Thanks Dr. Offit! I was able to listen to your article while I was getting ready to go to work this morning at my healthcare job! As a long time clinical laboratory scientist, I appreciate your viewpoint and information. Thanks and keep those posts coming!
I share your simultaneous hope and skepticism regarding nasal vaccines, based on the less than stellar results of flumist. Yet a combination of intranasal and intramuscular vaccination seems to be working quite well in early studies, and would provide a net positive, if not perfect, additional ladder out of this covid mess that’s still a leading cause of death and disability.
As my aunt (an immunologist) would say, “talk to your T cells.” We can’t get laser focused on just the IGA soldiers! I thought this was a good quote, and I’ll copy and paste the reference below it.
“Memory T cells that reside in lung tissue play a similarly useful role to antibodies in the mucosa. These white blood cells remain in affected tissue long after an infection has passed and remember pathogens they have encountered before. Thanks to their location in the lungs, they can respond quickly to viruses that enter through the airways." The co-first author draws attention to one of the observations the team made during their study: "We were able to show that prior intranasal vaccination results in the increased reactivation of these local memory cells in the event of a subsequent SARS-CoV-2 infection. Needless to say, we were particularly pleased with this result."
“The best protection against the SARS-CoV-2 was provided by double nasal vaccination, followed by the combination of a muscular injection of the mRNA vaccine and the subsequent nasal administration of the live attenuated vaccine. "This means the live vaccine could be particularly interesting as a booster,"
Well, the focus has been much on the immunoglobulins. But the problem is that it was known long before the covid pandemic. Immunoglobulin(Ig) production fades after the acute response of the B-cells. In this focus on the Ig, T-cells and memory B- and T-cells have entirely been forgotten, but for any form of long protection against disease, it is all about the memory cells. Acute protection fades, chronic protection via the memory cells however can last up to 40+ years.
I work at an immunology lab and the immunologist colleagues were very much surprised that the focus was so much on the acute response, and were even more so surprised when people were so disappointed when this acute response faded.
This whole charade around the Ig not lasting and this being known for over 10 years before the pandemic only shows how wrong science communication can go.
At issue, though, is whether we’re seeing a blunting of the cellular immune response by SARS-CoV-2, as studies have suggested. I agree that media hyped the potential to interrupt infection and transmission because of early results with wild-type virus, when in fact the intent was always mitigating severe illness and death.
I’ve been watching and listening to your appearances on TWiV. You’re able to provide information that’s accessible to a non-science geek. I am enjoying the sub stack information quite a lot. Thanks for making yourself available to us. Be well, and enjoy the new grand baby. My son is expecting our first grand baby in July! Pat
Given that nasal are not longer lasting for infection. But would nasal be just as effective? And if so it seems that they would avoid the myocarditis type side effects of young men.
Is there a place for something like a nasal spray that isn’t a replacement for a vaccine? Perhaps this spray would be protective for 2 to 4 weeks for the duration of mucosal anitbodies, and maybe even repeated if necessary. Might the resulting short term lowering of R value at crucial points in a pandemic be a powerful public health tool? A spray might be a lousy vaccine, but could it be something different and useful?
The question isn't whether the $5 billion allocated is wasted, but rather could it be spent better?
I'd argue it can, by testing subunit vaccines that target specific regions of the spike protein - namely the RBD (as proven by the Abdala vaccine), but also several of the other regions of the spike protein, where research groups have identified specific antibodies that strongly neutralise cell entry - which includes regions that are much more genetically conserved than the RBD.
Also, by focusing on specific neutralising regions, rather than the whole spike protein, this will further lower the likelihood of the rare autoimmune reactions that result from current vaccines. There is no risk of molecular mimicry/cross reactivity or B-cell cocapture if those regions of the spike protein aren't presented at all.
Focusing on conserved elements of the spike and nucleocapsid makes the most sense for a durable vaccine. Unfortunately, too many elements of the S1 and S2 proteins aren’t being conserved. The mRNA vaccines were/are subunit vaccines.
In the U.K. children receive a nasal spray vaccine against influenza, but as the flu season is relatively well defined then the fact that it’s short acting is probably irrelevant I would think. With SARS-CoV-2 there doesn’t seem to be a regular pattern as yet, therefore a nasal spray would be less appropriate due to the short term effects. Are there memory T cells in the mucosal areas?
