The key reason Pfizer passed was that executives didn't think patients would accept a new therapy that required injection to administer:
Despite our emerging results, the Pfizer executives in charge of research and external alliances told us the company did not want to develop a new diabetes therapy that required injection, a space held exclusively by insulin since 1922. They gave us a year to find a way to deliver GLP-1 via transnasal, transcutaneous, or oral administration. Effective delivery by any of these approaches would have been great, but we knew success was unlikely in the year they gave us. Our effort was predictably unsuccessful, and after four years, Pfizer terminated our agreement as permitted under the alliance contract.
The first commercial GLP-1 receptor agonist, Exenatide, went to market as an injectable medication in 2005 [1]. Orally delivered GLP-1 medications didn't come to market until 2019 when orally dosed semaglutide was approved as Rybelsus [2].
Now that injected GLP-1 drugs are among the most-prescribed drugs in America, I wonder if drug company executives are going to be more receptive to drug candidates that require injections. There are a lot of molecules (especially peptides) that are degraded by the digestive system; maybe people will be more willing to inject medications when so many have started self-injecting for GLP-1 drugs or know someone who has.
Bureaucracy? This is the same type of go/no-go decision that R&D orgs have to make with incomplete information and immense costs every day. But with less complete information (no in-human data → 70-90% failure rate) and more immense costs (a couple hundred million dollars to get it through trials).
The problem is the cost and risk profile of drug development. With those parameters where they are, there will be countless "bureaucratic errors" of foregone opportunities, most of which we'll never even learn about.
Technically, they disappeared because of limited resources. If every pharmaceutical organization had unlimited funding to run unlimited trials, then they would.
The proprietary injector mechanism like for Mounjaro makes it really easy for users. Even compounded versions of it use tiny insulin needles that have near zero pain when injected into the subcutaneous portion of like the stomach while pinched.
Source: I took compounded Mounjaro and compounded Ozempic/semaglutide.
Similarly, I grabbed one of the over-the-counter CGM biosensors (Stelo) to gather some data for a couple of weeks and the initial fear of "holy hell, I'm slamming a needle into my arm with something stuck to it" goes away as soon as you slap the injector release.
Just one little clap sound, you feel a little pat on your arm, and the sensor's already made it where it needed to with no pain.
When you remove the sensor it's a little bit of a shock when you see the sensor wire and realize just how small it was and how you never felt it run around inside your arm for a couple weeks.
fyi: the impact is an intentional decision. if your nerve endings are signaling something else(hot, cold, movement, etc), a needle prick can get blurred with the rest or ignored altogether. I suspect the bang/clag CGM applicators produce are much the same.
and, for me, its always been the needle moving around thats been mentally disturbing. digging around vecause they missed for the blood draw, trying to hold a large vaccination dose steady as it needs to be injected over 20seconds. So, I suspect the speed itself reduces discomfort.
I stopped taking compound Mounjaro a year ago. I started semaglutide in Sept and stopped because it made me sick (throwing up, other non desirable GI effects). My body couldn’t handle semaglutide.
Type 1 insulin user. One the alcohol should dry before the needle goes in. Two faster is better, within reason. Three about one in a few hundred shots hits a nerve bundle. That really hurts, but resolves after a short while. Both insulin and these GLP-1 injections are subcutaneous not intravenous which once a patient gets the skill it becomes like riding a bike, in that it becomes easier than imagined.
The only man to successfully battle and defeat glp-1's in war. his getting fit series is genuinely motivational. But not for any of the right reasons, lol.
Insulin users would have better answers to this question, since they might inject multiple times a day, whereas GLP-1 users typically inject only weekly.
But in either case, the answer for subcutaneous injections using needles sized 29g and smaller is no.
Injection drug user here. We're advised to rotate injection sites but the largest issue is actually the insulin (most of it diffuses into the bloodstream but there is a local effect, usually taking the form of increased fat accumulation at sites of repeated injection), not the "making holes in the skin" part.
I don't know the pharmacokinetics of GLP-1 drugs but my guess is that they don't have the same sort of effects on SC tissue?
Before I had a CGM I did somewhere around 20,000 blood glucose tests over the course of a decade using about 1 cm^2 of forearm and the skin there is clearly not in great shape -- but it's worsened on the level of "looks like the skin of someone who is a decade older or spent too long in the sun" rather than anything medically problematic.
