my understanding that the FDA approved Pfizer boosters only for people 18+, but why is that? I believe the initial data showed that teenagers had higher efficacy than older people, but I assume immunity would wane in kids just like it does in adults over time. Could you speak to this a bit? Thank you!
FDA has recommended Pfizer boosters for persons 65 and older, as well as anyone 18 and older who are exposed in their daily job (primarily healthcare workers). At this point there is reasonably good evidence that despite a loss of efficacy as the primary immunologic source for neutralizing antibody, they remain generally protective against infection leading to severe disease, hospitalization or death, which were the original goals of vaccine development (NOT prevention of any infection by SARS-CoV-2). Safety and efficacy were not assessed in the 12-18 cohort, or at least data have not been presented that I've seen, so there was no data on which to base a decision or recommendation.
There's an inverse age relationship (older people lose that effective response faster than younger people) to immune effect which is consistent with a decrease in the efficiency of the human immune system as you age. Thus, it can be suggested, at least until we get more data on the 18-18 cohort, that their vaccine-related response will be effective longer than older adults.
At this time Moderna has submitted a request to add boosters. FDA's analysis is luke-warm to that because the apparent immune response from the original 2-shot course (prime then boost) remains effective longer than that of the Pfizer vaccine.
At this time, unless you are immune-compromised, you have no need (according to the FDA) for a Moderna booster.
As the virus reproduces, its RNA isn't really too stable, so changes in base-pairs occur. These may be guided, could be accidental or could be caused by an exterior source like radiation. The result: The basic virus is still around (if it started a coronavirus it won't mutate into the rabies virus) but there are changes that may or may not impact other things.
Variants are trying, when they get into the wild, to accomplish one thing: Reproduce. They DO want to be able to evade an immune response, attach to whatever cellular receptor is allowing them into the cell, and to create a bunch of little viruses more or less in their own image.
A virus is nominally more fit if it can infect with fewer virus particles, or if it produces enough copies to overwhelm its competitors. If a virus mutates to the point it's producing a lot more copies of itself, it's likely more fit. If a virus mutates to where it kills its host reliably, it's like less fit.
Do pregnant women count as immunocompromised and "high risk" to warrant a booster? I've seen the CDC recommending shots for other high risk people, but no mention of pregnant women.
A couple of random thoughts. Mu and Delta were the first two variants that showed any significant change in the conformation of the spike protein that might cause problems for the "neutralizing" IgG created by the mRNA and adenovirus-vector rDNA vaccines. That was what raised the interest of the WMO. Although I should be paying more attention to international surveillance, I've got this odd limit on time, since i'm not embedded in a department or research group, so I've focused on the US, and for the most part, CONUS, looking at Alaska and Hawaii when needed...
Delta has shown us some nasty tricks. It produces more viral replication product (particles) per cycle than WHU-1 or Beta, for instance, and the minor changes in the S1 protein allow it to show more affinity for the ACE2 receptor. Mu shared some of these properties but not at the same level as Delta, hence, in my mind, its lower competitive advantage overall. Were we to solely look at the S1 conformation changes in Mu, we'd have expected its resistance to our antibodies to be a bigger advantage, but there are so many factors to consider here, sometimes the obvious fails to win.
The research I've read shows the current vaccines are adequately effective against Delta. Their efficacy against Mu would require more available virus, and clinical observation with adequate genomic testing would be simpler than an in vitro estimation of efficacy. That didn't work out.
As to whether we need a Delta-specific booster... I currently don't think so (but like so many other things in this pandemic, I might have to change my mind). At least in the US, and other countries where Delta's predominated, it's burned through the susceptible population virtually unimpeded, because so many who acquired this strain were unvaccinated, and didn't really believe in either the virus overall, or the use of NPIs for mitigation. The sharp upward trajectory, short time at peak and sharp downward trajectory are what I learned in school as the shape of a "normal" pandemic where nothing is, or can be done to mitigate its spread.
I've said earlier that I have little faith in immunity conferred by infection providing any longer, or better protection than immune response conferred by the vaccines. The "why" is that the infection-conferred immunity tends to be more specific to the variant you've contracted, and there's some serial evaluations of humeral immunity that suggest its duration is shorter than the vaccine-conferred humeral immunity. Activation and training of the cellular immune system is also interesting as there are a couple of papers suggesting that cellular immunity training and activation by naturally conferred response is much more variable than that initiated by the vaccines.
