Thanks so much for being willing to stay on the Covid beat from time to time. Your posts on it are always useful, and this one is no exception. I have fingers and toes crossed on new types of vaccines, and particularly the mucosal vaccine. Let us hope! Also, I want to give you a very BIG tip of the 🎩 for this comment on a graph: “Parenthetically, one pet peeve of mine is exemplified in the 2 graphics above—ageism. Look how they characterize older adults as crippled, needing a walker. That’s not right!” I wholeheartedly agree, and it’s not trivial: these images subliminally amplify who is within the 65+ demographic, particularly, and contribute to fomenting a lot of misunderstanding.
Agreed. The graphic illustrating the older adult also feeds into the misguided notion that those of us in that demographic aren't very functional and therefore not worth saving.
While it is probably quite true that many people are sick of covid, I have personally remained interested in learning more about this virus. So I certainly appreciate your post for today.
I've gotten every vaccine I was eligible to receive, and managed to avoid infection until very recently. Though I can't confirm it definitively, my infection was likely the result of JN.1 and my careless decision to not bother wearing a mask on my plane trip home after vacation. While the symptoms I experienced remained very mild and my illness was short-lived, I managed to infect several coworkers before I ever knew I was sick - which I terribly regret. Fortunately the people who I made sick have recovered, but it's been a difficult lesson to learn.
In my personal opinion, this is a sneaky virus. It can be just one maskless plane ride away.
I want to thank you for continuing to share relevant information regarding the SARS-CoV-2 variant landscape.
I am sick of the politics and misinformation that surround Covid, but NEVER the science. Thank you for enduring the brunt of the former, and bringing the latter to us. It is becoming significantly more difficult for me to find quality writing and sources on Covid. I appreciate you.
Ummm not everyone has forgotten about Covid. Ask anyone who is immunocompromised. I was surprised there was no mention in your update of PEMGARDA (Pemivibart), a pre-exposure
prophylaxis to help prevent COVID-19, which has just been granted an EUA by the FDA for the approx 6% of the population who are moderately or severely immune compromised because of a medical condition or because they receive treatments that suppress the immune system and are unlikely to have an adequate response to COVID-19 vaccination. It is administered by a one hour infusion and may need an additional dose every 3 months. Has anyone any direct experience with PEMGARDA -- please share any knowledge. https://www.fda.gov/media/177069/download
Thank you so much for staying on top of this. I was just hunting and scratching the internet for info and found nothing. Once again, I should have come here. Your post is cautionary but also hopeful. That’s greatly appreciated. And like many others, I found the depiction of older people inaccurate, insulting, and possibly dangerous. One could look at that and think it has nothing to do with them. Now we need to jump on Long Covid. I’ve been lucky and starting to come out of it just 18 months after the acute infection. Still not out of the woods and have to travel a long distance to get the care I need. Again, thank you so much.
Thanks as always for the cogent content, summing up dense science into concepts we can provide for our patients and others. I've noticed a big uptick in my elderly post-covid patients staying sicker for longer after non-covid infections and inflammations - suggesting their immune systems are somehow now hyper-reacting to mountains and molehills alike. I witness this also in non-elders with auto-immune spectrum disorders - longer flares, worse springtime pollen reactions in the last few years. The longer "tail" seems more likely to include the dreaded duo of cog "fog" and fatigue, also. I've speculated (metaphorically) that COVID has generated a kind of "immune PTSD" - the intense weirdness of the virus resulting in a longer-lasting immune overreaction going forward. If so, hopefully this moderates individually and as a public health issue.
@Dr Topol: “there’s plenty more ways that SARS-CoV2 can reinvent itself and find new ways or better ways to evade our immune response….. it hasn’t and won’t just “burn out. ….and why we need better vaccines to be prepared for that potential.” (ET).
