While the AstraZeneca vaccine is not yet authorized in the U.S., about 25 million people worldwide have received it. In March, many countries temporarily halted vaccination after dozens of reports of blood clots occurring mainly in younger people who received the shot and about 18 deaths. After reviewing the side effect, the European Medicines Agency (EMA) acknowledged the clot risk in April. Still, it concluded that the benefits of vaccination in protecting against COVID-19 outweighed the minor threat posed by clotting. However, the agency recommended that people under 30 be provided with other vaccines if they were available.
These two NEJM reports will reignite questions about the vaccine’s safety and potentially lead to new policies or even stricter monitoring of people who receive it. “The important thing is that the link to this peculiar problem of post-vaccination thrombosis, which was mysterious—we now have an explanation for it,” says Dr. Theodore Warkentin, professor of pathology and molecular medicine at McMaster University and a co-author of one of the papers.
The AstraZeneca vaccine relies on a modified adenovirus that causes cold-like symptoms in chimpanzees; the chimp virus serves as a vehicle for delivering genes coding for the COVID-19 virus’ spike protein. Whether the clotting side effect and the platelet-involved mechanism described in the two papers are related to this vector platform, it doesn’t bode well for the vector-based technology, which is only approved for use in a rabies vaccine for animals. It does not trevent any human diseases (other than COVID-19, of course).
“These results cast a shadow on this vaccine and now other vaccines—the Russian vaccine and Johnson & Johnson—relying on this technology,” says one vaccine expert who did not wish to be identified. “Now, all of these will be looked at with higher scrutiny, and they should be.” On April 9, the EMA announced it is currently reviewing Johnson & Johnson-Janssen vaccine after four reports of clots in people vaccinated with the shot were reported, one of which was fatal. One of the NEJM studies, conducted in Germany and Austria, included 28 people immunized with the AstraZeneca photo and developed clots (11 of them in more detail as they provided additional samples).
All 28 developed different clots, or thromboses, five to 16 days after vaccination, and all had made antibodies against platelets. Six of the 28 died from clotting complications. In the other study, five healthcare workers in Norway vaccinated with the AstraZeneca vaccine and developed clots seven to 10 days later also had high levels of platelet-specific antibodies; three died. Warkentin has studied a similar condition of immune system activation involving platelets known as heparin-induced thrombocytopenia (HIT). That condition is caused when people taking heparin, a blood thinner, for unknown reasons develop an immune reaction against it, producing antibodies against platelet clumps that can lead to clots in blood vessels instead of preventing clots.
In this condition, people experience a drop in platelet counts as the platelets begin aggregating. It’s a rare but well-known side effect of heparin, which doctors give to patients during surgery to prevent clots—but which, in the case of HIT, has the opposite effect. Warkentin and his team reported the first cases of so-called spontaneous HIT, in which the immune system is activated against platelets even if people have not received heparin. That’s very close to what is happening to the people developing clots after getting vaccinated with the AstraZeneca shot, he says, adding that “spontaneous HIT provides the roadmap for understanding this condition.”
But that roadmap won’t likely clarify why these people are developing the clots in reaction to the vaccine in the first place. “What is it? Is it something unique to the adenovirus vector or the amount of adenovirus given?” says the vaccine expert. Holme, a co-author of the Norwegian study, says that the cases of clotting among vaccinated people are rare but problematic. “This devastating adverse event occurs very, very seldomly,” he says. “But for me, it’s tough to see healthy people in their 30s and 40s dying [after receiving] the vaccine when they probably would have been fine with a COVID-19 infection.”
Regulators and public health experts are now faced with deciding how to advise the public about getting vaccinated with the AstraZeneca shot. If the AstraZeneca vaccine were the only one to treat COVID-19, the risk-benefit calculus would be very different. The risk posed by clotting might be considered worth it in light of the overall risk of complications and death associated with COVID-19. But several other vaccines are safe and effective—from Pfizer-BioNTech, Moderna—and aren’t associated with the same clotting risk, or, in the case of Johnson & Johnson-Janssen, the same level of clotting risk so far. Hence, the risk-benefit considerations shift in favor of relying on one of these alternatives.
“As a clinician, if this mechanism is confirmed, and is, in fact, true, it would give me pause about proceeding with administration of this [AstraZeneca] vaccine until this side effect has been further characterized,” says Dr. Sahil Parikh, associate professor of medicine at Columbia University who specializes in treating circulatory problems including clots. If the vaccine continues to be used, doctors should start alerting patients about the risk and monitoring people for signs of clotting. Warkentin says symptoms include blurry vision, headache, weakness in their extremities, shortness of breath, chest pain, or unusual swelling in the arms and legs about five days after vaccination. Doctors can test quickly for abnormal antibodies and then prescribe blood thinning treatments that don’t include heparin.
Holme says the two patients in his study were also successfully treated with immune globulin to help reduce the tendency of the immune cells to clump together with the platelets. In any case, this leaves AstraZeneca and its academic partners from Oxford University with a problem. The company has not yet filed for authorization in the U.S.; if it does, it would likely face difficult questions about the risk of its vaccine from regulatory reviewers. It’s a different scenario for the rest of the world, however. The World Health Organization and the European Union have authorized the vaccine. Public health leaders were looking to the AstraZeneca vaccine to protect much of the world’s population since the shot is less expensive and doesn’t require storage under freezer temperatures as the vaccines from Pfizer-BioNTech and Moderna, the currently most widely available photos, do. But if the image requires additional monitoring and resources to treat potential blood clot complications, that could negate the cost and storage advantages of the vaccine.