> I don't know the pharmacokinetics of GLP-1 drugs but my guess is that they don't have the same sort of effects on SC tissue?
They do, but nothing like insulin does. GLP-1 drugs are more centrally and viscerally active than subcutaneously active, so the effects locally are more related to the physics of injecting solutions subcutaneously than the drugs themselves. They're also much smaller doses than are needed for insulin in general, so the volume averaged over a week is pretty tiny.
Also, as a result of the relative lack of local activity, injection sites are basically unlimited (anywhere from above the knee to above the elbow, except the neck) without fear of lipohypertrophy in the local area.
I’ve been diabetic for 30 years, and for more than twenty of those I did multiple daily measurements by pricking my fingertips and multiple insulin injections per day. Now I wear a sensor that I replace every two weeks and a catheter (which I change about once a week).
I really don’t understand this phobia of needles at all. After two days with one system or the other, you get used to it—there’s no pain, it’s just a mental issue of “having to make the gesture.”
My friends used to laugh at how normal it was for me to inject insulin outside a restaurant, while walking, chatting, and smoking at the same time.
Pfizer has been resting on their laurels ever since it struck gold with boner pills and Lipitor. Viagra made it rain beaucoup bucks and rewired the entire firm to prioritize commercial sales and marketing over real scientific clinical development. Pfizer is optimized for sales over research and development. Now they primarily acquire and license a bunch of me-too drugs and late-stage acquisitions vs creating their own homegrown breakthroughs.
Pfizer's strengths are regulatory compliance, M&A and global manufacturing. They suck at research and clinical development. Losing the GLP-1 race was predictable as they simply don't prioritize emerging science compared to other mid-sized and large pharmas.
GLP-1 is a drug target, not a drug. It's actually a hormone.
There are many drugs that have been developed since then, and each approval seems to have slightly better drug properties.
The age of research on a drug is not very indicative of safety, either. Rather, broad study and time are far better. I'd take five years of clinical trials on hundreds of thousands of people over 5000 years old research on hundreds of people.
The first generation of GLP-1 agonists are out of patent protection. Teva is producing a generic liraglutide (aka Victoza / Saxenda). Ozempic (semiglutide) and Mounjaro (tirzepatide) have protection until after 2031 in the US, I think it's less in other countries.
Incredibly bothersome that these executives can rise so high and get paid so much despite having such terrible decisionmaking skills.
An injection to cure obesity is a small price to ask, as any person that has been obese will tell you. They could have determined this from a simple survey.
What was the human cost of their decision? Maybe an entire delayed decade of progress? How many people died, that could have been saved?
I would love to meet some of these executives and understand what they were thinking, and if they understand/regret the impact of their foolishness.
At the time it was not clear that GLP-1 solves obesity problem so effectively - many drugs suppress hunger (eg amphetamines), it's just that GLP-1 works long term and does not have significant side effects. Hard to predict without hindsight.
Insulin is injectable so GLP-1 was thought to be at best marginal improvement over already existing protocol - so likely profitable product but not excessively so. Company has limited resources so decisions on cuts have to be made and some of those decisions are naturally wrong - drugs are unpredictable.
On regret - they missed on 30B+ of profits so of cause they regret it.
So much of pharmaceutical development is educated guess work. For every promising compound even brought to human trials there were likely 10s-100s of others that were abandoned or neglected for lack of resources to pursue them all. Without the benefit of hindsight there are bound to be mistakes made.
> An injection to cure obesity is a small price to ask, as any person that has been obese will tell you. They could have determined this from a simple survey.
You're missing the primary point: GLP-1 was investigated as another me-too diabetes drug, for which there were many injectable drugs available.
It wasn't until much much later that it was discovered to be an obesity drug. It was a completely coincidental and accidental discovery.
It turns out that most science is like that. We make the most important discoveries unexpectedly and by chance. Which is why you should always distrust the politicians that mock and ridicule science for sounding ordinary or obvious. That's where the real magic happens.
You should always distrust politicians on science issues. Even if they come from a science background. Being a successful politician is orthogonal to being a brilliant scientist.
"It wasn't until much much later that it was discovered to be an obesity drug. It was a completely coincidental and accidental discovery."
