A key ingredient in Johnson & Johnson’s Covid-19 vaccine could explain the possible link between the shots and the extremely rare blood clots reported in six patients in the U.S.
The technology used in the drugmaker’s vaccine, called an adenovirus, is used to prompt an immune response against the coronavirus. But some experts say that it could instead — in rare cases — prompt an immune response against certain components in the blood that cause clotting.
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Rollout of Johnson & Johnson's vaccine was paused Tuesday, after six recipients developed a combination of severe blood clots in the brain called cerebral venous sinus thrombosis, or CVST, and low levels of platelets. One person died and another remains in critical condition, Dr. Peter Marks, director for the Center for Biologics Evaluation and Research at the Food and Drug Administration, said during a media briefing.
The cases appear to be exceedingly rare. Out of more than 7 million Johnson & Johnson shots administered, six patients developed the clots.
An advisory committee for the Centers for Disease Control and Prevention will meet Wednesday afternoon to discuss the cases and possible changes to the recommended use of the vaccine. It could be that there are other clotting risk factors linking the cases.
Meanwhile, some experts suspect the key technology used to make the Johnson & Johnson vaccine — as well as the AstraZeneca vaccine — may play a role in the blood clots. The AstraZeneca vaccine, which is not yet authorized for any use in the U.S., has been linked to rare occurrences of blood clots in Europe and the United Kingdom.
Last week, the European Medicines Agency and the U.K.'s Medicines and Healthcare products Regulatory Agency acknowledged the link between the AstraZeneca shot and the potential for blood clotting problems. These warnings came as a study published in the New England Journal of Medicine linked the AstraZeneca vaccine to reports of rare blood clots in 11 patients — nine of them women — in their 20s, 30s and 40s in Germany and Austria.
Both the AstraZeneca and the Johnson & Johnson vaccines use an inactivated form of a common cold virus, called an adenovirus, to teach the immune system to recognize the spike protein found of the surface of the coronavirus.
In both products, the adenovirus is genetically modified so it does not cause cold symptoms. In the AstraZeneca vaccine, the modified virus comes from chimpanzees; in Johnson & Johnson's, the virus comes from humans.
No such clotting issues have been reported with the Covid-19 vaccines made by Pfizer-BioNTech or Moderna, health officials said. Those vaccines use a different type of technology, called messenger RNA, or mRNA.
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Experts believe it's possible that on rare occasions, the adenovirus itself could lead to clotting, due to a reaction involving platelets.
Indeed, the New England Journal of Medicine analysis suggested the adenovirus as the mechanism at play.
"Most of these patients are developing antibody against what's caused platelet factor 4, which causes platelets to clump together," said Dr. Greg Poland, director of the Mayo Clinic's Vaccine Research Group in Rochester, Minnesota.
"We also know that adenoviruses themselves can cause platelet activation and binding," said Poland, who is also a consultant for multiple Covid-19 vaccine manufacturers, including Johnson & Johnson.
Platelets play a critical role in blood clotting, which is important for healing cuts and other wounds. When an injury occurs, platelets in the blood are activated, rushing to the site of the injury and forming a clot.
But sometimes, platelets can become activated when there is no injury, leading to clots in the blood vessels that can cut off blood flow to key organs such as the heart, lungs or brain.
Counterintuitively, a common blood thinner called heparin — meant to reduce clots — can trigger a clotting condition called heparin-induced thrombocytopenia. (Thrombocytopenia means low platelet levels.) The reaction is rare, occurring in up to 5 percent of patients who receive the drug.
"Some patients develop antibodies against the heparin molecule," said Dr. Hugh Cassiere, director of critical care services at Sandra Atlas Bass Heart Hospital at North Shore University Hospital, part of Northwell Health, on Long Island, New York. "Those antibodies activate the platelets to start clotting."
Experts hypothesize that in very rare instances, the adenoviruses used in the Johnson & Johnson and the AstraZeneca Covid-19 vaccines might prompt the body to make antibodies similar to what's seen in heparin-induced thrombocytopenia.
Timing of symptoms may also provide evidence that antibodies play a role. The six patients developed symptoms within 2 weeks of receiving the shot — the amount of time it takes for the body to build the antibodies.
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But current evidence suggests the risk of blood clots is exceedingly rare.
"This is a situation of risk versus risk," said John Grabenstein, a former executive director of medical affairs for vaccines at Merck and a former Department of Defense immunologist. "There is a larger risk of getting Covid-19 disease, and a presumably lesser risk of this blood clotting disorder."
Marks, of the FDA, said those rare cases must be treated differently than typical blood clots, for which heparin is the standard of care. These specific blood clots in the brain may require different types of blood thinners, according to him.
For those with a cerebral venous sinus thrombosis, "heparin may be dangerous, and alternative treatments need to be given, preferably under the guidance of physicians experienced in the treatment of blood clots," Marks said Tuesday.
There are a handful of other vaccines that use the adenovirus technology, including Johnson & Johnson's Ebola vaccine. But those have been used on far fewer people than the Covid-19 vaccines. It's only when medications or vaccines are given to a huge number of people that investigators find rare side effects.
Meanwhile, identifying even a minuscule risk is a "great reflection of a system that's working," said Dr. Julie Morita, a former health commissioner at the Chicago Department of Public Health, who is the executive vice president of the Robert Wood Johnson Foundation. The Robert Wood Johnson Foundation owns stock in Johnson & Johnson, but operates independently of the company.
"The fact that the CDC and FDA have paused the vaccinations and now are working with health care providers so they know how to treat people who have these side effects, and also working to detect more of these cases," Morita said, "should give people confidence in the vaccines that are currently available."
