CHRIS WHITTY, England’s chief medical officer, vividly recalls a nerve-racking moment on December 8th 2020. That was the day when England became the first country to roll out a covid-19 vaccine, a jab developed by Pfizer and BioNTech. Near midnight on vaccination day one “We were discussing it and just thinking ‘What are we dealing with here? These are small numbers and we’ve already had several dangerous near misses’,” said Dr Whitty in a recent talk at the Royal Society of Medicine. In some people, it had turned out, the vaccine sets off anaphylaxis, a life-threatening allergic reaction. But this is rare. It occurred just once among the 22,000 or so people vaccinated in the trial, which could have been by chance. Now, with hundreds of millions vaccinated, the rate at which it occurs is clearer: five per million.
Fortunately, this side-effect is not only extremely rare but shows up soon after the jab. And treatment for it exists. Everyone who receives the Pfizer vaccine is now asked to stick around for 15 minutes, just in case. There have been no deaths from anaphylaxis related to the vaccine.
As millions of jabs of various covid-19 vaccines are administered every day, such rare adverse reactions will inevitably emerge. On April 7th both Britain’s health officials and the European Medicines Agency (EMA), which regulates drugs in the European Union, said there is strong evidence that AstraZeneca’s covid-19 vaccine may be linked with very rare blood clots, often in the brain or the abdomen. The EMA experts reached their conclusion based on a review of 86 reported cases, 18 of which were fatal. Britain’s experts reached the same conclusion from data on 79 cases, 19 of which were fatal. Both the EMA and Britain’s drug regulator concluded that the vaccine’s benefits outweigh the potential risk of the clots. But Britain’s officials, armed as usual with some nifty charts for their televised briefing, said that for people under 30 the risks and benefits from the vaccine were “finely balanced”, so a different jab may be preferable.
The investigation of the suspected clots from the AstraZeneca jab has been a prime example of the challenge of sorting the signal of a vaccine’s side-effects from the cacophony of medical emergencies that happen to millions of people every day. Vaccine-safety experts have two ways to untangle whether a rare medical problem is caused by a vaccine, says Kathryn Edwards of the Vanderbilt University School of Medicine, in Nashville, Tennessee. They can compare its rate in vaccinated people against the “background” rates of it that are observed in the unvaccinated. And they can look for unusual features of the medical condition being investigated.
The first signals emerged in late February, when doctors in several European countries noticed clusters of blood clots in people recently given the AstraZeneca jab, some of whom died. Most were women under 60, which was not terribly surprising because many EU countries were, at first, not convinced that the jab worked in the elderly and used it largely for essential workers, such as nurses, teachers and social-care workers—professions in which most employees are women.
The EMA’s data as of March 22nd suggested that the rate of brain clots in people under the age of 60 who had had AstraZeneca’s vaccine was one in 100,000—higher than would be expected normally. Precisely how much higher, though, is hard to tell. The rates of such rare and difficult-to-diagnose conditions vary a lot by country, age and sex. Estimates of the incidence of such brain clots have ranged from 0.22 to 1.57 cases per 100,000 people per year, and they are more common in younger people and women.
As doctors began to look more closely, something curious emerged. Many patients with suspected clots from the vaccine had unusually low levels of platelets. These are fragments of special precursor cells that float in the blood. Their job is to form blood clots (they rush to the site of a cut or other bleeding). Low platelet levels therefore usually result in uncontrolled bleeding, not clots.
With this new information to hand, Britain’s medical regulators searched their data on vaccinated people for the unusual tandem of clots and low platelet counts. They found four cases per million people vaccinated, a rate several times lower than in the EU. One explanation is that Britain, unlike the rest of Europe, had used the jab primarily in older people. The rate at which the clots occurred in Britain declined steadily with age. Importantly, Britain’s experts found that the clots occurred as much in men as they did in women.
This combination of blood clots and low platelet counts is something that doctors know how to diagnose and treat, says Jean Marie Connors, a haematologist at Brigham and Women’s Hospital, in Boston. It resembles a condition seen in some people who are given heparin, a drug used widely to treat blood clots. For unknown reasons, some people develop an immune reaction to heparin, which results in blood clotting so profound that it depletes their platelets. The same reaction appears to be provoked by the vaccine.
Medical societies in several countries have already issued guidelines to doctors on how to spot and treat this rare reaction to the AstraZeneca vaccine. With vigilance and appropriate care, the extremely rare deaths that may result from it will become even rarer.