And yes, we mention RFK Jr, Vinay Prasad, and get into a spicy give and take about whether a subgroup analysis provides a false positive or true positive result.
My clinic only stocks the standard dose flu vaccine. We do not have the high dose flu vaccine to give to patients. This study is very helpful for me. My choice has been encouraging patients to get the high dose flu vaccine at the risk that they won’t get any flu vaccine at all versus giving them the lower dose flu vaccine. The study clearly from my point of view makes the decision to give the low dose vaccine in the clinic a much better decision except for the rare motivated patient who really will make the trip to the pharmacy.
"Are there economic stakes..." said Dr. Foy. I really appreciate that question. An approximation of the "societal cost" follows.
From AI:
Walmart: $111.60 for high-dose; $46.46 for standard.
CVS: $128.99 for high-dose; $68.99 for standard.
Walgreens: $108.99 for high-dose; $58.99 for standard.
Costco (members): $61.99 for high-dose; $21.99 for standard.
About 70% of people age 65 and older get a flu shot, which based on conversation here, will be the high dose shot. According to census.gov, the number of people age 65 and above in the US was 61.2 million in 2024. So 42.84 million would get a high dose flu shot.
The lowest delta between the two flu shot doses is $40 at Costco. If everyone bought a membership and went to Costco, the increased cost for healthcare is $1.7 billion for the high dose over the standard dose. If everyone went to Walmart the increase to healthcare would be $2.8 billion.
I leave it to the three of you to decide if there are better things to spend that money on.
FYI, Mark Cuban cost plus pharmacy Pradaxa 150 mg twice daily three month supply $61.51. Spread the word so many patients get an LAAO due to cost and this could be a game changer.
1 mRNA - as mentioned still major problems with no "cut off" mechanism for the production of the spike protein etc -should be bannned until proven safe , not relying on the safe and effective mantra
2 Moderna - FDA No sympathy for Big Pharma , already milked the country of billions , control the media through advertising , control hospitals , academia . The health agencies are not there to support Big Pharma profits
3 Flu vaccines are historically problematic ( despite this the CDC has previously ignored evidence , promoting vaccines as a religious belief ) . The problem - Original Antigenic Sin (OAS) refers to the observation that if someone is vaccinated for a different strain than what is currently circulating (e.g., of the flu) they tend to have a worse immune response than those who were never vaccinated. Furthermore, multiple studies have shown that OAS affects completely different species (e.g., if you receive an influenza vaccine, you are less able to mount a response to “flus” caused by other respiratory viruses) and that OAS can persist for at least a year after vaccination.
4 Why no mention of Early Treatment options. Doctors should be helping and discussing these options with patients in the name of informed consent and not being anti- early treatment. The medical establishment together with big Pharma during covid made war on early treatment options , repurposed drugs , vitamins etc. I would like to hear from doctors who treat and support patients. I am in my seventies and have stopped taking the useless flu vaccine and take responsibility for my health . My vit D levels are high and hardly get flu . When one starts to get the symptons - I up the vit c on an hourly basis - would prefer vit c IV , take zinc , anti-viral nasal sprays , mouth washes , hydrogen peroxide and rest , also from eating. This works for me and others . Personally I am more interested in hearing about successes doctors in the trenches are having , how people themselves are maintaining good health and treating themselves than reading the rigged trials done by the industry themselves
Has Moderna addressed the pseudouridine in the mRNA? Some are still producing the "spike" protein and their bodies are not able to degrade the modmRNA. I think modmRNA technology needs to go through proper trials to show the risks
It is unfortunate that the flu vaccine trial didn't include a saline placebo control group. The microscopically small differences in the primary endpoint with extremely low incidence levels could mean that both were tremendously effective or, possibly, completely ineffective. I suspect the latter. My anecdotal experience over many years of practice with a high percentage of elderly patients led me to conclude that the flu shots were useless.
When running a comparative trial, the "new" agent (vaccine, drug, device) must be compared with the "standard of care". The investigator has to offer the subject who will be randomized to one of two or more treatments. In case of the flu vaccines, the standard of care is the standard dose of a "traditional" flu vaccine - or for those over 65 the high dose (subject to the points made in the article). To offer placebo which provides no protection from flu would not be appropriate or acceptable in a flu prevention trial.
That may be your opinion on standard of care for colds and flu. But many physicians would disagree. Studies on antiviral medications and vaccines have not shown enough evidence of success to be considered as a standard of care. I certainly understand why the manufacturers don't want a comparison to a placebo. But where do the ethical issues come into play?