All true, BUT with so much vaccine hesitancy and a certain skepticism about Paxlovid, the pure antiviral with many cautions, precise timing, some rebound, and question of efficacy with recent variants, there needs to be more effort towards other therapeutics. Repurposed drugs, in particular. Medical science must be bold and not be abrogate the need to add therapy to prevention. We can’t leave 25-30% of the population vulnerable by virtue of vaccine hesitancy, resistance, incomplete coverage, or other reasons. Other repurposing has not had the attention received by repurposing HCQ or ivermectin, both of which have shown poor outcomes in traditional RCTs as well as off-label prescribing by advocate clinicians unwilling to simply ring their hands and do nothing when corporate mandated EUA protocols aren’t effective. Other than Pfizer’s combo capsule, a type of repurposing, no other products have had scrutiny enough to appear in journals or the front page of newspapers. Our team has been working tirelessly for 5 years treating COVID19 inpatient and outpatient victims; by collaborating with an International research lab of excellence and readily shared our outcomes with the FDA’s/NIH/NCATS CDRC consortium via CURE ID mobile case reports. Our repurposed product has achieved what one CUREID Founder dubbed “a loud and clear signal” providing credible reasons to scrutinize our reports but have not done so. Our research lab collaborators have taken our well-conceived concepts to design exquisite studies confirming our hypotheses as to the targets and the physiological base. The sexy Molecular screening of potential chemicals requires too much time and few drug candidates ever make the cut to human use. Let’s chalk up the HCQ and ivermectin efforts as history, but not disparage other repurposing. Match pharmaceutical to biologic events and not any one drug to a single disease. We must be bold and, by definition, repurposed drugs have achieved a safety record that provides a huge advantage over the unknown
Quick Q, Dr. T - what is your go-to resource for valid Rx and non-Rx approaches to post-Covid fatigue and cognitive difficulties? Lots of stray info out there about supplements here and there with little evidence base....Thanks for all you do.
@Dr Saxima: Perhaps you would find the research from our Biochemistry/Immunology collaborators helpful for your understanding about our concepts of the COVID19 and PASC. Gold Std EBM RCTs aren’t available but in our desperation to help and not harm with some sound biological reasoning, starting in early 2020 we saw some striking outcomes in a very short time frame with no ADRs from our protocols. It’s held fast - consistent, durable and no reports of PASC. It begs for scrutiny and a blessing yet the concepts are sound and these exquisite experiments confirm what we have seen clinically so far as addressing the ultimate targets is concerned.
“The role of α7 nicotinic acetylcholine receptors in post-acute sequelae of covid-19” Maryna Skok
The latest experiment capitalizing on a therapeutic approach for COVID19 thru S-protein RBD-ACE2 binding interference is by incorporating a universal molecular chaperone, the a7nAChR that is contiguous to the ACE2. Triggering this critical molecular chaperone and potent anti-inflammatory protects this critical gateway for viral entry. The therapeutic is a positive allosteric modulator with a urea motif, specifically hydroxyUREA (HU). It is an inexpensive drug being used in a legitimate repurposed way. It has decades of use in other disorders, most on continuous use basis. Our clinical experiences, however anecdotal, support its use for early, middle and late stages of COVID19 without regard to viral variants, to date. Others have approached therapy based on the S protein-RBD-ACE2 gateway but newer variants mutated to circumvent this gateway. Dr Skok et al have demonstrated that this approach can be utilized,but only by addressing the a7NAChR chaperone contiguous with the ACE2 receptor and without interfering with the ACE2 enzymatic function. These unique discoveries need validation and the repurposed drug HU as a modulator should be placed at a priority for study in non-commercial lab research facilities for the benefit of the public at large and not stockholders investment requirements. Have a look and ask any questions:
Olena Kalashnyk, Olena Lykhmus, Raymond Sullivan, Serhiy Komisarenko, Maryna Skok
I still live in Covidlandia too! I just wrote a post in defensive of Paxlovid, against the popular grain right now. By the way, any idea what the offramp is for the self replicating mRNA? How many cycles of replication are there, I could look this up, but just the top of your head if you know! That would be my top hmmmm… but glad to learn trials are showing potential superiority of this tech.
So I read through this article in Cell, which was highly educational, but it stopped short of answering this question about how long replication persists- but did caution that clearance could be a problem in immunocompromised and pregnant patients.