I propose this is because infection-conferred immunity has the entire spectrum of antigenic triggers from a particular strain and may in fact train IgG to look for a more complete component, where the vaccines provide triggers for fragments of proteins, which allow less-specific response, but a response more tailored to the spike and plasmid capsule of this species of coronavirus... so is likely more effective overall.
What this suggests to me, today, pending more research, and likely another wave of cases down the road, is that the current set of vaccines authorized or approved in the US today are effective as they are.
Most likely, we don't still have a lot of unvaccinated, Delta-susceptible individuals left. Part of the reason is, I'm convinced (again... as of today at 0715) that recent prior infection likely confers some protection for at least 90 and as long as 180 days against the general SARS-CoV-2 virus regardless of which variant lineage it claims. As a result, I think we're looking at 4-6 month of relative quiet, when, hopefully, all our holdouts will get vaccinated and Merck and others will get their COVID-specific antivirals out to clinical availability. And then, I expect we'll see anther wave, caused by a variant imported via air transport from a part of the world still serving as an incubator for new variants because they're inadequately vaccinated. And the public will have already told us that, to them, the pandemic's over.
My thoughts, so there's no one else to blame organizationally...
You’ve made great points.
Why do you think we don’t have many delta susceptible people left?
I understand your infection conferred immunity thoughts; however, I have questions.
Would severity of a case correlate with the level of immunity?
Are those who had cases with very little symptoms more likely to be reinfected than those who were hospitalized?
I guess in my thoughts delta is behaving kinda like a low temperature fire: it has burned through a lot of the grasses quickly; and, left large swaths of grass and all the trees and shrubs unburned as it’s moved through the states.
It packed hospitals with dry patches of grass; but, didn’t come close to burning all of the dry grass, due to how quickly it moved.
Do you think the fires could be relit, or did delta act like a “natural” controlled burn: essentially isolating the susceptible populations enough to “protect” them?
I’m not sure if I was clear in my questions; but, I’ll give it a go anyway. ;)
Lots of questions!
1. Delta primarily affected unvaccinated persons. It also affected vaccinated people at a level well above what we expected, but.. the absolute, and relative number of affected vaccinated people remained small. Those who are unvaccinated, and who had no prior exposure, or at least did not contract COVID were the primary players in the pool of susceptible individuals. Without interventions, and as I generalized earlier, unvaccinated individuals, by and large, were also the ones who didn't bother with masks, and attended crowded venues. There are, of course, exceptions, but considering the stories friends and former colleagues told me about denial in the ERs and ICUs (and, it's similar to what you've seen on the news), too many declared the pandemic a hoax. We'll see pockets of unvaccinated, susceptible people pop up, get sick and create a small spike, but consider that reports indicate that typically over 94% of the COVID patients in-hospital were unvaccinated. That's a LOT of people and while I've not run the estimate yet, I suspect it tops out around 30-35% of the total US population.
2. CDC continues to maintain that severity of illness is often associated with high levels of circulating antibody. However, that's not bee borne in practice either anecdotally nor by observational studies. the relationship's all over the place. Anecdotally, I had a case so mild I thought I needed antihistamines: I thought it was allergies but antihistamines didn't have any effect. When I lost my sense of smell and everything started tasting odd, I was tested and came out positive, but it was so long since exposure and subsequent symptom onset, such as it was, that I was released from home isolation immediately.
3. We don't know if severity of illness correlates with level of immunity. I had a mild case, but had high measured titers (I was part of the convalescent plasma study as a plasma donor, and the local principal investigator and I became friends; he shared my titers sequentially with me. My wife had a more severe case, but her last assay reported levels too low to determine if she retained immunity.
4. Again, an unknown. anecdotally, a patient I know has been infected 3 times, with genotyping each time confirming a different variant each time. She's never been hospitalized, although she came close on rounds 2 and 3. When she was finally cleared for vaccination, she had a profound reaction, not quite textbook anaphyllaxis but close enough, that she's now on the "don't get that vaccine again" list. Young, healthy otherwise, no chronic medical conditions.