Define "much much later"
It was known by the early 1990s that GLP-1 slowed stomach emptying, with a key study in 1993 demonstrating its effects on gastrointestinal functions like gastric emptying, leading to longer feelings of fullness, which is the central mechanism at work here. See, e.g., https://pubmed.ncbi.nlm.nih.gov/35635627/
It just took eons for someone to decide that therefore maybe it was worth thinking about for weight loss.
That part is due to lack of exec vision - the fact that weight loss was not commonly treated with drugs (amphetamines work, but ...) meant they never thought really that hard about it.
To be fair, that lackof vision is not unreasonable in the sense that they have both plenty of high value targets, and plenty of arrows to shoot at them. Most of the arrows miss of course, but that's okay.
There is not always tremendous incentive to try new targets until they start missing the target too much, or the value of existing targets drops.
They almost certainly give up on, or ignore/drop/whatever, a near infinite number of things that may have turned into life saving drugs, billion dollar blockbusters, you name it.
At least right now, that's how this kind of thing works, for better or worse.
However, this is quite separate from when x was discovered to be a y, as it is here.
FWIW - I'll offer another lack of vision in the same vein - by slowing stomach emptying significantly, GLP-1 also causes the same amount of alcohol to do significantly less damage, because it enters your small intestine in much smaller amounts and over a much longer period of time. So much so that is a very effective treatment for alcoholism because it both reduces alcohol craving, and causes significant amounts of alcohol to do less damage. See, e.g., newly published studies like https://pubmed.ncbi.nlm.nih.gov/37192005/ and https://jamanetwork.com/journals/jamapsychiatry/fullarticle/...
Again, this should have been somewhat obvious to study a long time ago, but it wasn't started until 2 years ago.
It also turns out to reduce drug cravings, which is more unexpected, but would have been discovered much earlier with better vision.
This story is about Pfizer stopping funding in 1991, and I guess that 1993 is not really "much much later"! However a single paper in 1993, had it been three years earlier, may not have been enough to keep a research program alive, especially if the funders were primarily interested in diabetes and funded for diabetes.
Every major discovery in biology looks like GLP-1: apparently locking in finding a new class of targets and or therapies. It's very easy to string together promising theories from sets of papers, but far harder to establish them with hard data tha comes at the cost of actual humans using the potential drug in trials.
I'm told that one of the very few parts of the stock market where subject matter experts can generate alpha is in biotech, by following the data of small biotech closely. However the fortunes of individuals and the market as a whole is largely downstream of larger macroeconomic forces, such as Fed interest rate changes, that determine the level of investment in new high risk economic activity versus keeping money in bonds.
Am I the only one that remembers a HUUUGE public media push in the US framing "injecting [any] drug is bad"? with a complete lack of reguard for diabetics, people with fatal allergies, and a host of other people who need to carry, or use needles w/ meds regularly?
> Despite our emerging results, the Pfizer executives in charge of research and external alliances told us the company did not want to develop a new diabetes therapy that required injection,
Well, COVID certainly put an end to those fears (by consumers). Coincidentally, obesity was also said to increase COVID risk. Hollywood couldn’t have scripted it - no pun intended - any better.
Wait -your angle is that covid vaccination increased people‘s acceptance of injectable pharmaceutics and covid / its vaccine was made up (or blown out of proportion) so people would get more ozempic?
This is subscriber-walled, but the full article is available here:
https://web.archive.org/web/20240909093450/https://www.statn...
The key reason Pfizer passed was that executives didn't think patients would accept a new therapy that required injection to administer:
Despite our emerging results, the Pfizer executives in charge of research and external alliances told us the company did not want to develop a new diabetes therapy that required injection, a space held exclusively by insulin since 1922. They gave us a year to find a way to deliver GLP-1 via transnasal, transcutaneous, or oral administration. Effective delivery by any of these approaches would have been great, but we knew success was unlikely in the year they gave us. Our effort was predictably unsuccessful, and after four years, Pfizer terminated our agreement as permitted under the alliance contract.
The first commercial GLP-1 receptor agonist, Exenatide, went to market as an injectable medication in 2005 [1]. Orally delivered GLP-1 medications didn't come to market until 2019 when orally dosed semaglutide was approved as Rybelsus [2].
Now that injected GLP-1 drugs are among the most-prescribed drugs in America, I wonder if drug company executives are going to be more receptive to drug candidates that require injections. There are a lot of molecules (especially peptides) that are degraded by the digestive system; maybe people will be more willing to inject medications when so many have started self-injecting for GLP-1 drugs or know someone who has.