So I asked Claude.ai and got this probably correct answer:
“ How are self-amplifying mRNA vaccines eventually cleared?”
Answer:
Self-amplifying mRNA vaccines work by delivering instructions to the body's cells to produce the antigen protein (like the spike protein of SARS-CoV-2). This mRNA gets taken up by cells and amplifies itself through an RNA replication process before being translated into the antigen protein.
Eventually, the mRNA from these vaccines gets degraded and cleared from the body through natural cellular processes in the following ways:
RNA degradation pathways: Cells have inherent mechanisms to degrade exogenous RNA, including specific enzymes like RNases that break down the mRNA strands.
mRNA instability: The mRNA molecules used in vaccines are usually engineered to be intrinsically unstable and break down over time (days to weeks) inside the cell.
Protein synthesis termination: Once enough antigen protein is produced, the cells stop translating the mRNA, allowing it to be degraded.
Cell turnover: The majority of transfected cells that take up the mRNA vaccine will eventually undergo programmed cell death and be replaced by new cells without the vaccine mRNA.
Immune clearance: The immune system may also help clear residual RNA fragments from vaccination through immune surveillance mechanisms.
So in summary, while the mRNA amplifies transiently inside cells, it does not persist indefinitely and gets cleared through a combination of programmed instability, cell turnover, RNA degradation pathways, and immune mechanisms over the course of days to weeks after vaccination.
~
Still makes me cautiously optimistic, so I’ll watch for the in vivo science to keep emerging!
Thanks so much for being willing to stay on the Covid beat from time to time. Your posts on it are always useful, and this one is no exception. I have fingers and toes crossed on new types of vaccines, and particularly the mucosal vaccine. Let us hope! Also, I want to give you a very BIG tip of the 🎩 for this comment on a graph: “Parenthetically, one pet peeve of mine is exemplified in the 2 graphics above—ageism. Look how they characterize older adults as crippled, needing a walker. That’s not right!” I wholeheartedly agree, and it’s not trivial: these images subliminally amplify who is within the 65+ demographic, particularly, and contribute to fomenting a lot of misunderstanding.
Agreed. The graphic illustrating the older adult also feeds into the misguided notion that those of us in that demographic aren't very functional and therefore not worth saving.
That is exactly the point, and you said it a lot more succinctly than I did. Thank you!
Thank you for staying on this, Dr. Topol!
Apprentice your note!
It's about time we got the nasal vaccine.
While it is probably quite true that many people are sick of covid, I have personally remained interested in learning more about this virus. So I certainly appreciate your post for today.
I've gotten every vaccine I was eligible to receive, and managed to avoid infection until very recently. Though I can't confirm it definitively, my infection was likely the result of JN.1 and my careless decision to not bother wearing a mask on my plane trip home after vacation. While the symptoms I experienced remained very mild and my illness was short-lived, I managed to infect several coworkers before I ever knew I was sick - which I terribly regret. Fortunately the people who I made sick have recovered, but it's been a difficult lesson to learn.
In my personal opinion, this is a sneaky virus. It can be just one maskless plane ride away.
I want to thank you for continuing to share relevant information regarding the SARS-CoV-2 variant landscape.
Thank you. I got hit by JN'1 in early December after having avoided this virus and wrote about it. Agree with your assessment.
Dr. Topol,
I am sick of the politics and misinformation that surround Covid, but NEVER the science. Thank you for enduring the brunt of the former, and bringing the latter to us. It is becoming significantly more difficult for me to find quality writing and sources on Covid. I appreciate you.
