Young men and boosters: more harm than good?

New data suggest Pfizer boosters are unlikely to decrease Covid-19 hospitalizations in males under 30, but will hospitalize a few with myocarditis.

Ever since the Biden Administration announced plans to make booster shots available for most adults, the group that I have been most worried about has been young males. That’s because, while rare, an inflammatory condition of the heart called myocarditis had been linked to both the Pfizer and Moderna Covid-19 vaccines, with far higher rates occurring after the 2nd dose. Given the small risk of myocarditis, however, it was clear that the initial 2-dose series provided important protection against severe Covid-19 for all age groups, even in younger ones in which severe disease was already unusual. In short, vaccines would prevent far more hospitalizations due to Covid-19 than they would ever cause due to side effects.

Enter boosters.

If the vaccines continued to work well in young males, even after 6 months or longer, could a 3rd dose do anything to decrease their already exceedingly low rates of Covid-19 hospitalization? And would those 3rd doses hospitalize a small number of them with vaccine-associated myocarditis? In other words, for males ages 18-29 in particular, could a 3rd dose of Pfizer possibly offer more harm than benefit with respect to hospitalizations? This unanswered question is what drove a colleague and I to question whether it was too soon to offer boosters to a majority of adults in the United States.

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In the past week, important new data have emerged that help to answer this question. Based on what we’ve learned, it indeed appears that Pfizer boosters likely offer more harm than benefit for males under 30 with respect to hospitalization, and possibly for older males up to a certain age — where the balance tips is unclear. For other demographics, boosters appear to be safe, while offering reductions in infection across the board, and reductions in severe disease in people over 40. Whether these benefits are short-lived or longer-lasting remains to be seen. But we at least know that 3rd doses are safe for all females over 16, and older males.

However, for males ages 18-29, and possibly somewhat older males, it seems that 3rd doses of Pfizer are likely to cause more hospitalizations (due to myocarditis) than they will prevent (from Covid-19) in the coming 6 months.

Based on what we’ve learned, it indeed appears that Pfizer boosters likely offer more harm than benefit for males under 30 with respect to hospitalization.

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How did I reach this conclusion? By combining the safety framework used by the Centers for Disease Control and Prevention with data appearing in a handful of newly released medical research papers. First, we have an update in the estimates of the rate of post-vaccine myocarditis. Second, we have an update on how well Pfizer’s vaccine has performed during the Delta era.

First, let’s understand the CDC’s benefit-risk framework. Back in September, during a meeting of its vaccine safety committee, the benefits and risks of boosters were discussed and debated. Because much was unknown, experts made some important assumptions. First, for males 18-29, the rate of vaccine-associated myocarditis was estimated to be approximately 13-26 cases per million recipients. Next, experts assumed that vaccine effectiveness for this group was 90.7% (an average of various sources) and that boosters could raise that to 95%. Based on circulating coronavirus case counts at the time, it was estimated that for every 1 million booster doses given to young males, around 100 Covid-19 hospitalizations would be prevented in the coming 6 months. The implication was that decreasing Covid-19 hospitalization by 100 cases for every million people boosted would be worth the 13-26 vaccine-related myocarditis hospitalizations that would be expected to occur concurrently. So, the scales appeared to tip in favor of boosting, provided that case counts remained high, and if the myocarditis estimates weren’t wildly off.

Why was I skeptical of this? Because I was convinced that the myocarditis rates were likely higher than the CDC's estimate, especially in a 3rd dose (I was more pessimistic than the CDC on this). Meanwhile, I believed that the vaccines were likely performing better than 91% in terms of effectiveness against hospitalization in the young (I was more optimistic than the CDC on this). This is probably why the CDC’s safety panel voted against boosters for adults with increased risk of exposure to Covid-19, such as healthcare workers. (The panel voted in favor of permitting boosters for adults ages 18-49 with certain Covid-19 risk factors, though there exists no evidence that two doses are inadequate for most of them, other than those with severely compromised immune systems). In my view, too much was unknown, and the young and vaccinated were not responsible for the Delta surge. When CDC Director Dr. Rochelle Walensky allowed boosters for most adults ages 18-49 (in part overruling the CDC's safety advisory panel), I disagreed with the decision. It wasn’t that I was certain that it was the wrong decision; it was that I didn’t know, and nobody could.