[1] https://en.wikipedia.org/wiki/Exenatide
[2] https://en.wikipedia.org/wiki/Semaglutide#Legal_status
FWIW, Novo Nordisk also tried to kill their GLP-1 effort several times according to the project lead, Lotte Bjerre Knudsen: https://archive.is/oLnBl
In large organizations, I guess a big chunk of success comes from being able to navigate all these political ups and downs.
I wonder how many other great medical innovations have disappeared because of such bureaucracy.
Bureaucracy? This is the same type of go/no-go decision that R&D orgs have to make with incomplete information and immense costs every day. But with less complete information (no in-human data → 70-90% failure rate) and more immense costs (a couple hundred million dollars to get it through trials).
The problem is the cost and risk profile of drug development. With those parameters where they are, there will be countless "bureaucratic errors" of foregone opportunities, most of which we'll never even learn about.
Technically, they disappeared because of limited resources. If every pharmaceutical organization had unlimited funding to run unlimited trials, then they would.
How long do you have?
https://www.sciencenews.org/article/vaccine-beer-polyomaviru...
Self-injecting feels like a scary, painful, dangerous procedure and becomes completely boring by the third repetition.
The proprietary injector mechanism like for Mounjaro makes it really easy for users. Even compounded versions of it use tiny insulin needles that have near zero pain when injected into the subcutaneous portion of like the stomach while pinched.
Source: I took compounded Mounjaro and compounded Ozempic/semaglutide.
Similarly, I grabbed one of the over-the-counter CGM biosensors (Stelo) to gather some data for a couple of weeks and the initial fear of "holy hell, I'm slamming a needle into my arm with something stuck to it" goes away as soon as you slap the injector release.
Just one little clap sound, you feel a little pat on your arm, and the sensor's already made it where it needed to with no pain.
When you remove the sensor it's a little bit of a shock when you see the sensor wire and realize just how small it was and how you never felt it run around inside your arm for a couple weeks.
fyi: the impact is an intentional decision. if your nerve endings are signaling something else(hot, cold, movement, etc), a needle prick can get blurred with the rest or ignored altogether. I suspect the bang/clag CGM applicators produce are much the same.
and, for me, its always been the needle moving around thats been mentally disturbing. digging around vecause they missed for the blood draw, trying to hold a large vaccination dose steady as it needs to be injected over 20seconds. So, I suspect the speed itself reduces discomfort.
Do you still take it? I'm looking for some more information on compounded GLP-1 and their safety.
I stopped taking compound Mounjaro a year ago. I started semaglutide in Sept and stopped because it made me sick (throwing up, other non desirable GI effects). My body couldn’t handle semaglutide.
Reportedly retatruide doesn’t cause nausea in as many people, but can still cause diarrhea. May still be worth looking into if you’re interested
Type 1 insulin user. One the alcohol should dry before the needle goes in. Two faster is better, within reason. Three about one in a few hundred shots hits a nerve bundle. That really hurts, but resolves after a short while. Both insulin and these GLP-1 injections are subcutaneous not intravenous which once a patient gets the skill it becomes like riding a bike, in that it becomes easier than imagined.
It really helps that the needles are hair-thin and short.
Are you using this?
Yes.
For a brief moment I thought you were Stavros Halkias.
The only man to successfully battle and defeat glp-1's in war. his getting fit series is genuinely motivational. But not for any of the right reasons, lol.
I concur, exactly the way I felt before and after.
Isn't there some long term harm to the skin if you do this often?
Insulin users would have better answers to this question, since they might inject multiple times a day, whereas GLP-1 users typically inject only weekly.
But in either case, the answer for subcutaneous injections using needles sized 29g and smaller is no.
Injection drug user here. We're advised to rotate injection sites but the largest issue is actually the insulin (most of it diffuses into the bloodstream but there is a local effect, usually taking the form of increased fat accumulation at sites of repeated injection), not the "making holes in the skin" part.
I don't know the pharmacokinetics of GLP-1 drugs but my guess is that they don't have the same sort of effects on SC tissue?
Before I had a CGM I did somewhere around 20,000 blood glucose tests over the course of a decade using about 1 cm^2 of forearm and the skin there is clearly not in great shape -- but it's worsened on the level of "looks like the skin of someone who is a decade older or spent too long in the sun" rather than anything medically problematic.