Much appreciated. We can still get hit hard in the times ahead while being lulled into SARS-CoV-2 somnolence
Ummm not everyone has forgotten about Covid. Ask anyone who is immunocompromised. I was surprised there was no mention in your update of PEMGARDA (Pemivibart), a pre-exposure
prophylaxis to help prevent COVID-19, which has just been granted an EUA by the FDA for the approx 6% of the population who are moderately or severely immune compromised because of a medical condition or because they receive treatments that suppress the immune system and are unlikely to have an adequate response to COVID-19 vaccination. It is administered by a one hour infusion and may need an additional dose every 3 months. Has anyone any direct experience with PEMGARDA -- please share any knowledge. https://www.fda.gov/media/177069/download
Thank you so much for staying on top of this. I was just hunting and scratching the internet for info and found nothing. Once again, I should have come here. Your post is cautionary but also hopeful. That’s greatly appreciated. And like many others, I found the depiction of older people inaccurate, insulting, and possibly dangerous. One could look at that and think it has nothing to do with them. Now we need to jump on Long Covid. I’ve been lucky and starting to come out of it just 18 months after the acute infection. Still not out of the woods and have to travel a long distance to get the care I need. Again, thank you so much.
So glad you're onto recovery from Long Covid!
Thanks as always for the cogent content, summing up dense science into concepts we can provide for our patients and others. I've noticed a big uptick in my elderly post-covid patients staying sicker for longer after non-covid infections and inflammations - suggesting their immune systems are somehow now hyper-reacting to mountains and molehills alike. I witness this also in non-elders with auto-immune spectrum disorders - longer flares, worse springtime pollen reactions in the last few years. The longer "tail" seems more likely to include the dreaded duo of cog "fog" and fatigue, also. I've speculated (metaphorically) that COVID has generated a kind of "immune PTSD" - the intense weirdness of the virus resulting in a longer-lasting immune overreaction going forward. If so, hopefully this moderates individually and as a public health issue.
@Dr Topol: “there’s plenty more ways that SARS-CoV2 can reinvent itself and find new ways or better ways to evade our immune response….. it hasn’t and won’t just “burn out. ….and why we need better vaccines to be prepared for that potential.” (ET).
All true, BUT with so much vaccine hesitancy and a certain skepticism about Paxlovid, the pure antiviral with many cautions, precise timing, some rebound, and question of efficacy with recent variants, there needs to be more effort towards other therapeutics. Repurposed drugs, in particular. Medical science must be bold and not be abrogate the need to add therapy to prevention. We can’t leave 25-30% of the population vulnerable by virtue of vaccine hesitancy, resistance, incomplete coverage, or other reasons. Other repurposing has not had the attention received by repurposing HCQ or ivermectin, both of which have shown poor outcomes in traditional RCTs as well as off-label prescribing by advocate clinicians unwilling to simply ring their hands and do nothing when corporate mandated EUA protocols aren’t effective. Other than Pfizer’s combo capsule, a type of repurposing, no other products have had scrutiny enough to appear in journals or the front page of newspapers. Our team has been working tirelessly for 5 years treating COVID19 inpatient and outpatient victims; by collaborating with an International research lab of excellence and readily shared our outcomes with the FDA’s/NIH/NCATS CDRC consortium via CURE ID mobile case reports. Our repurposed product has achieved what one CUREID Founder dubbed “a loud and clear signal” providing credible reasons to scrutinize our reports but have not done so. Our research lab collaborators have taken our well-conceived concepts to design exquisite studies confirming our hypotheses as to the targets and the physiological base. The sexy Molecular screening of potential chemicals requires too much time and few drug candidates ever make the cut to human use. Let’s chalk up the HCQ and ivermectin efforts as history, but not disparage other repurposing. Match pharmaceutical to biologic events and not any one drug to a single disease. We must be bold and, by definition, repurposed drugs have achieved a safety record that provides a huge advantage over the unknown
Thank you, Eric. We appreciate you keeping us informed!
Quick Q, Dr. T - what is your go-to resource for valid Rx and non-Rx approaches to post-Covid fatigue and cognitive difficulties? Lots of stray info out there about supplements here and there with little evidence base....Thanks for all you do.
I wish there were validated treatments out there, but there aren't so much of what you'll see is unsubstantiated (and some predatory).
@Dr Saxima: Perhaps you would find the research from our Biochemistry/Immunology collaborators helpful for your understanding about our concepts of the COVID19 and PASC. Gold Std EBM RCTs aren’t available but in our desperation to help and not harm with some sound biological reasoning, starting in early 2020 we saw some striking outcomes in a very short time frame with no ADRs from our protocols. It’s held fast - consistent, durable and no reports of PASC. It begs for scrutiny and a blessing yet the concepts are sound and these exquisite experiments confirm what we have seen clinically so far as addressing the ultimate targets is concerned.