"For healthy, young people, three doses of the mRNA vaccines made by Pfizer and Moderna likely offer a high level of protection against severe illness for years. "
How would you know? Are there studies that support this? Please cite them. Given the adverse events that young people experience with these vaccines and the harmless nature of the virus on young people, there appears to me no justification for a young person to ever take one of these shots.
There has been a focus on the development of antibodies (immunoglobulins) which decline naturally once a pathogen has been cleared. The part of the immune system that gets forgotten or overlooked are the memory cells. It is these that trigger a faster immune response if you become reinfected. This is how vaccines work and how the immune system works following infection. If you become infected with a novel pathogen then your adaptive immune system takes around 4 days to kick in, this peaks between 7 & 14 days post infection. Once the pathogen is cleared the antibodies start to decline but some T cells and B cells that have been created in response to the pathogen turn into memory cells that remain. If you are infected by the same pathogen then these memory cells respond and your adaptive immune system kicks in and peaks within 2 days, thus preventing serious illness. Vaccines work in exactly the same way with the advantage that you don’t become seriously ill like you may with acute infection.
Is there any comparison with polio vaccine where a combined series of injectable followed by oral can safely protect recipients while also reducing circulation of wild-type virus in the community (serum and GI tract immunity)? Or are the two viruses so different that the comparison is not valid?
Through the course of this pandemic, and likely also in future viral outbreaks, the emphasis, especially in the popular press and in the case of vaccine skeptics, has been on IgG response, for the most part. Some of us have been proponents of looking at an IgA response if we want to actually reduce what you acknowledge is relatively short-lived humoral reduction of even mild infections. Indeed, the original intent of the vaccine rapid development plan was to reduce deaths, hospitalizations and severe disease, but this message didn't survive first encounter with the public. Recruitment and training of the cellular component was, at least to me, the object of the exercise. We now know that infection-derived immunity is more specific to the variant causing infection, and as expected, IgG duration is fleeting. I want to see the results of the ongoing nasal vaccine studies, especially if they're paired with the intramuscular vaccines that we have seen produce significant training of the cellular component.
Thanks Dr. Offit! I was able to listen to your article while I was getting ready to go to work this morning at my healthcare job! As a long time clinical laboratory scientist, I appreciate your viewpoint and information. Thanks and keep those posts coming!
Always spot on, Paul. They hype about nasal vaccines ignores basic immunology.
I share your simultaneous hope and skepticism regarding nasal vaccines, based on the less than stellar results of flumist. Yet a combination of intranasal and intramuscular vaccination seems to be working quite well in early studies, and would provide a net positive, if not perfect, additional ladder out of this covid mess that’s still a leading cause of death and disability.
As my aunt (an immunologist) would say, “talk to your T cells.” We can’t get laser focused on just the IGA soldiers! I thought this was a good quote, and I’ll copy and paste the reference below it.
“Memory T cells that reside in lung tissue play a similarly useful role to antibodies in the mucosa. These white blood cells remain in affected tissue long after an infection has passed and remember pathogens they have encountered before. Thanks to their location in the lungs, they can respond quickly to viruses that enter through the airways." The co-first author draws attention to one of the observations the team made during their study: "We were able to show that prior intranasal vaccination results in the increased reactivation of these local memory cells in the event of a subsequent SARS-CoV-2 infection. Needless to say, we were particularly pleased with this result."
“The best protection against the SARS-CoV-2 was provided by double nasal vaccination, followed by the combination of a muscular injection of the mRNA vaccine and the subsequent nasal administration of the live attenuated vaccine. "This means the live vaccine could be particularly interesting as a booster,"
https://www.news-medical.net/amp/news/20230404/Live-attenuated-nasal-vaccine-elicits-superior-immunity-to-SARS-CoV-2-variants-in-hamsters.aspx
Thoughts?
Well, the focus has been much on the immunoglobulins. But the problem is that it was known long before the covid pandemic. Immunoglobulin(Ig) production fades after the acute response of the B-cells. In this focus on the Ig, T-cells and memory B- and T-cells have entirely been forgotten, but for any form of long protection against disease, it is all about the memory cells. Acute protection fades, chronic protection via the memory cells however can last up to 40+ years.
I work at an immunology lab and the immunologist colleagues were very much surprised that the focus was so much on the acute response, and were even more so surprised when people were so disappointed when this acute response faded.
This whole charade around the Ig not lasting and this being known for over 10 years before the pandemic only shows how wrong science communication can go.