> I don't know the pharmacokinetics of GLP-1 drugs but my guess is that they don't have the same sort of effects on SC tissue?
They do, but nothing like insulin does. GLP-1 drugs are more centrally and viscerally active than subcutaneously active, so the effects locally are more related to the physics of injecting solutions subcutaneously than the drugs themselves. They're also much smaller doses than are needed for insulin in general, so the volume averaged over a week is pretty tiny.
Also, as a result of the relative lack of local activity, injection sites are basically unlimited (anywhere from above the knee to above the elbow, except the neck) without fear of lipohypertrophy in the local area.
I’ve been diabetic for 30 years, and for more than twenty of those I did multiple daily measurements by pricking my fingertips and multiple insulin injections per day. Now I wear a sensor that I replace every two weeks and a catheter (which I change about once a week).
I really don’t understand this phobia of needles at all. After two days with one system or the other, you get used to it—there’s no pain, it’s just a mental issue of “having to make the gesture.”
My friends used to laugh at how normal it was for me to inject insulin outside a restaurant, while walking, chatting, and smoking at the same time.
No. So long as you rotate your injection site. My son is T1 and before his pump was getting 4-6 injections a day.
To the skin? Probably not.
Heroin addicts and presumably anyone else who frequently injects into a vein can cause damage to the veins.
Yes, but only if you do it in the same spot every time.
Seems completely negligible to the normal amount of tiny cuts and scrapes you accumulate on any given day.
[dead]
Pfizer has been resting on their laurels ever since it struck gold with boner pills and Lipitor. Viagra made it rain beaucoup bucks and rewired the entire firm to prioritize commercial sales and marketing over real scientific clinical development. Pfizer is optimized for sales over research and development. Now they primarily acquire and license a bunch of me-too drugs and late-stage acquisitions vs creating their own homegrown breakthroughs.
Pfizer's strengths are regulatory compliance, M&A and global manufacturing. They suck at research and clinical development. Losing the GLP-1 race was predictable as they simply don't prioritize emerging science compared to other mid-sized and large pharmas.
It's worth bearing in mind that the reality of self-injector pens with tiny needles today is not the reality of syringes 30 years ago.
https://archive.ph/2024.09.09-143955/https://www.statnews.co...
(2024)
Nice.
This tells me that research on the drug is old and that increases security on its use.
GLP-1 is a drug target, not a drug. It's actually a hormone.
There are many drugs that have been developed since then, and each approval seems to have slightly better drug properties.
The age of research on a drug is not very indicative of safety, either. Rather, broad study and time are far better. I'd take five years of clinical trials on hundreds of thousands of people over 5000 years old research on hundreds of people.
It's so old, the patent is nearing expiration.
The first generation of GLP-1 agonists are out of patent protection. Teva is producing a generic liraglutide (aka Victoza / Saxenda). Ozempic (semiglutide) and Mounjaro (tirzepatide) have protection until after 2031 in the US, I think it's less in other countries.
That’s usually the case for new classes of drugs.
Not necessarily. If it just sits on a shelf, there is no new data on it's use in humans.
Incredibly bothersome that these executives can rise so high and get paid so much despite having such terrible decisionmaking skills.
An injection to cure obesity is a small price to ask, as any person that has been obese will tell you. They could have determined this from a simple survey.
What was the human cost of their decision? Maybe an entire delayed decade of progress? How many people died, that could have been saved?
I would love to meet some of these executives and understand what they were thinking, and if they understand/regret the impact of their foolishness.
At the time it was not clear that GLP-1 solves obesity problem so effectively - many drugs suppress hunger (eg amphetamines), it's just that GLP-1 works long term and does not have significant side effects. Hard to predict without hindsight.
Insulin is injectable so GLP-1 was thought to be at best marginal improvement over already existing protocol - so likely profitable product but not excessively so. Company has limited resources so decisions on cuts have to be made and some of those decisions are naturally wrong - drugs are unpredictable.
On regret - they missed on 30B+ of profits so of cause they regret it.
So much of pharmaceutical development is educated guess work. For every promising compound even brought to human trials there were likely 10s-100s of others that were abandoned or neglected for lack of resources to pursue them all. Without the benefit of hindsight there are bound to be mistakes made.