No, it's not opinion. Did you listen to the "Sensible Medicine" discussion? That is why Vinay Prasad challenged Moderna's trial design. He said that they should have used the high dose vaccine as a comparator, which he said was the appropriate standard of care. It is not physician's opinion that dictates how you do a trial. I have been working in clinical development designing trials for half of my career (I'm retired now). Let me ask you - if you are suspicious of vaccines, would you volunteer for a flu vaccine trial? If you're not, why would you volunteer if you didn't know you would get at least the right comparator?
Regarding the Moderna Influenza Vaccine NDA file, as you mention agreements were made between FDA and Moderna because the trial included patients aged 50 years or over (based on articles I read in the Wall Street Journal) and Clinicaltrials.gov. Though FDA argued initially for the high dose vaccine as a comparator, it was not appropriate for those aged 50 - 65. Also, the high dose vaccine is not used in many of the countries where the trial was conducted. The analysis of groups where the high dose vaccine was given vs standard dose as a comparator would have been nightmarish. I suspect they argued as you did about the first paper that the data in support of the high dose is not sufficiently strong to insist on it as the comparator in the >65 group though we are not privy to the document record for the pre-trial discussions. And as you noted, FDA ultimately agreed that the trial design was acceptable though they never commit to approval until they see the data. As it turned out, the vast majority of subjects were in the 50 - 65 group and I understand that FDA has agreed to look at the current submission as well as a subgroup analysis. That is certainly appropriate.
As I recall, the overall efficacy in lowering hospitalizations due to influenza (confirmed by PCR) was significant, though again it's difficult to determine how solid the conclusion is because we can't see the statistics. The reduction of infections and the antibody titers supported that conclusion.
The real issue here is that companies invest massive amounts of money not to mention time and personnel on such trials. Trials are also important to the patients who participate in them. Can you imagine as a patient being told that FDA changed the rules after you offered your own risk exposure to a new agent and your time for nothing! For Vinay to overrule his own staff and reject the file before review was indeed outrageous and if his decision had been allowed to stand, would have had a profoundly negative effect not just on vaccine development, but on all drug development.
If the Moderna flu trial data was initially deemed so flawed as to not even be worthy of formal review….that does remove the suspense of whether it’s going to be approved or not 😉
so just goes to show you the myth of flu vaccines persists. i thought their principal effectiveness was against virulence because of the mismatch of vaccinated vs. circulating strains making them less effective against incidence.
on the incidence front, while you cite the comparison of the incidence of influenza like illness between standard and high dose vaccines–with high dose thus qualifying as the current standard of care for 65 plus–you don't mention the difference as between no vaccine (which i realize there was no such cohort in the study discussed, just looking for some reference for what you consider the best studies in that arena). Apparently there isn't an endpoint of number of days in bed, or seriousness of respiratory symptoms on some scale to help us understand what the flu vaccine is accomplishing between incidence and hospitalization which honestly matters more to me given me most recent bout of flu which made covid look like a walk in the park.
I feel like that might be helpful frame of thinking to consider what covid vaccines and boosters are and aren't doing (RSV too I guess). and where does the pneumonia vaccine fit into this if one of the endpoints for flu studies is pneumonia?
i'm not anti-mRNA by nature and it actual seems like, if the manufacturing ramp is short, it could be aimmed at circulating strains so it 'ought' to do better? but given that high dose already does better than standard (as a consumer i didn't know there was a difference and early article about the moderna trial with the names of the vaccines on racket news ( https://www.racket.news/p/fdas-straight-shooter-dont-bring ) did not explain why the vaccine in the trial was considered less effective or even introduce the terms "standard" and "high dose".
I would like more info on pre-Vinay FDA debate with moderna over proper comparator for context of his action. sensible medicine is the place i've heard the most sensible discourse about this and hope to hear more. I very much like that this isn't one-sided. I hope andrew had as much wonderment about biden cancelling the Keystone pipeline that was permitted and under construction when he became president. and I likewise fault the trump administration for trying to close the door on permitted projects such as offshore wind even if I think they are absurd from a cost-benefit perspective and he is doing right by the consumer. Although i have no problem changing subsidy policy that may make them unaffordable to build. Government subsides are not a permit or a contract and are the very thing you expect to change when the voters vote for change. not sure how all this plays into vaccine development policies but would like to understand better.
