Hi Robert! Thanks for sharing this. I am actually closely affiliated with the authors of this study--the person pictured, Dr. Kris White, sat behind me in the lab for 7 years and we are still in touch. The senior author was a collaborator of mine on my thesis. I know half of the other authors personally.
I have very intentionally not covered it in the newsletter for one very specific reason, though. It's too early days to make a lot of hay out of the effects of this drug, and I'm afraid about being misleading. Early development of therapeutics--even early clinical development--can contain a lot of promise that doesn't bear out. I do not want to tout something that could become the next false hope.
I'm going to be following the story, and when Phase 3 trial results become apparent, I may cover it in depth.
Hi, John. You wrote, "For this reason, I don’t believe the effect of increased efficacy with longer time between doses will be generalizable to other vaccine designs. It might apply to other viral vector-type COVID-19 vaccines, though, like the Johnson and Johnson vaccine. Maybe we’ll find out in future studies." J&J is actually running ENSEMBLE 2, a Phase 3 study of their vaccine using two doses, with dose 2 administered on Day 57 (counting from first shot as Day 1). Results due pretty soon, IIRC. Took longer than ENSEMBLE (single dose), presumably because of that two-month wait.
Yep. I made reference to ENSEMBLE 2 in my coverage of the J&J vaccine a little while ago. However, ENSEMBLE 2 doesn't explore the impact of variation in dose timing on vaccine efficacy, using only one fixed dosing schedule. So it won't directly address this exact question. It'll give some indirect insight, though, since the inter-dose period is pretty long compared to what AZ-Oxford used in their first trial.
You might know this: once one has been exposed to an antigen, how long does it take for memory cells to reach maximum proliferation? Your proposed mechanism (decreasing sensitivity to the carrier virus) makes sense, but I can visualize one in which it takes six weeks or more for the memory cells to fully develop and "prime" the immune systems. (I'm using "memory cell" loosely to include both T and B cell lines.) Of course, both mechanisms could be operating simultaneously (and even synergistically).
This is a little bit out of my wheelhouse, but I do know the estimates. Memory cell populations tend to appear on the order of weeks postinfection; I have heard about 3 in the past, though I understand that the population can continue to mature for quite some weeks after that. Of course, memory cell populations are quite small though and they take time to proliferate in response to a new infection. While this is usually fast enough to respond to a new infection, I don't think it would really be fast enough to prevent a viral vector vaccine from functioning *necessarily*.
I would expect if there is interference with the viral vector vaccine, it would be due to more active measures than proliferating memory cells; specifically either effector T cells or circulating antibodies are what I would anticipate to be the source of such interference. While it can take months for antibody levels to really decline, antigen-specific effector T cell populations can reduce in a matter of weeks as well. I'm beginning to think that T cells are rather important for the immune response to COVID-19, as perhaps only tangentially related point.
The hypothesis that it takes time for a memory cell population to be fully matured such that the boost would be effective is interesting, although it is defied by the fact that boosting the mRNA vaccines just 21-28 days after the prime produces a clear enhancement of the antibody response. Clearly it is possible to boost a SARS-CoV-2 response and get efficacy gains with a boost occurring only 3-4 weeks after the prime. But for some reason, with this viral vector vaccine, boosting on that timeframe appears to actually harm the overall efficacy. My hypothesis that it has to do with the response to the vector is based on the fact that the viral vector is the main difference between this vaccine vs the mRNA vaccines.
Of course, sometimes when you hear hoofbeats, it's actually zebras. It could be that the reason for this kinetic issue has something to do with the fact that this vaccine actually infects cells with an incompetent virus rather than just providing mRNA. The kinetics of the immune response to these two different mechanisms may be, well, different, and that could be part of it. I'm not an adaptive immunologist so while I can come up with hypotheses, I can't feel extremely confident in them.
