The FDA Calls for Pausing the Use of the Johnson & Johnson COVID-19 Vaccine

The United States Food and Drug Administration (FDA) and the Centers for Disease Control (CDC) have recommended pausing the use of the Johnson & Johnson (Janssen) COVID-19 vaccine. In addition, Janssen has declared that it will "proactively delay" the rollout of the vaccine in Europe.

To date, six cases of blood clots in combination with low platelets have been reported in recipients of the Janssen COVID-19 vaccine. All of the cases reported have occurred in women.

"In these cases, a type of blood clot called cerebral venous sinus thrombosis (CVST) was seen in combination with low levels of blood platelets (thrombocytopenia). All six cases occurred among women between the ages of 18 and 48, and symptoms occurred 6 to 13 days after vaccination," the FDA statement reads.

COVID-19 vaccines and blood clots: What do we know?

The announcement echoes recent events in Europe where the rollout of the Oxford–AstraZeneca COVID-19 vaccine Vaxzevria (research name ChAdOx1-S [recombinant]) was halted by certain European leaders after reports of blood clots. Last week, the European Medicines Agency (EMA) declared that the overall benefit-risk remains positive for Vaxzevria: "The reported combination of blood clots and low blood platelets is very rare, and the overall benefits of the vaccine in preventing COVID-19 outweigh the risks of side effects." The agency stated that unusual blood clots with low blood platelets should be listed as a very rare side effect of the AstraZeneca vaccine.

The Oxford–AstraZeneca and Janssen COVID-19 vaccines are manufactured using the same technology platform: adenoviral vectors. However, they use two different adenoviral vectors to transport the spike glycoprotein gene into the vaccine recipients' arm.

Viral vectors are commonly adopted to deliver genetic material into cells. Could the specific technology that is being used in the AstraZeneca–Oxford/ Janssen COVID-19 vaccines be behind the rare clotting incidents? At Present it is too soon to draw any firm conclusions or to identify a causal link.

Professor Adam Finn from the University of Bristol said, "The numbers of cases are, once again, very small but the combination of severe thrombosis with thrombocytopenia is characteristic of the cases that have been reported previously […] This development does raise the possibility that at least some adenovirus vectors, either of themselves or in combination with the SARS-CoV-2 spike protein gene, can cause this idiosyncratic reaction in a very small proportion of individuals."

A recent paper published in The New England Journal of Medicine by Andreas Greinacher and colleagues explored the pathogenesis of the unusual clotting disorder observed in individuals from Germany and Austria that had received the Oxford–AstraZeneca COVID-19 vaccine. In this study, 28 patients tested positive for an antibody that binds to a molecule known as platelet factor 4, or PF4.

"Interactions between the vaccine and platelets or between the vaccine and PF4 could play a role in pathogenesis. One possible trigger of these PF4-reactive antibodies could be free DNA in the vaccine," the authors write in the paper. Greinacher said that it "resembles a syndrome in which similar antibodies can be triggered by the blood-thinning treatment heparin".

Based on the necessity of COVID-19 vaccines to navigate the global pandemic, Finn regarded the investigation of this phenomenon as now being an "extremely urgent international priority". Accordingly, the FDA press release states that the CDC will convene a meeting of the Advisory Committee on Immunization Practices (ACIP) "to further review these cases and assess their potential significance."

It is important to remember that these incidents are rare

Dr Carlos del Rio, executive associate dean of the Emory University School of Medicine at Grady Health System emphasized that the reports of unusual blood clotting in COVID-19 vaccine recipients are still extremely rare: "It's a very rare event. You are talking about one per million, and when you give millions of doses of vaccines, you will see events like this that you couldn't see in the clinical trial just because you didn't have millions of people enrolled."

del Rio's thoughts are further echoed in the FDA's statement which reads, "Right now, these adverse events appear to be extremely rare. COVID-19 vaccine safety is a top priority for the federal government, and we take all reports of health problems following COVID-19 vaccination very seriously."

"You are talking about one per million, and when you give millions of doses of vaccines, you will see events like this that you couldn't see in the clinical trial just because you didn't have millions of people enrolled," – Dr Carlos del Rio.

The decision to pause the rollout has therefore been interpreted as "highly precautionary" by some, including Dr Peter English, retired consultant in communicable disease control, who said, "The regulators will be trying to estimate how many such cases would have been expected by chance, and thus what the risk (if any) of vaccination would be […] Even if all of the cases were caused by the vaccine, the risk of less than one in a million would have to be set against the benefits of protection from COVID-19 disease; a disease which, in itself, causes clotting in many cases."

English is concerned as to the potential impact that the call for a pause may have on confidence in vaccination. "We must hope that, if it does, this will be temporary; and that the rapid action and openness will inspire confidence that vaccine safety is taken extremely seriously.”