LONDON – The EMA’s safety committee has concluded that unusual blood clots with low blood platelets are a rare side effect of Johnson & Johnson Inc.’s COVID-19 vaccine and that a warning should be added to the label.

The decision is based on all available evidence, which currently consists of eight reports from the U.S. of serious cases of thrombosis, one of which was fatal. All cases were in people under 60 years of age, and within three weeks after vaccination, the majority in women. One case occurred during the clinical trials.

However, as with the similar reports for Astrazeneca plc’s COVID-19 vaccine, no specific risk factors have been identified.

Also in common with Astrazeneca’s vaccine, the reported cases involved unusual cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis in the abdomen, and in arteries, together with low levels of blood platelets and sometimes bleeding. “The cases reviewed were very similar to the cases that occurred with the COVID-19 vaccine developed by Astrazeneca,” the EMA said.

The reported combination of blood clots and low blood platelets is very rare, and the overall benefits of Johnson & Johnson’s vaccine in preventing COVID-19 outweigh the risks of side effects, the EMA concluded.

Around 7 million people had received the single dose Johnson & Johnson vaccine in the U.S. at the point of the data cutoff on April 5.

On April 20, Johnson & Johnson reported $100 million in sales of the vaccine in its first-quarter financial results.

Rollout of the Johnson & Johnson vaccine was on hold in Europe pending the safety review, but J&J issued an announcement shortly after the EMA’s decision, stating it will update the label as recommended and will resume shipment of the COVID-19 vaccine in the European Union, Norway and Iceland.

The vaccine’s use was suspended in the U.S. on April 13, pending a review on April 14 that was inconclusive. South Africa also earlier suspended its use, but reversed that on April 17.

The EMA has beaten the FDA to the draw in conducting its review of the U.S. cases of the serious adverse events. Emer Cooke, executive director of the EMA, said that was possible because of the agency’s earlier experience of looking into the similar cases seen with Astrazeneca’s vaccine.

“We had already done a very detailed review of Astrazeneca, which gave us the experience to come to a conclusion in the context of [Johnson & Johnson’s] vaccine,” Cooke told attendees of a press briefing.

“It was important for us to accelerate the review as the vaccine rollout was due to start very shortly,” Cooke said. “It is a very rare effect, but that also makes it very important for doctors and patients to be aware of the signs. Early intervention by a specialist can change outcomes.”

EU member states will now have to make their own decisions on how/if to roll out the Johnson & Johnson vaccine, based on the national situation in terms of the level of infections and the numbers in hospital and intensive care, and the availability of other vaccines, Cooke said.

“The benefits of the vaccine continue to outweigh the risks and now we have detailed [them] in the labeling to alert to these risks, so we are confident it can be rolled out appropriately,” said Cooke.

On April 13, Johnson & Johnson unilaterally decided to delay rollout in Europe, telling governments to store doses already received while EMA conducted its review.

Search for the causes

It is not possible to say if rare blood clots with thrombocytopenia are as common with Johnson & Johnson’s vaccine as with Astrazeneca’s. Although the EMA has a file of 287 cases relating to the Astrazeneca product, of which 142 occurred in Europe, far more doses of that vaccine have been administered, noted Sabine Straus, chair of the EMA’s pharmacovigilance committee.

The EMA also has records of 25 cases of similar rare clots in people who received the Pfizer Inc./Biontech SE vaccine, but a huge number of doses have been administered and the number of those adverse events is lower than might be expected to occur in the general population, Straus noted. The EMA is not looking at those for a safety signal.

Similarly, there is no pharmacovigilance alarm about five cases reported in people who received the Moderna Inc. vaccine.

The EMA again said one plausible hypothesis to explain the combination of blood clots and low blood platelets is an immune response that leads to a condition similar to one seen in heparin-induced thrombocytopenia (HIT), when patients mount an immune response to the anticoagulant.

Straus said that although the end result of the immune cascade has been documented, it is not known what the precise trigger is, or if the cause could be a class effect in adenoviral vectored vaccines.

While both vaccines use those vectors, Johnson & Johnson’s uses a human adenovirus and Astrazeneca’s a chimpanzee adenovirus, she noted. They also target different regions of the viral spike protein. “We see the similarities, but it is too early to draw any further conclusions,” said Straus.

If there is a class effect related to the vectors, that could have implications for the Russian Sputnik V vaccine, which uses two different human adenoviral vectors, one for each dose. The EMA currently is reviewing the Sputnik V file. “The review of the Sputnik dossier is at an early stage, so we have not got to the point of looking at pharmacovigilance reports,” Cooke said. “But we are now paying extra attention to it and it will be the responsibility of the company to submit [any adverse events].”

There remain more questions than answers about the risk factors that make anyone likely to suffer from the unusual blood clots. One of the Johnson & Johnson cases was a woman taking oral contraceptives, which is known to be a thrombosis risk. “Otherwise, we have not identified any risk factors in the Johnson & Johnson [cases],” said Straus.

The EMA has commissioned more research on risk factors, she said. “It would be extremely helpful if we had more information about what we should look out for.”