No doubt I will hear what some adaptive immunologists have to say about this soon, and I'll report back on that.
https://health.mountsinai.org/blog/researchers-identify-promising-new-antiviral-drug-for-covid-19/?j=12009&sfmc_sub=45056&l=15_HTML&u=213847&mid=100003651&jb=45
Hi Robert! Thanks for sharing this. I am actually closely affiliated with the authors of this study--the person pictured, Dr. Kris White, sat behind me in the lab for 7 years and we are still in touch. The senior author was a collaborator of mine on my thesis. I know half of the other authors personally.
I have very intentionally not covered it in the newsletter for one very specific reason, though. It's too early days to make a lot of hay out of the effects of this drug, and I'm afraid about being misleading. Early development of therapeutics--even early clinical development--can contain a lot of promise that doesn't bear out. I do not want to tout something that could become the next false hope.
I'm going to be following the story, and when Phase 3 trial results become apparent, I may cover it in depth.
Hi, John. You wrote, "For this reason, I don’t believe the effect of increased efficacy with longer time between doses will be generalizable to other vaccine designs. It might apply to other viral vector-type COVID-19 vaccines, though, like the Johnson and Johnson vaccine. Maybe we’ll find out in future studies." J&J is actually running ENSEMBLE 2, a Phase 3 study of their vaccine using two doses, with dose 2 administered on Day 57 (counting from first shot as Day 1). Results due pretty soon, IIRC. Took longer than ENSEMBLE (single dose), presumably because of that two-month wait.
Yep. I made reference to ENSEMBLE 2 in my coverage of the J&J vaccine a little while ago. However, ENSEMBLE 2 doesn't explore the impact of variation in dose timing on vaccine efficacy, using only one fixed dosing schedule. So it won't directly address this exact question. It'll give some indirect insight, though, since the inter-dose period is pretty long compared to what AZ-Oxford used in their first trial.
You might know this: once one has been exposed to an antigen, how long does it take for memory cells to reach maximum proliferation? Your proposed mechanism (decreasing sensitivity to the carrier virus) makes sense, but I can visualize one in which it takes six weeks or more for the memory cells to fully develop and "prime" the immune systems. (I'm using "memory cell" loosely to include both T and B cell lines.) Of course, both mechanisms could be operating simultaneously (and even synergistically).
This is a little bit out of my wheelhouse, but I do know the estimates. Memory cell populations tend to appear on the order of weeks postinfection; I have heard about 3 in the past, though I understand that the population can continue to mature for quite some weeks after that. Of course, memory cell populations are quite small though and they take time to proliferate in response to a new infection. While this is usually fast enough to respond to a new infection, I don't think it would really be fast enough to prevent a viral vector vaccine from functioning *necessarily*.
I would expect if there is interference with the viral vector vaccine, it would be due to more active measures than proliferating memory cells; specifically either effector T cells or circulating antibodies are what I would anticipate to be the source of such interference. While it can take months for antibody levels to really decline, antigen-specific effector T cell populations can reduce in a matter of weeks as well. I'm beginning to think that T cells are rather important for the immune response to COVID-19, as perhaps only tangentially related point.
The hypothesis that it takes time for a memory cell population to be fully matured such that the boost would be effective is interesting, although it is defied by the fact that boosting the mRNA vaccines just 21-28 days after the prime produces a clear enhancement of the antibody response. Clearly it is possible to boost a SARS-CoV-2 response and get efficacy gains with a boost occurring only 3-4 weeks after the prime. But for some reason, with this viral vector vaccine, boosting on that timeframe appears to actually harm the overall efficacy. My hypothesis that it has to do with the response to the vector is based on the fact that the viral vector is the main difference between this vaccine vs the mRNA vaccines.
Of course, sometimes when you hear hoofbeats, it's actually zebras. It could be that the reason for this kinetic issue has something to do with the fact that this vaccine actually infects cells with an incompetent virus rather than just providing mRNA. The kinetics of the immune response to these two different mechanisms may be, well, different, and that could be part of it. I'm not an adaptive immunologist so while I can come up with hypotheses, I can't feel extremely confident in them.
No doubt I will hear what some adaptive immunologists have to say about this soon, and I'll report back on that.