“The role of α7 nicotinic acetylcholine receptors in post-acute sequelae of covid-19” Maryna Skok
https://doi.org/10.1016/j.biocel.2024.106519
Also: @Hydroxyurea interaction with α7 nicotinic acetylcholine receptor can underlie its therapeutic efficacy upon COVID-19”
Olena Lykhmus a, Olena Kalashnyk et al
@Greg Saxima and interested clinicians:
The latest experiment capitalizing on a therapeutic approach for COVID19 thru S-protein RBD-ACE2 binding interference is by incorporating a universal molecular chaperone, the a7nAChR that is contiguous to the ACE2. Triggering this critical molecular chaperone and potent anti-inflammatory protects this critical gateway for viral entry. The therapeutic is a positive allosteric modulator with a urea motif, specifically hydroxyUREA (HU). It is an inexpensive drug being used in a legitimate repurposed way. It has decades of use in other disorders, most on continuous use basis. Our clinical experiences, however anecdotal, support its use for early, middle and late stages of COVID19 without regard to viral variants, to date. Others have approached therapy based on the S protein-RBD-ACE2 gateway but newer variants mutated to circumvent this gateway. Dr Skok et al have demonstrated that this approach can be utilized,but only by addressing the a7NAChR chaperone contiguous with the ACE2 receptor and without interfering with the ACE2 enzymatic function. These unique discoveries need validation and the repurposed drug HU as a modulator should be placed at a priority for study in non-commercial lab research facilities for the benefit of the public at large and not stockholders investment requirements. Have a look and ask any questions:
Olena Kalashnyk, Olena Lykhmus, Raymond Sullivan, Serhiy Komisarenko, Maryna Skok
https://doi.org/10.1016/j.bbrc.2024.149825
Thank you again for your valuable explanations and insights.
I still live in Covidlandia too! I just wrote a post in defensive of Paxlovid, against the popular grain right now. By the way, any idea what the offramp is for the self replicating mRNA? How many cycles of replication are there, I could look this up, but just the top of your head if you know! That would be my top hmmmm… but glad to learn trials are showing potential superiority of this tech.
Unsure of the N of cycles, which differs for the different sams
So I read through this article in Cell, which was highly educational, but it stopped short of answering this question about how long replication persists- but did caution that clearance could be a problem in immunocompromised and pregnant patients.
https://www.cell.com/trends/biotechnology/fulltext/S0167-7799(23)00154-3
So I asked Claude.ai and got this probably correct answer:
“ How are self-amplifying mRNA vaccines eventually cleared?”
Answer:
Self-amplifying mRNA vaccines work by delivering instructions to the body's cells to produce the antigen protein (like the spike protein of SARS-CoV-2). This mRNA gets taken up by cells and amplifies itself through an RNA replication process before being translated into the antigen protein.
Eventually, the mRNA from these vaccines gets degraded and cleared from the body through natural cellular processes in the following ways:
RNA degradation pathways: Cells have inherent mechanisms to degrade exogenous RNA, including specific enzymes like RNases that break down the mRNA strands.
mRNA instability: The mRNA molecules used in vaccines are usually engineered to be intrinsically unstable and break down over time (days to weeks) inside the cell.
Protein synthesis termination: Once enough antigen protein is produced, the cells stop translating the mRNA, allowing it to be degraded.
Cell turnover: The majority of transfected cells that take up the mRNA vaccine will eventually undergo programmed cell death and be replaced by new cells without the vaccine mRNA.
Immune clearance: The immune system may also help clear residual RNA fragments from vaccination through immune surveillance mechanisms.
So in summary, while the mRNA amplifies transiently inside cells, it does not persist indefinitely and gets cleared through a combination of programmed instability, cell turnover, RNA degradation pathways, and immune mechanisms over the course of days to weeks after vaccination.
~
Still makes me cautiously optimistic, so I’ll watch for the in vivo science to keep emerging!
Thanks for the reply-