Why the Covid-19 vaccine safety numbers are still fuzzy

When federal officials paused administration of the Johnson & Johnson vaccine after six cases of a rare clotting disorder, one fatal, among the 6.9 million people who had received the vaccine, many critics noted that the chance of a serious ailment was so rare as to be negligible — less frequent than being struck by lightning.

But that roughly one-in-a-million rate is far from certain. Doctors may ultimately find the vaccine is not responsible for the ailment. However, if the two are linked, it’s also possible that the chance of an adverse effect will be higher, even if it remains low.

“Numbers seem quite solid, like, ‘Oh, it’s 10,’” said Caitlin Rivers, an assistant professor at Johns Hopkins University, who studies infectious disease. She said epidemiologists deal with similar matters of uncertainty at the beginning of disease outbreaks. “But they’re estimates, and they will need to be refined, and they may need to be refined a lot, especially since they are small numbers.”

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How do we know how common this event is?

If there is a connection between the vaccine and this rare syndrome, new cases are likely to emerge now that the word is out. Regulators announced the pause in part to alert doctors to the existence of this syndrome; as people begin looking, they may be more likely to find and report it. With numbers so low, the addition of even a few more cases could increase the rate. (In the last few days, Johnson & Johnson has reported two more possible cases, one in a woman, and one in a man.)

If there’s a link between the vaccine and the syndrome, more people who already got shots might still develop the clotting problem, since it appears to show up within a few weeks of vaccination. About half of Americans who received the Johnson & Johnson shot got it this month, according to government estimates. One reason the Centers for Disease Control and Prevention vaccine safety committee wants to wait longer before updating any guidance on the shot is to see what happens with this group. Since the pause was first recommended, the government count of Americans who have received the shot has increased to 7.7 million.

It may turn out that only some segments of the population are at high risk of this problem, in the same way that some populations are at higher risk of serious issues from certain diseases. Most of the cases so far have been in women between 18 and 50. If we look at six cases in that population, the syndrome looks somewhat more common, though still very rare.

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If more cases are reported, it’s also possible that this gendered pattern will disappear.

Dr. Tom Shimabukuro, a vaccine safety expert at the CDC who presented numbers to the vaccine safety board this week, said all of the current calculations are still “crude.”

How can we tell that the clots wouldn’t have happened anyway?

It’s hard to tell right now. Studies of such events typically compare people who are given a medication or vaccine with a control group of people who didn’t. With a rare disorder like this, that comparison couldn’t be easily made using clinical trials. Researchers are conducting a large study of the health records of 12 million patients called the Vaccine Safety Datalink, comparing medical records of people who are vaccinated earlier with those who get their shots later — a system that doesn’t rely on voluntary reporting. Those results will take a while.

Researchers also look at what’s called a background rate of serious events: the odds someone could have a health problem even if he or she never got a vaccine. Comparing the rate of events among people who get a vaccine with the rate in the overall population can give a sense of whether a given patient’s outcome may be because of the vaccine, or is more likely to just be a coincidence.

Women under 50 — the group that may be at risk of the particular type of blood clot that authorities have seen in the vaccinated patients — are more likely than the general population to have these blood clots just by being alive.

What is a rate we should care about?

Many medications given to sick people can have serious side effects for some fraction of those who take them. Doctors and patients routinely weigh such risks against the benefits of medical treatment.

Birth control pills with estrogen have been frequently discussed this week because they are a common medication carrying a risk of blood clots. Clots caused by birth control pills are different from the syndrome associated with the Covid-19 vaccines, and some experts caution about comparing them directly. The kind of clots caused by oral contraceptives typically form in patients’ legs, not in their brains, but they can still be serious. The pills more than double a typical woman’s risk of such an event, meaning between 3 and 9 women out of 10,000 taking the pills for a year will develop a clot. (Pregnancy, the condition birth control pills are often prescribed to prevent, causes an even higher risk of blood clots.)

“I’ll often say the risk of getting a blood clot with birth control pills is kind of similar to having a really serious reaction to penicillin,” said Dr. Raegan McDonald-Mosley, an obstetrician-gynaecologist and CEO of Power to Decide, a group devoted to reducing unintended pregnancy. She frequently discusses blood clot risk with her patients, telling them the increase in risk and the overall magnitude of that risk. Most patients, she said, select their form of birth control based on other considerations.

(Penicillin, a widely used antibiotic, causes serious allergic reactions in between 1 and 5 patients for every 10,000 who take it.)

For vaccines, however, the threshold for safety is generally higher than for other kinds of medications. As many researchers have noted, Covid-19 puts people at risk of serious blood clots, too — much more so than any plausible estimate of the vaccine effect. But not everyone who fails to get vaccinated is going to get sick.

“The disease you get by chance, and the vaccine you get by choice, and that’s what makes it harder,” said Dr. Steven Black, an emeritus professor of pediatrics at Cincinnati Children’s Hospital, who studies vaccine safety.

For other vaccines, the risk of serious adverse events is much lower than for birth control pills or penicillin — they generally occur in fewer than 1 in 100,000 who receive a given vaccine. That rate is “clearly much, much less than would be tolerated for a drug,” said Dr. Nicola Klein, director of the Kaiser Permanente vaccine study center, who is involved in the Vaccine Safety Datalink study.

Most other vaccines protect against diseases that tend to be rare. By contrast, Covid-19 remains widespread throughout the United States and many parts of the world. Given the seriousness of the illness and its ease of spread, the value of vaccination may be higher now than it is when such trade-offs are usually considered.