> An injection to cure obesity is a small price to ask, as any person that has been obese will tell you. They could have determined this from a simple survey.
You're missing the primary point: GLP-1 was investigated as another me-too diabetes drug, for which there were many injectable drugs available.
It wasn't until much much later that it was discovered to be an obesity drug. It was a completely coincidental and accidental discovery.
It turns out that most science is like that. We make the most important discoveries unexpectedly and by chance. Which is why you should always distrust the politicians that mock and ridicule science for sounding ordinary or obvious. That's where the real magic happens.
You should always distrust politicians on science issues. Even if they come from a science background. Being a successful politician is orthogonal to being a brilliant scientist.
"It wasn't until much much later that it was discovered to be an obesity drug. It was a completely coincidental and accidental discovery."
Define "much much later"
It was known by the early 1990s that GLP-1 slowed stomach emptying, with a key study in 1993 demonstrating its effects on gastrointestinal functions like gastric emptying, leading to longer feelings of fullness, which is the central mechanism at work here. See, e.g., https://pubmed.ncbi.nlm.nih.gov/35635627/
It just took eons for someone to decide that therefore maybe it was worth thinking about for weight loss.
That part is due to lack of exec vision - the fact that weight loss was not commonly treated with drugs (amphetamines work, but ...) meant they never thought really that hard about it.
To be fair, that lackof vision is not unreasonable in the sense that they have both plenty of high value targets, and plenty of arrows to shoot at them. Most of the arrows miss of course, but that's okay.
There is not always tremendous incentive to try new targets until they start missing the target too much, or the value of existing targets drops.
They almost certainly give up on, or ignore/drop/whatever, a near infinite number of things that may have turned into life saving drugs, billion dollar blockbusters, you name it.
At least right now, that's how this kind of thing works, for better or worse.
However, this is quite separate from when x was discovered to be a y, as it is here.
FWIW - I'll offer another lack of vision in the same vein - by slowing stomach emptying significantly, GLP-1 also causes the same amount of alcohol to do significantly less damage, because it enters your small intestine in much smaller amounts and over a much longer period of time. So much so that is a very effective treatment for alcoholism because it both reduces alcohol craving, and causes significant amounts of alcohol to do less damage. See, e.g., newly published studies like https://pubmed.ncbi.nlm.nih.gov/37192005/ and https://jamanetwork.com/journals/jamapsychiatry/fullarticle/...
Again, this should have been somewhat obvious to study a long time ago, but it wasn't started until 2 years ago.
It also turns out to reduce drug cravings, which is more unexpected, but would have been discovered much earlier with better vision.
This story is about Pfizer stopping funding in 1991, and I guess that 1993 is not really "much much later"! However a single paper in 1993, had it been three years earlier, may not have been enough to keep a research program alive, especially if the funders were primarily interested in diabetes and funded for diabetes.
Every major discovery in biology looks like GLP-1: apparently locking in finding a new class of targets and or therapies. It's very easy to string together promising theories from sets of papers, but far harder to establish them with hard data tha comes at the cost of actual humans using the potential drug in trials.
I'm told that one of the very few parts of the stock market where subject matter experts can generate alpha is in biotech, by following the data of small biotech closely. However the fortunes of individuals and the market as a whole is largely downstream of larger macroeconomic forces, such as Fed interest rate changes, that determine the level of investment in new high risk economic activity versus keeping money in bonds.
Am I the only one that remembers a HUUUGE public media push in the US framing "injecting [any] drug is bad"? with a complete lack of reguard for diabetics, people with fatal allergies, and a host of other people who need to carry, or use needles w/ meds regularly?
> Despite our emerging results, the Pfizer executives in charge of research and external alliances told us the company did not want to develop a new diabetes therapy that required injection,
Well, COVID certainly put an end to those fears (by consumers). Coincidentally, obesity was also said to increase COVID risk. Hollywood couldn’t have scripted it - no pun intended - any better.
Wait -your angle is that covid vaccination increased people‘s acceptance of injectable pharmaceutics and covid / its vaccine was made up (or blown out of proportion) so people would get more ozempic?
No. Not my angle. That is exactly what happened.
Injections are no longer a only-if-absolutely-necessary. The stigma is mitigated.
Flu shots were accepted as a routine thing long before 2020. I don't think the stigma existed in the way you're imagining.
Accepted? By who? You’ve misread the room