Now we know much more. We can update the benefit-risk analysis by applying newly released data to the CDC’s safety framework. First, two studies from Israel appearing in the New England Journal of Medicine last week found that for young males, the rate of vaccine-associated myocarditis was substantially higher than the CDC’s previous estimate. Among males 16-29, it looks like rather than 13-26 cases per million after 2nd doses of the Pfizer vaccine, the rate was actually around 107 per million. In another study, the highest risk group (males 25-29), experienced around 150 myocarditis cases per million after 2nd doses. Virtually all of these cases would require hospitalization. The Israeli numbers are likely to be more accurate than previous CDC estimates because Israeli data came from their comprehensive national database, rather than the quasi-voluntary reporting systems that we have here. While this may all sound like bad news, the upside is that myocarditis remained rare, and most of the cases were mild.

Then over the weekend, we received some good news for the vaccines. In a preprinted study (not yet peer reviewed) carried out by staff of the New York State Department of Health and appearing in medRxiv, researchers found that among adults ages 18-49, the initial 2-dose Pfizer series continued to provide 95.5% effectiveness against hospitalization as recently as August, well into the Delta period. Even among January and February Pfizer recipients, vaccine effectiveness remained above 93%. Even more recent New York data suggest that the vaccines have remained steady; in fact, effectiveness appears to have improved a bit during September.

Remember: the CDC assumed that boosters could increase vaccine effectiveness to 95%. So, if the vaccine effectiveness remains at or near 95%, that means the number of Covid-19 hospitalizations that could be prevented by boosting 1 million young males would be zero, or close to it. Meanwhile, if rates of myocarditis after the 3rd dose replicate 2nd dose rates, up to 150 cases per million could occur in the highest risk group (males 25-29).

The conclusion is clear: boosting males 18-29 stands to cause more hospitalizations than it will prevent. Plus, as the CDC pointed out in September, if case counts fall (as they already have), the likelihood of benefit from boosting young males would only become smaller. (Note: Technically, if the vaccine continues to be 95% effective against hospitalization, more females 18-29 could be hospitalized with myocarditis than Covid-19 hospitalizations prevented by boosters. But the myocarditis numbers appear so low in females under ages 30—1 to 4 in a million—that it’s difficult to imagine those rates exceed background noise in any meaningful way.

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What does this mean for males 18-29 who receive boosters? Ironically, the most common outcome for boosting this demographic —and actually all demographics—can be summarized in one word: nothing. That may sound surprising, but it’s true. It speaks to how well the vaccines are performing and the degree to which we have slowed down this virus (not that we’ve done that well in many regions) and defanged it. For example, currently here in Massachusetts, around 1 in 8,100 people are experiencing breakthrough infections daily and of that a small fraction are hospitalized. If that continues, over the next 6 months, 2.2% of us would experience a breakthrough infection, most of which would be mild. If every one of us received boosters and that decreased infections by a factor of 20, around 97.9% of us would experience no change in outcome: no infection either way. Yes, up to 2.1% of that initial 2.2% could avoid a breakthrough over 6 months, although even that unrealistically assumes that booster effectiveness against infection will not wane (which it likely will). In case it isn’t clear yet, these vaccines were not designed to, nor do they provide, long-lasting protection against infection; they were designed to provide long-lasting protection against severe illness and, so far, they do.

Because of this all, I sent CDC Director Dr. Rochelle Walensky a memorandum yesterday (see below). Towards the end of that document, I mentioned that even with this new information, some males 18-29 might still want to receive boosters. Perhaps some will be willing to take on a higher (though still small) risk of hospitalization in order to decrease the higher chance of a breakthrough infection, even if only temporarily. While Long Covid appears far less likely with vaccines, we don’t know whether boosters might decrease that further. Some people may also worry about spreading the virus to people they live with who are too young to be vaccinated or who are immune-compromised and for whom even 3 doses does not suffice. In areas of low vaccine acceptance where hospital capacity is an issue, boosters could make a dent in local infection rates. For people in these situations and others, shouldering a little more myocarditis risk than expected may not dissuade them from boosting. And that's fine, provided that they are acting on the most complete information available. But if we are to do as Dr. Walensky suggested, which is to weigh the risks and benefits of boosters for most adults 18-49, we owe it to everyone to let them know precisely what those are.

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What are your questions and comments? Please join the conversation below!

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Below are screenshots of the memorandum that I sent to CDC Director Dr. Rochelle Walensky on Tuesday, October 12th.

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