FDA Needs More Data to Decide on J&J Vaccine Clotting Problem

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The U.S. Food and Drug Administration (FDA)’s Advisory Committee on Immunization Practices (ACIP) met yesterday to make a recommendation on the current pause of the Johnson & Johnson COVID-19 vaccine. The committee, however, declined to make a recommendation, indicating they needed more information about the rare blood clots observed in a handful of patients.

Both the AstraZeneca-Oxford and Johnson & Johnson COVID-19 vaccines have been associated with extremely rare, but potentially life-threatening blood clots that were observed in six cases out of almost 7 million doses. The FDA and the Centers for Disease Control and Prevention (CDC) have recommended a pause in the use of the J&J vaccine in the U.S. The AstraZeneca vaccine is not yet authorized in the country, with several European countries halting the distribution of that vaccine as well.

ACIP reported that they would look for a time to meet again in the next seven to 10 days, so the vaccine rollout won’t be delayed unnecessarily if they decide it’s safe.

“We will find a time to reconvene,” said ACIP executive secretary Amanda Cohn. “We will try to identify what that date is by Friday of this week so that people have a little bit more time to get it on the calendars.”

The blood clots are called cerebral venous sinus thromboses (CVST). The cases were a 45-year-old woman who died; a 38-year-old who has yet to recover; an 18-year-old woman still unrecovered; a 48-year-old woman yet to recover; a 26-year-old woman yet to recover; and a 28-year-old woman whose status is unknown. There may be a seventh case, a 59-year-old who hasn’t recovered, but her blood clots are different from the others.

“I’d like to reiterate that based on the current data, Janssen believes the overall benefit-risk profile for our vaccine is positive across the population for which it’s authorized," Aran Maree, chief medical officer for pharmaceuticals at J&J’s Janssen vaccine division, told ACIP. "We strongly support ensuring awareness of the signs and symptoms of this very rare event, as well as recommendations to ensure the correct diagnosis, treatment and reporting by health care professionals.”

The recommendation for appropriate treatment may be the most important part. Typically blood clots would be treated with the blood thinner heparin, but in the case of these unusual and rare clots, heparin makes things worse. Four of the six cases were treated with heparin when they first developed symptoms.

Members of ACIP noted that they didn’t want to vote for or against the use of the vaccine, they just didn’t have enough information. 

“I do not want to vote on this issue today,” said Beth Bell, a clinical professor at the University of Washington in Seattle, at the meeting. “I do not want to vote not to recommend the vaccine – I think that is not really something I necessarily believe. I just don’t feel there’s enough information to make an evidence-based decision. We won’t have all the information, but I think there are some things that we can gather relatively quickly, which all have to do with the benefit/risk balance.”

One thing Bell also noted was that it was not clear if the blood clots observed in the people who received the J&J vaccine were the same as the ones seen in the UK and Europe in people who received the AstraZeneca vaccine.

The vaccines have not been definitively tied to the clots, and there are currently only theories as to why the vaccines might cause these rare blood clots.

The J&J and AstraZeneca vaccines are built on an adenovirus, one from chimpanzees for the AstraZeneca, human for J&J. The adenovirus is a common cold virus, and is used as a vector to carry a gene for the COVID-19 virus’s spike protein. Once injected, it manufactures the spike protein, where the immune system is programmed to identify it and attack it if it sees it again.

Although there is not enough data to know for certain, the predominant theory to the blood clots is an unusual and rare immune response similar to heparin-induced thrombocytopenia (HIT). In HIT, the immune system produces reacts to a complex of heparin and platelet factor 4 (PF4), which results in platelets clotting. There is some evidence that the patients involved had antibodies to PF4.

University of Greifswald (Germany) researchers began calling the mechanism of clots in the AstraZeneca case vaccine-induced prothrombotic immune thrombocytopenia, but are now calling it vaccine-induced immune thrombotic thrombocytopenia (VITT). There is currently not enough data to know if this is correct or if the clots associated with the J&J vaccine have a similar mechanism, assuming that the vaccine is the cause of the clots.

DNA has a negative charge, just like heparin, which might help in binding it to PF4, which has a positive charge. That bound complex may trigger the production of antibodies, which could flag the body to increase blood coagulation.

But they also theorize that these patients may have antibodies already present and the vaccines just boost them. Additional work will need to be conducted. 

Not all members of the committee supported the pause.

“We are in a situation where not making a decision is tantamount to making a decision,” Nirav Shah, director of Maine’s Center for Disease Control and Prevention and representative for the Association of State and Territorial Health Officials, said.

Camille Kotton of Massachusetts General Hospital and Harvard Medical School also questioned the pause. “Putting the vaccine on pause for those of us that are frontline health care workers has really been devastating. I agree in general that we don’t have data to make a decision at this time. But we were planning on using this vaccine in the state of Massachusetts for people who are homebound and otherwise not able to get a vaccine. We were planning on using it for our vulnerable in-patient population often with many comorbidities and at high risk for disease but who haven’t been able to get vaccinated otherwise. And then it was certainly going to be used in what may be otherwise underserved populations or populations that aren’t able to get mRNA vaccines.”

Another member of ACIP, Paul Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia called it “an unfortunate non-decision.”

He went on to say, “One thing they could have said was, ‘Just explain to people that there is this very rare, but very real side effect, remembering that of every million people that get Covid, 1,850 will die.’ There are no risk-free choices —just choices to take different risks.”

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