In 2021, just months after the first coronavirus vaccines appeared, concern has been growing about the extremely rare but sometimes fatal results of some vaccines. Two related vaccines — one from AstraZeneca and the other from Johnson & Johnson — have been linked to dangerous blood clotting.
Of the nearly 19 million doses of the Johnson & Johnson version administered in the United States during the first two years of the pandemic, at least 60 such cases have been identified. Nine of them were fatal. In the United Kingdom, where nearly 50 million doses of the AstraZeneca vaccine have been administered, 455 cases have occurred; 81 people died. In Germany, at least 71 cases also linked to AstraZeneca have been identified. By late spring, both the AstraZeneca vaccine and the Johnson & Johnson vaccine were temporarily halted in use and eventually withdrawn from the market. But the mystery surrounding the rare blood clots caused by these vaccines still remains.
Now researchers believe they have solved the case. They have strong evidence on how blood clotting occurs, and believe their findings could help make similar vaccines safer. Understanding the problem of blood clotting is important, they say, because vaccines of this type could be essential to protecting people during future pandemics.
The team that initially gave this condition a name — vaccine-induced immune thrombocytopenia, or VITT — included Andreas Grenacher, a blood expert at the University of Greifswald, in Germany. Going back to 2021, as cases of VITT appeared, he and others weren’t sure what caused them. One theory was that it was caused by the body’s accidental reaction to the type of virus used in both the AstraZeneca and Johnson & Johnson vaccines: adenoviruses, which were designed to prompt the body to recognize the pandemic coronavirus but were unable to replicate and were considered harmless to people. Scientists have observed that patients with VITT have visible markers in their blood, which are antibodies that bind to a chemical signal released by platelets. The reaction to the adenovirus may have caused immune cells to mistakenly go after a blood component and cause clotting. An alternative theory was that the body was reacting to a part of the coronavirus called the “spike protein,” which appeared as part of the immunization.
In a study published today in New England Journal of MedicineGreenacher and colleagues showed that the first theory was correct: VITT was a response to adenovirus. They discovered another development: This immune overreaction occurred in people who were genetically susceptible to it.
In the study, Greinacher and colleagues examined antibodies found in stored blood from 21 patients with VITT. Among those antibodies, they found a subset that can attach to part of the adenovirus and one of the body’s molecules, PF4, that can affect blood clotting. A person who received one of the adenovirus vaccines but did not have a reaction also had antibodies against the same part of the adenovirus. But more importantly, this person’s antibodies did it no Cross-reaction with PF4.
These antibody molecules also provided clues about the immune cells that made them. Scientists were able to link the immune cells responsible for VITT to patients who have two specific types of DNA. A large survey of 100 VITT patients found that all of them had immune cells containing one of these gene types, which is far from universal. This suggests to researchers that the presence of these specific variants is a strong risk factor for blood clotting after adenovirus vaccination.
But the study also showed that this genetic background by itself was not enough to cause VITT. The immune cells that made the dangerous antibodies had experienced a small additional genetic change, and this additional mutation prompted them to produce those cross-reactive molecules.
In the past, scientists have suggested that genetic predisposition may explain some of the adverse events that occur after vaccination. For example, some data suggested that some people were genetically susceptible to developing narcolepsy after using a version of the swine flu vaccine that was briefly used in Europe. But the new study by Greenacher and his team is the first to provide concrete evidence of how people with a certain type of DNA can develop self-destructive antibodies after vaccination. Arnold Lining Guo, a biomedical engineer at the University of Sydney who has studied blood clotting, told me that the research was a landmark discovery, in part because of how elegant it was at explaining the way in which a particular genetic trait, combined with a particular chance mutation in particular cells, leads to the formation of VITT. Because the study shows that numerous Genetic changes are involved, he said, which finally explains why this immune reaction is so rare.
This discovery will help guide researchers more than it will influence vaccination options for individual patients. Jennifer Juneau, a vaccine researcher at the University of Melbourne, points out that most vaccine recipients will not know their genetic predisposition to an adverse event. But this kind of work will help improve vaccine design — especially in the field of “precision vaccinology,” where vaccines are tailored to individual traits, Joan Reid, director of the Center for Immunology and Allergy Research at the Westmead Institute in Australia, told me.
These findings also mean that adenovirus-based vaccines could be made safer if they can be designed without the region of the protein that causes the dangerous antibodies in VITT. “Instead of abandoning an entire vaccine platform because of a rare issue, we can engineer around a specific issue, and that’s the power of this kind of science,” Joanne 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 treating it, helps boost public confidence in vaccines as well. Adenovirus-based vaccines remain vital, including developing vaccines for diseases that mostly affect low- and middle-income countries, Greenacher told me.. Vaccines could also be useful in any future pandemic, because their production can be scaled up relatively quickly.
However, this study may not have fully answered the question of why adenovirus-based COVID vaccines cause thrombosis. A study published last year by Guo’s group suggested that a separate biophysical mechanism may cause a viral component found in the AstraZeneca vaccine to directly aggregate platelets, independent of the immune reaction identified in VITT. A bigger mystery also remains open: why the infection itself is sometimes associated with dangerous blood clotting. Rashad Bavari, an immunologist at King’s College London, told me that the new study — because it shows how similarities between a virus particle and a fungal protein involved in clotting can confuse the immune system — could shed light on this question. Ultimately, understanding why viruses can trigger exaggerated immune responses may help limit the harmful complications caused by the disease to begin with.