NFN but: is it patentable to just give a higher dose of essentially the same thing? I realize you might want to test that for safety (and effectiveness if government or insurance is paying) and so granting some kind of monopoly on an approach is compensatory but is it so by way of patenting which theoretically forecloses its good graces to the obvious. as to obviousness, i concede that "if some is good more is better" ignores "the dose makes the poison" but i'm mildly perplexed on this.
more importantly, in my mind because of the origin of more vaccine skepticism, how does this kind of sorting apply to what exists for testing of covid vaccines/boosters? I'm a skeptic not because they are mRNA (agree that RFKJ makes this sometimes difficult to disaggregate as a matter of public perception) but because I feel like the FDA for years has skirted the question of what covid vaccines actually accomplish[ed]. I'm still in the dark, maybe from lack of study or is it lack of studies, as to whether the end point for covid 'boosters' is incidence of covid like illness (guess that is vaguely distinguishable from flulike illness) or hospitalization for covid like illness. seems like the adverse effects of covid 'boosters', though small and perhaps cohort oriented has me going the natural immunity route for now, i.e. get covid every couple years. for me this has been far less traumatic than the last time I had the flu (and had covid twice in my mid 60s but I was mid40s last time i had the flu)–your mileage may differ.
are there any studies with endpoints or data on how these vaccines affect patient experience over incidence but short of hospitalization. how many days in bed, out of work, how severe discomfort. am i asking too much?
I am a private clinical allergist/immunologist in Arizona. Thank you for reviewing the influenza vaccine study. I advise against intramuscular vaccination as antigen presentation by myocytes does not produce tissue resident memory in our mucosal interfaces. Intramuscular vaccination became the convention from archaic IG agglutination studies in the early 1920s or so away from centuries of skin vaccination and mucosal vaccination. FDA approved Fluzone-Intradermal in 2008 but taken off market due to commercial failure. Cutaneous vaccination is better with cross-talk to our mucosal associated lymph tissue. It is likely safer without thrombosis which is way under-reported. I have read about universal flu shots since 1996 but see the political failures. Also, we just saw Pfizer "bury" the data on adverse events with mRNA influenza in 2023 season. NEJM article 11-25 was only 18-64 yo. Where is the third group that doesn't want a vaccine. This needs a total overhaul. I am campaigning for better mucosal/cutaneous vaccines. Not live-attenuated though. Core "dead" components would hopefully be safer. Flumist could be better!! Cmon public health!! Muscles are for movement and not restricting pathogen entry like mucosal immunity.
My clinic only stocks the standard dose flu vaccine. We do not have the high dose flu vaccine to give to patients. This study is very helpful for me. My choice has been encouraging patients to get the high dose flu vaccine at the risk that they won’t get any flu vaccine at all versus giving them the lower dose flu vaccine. The study clearly from my point of view makes the decision to give the low dose vaccine in the clinic a much better decision except for the rare motivated patient who really will make the trip to the pharmacy.
"Are there economic stakes..." said Dr. Foy. I really appreciate that question. An approximation of the "societal cost" follows.
From AI:
Walmart: $111.60 for high-dose; $46.46 for standard.
CVS: $128.99 for high-dose; $68.99 for standard.
Walgreens: $108.99 for high-dose; $58.99 for standard.
Costco (members): $61.99 for high-dose; $21.99 for standard.
About 70% of people age 65 and older get a flu shot, which based on conversation here, will be the high dose shot. According to census.gov, the number of people age 65 and above in the US was 61.2 million in 2024. So 42.84 million would get a high dose flu shot.
The lowest delta between the two flu shot doses is $40 at Costco. If everyone bought a membership and went to Costco, the increased cost for healthcare is $1.7 billion for the high dose over the standard dose. If everyone went to Walmart the increase to healthcare would be $2.8 billion.
I leave it to the three of you to decide if there are better things to spend that money on.
FYI, Mark Cuban cost plus pharmacy Pradaxa 150 mg twice daily three month supply $61.51. Spread the word so many patients get an LAAO due to cost and this could be a game changer.
I just loved the “It’s Beautiful…” with opening review of a large RCT for flu vaccine.
LOVE this discussion! Well done gentlemen. If you’re interested in a full on geek fest for subgroup interpretation, can check out my windy piece on a tranexamic acid study. (https://researchtranslation.substack.com/p/the-bigger-they-are-the-harder-they). Thank you for this fun one.
1 mRNA - as mentioned still major problems with no "cut off" mechanism for the production of the spike protein etc -should be bannned until proven safe , not relying on the safe and effective mantra
2 Moderna - FDA No sympathy for Big Pharma , already milked the country of billions , control the media through advertising , control hospitals , academia . The health agencies are not there to support Big Pharma profits
3 Flu vaccines are historically problematic ( despite this the CDC has previously ignored evidence , promoting vaccines as a religious belief ) . The problem - Original Antigenic Sin (OAS) refers to the observation that if someone is vaccinated for a different strain than what is currently circulating (e.g., of the flu) they tend to have a worse immune response than those who were never vaccinated. Furthermore, multiple studies have shown that OAS affects completely different species (e.g., if you receive an influenza vaccine, you are less able to mount a response to “flus” caused by other respiratory viruses) and that OAS can persist for at least a year after vaccination.
