In 2021, just months after the first COVID vaccines debuted, concern was growing about an exceedingly rare but sometimes deadly outcome of certain shots. Two related vaccines—one from AstraZeneca and the other from Johnson & Johnson—were linked to dangerous blood clotting.
Out of almost 19 million doses of Johnson & Johnson’s version given in the United States during the first two years of the pandemic, at least 60 such cases were identified. Nine of them were fatal. In the United Kingdom, where almost 50 million doses of the AstraZeneca shot were given, 455 cases occurred; 81 people died. In Germany, at least 71 cases were identified, also linked to AstraZeneca. By late spring, use of both the AstraZeneca and the Johnson & Johnson vaccine was paused, and ultimately both were pulled from the market. But the mystery surrounding the rare blood clotting caused by these vaccines lingered.
Now researchers believe they have cracked the case. They have hard evidence for how the blood clotting happened, and they believe that their findings could help make similar vaccines even safer. Understanding the blood-clotting problem is important, they say, because vaccines of this type could be essential in protecting people during future pandemics.
The team that initially gave this condition a name—vaccine-induced immune thrombotic thrombocytopenia, or VITT—included Andreas Greinacher, a blood expert at the University of Greifswald, in Germany. Back in 2021, as the cases of VITT emerged, he and others were unsure of what precipitated them. One theory was that they were caused by the body’s accidental reaction to the type of virus used in both the AstraZeneca and Johnson & Johnson vaccines: adenoviruses, which had been engineered to prompt the body to recognize the pandemic coronavirus but were unable to replicate and considered harmless to people. Scientists had noticed that patients with VITT had telltale markers in their blood—antibodies that bind to a chemical signal released by platelets. Maybe a reaction to the adenovirus was causing immune cells to mistakenly go after a blood component and precipitate clotting. An alternative theory was that the body was reacting to a portion of the coronavirus called “spike protein,” which showed up as part of the immunization.
In a study published today in The New England Journal of Medicine, Greinacher and his colleagues show that the first theory was correct: VITT was a response to the adenovirus gone awry. And they discovered a further twist: This immune overreaction happened in people who were genetically prone to it.
In the study, Greinacher and his colleagues looked at the antibodies in stored blood from 21 patients with VITT. Among those antibodies, they found a subset that could glom on to a portion of the adenovirus and to one of the body’s own molecules, PF4, that can influence blood clotting. A person who received one of the adenovirus vaccines but did not have a reaction also had antibodies against that same part of the adenovirus. But, crucially, that person’s antibodies did not cross-react with PF4.
Those antibody molecules also offered clues about the immune cells that made them. And the scientists were able to link the immune cells responsible for VITT to patients who had two specific DNA variants. A wider survey of 100 VITT patients found that all of them had immune cells with one of these genetic types—which are far from universal. This signaled to the researchers that having these particular variants is a strong risk factor for blood clotting following an adenovirus vaccine.
But the study also showed that this genetic background on its own was not enough to cause VITT. The immune cells that made the dangerous antibodies had experienced an additional small genetic change, and that extra mutation had prompted them to produce those cross-reactive molecules.
In the past, scientists have suggested that genetic predispositions might explain some adverse events that happen after vaccination. For example, some data have indicated that certain people were genetically prone to developing narcolepsy following a version of swine-flu vaccine that was briefly used in Europe. But the new study from Greinacher and his team is the first to provide concrete evidence of how people with a particular DNA variant can develop self-sabotaging antibodies following a vaccination. Arnold Lining Ju, a biomedical engineer at the University of Sydney who has studied blood clotting, told me that the paper was a landmark finding in part because of how elegantly it explains the way a specific genetic trait, combined with a particular chance mutation in certain cells, creates VITT. And because the study shows that multiple genetic changes are involved, it finally explains why this immune reaction is so rare, he said.
This discovery will help guide researchers more than it will influence vaccination choices for individual patients. Most vaccine recipients will not know their genetic predisposition to an adverse event, Jennifer Juno, a vaccine researcher at the University of Melbourne, points out. But this type of work will help improve vaccine design—particularly in the field of “precision vaccinology,” in which vaccines are tailored to individual traits, Joanne Reed, the director of the Centre for Immunology and Allergy Research at the Westmead Institute in Australia, told me.
These results also mean that adenovirus-based vaccines could be made safer if they can be designed without the protein region that triggered the dangerous antibodies in VITT. “Instead of abandoning an entire vaccine platform because of a rare problem, we can engineer around the specific issue, and that’s the power of this kind of science,” Joann Arce of the Precision Vaccines Program at Boston Children’s Hospital told me. The hope is that understanding the biology of a rare event like VITT, and then addressing it, helps bolster public trust in vaccines too. Greinacher told me that adenovirus-based vaccines remain vital, including for the development of vaccines for diseases that affect mostly low- and middle-income countries. The shots could also be useful in a future pandemic, because they can be scaled up in production relatively quickly.
Still, this one study may not have entirely answered the question of why adenovirus-based COVID vaccines caused clotting. A study published last year from Ju’s group suggested that a separate biophysical mechanism might cause a viral component found in the AstraZeneca vaccine to directly aggregate platelets, independent of the immune reaction identified in VITT. And a bigger mystery remains open too—why infections themselves are sometimes associated with dangerous blood clotting. Rushad Pavri, an immunologist at King’s College London, told me that the new study—because it shows how similarities between a virus particle and an innate protein involved in clotting can confuse the immune system—can shed light on that question. Ultimately, understanding why viruses can provoke immune overreactions might help limit damaging complications from sickness to begin with.
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