Taking safety signals seriously is imperative; the US CDC & others have failed to do that
The goal of vaccination programs is to protect people from diseases as safely as possible. Vaccines and diseases are not supposed to have harms that are even in the same ball-park as each other; Vaccines are supposed to be much, much, much safer than the diseases they prevent or diminish. When it comes to an 80 year old who never had COVID19—back in Jan 2021— there is no doubt about it; the benefit of 2 doses of mRNA vaccines is orders of magnitude greater than any known or unknown risk, and should be pursued.
When it comes to young men— both past and present— the story is complicated and nuanced. As early as Feb 2021, we had reports from Israel that young men were experiencing myocarditis— an inflammation of the wall of the heart— after COVID19 vaccine administration. Preliminary figures varied but reports placed it in the 1/3000 to 1/5000 ballpark. Many were hospitalized.
That 1/3-5k ballpark is deeply concerning. Suddenly it was clear that myocarditis was a serious safety concern in this age/sex group that meant, we ought to make a concerted effort to lower harms in this group. Here are some things we could have done (either under the auspices of a randomized trial) or as part of a natural experiment.
- Just give 1 dose (it was clear dose 2 had much higher rates of myocarditis) and dose 1 provided the bulk of the protection against hospitalization. We could follow outcomes as part of natural experiments.
- Provided exemptions for people who had and recovered from covid or those with + nucleocapsid Ab. It remains unclear how much a 22 year old who had and recovered from COVID benefits from vaccination (with respect to clinical endpoints not Ab titers)
- Tested lower doses of the vaccine (Pfizer was 30micrograms/ Moderna 100mcg); we could have administered lower doses, spread the timing of the doses apart (other nations did this, we did it too late) and measured rates of hospitalization; This could have been done as part of a national effort led by CDC (Can you lower myocarditis with a lower dose & preserve most of the efficacy?)
- Banned the use of Moderna. It was clear that Moderna was associated with a higher rate of myocarditis, and other nations & Kaiser Portland moved swiftly against it.
- Set a higher bar for boosters in young men; as the 3rd dose can cause myocarditis and it is not clear how much this benefits them.
- Immediately stopped pushing doses in all adults who have had and recovered from Omicron, pending a new trial in this population.
Just as with Vaccine Induced Thrombocytopenia and Thrombosis caused by J&J, which I wrote about at the time, loud physician voices not trained in data-interpretation downplayed the concerns on social media. In the case of VITT, they said it was just like a blood clot in the leg (it isn’t), and in the case of myocarditis they repeated that it was “mostly mild” and had to occur less often than myocarditis post infection. Of course, for a 22 year old man who already had 1 dose of Moderna, it was clear that he had 2 choices going forward (a) breakthrough or (b) breakthrough after the 2nd dose. The latter path certainly has a higher rate of myocarditis than the former.
Many doctors missed the plot: the purpose of talking about myocarditis is not to be critical of vaccines— they are a tremendous good— but to take seriously safety signals so that we can personalize or tailor appropriate vaccine strategies to the right ages to maximize efficacy and minimize harm. That’s Medicine 101.
Enter the new Thailand study. The US FDA has specifically asked Pfizer to prospectively assess the incidence of subclinical myocarditis for young people at time of EUA as part of post market commitments.
In keeping with the FDA’s tradition of being lax, the agency gave Pfizer till 2022 and 2024 to provide these data. That’s pretty shitty for a live problem that affects millions of boys, where the information can be generated in 1 month by a company shoveling billions into its pockets.
What happens next? Does the CDC skip Pfizer and go ahead and run biomarkers on the next 1000 kids who get the vax? pre-and post doses? with and without a control getting vax a month later? How about UK or WHO? Sadly, no one did. We turn to the first, and only prospective evaluation, and it comes from Thailand.
I will get right to the point. The authors ran a bunch of tests on kids (202 boys, 99 girls) aged 13-18 who got the 2nd dose of Pfizer, after getting the first dose without adverse events. The EKG changes in the pre-print are not the story. The story are rates of cardiac biomarkers and how often they are elevated. 3 patients had chest pain and biomarker elevation; 4 patients had no chest pain but elevated cardiac biomarkers. These were all in boys.
7/202 boys had overt or subclinical myocarditis (3.5%) or roughly 2 orders of magnitude more common than prior reports from passive adverse event reporting of myocarditis.
I want to quote a section from cardiologist Dr. Anish Koka, who has written a nice and more detailed post on this paper:
- I can assure you, and the mostly ER doctor contingent on twitter that brays about “mild myocarditis”, that there are no cardiologists who want to see their child have a cardiac troponin that is 2x normal or 40x normal after administration of some therapeutic. What exactly does one to do with an adolescent with a troponin that is 2x normal that is asymptomatic? Given the theoretical risk of malignant cardiac arrhythmias I would imagine most cardiologists would follow the current guidelines for myocarditis and advise against strenuous cardiac activity for some months. Sudden cardiac death in young athletes is obviously a fearsome complication that is very real and it is likely some proportion of sudden cardiac death is from subclinical myocarditis.
What is the point?
The toothpaste is largely out of the tube for initial vaccine decisions; All we can do is try to move forward making the best medical decisions. The results of this study should be a call to arms. Here are several take-home messages:
- The fact the US, CDC, NIAID, FDA, etc etc. have to rely on a Thailand preprint for the first prospective study of cardiac biomarkers is mind-boggling negligence. The US and this CDC have shown that either they are incompetent to take safety signals seriously, or indifferent to safety. They earn Grade F. This study should have been done in the USA, by Pfizer 1 month after EUA was granted. End of story.
- We have to rethink the safety/ efficacy of the original series for the few adolescent men who have not had covid and not been vaccinated. Lower doses, longer time between doses, omitting dose 2, must all be tested.
- Because #2 comprises so few boys, this mainly has implications going forward for our indefinitely booster plans:
- Boosters should not be mandated without robust RCT evidence of benefit to others. (that has never happened)
- We must run large RCTs of boosters in this age group and test lower doses— looking for optimal safety/ efficacy before we move forward.
- Every time you change the spike protein construct, you might get LESS myocarditis, but you might also get MORE myocarditis. Novavax proves it is not the mRNA but spike that is the issue. Vaccine makers must be tasked to generate clinical data and not mere Ab titer data for approval.
- Use of EUA for any further vaccine outside of nursing home patients no longer makes sense, traditional BLA is needed for more doses.
- The US CDC should issue an apology for not taking safety signal more seriously, and work to build back trust in vaccines. Already, there is spillover into childhood immunization— a dangerous precedent.
- Pre-pandemic, I lamented that doctors who spent a large percentage of their intellectual time debunking cupping or other obviously useless things were not providing much value for science education, and COVID19 vaccine debates vindicate that view. These groups have been absolutely unable to shatter their pre-existing heuristics (vaccine good/ any concern bad) to novel products with fundamental different risk benefit. The real lesson is that careful understanding of EBM remains poorly taught to doctors; instead many think by blind allegiance to political party or relying on simple rules that serve them well in times of peace, but fall apart in times of war.
- There has to be a point where we conclude that the benefit of the nTH dose of the vaccine is outweighed by the harm. That is true for all drug products, and that is true here. These findings suggest that may come faster than we think, or may already have passed.
- Anyone who had COVID should be exempt from any further vaccine or booster requirement until credible data is generated in these groups— data of net clinical benefit.
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