4 Why no mention of Early Treatment options. Doctors should be helping and discussing these options with patients in the name of informed consent and not being anti- early treatment. The medical establishment together with big Pharma during covid made war on early treatment options , repurposed drugs , vitamins etc. I would like to hear from doctors who treat and support patients. I am in my seventies and have stopped taking the useless flu vaccine and take responsibility for my health . My vit D levels are high and hardly get flu . When one starts to get the symptons - I up the vit c on an hourly basis - would prefer vit c IV , take zinc , anti-viral nasal sprays , mouth washes , hydrogen peroxide and rest , also from eating. This works for me and others . Personally I am more interested in hearing about successes doctors in the trenches are having , how people themselves are maintaining good health and treating themselves than reading the rigged trials done by the industry themselves
Has Moderna addressed the pseudouridine in the mRNA? Some are still producing the "spike" protein and their bodies are not able to degrade the modmRNA. I think modmRNA technology needs to go through proper trials to show the risks
It is unfortunate that the flu vaccine trial didn't include a saline placebo control group. The microscopically small differences in the primary endpoint with extremely low incidence levels could mean that both were tremendously effective or, possibly, completely ineffective. I suspect the latter. My anecdotal experience over many years of practice with a high percentage of elderly patients led me to conclude that the flu shots were useless.
That would be unethical - no company would do that, and the previous FDA would definitely not approve.
Why would that be unethical?
When running a comparative trial, the "new" agent (vaccine, drug, device) must be compared with the "standard of care". The investigator has to offer the subject who will be randomized to one of two or more treatments. In case of the flu vaccines, the standard of care is the standard dose of a "traditional" flu vaccine - or for those over 65 the high dose (subject to the points made in the article). To offer placebo which provides no protection from flu would not be appropriate or acceptable in a flu prevention trial.
That may be your opinion on standard of care for colds and flu. But many physicians would disagree. Studies on antiviral medications and vaccines have not shown enough evidence of success to be considered as a standard of care. I certainly understand why the manufacturers don't want a comparison to a placebo. But where do the ethical issues come into play?
No, it's not opinion. Did you listen to the "Sensible Medicine" discussion? That is why Vinay Prasad challenged Moderna's trial design. He said that they should have used the high dose vaccine as a comparator, which he said was the appropriate standard of care. It is not physician's opinion that dictates how you do a trial. I have been working in clinical development designing trials for half of my career (I'm retired now). Let me ask you - if you are suspicious of vaccines, would you volunteer for a flu vaccine trial? If you're not, why would you volunteer if you didn't know you would get at least the right comparator?
Regarding the Moderna Influenza Vaccine NDA file, as you mention agreements were made between FDA and Moderna because the trial included patients aged 50 years or over (based on articles I read in the Wall Street Journal) and Clinicaltrials.gov. Though FDA argued initially for the high dose vaccine as a comparator, it was not appropriate for those aged 50 - 65. Also, the high dose vaccine is not used in many of the countries where the trial was conducted. The analysis of groups where the high dose vaccine was given vs standard dose as a comparator would have been nightmarish. I suspect they argued as you did about the first paper that the data in support of the high dose is not sufficiently strong to insist on it as the comparator in the >65 group though we are not privy to the document record for the pre-trial discussions. And as you noted, FDA ultimately agreed that the trial design was acceptable though they never commit to approval until they see the data. As it turned out, the vast majority of subjects were in the 50 - 65 group and I understand that FDA has agreed to look at the current submission as well as a subgroup analysis. That is certainly appropriate.
As I recall, the overall efficacy in lowering hospitalizations due to influenza (confirmed by PCR) was significant, though again it's difficult to determine how solid the conclusion is because we can't see the statistics. The reduction of infections and the antibody titers supported that conclusion.
The real issue here is that companies invest massive amounts of money not to mention time and personnel on such trials. Trials are also important to the patients who participate in them. Can you imagine as a patient being told that FDA changed the rules after you offered your own risk exposure to a new agent and your time for nothing! For Vinay to overrule his own staff and reject the file before review was indeed outrageous and if his decision had been allowed to stand, would have had a profoundly negative effect not just on vaccine development, but on all drug development.