At issue, though, is whether we’re seeing a blunting of the cellular immune response by SARS-CoV-2, as studies have suggested. I agree that media hyped the potential to interrupt infection and transmission because of early results with wild-type virus, when in fact the intent was always mitigating severe illness and death.
I’ve been watching and listening to your appearances on TWiV. You’re able to provide information that’s accessible to a non-science geek. I am enjoying the sub stack information quite a lot. Thanks for making yourself available to us. Be well, and enjoy the new grand baby. My son is expecting our first grand baby in July! Pat
If nasal vaccines provide several months of protection from mild disease, I might want to take it as a top-up 6 months after an intramuscular vaccine.
oral vaccines are clearly the way to go
Given that nasal are not longer lasting for infection. But would nasal be just as effective? And if so it seems that they would avoid the myocarditis type side effects of young men.
Is there a place for something like a nasal spray that isn’t a replacement for a vaccine? Perhaps this spray would be protective for 2 to 4 weeks for the duration of mucosal anitbodies, and maybe even repeated if necessary. Might the resulting short term lowering of R value at crucial points in a pandemic be a powerful public health tool? A spray might be a lousy vaccine, but could it be something different and useful?
The question isn't whether the $5 billion allocated is wasted, but rather could it be spent better?
I'd argue it can, by testing subunit vaccines that target specific regions of the spike protein - namely the RBD (as proven by the Abdala vaccine), but also several of the other regions of the spike protein, where research groups have identified specific antibodies that strongly neutralise cell entry - which includes regions that are much more genetically conserved than the RBD.
Also, by focusing on specific neutralising regions, rather than the whole spike protein, this will further lower the likelihood of the rare autoimmune reactions that result from current vaccines. There is no risk of molecular mimicry/cross reactivity or B-cell cocapture if those regions of the spike protein aren't presented at all.
Focusing on conserved elements of the spike and nucleocapsid makes the most sense for a durable vaccine. Unfortunately, too many elements of the S1 and S2 proteins aren’t being conserved. The mRNA vaccines were/are subunit vaccines.
In the U.K. children receive a nasal spray vaccine against influenza, but as the flu season is relatively well defined then the fact that it’s short acting is probably irrelevant I would think. With SARS-CoV-2 there doesn’t seem to be a regular pattern as yet, therefore a nasal spray would be less appropriate due to the short term effects. Are there memory T cells in the mucosal areas?
"For healthy, young people, three doses of the mRNA vaccines made by Pfizer and Moderna likely offer a high level of protection against severe illness for years. "
How would you know? Are there studies that support this? Please cite them. Given the adverse events that young people experience with these vaccines and the harmless nature of the virus on young people, there appears to me no justification for a young person to ever take one of these shots.
If natural infection does not give lasting protection even though it enters through mucosal membranes, why should a nasal spray be any better?
There has been a focus on the development of antibodies (immunoglobulins) which decline naturally once a pathogen has been cleared. The part of the immune system that gets forgotten or overlooked are the memory cells. It is these that trigger a faster immune response if you become reinfected. This is how vaccines work and how the immune system works following infection. If you become infected with a novel pathogen then your adaptive immune system takes around 4 days to kick in, this peaks between 7 & 14 days post infection. Once the pathogen is cleared the antibodies start to decline but some T cells and B cells that have been created in response to the pathogen turn into memory cells that remain. If you are infected by the same pathogen then these memory cells respond and your adaptive immune system kicks in and peaks within 2 days, thus preventing serious illness. Vaccines work in exactly the same way with the advantage that you don’t become seriously ill like you may with acute infection.
Is there any comparison with polio vaccine where a combined series of injectable followed by oral can safely protect recipients while also reducing circulation of wild-type virus in the community (serum and GI tract immunity)? Or are the two viruses so different that the comparison is not valid?
Through the course of this pandemic, and likely also in future viral outbreaks, the emphasis, especially in the popular press and in the case of vaccine skeptics, has been on IgG response, for the most part. Some of us have been proponents of looking at an IgA response if we want to actually reduce what you acknowledge is relatively short-lived humoral reduction of even mild infections. Indeed, the original intent of the vaccine rapid development plan was to reduce deaths, hospitalizations and severe disease, but this message didn't survive first encounter with the public. Recruitment and training of the cellular component was, at least to me, the object of the exercise. We now know that infection-derived immunity is more specific to the variant causing infection, and as expected, IgG duration is fleeting. I want to see the results of the ongoing nasal vaccine studies, especially if they're paired with the intramuscular vaccines that we have seen produce significant training of the cellular component.
Your thoughts?