But even the largest clinical trials are not designed to detect extremely rare side effects, which might occur in fewer than 1 case per 10,000 vaccinations. Because hundreds of millions of people are now being vaccinated against COVID-19, it makes sense that even very rare events — such as severe allergic reactions or blood clots — will start to appear in safety reports, Bastian says. The challenge now is to work out which of these events are actually linked to the vaccine.

In the United States, the National Institute of Allergy and Infectious Diseases has begun organizing a clinical trial to understand the allergy risks of COVID-19 vaccines based on messenger RNA (mRNA). The mRNA vaccine made by Pfizer in New York City and BioNTech in Mainz, Germany, is associated with a rate of five cases of severe allergic reaction per million doses, and the one made by Moderna in Cambridge, Massachusetts, is associated with a rate three cases per million doses. Those affected seem to be mainly women and people with a history of allergies.

Stacie Jones, an allergist and immunologist at the University of Arkansas for Medical Sciences in Little Rock, and her colleagues are leading a study at one of 30 locations across the United States to better understand the proportion of these reactions that occur in people with a history of allergies, compared with a control group. These allergic reactions are “extremely rare,” says Jones. If the study does observe an increased rate of severe allergic reactions in this carefully controlled trial, that will allow the researchers “to know who is at risk, and to define that risk” so that physicians can provide better advice, she says.