If the Moderna flu trial data was initially deemed so flawed as to not even be worthy of formal review….that does remove the suspense of whether it’s going to be approved or not 😉
so just goes to show you the myth of flu vaccines persists. i thought their principal effectiveness was against virulence because of the mismatch of vaccinated vs. circulating strains making them less effective against incidence.
on the incidence front, while you cite the comparison of the incidence of influenza like illness between standard and high dose vaccines–with high dose thus qualifying as the current standard of care for 65 plus–you don't mention the difference as between no vaccine (which i realize there was no such cohort in the study discussed, just looking for some reference for what you consider the best studies in that arena). Apparently there isn't an endpoint of number of days in bed, or seriousness of respiratory symptoms on some scale to help us understand what the flu vaccine is accomplishing between incidence and hospitalization which honestly matters more to me given me most recent bout of flu which made covid look like a walk in the park.
I feel like that might be helpful frame of thinking to consider what covid vaccines and boosters are and aren't doing (RSV too I guess). and where does the pneumonia vaccine fit into this if one of the endpoints for flu studies is pneumonia?
i'm not anti-mRNA by nature and it actual seems like, if the manufacturing ramp is short, it could be aimmed at circulating strains so it 'ought' to do better? but given that high dose already does better than standard (as a consumer i didn't know there was a difference and early article about the moderna trial with the names of the vaccines on racket news ( https://www.racket.news/p/fdas-straight-shooter-dont-bring ) did not explain why the vaccine in the trial was considered less effective or even introduce the terms "standard" and "high dose".
I would like more info on pre-Vinay FDA debate with moderna over proper comparator for context of his action. sensible medicine is the place i've heard the most sensible discourse about this and hope to hear more. I very much like that this isn't one-sided. I hope andrew had as much wonderment about biden cancelling the Keystone pipeline that was permitted and under construction when he became president. and I likewise fault the trump administration for trying to close the door on permitted projects such as offshore wind even if I think they are absurd from a cost-benefit perspective and he is doing right by the consumer. Although i have no problem changing subsidy policy that may make them unaffordable to build. Government subsides are not a permit or a contract and are the very thing you expect to change when the voters vote for change. not sure how all this plays into vaccine development policies but would like to understand better.
NFN but: is it patentable to just give a higher dose of essentially the same thing? I realize you might want to test that for safety (and effectiveness if government or insurance is paying) and so granting some kind of monopoly on an approach is compensatory but is it so by way of patenting which theoretically forecloses its good graces to the obvious. as to obviousness, i concede that "if some is good more is better" ignores "the dose makes the poison" but i'm mildly perplexed on this.
more importantly, in my mind because of the origin of more vaccine skepticism, how does this kind of sorting apply to what exists for testing of covid vaccines/boosters? I'm a skeptic not because they are mRNA (agree that RFKJ makes this sometimes difficult to disaggregate as a matter of public perception) but because I feel like the FDA for years has skirted the question of what covid vaccines actually accomplish[ed]. I'm still in the dark, maybe from lack of study or is it lack of studies, as to whether the end point for covid 'boosters' is incidence of covid like illness (guess that is vaguely distinguishable from flulike illness) or hospitalization for covid like illness. seems like the adverse effects of covid 'boosters', though small and perhaps cohort oriented has me going the natural immunity route for now, i.e. get covid every couple years. for me this has been far less traumatic than the last time I had the flu (and had covid twice in my mid 60s but I was mid40s last time i had the flu)–your mileage may differ.
are there any studies with endpoints or data on how these vaccines affect patient experience over incidence but short of hospitalization. how many days in bed, out of work, how severe discomfort. am i asking too much?
I am a private clinical allergist/immunologist in Arizona. Thank you for reviewing the influenza vaccine study. I advise against intramuscular vaccination as antigen presentation by myocytes does not produce tissue resident memory in our mucosal interfaces. Intramuscular vaccination became the convention from archaic IG agglutination studies in the early 1920s or so away from centuries of skin vaccination and mucosal vaccination. FDA approved Fluzone-Intradermal in 2008 but taken off market due to commercial failure. Cutaneous vaccination is better with cross-talk to our mucosal associated lymph tissue. It is likely safer without thrombosis which is way under-reported. I have read about universal flu shots since 1996 but see the political failures. Also, we just saw Pfizer "bury" the data on adverse events with mRNA influenza in 2023 season. NEJM article 11-25 was only 18-64 yo. Where is the third group that doesn't want a vaccine. This needs a total overhaul. I am campaigning for better mucosal/cutaneous vaccines. Not live-attenuated though. Core "dead" components would hopefully be safer. Flumist could be better!! Cmon public health!! Muscles are for movement and not restricting pathogen entry like mucosal immunity.
Wow, can’t believe you’re already up to 20! Thanks for bringing back “fortnight”. I remember reading British books as a kid and having to look it up.
Give us another word and we'll try to work it in!