5. Delta caught a lot of the unvaccinated population. Its actions were similar to a wildfire but it didn't leave too many easy targets around. The case curve normalized to 100k people and the transmission rate curve are rather classic (is there a classic pandemic?) rapid-rise/rapid-decay for an outbreak with lots of susceptible people and little intervention. In fact, it did pack the hospitals, but it didn't leave a lot of the real population centers with big pockets of unvaccinated unscathed. I guess I'm not sure what you mean by a controlled burn... SInce we've learned a lot about caring for COVID-19 cases and getting people to eventually recover, outcomes were different than last spring, or even this past winter.
So, if the vax works better against Delta than Mu, you might expect Mu to have a fitness advantage in vaxxed folk. But, with so many people being vaxxed, the prevalence of Mu hasn't increased. Am I thinking about this correctly?
yes... and no. Some of the substitutions in the Mu variant were thought to, perhaps, change the shape of the spike protein sufficiently to make IgG binding onto the binding difficult. We can hypothesize and model thing all day long but in the long run, in a biological system, we also need to look at the real data. In the real world, the antibody binding doesn't appear to have been as impacted on Mu as originally thought, so it didn't compete well with Delta.
As for it competing better in vaccinated persons, the vaccines still provide a degree of immunity that is non-trivial. The chance of evading all the different immune processes encoded in the new vaccines is low.
We know the flu vaccine gets updated every year to account for new variants. Does the flu vaccine repeatedly go through efficacy studies & a whole new approval process every single year (as you described above in #3 would be needed for a vaccine for the Delta variant)?
Hi, Dr. Jetelina. Would you be able to address boosters for children 12+? I haven't heard a thing about whether it's anticipated or recommended. It's my understanding that the FDA approved Pfizer boosters only for people 18+, but why is that? I believe the initial data showed that teenagers had higher efficacy than older people, but I assume immunity would wane in kids just like it does in adults over time. Could you speak to this a bit? Thank you!
FDA has recommended Pfizer boosters for persons 65 and older, as well as anyone 18 and older who are exposed in their daily job (primarily healthcare workers). At this point there is reasonably good evidence that despite a loss of efficacy as the primary immunologic source for neutralizing antibody, they remain generally protective against infection leading to severe disease, hospitalization or death, which were the original goals of vaccine development (NOT prevention of any infection by SARS-CoV-2). Safety and efficacy were not assessed in the 12-18 cohort, or at least data have not been presented that I've seen, so there was no data on which to base a decision or recommendation.
There's an inverse age relationship (older people lose that effective response faster than younger people) to immune effect which is consistent with a decrease in the efficiency of the human immune system as you age. Thus, it can be suggested, at least until we get more data on the 18-18 cohort, that their vaccine-related response will be effective longer than older adults.
So if we got Moderna we should ask for a booster? The messages are confusing.
At this time Moderna has submitted a request to add boosters. FDA's analysis is luke-warm to that because the apparent immune response from the original 2-shot course (prime then boost) remains effective longer than that of the Pfizer vaccine.
At this time, unless you are immune-compromised, you have no need (according to the FDA) for a Moderna booster.
What is mutational fitness? Could you talk about how that is measured and what it means? Thanks
As the virus reproduces, its RNA isn't really too stable, so changes in base-pairs occur. These may be guided, could be accidental or could be caused by an exterior source like radiation. The result: The basic virus is still around (if it started a coronavirus it won't mutate into the rabies virus) but there are changes that may or may not impact other things.
Variants are trying, when they get into the wild, to accomplish one thing: Reproduce. They DO want to be able to evade an immune response, attach to whatever cellular receptor is allowing them into the cell, and to create a bunch of little viruses more or less in their own image.
A virus is nominally more fit if it can infect with fewer virus particles, or if it produces enough copies to overwhelm its competitors. If a virus mutates to the point it's producing a lot more copies of itself, it's likely more fit. If a virus mutates to where it kills its host reliably, it's like less fit.
Should people living in the household of someone high risk also get the booster?
Do pregnant women count as immunocompromised and "high risk" to warrant a booster? I've seen the CDC recommending shots for other high risk people, but no mention of pregnant women.