Scientists are exploring why some individuals who receive certain coronavirus vaccines develop a serious type of blood clot, with emerging research suggesting it may have something to do with the technology used to develop the vaccines.

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Regulators pause AstraZeneca, J&J vaccines

According to STAT News, two vaccines—one developed by AstraZeneca and the University of Oxford, and another developed by Johnson & Johnson (J&J)—have come under scrutiny in recent weeks amid reports that, in very rare instances, patients who've received either vaccine developed a serious type of blood clot called cerebral venous sinus thrombosis (CVST). 

To review these cases more closely, regulators in Europe have temporarily suspended use of AstraZeneca's vaccine, which has not yet been authorized for use in the United States, noting that it may be linked to roughly 169 cases of CVST out of the 34 million AstraZeneca shots administered in the European Economic Area. Similarly, U.S. officials this week recommended pausing the use of J&J's vaccine, which has been linked to six cases of CVST among the nearly 7 million people who've received that vaccine so far.

Instances of the clots remain extremely rare for both vaccines. However, researchers are investigating whether there's any link between the vaccine itself and CVST, and whether such blood clots could occur with any other vaccines in use or authorized in the future.  

Two new papers published this week in the New England Journal of Medicine examining the AstraZeneca vaccine appear to provide a partial, though tentative, explanation, according to STAT News.

A potential link to adenovirus?

According to STAT News, the papers found that the instances of CVST occurring in the handful of patients who've received the AstraZeneca vaccine are very similar to the rare blood clots occasionally seen among patients treated with the blood thinner heparin.

Specifically, the papers found that some patients who developed CVST after receiving the AstraZeneca vaccine had high levels of antibodies to platelet factor 4, an important clotting protein. Those antibodies were the same type seen among the rare patients who develop clots after being treated with heparin. While that explanation doesn't specify why the AstraZeneca vaccine may be producing those antibodies or whether other vaccines will similarly do so, it does provide a launch pad for the leading hypothesis, the Los Angeles Times reports: certain patients are experiencing a reaction to the adenovirus used to develop the vaccine. 

According to STAT News, all currently authorized vaccines in the United States and Europe teach the body to generate antibodies to the spike protein in SARS-CoV-2 that causes Covid-19. The vaccines developed by Pfizer-BioNTech and Moderna use mRNA for this function. However, both the AstraZeneca vaccine and the J&J vaccine used different variations of an adenovirus—effectively, a cold virus stripped of its ability to sicken—to sneak genetic coding for the spike protein into an individual's cells, effectively teaching their body how to identify and attack the spike protein.

Paul Offit, the director of the Vaccine Education Center at Children's Hospital of Philadelphia and member of an FDA committee involved in reviewing vaccine data, said researchers are not yet sure how the adenovirus is generating this response in a few vaccine recipients, whether it's mimicking platelet factor 4, or whether other types of adenoviruses could do the same. But he suspects it's linked.

"There is going to be something about the adenovirus—whether it's adenoviral DNA or an adenovirus protein—that complexes with platelet factor 4," he said. "So that will be determined, I suspect soon."

Separately, Theodore Warkentin, a professor at McMaster University, co-author on one of the NEJM papers and an expert on the clots caused by heparin, said free DNA—that is, DNA not included in the virus—may, if exposed to platelet factor 4, itself cause the immune system to develop antibodies against platelet factor 4. If so, it's unclear that risk would vary among vaccines.

Officials continue investigations

For now, FDA is assessing data from clinical trials of several vaccines that use these viral vectors, including J&J's Ebola vaccine. 

Peter Marks, director of FDA's Center for Biologics Evaluation and Research, said while he was hesitant to say the blood clot issues are a "class effect" shared by all adenovirus vector vaccines, "[i]t's plainly obvious to us already that what we're seeing with the [J&J] vaccine looks very similar to what was being seen with the AstraZeneca vaccine." He added, "We can't make some broad statement yet, but obviously, they are from the same general class of viral vectors."

However, John Moore, a professor of microbiology and immunology at Weill Cornell Medical College, said while assessing whether there is a common link to the adenoviruses is "a reasonable speculation, and it's a line of research and investigation," that "doesn't mean it's proven."

According to Reuters, other researchers around the globe are investigating different avenues as well, such as whether the SARS-CoV-2 virus itself could affect coagulation.

"There are many hypotheses, and some of them may play a role," Eric van Gorp, a virologist at Erasmus Medical Centre in Rotterdam, said. "We are at the beginning, and—as it goes in research—it may be that we can find the clue at once, or it may be that it goes step by step."

Experts balance transparency, messaging

Ultimately, however, officials in their investigations and messaging are trying to balance the benefits of vaccination and the potential risks of serious—although rare—side effects, STAT News reports.

David Juurlink, head of the division of Clinical Pharmacology and Toxicology at Sunnybrook Health Sciences Centre in Canada, pointed out that many people accept the risk of serious side effects to very common medications, such as NSAIDs and sleeping aids, without a second thought.

"No one even thinks about this," he said. "They want their pain gone, they take something they can get without having to interact with a doctor or let alone a health professional. And people sometimes die over this."

In comments he made before U.S. officials recommending pausing use of J&J's vaccine, Juurlink said that for some patients, the risks of the AstraZeneca vaccine are outweighed by its benefits. "'Any port in a storm' is a little bit trite to say, but if the only vaccine a 52-year-old who's carrying a few extra pounds and maybe has diabetes can get is the AstraZeneca vaccine, I still think that that is the right call."

Separately, Behnood Bikdeli, a cardiologist at Harvard Medical School and Brigham and Women’s Hospital who studies clotting and Covid-19, said, "The more challenging issue is how do we make a responsible, right communication to the public. We want to be transparent, but we want to make sure that we're not scaring people out of proportion. In order of magnitude, the problem is Covid" (Herper, STAT News, 4/13; Lauerman/Langreth, Bloomberg, 4/14; Steenhuysen/Kelland, Reuters, 4/13; Healy, Los Angeles Times, 4/13).