J&J COVID-19 Vaccine Pause Expected To Be Brief, But Subsequent Use May Be Restricted
Executive Summary
CDC’s ACIP likely to discuss criteria needed to lift pause and whether to recommend that the vaccine not be used in specific groups. Former CBER official says FDA and CDC will look at reports for other adenovirus vector vaccines, including J&J’s Ebola vaccine, and the biological plausibility that cases of rare blood clots are directly associated with the vaccine.
The US Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices will take the immediate next steps to determine what happens with Johnson & Johnson’s COVID-19 vaccine following the call for a pause in its administration. Experts believe use of the vaccine will resume as government agencies continue to investigate the cause of severe rare blood clots in women aged 18 to 48 and that there is a possibility a subgroup will be directed to use other vaccines.
Norman Baylor, former director of the Office of Vaccine Research and Review in the FDA’s Center for Biologics Evaluation and Research, said ACIP, which is meeting on 14 April, will probably discuss how long the pause should last, the criteria needed to lift it, and if there should be a formal recommendation not to use the vaccine. He said the committee could recommend that Pfizer Inc. and Moderna, Inc.’s COVID-19 vaccines be used in this age group, continue the pause until there is more information, or go further and recommend not using the vaccine at all.
“Just based on benefit-risk,” one would continue using the vaccine, he said, with a caution for those in the category of people who have had the rare adverse event.
The US Food and Drug Administration and CDC announced on 13 April that there have been six reported cases in the US of a rare blood clot called cerebral venous sinus thrombosis (CVST) seen in combination with low levels of platelets in individuals who received J&J’s vaccine. All the cases occurred in women between the ages of 18 and 48, with symptoms appearing six to 13 days after vaccination. The agencies said that they were recommending a pause in the use of the vaccine “out of an abundance of caution” until ACIP’s review and FDA’s investigation of the cases is completed.
The six cases were reported in the Vaccine Adverse Event Reporting System (VAERS), which is co-managed by FDA and CDC. The grand dame of vaccine safety surveillance, VAERS has been joined by several new systems aimed at monitoring the massive rollout of the coronavirus vaccines. (Also see "Pandemic Perspectives: Safety Monitoring Boost For COVID Vaccines Creating ‘A New Normal’ For Pharmacovigilance" - Pink Sheet, 12 Mar, 2021.)
Baylor, who is now president and CEO of Biologics Consulting, said that as part of their investigation, the agencies will look at adverse event reports with other vaccines as well, including J&J’s Ebola vaccine and other investigational adenovirus vector vaccines. He said there may have been adverse event reports in clinical trials, though it takes millions of doses to see such rare events. “I’m not optimistic that you will see something with these, but you have to look,” he said.
AstraZeneca PLC’s COVID vaccine also uses an adenovirus vector and has been restricted in various ways in Europe after reports of blood clots in younger recipients. The company has yet to seek emergency use authorization in the US. (Also see "France To Replace AstraZeneca Booster With mRNA Jab In Under-55s" - Pink Sheet, 12 Apr, 2021.)
For the J&J shot, FDA and CDC will also evaluate the biological plausibility that the adverse event is directly associated with the vaccine and try to find out what is causing it and if there is something about the individual that prompts the reaction, Baylor said.
Restrictions In Age Group Are ‘Entirely Conceivable’
Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, spoke about J&J’s vaccine at the White House’s 13 April daily press briefing. He said calling for the pause allows FDA and CDC to further investigate the cases of blood clots to understand their mechanisms and get more details on the individuals involved. He said they are looking for clues of other things that are going on and whether there are common denominators among women who had the adverse events.
Fauci noted that there have been six cases among 6.85m doses of J&J vaccine distributed in the US, which he said is “less than one in a million.”
Asked if women under the age of 50 should be excluded from receiving J&J’s vaccine, he said “it is entirely conceivable, making no predictions, that there may be some restriction in an age group or not. We don’t know that now.”
He was also asked if he was ruling out the possibility that the vaccine could be removed from the market. “I think it would be premature to comment on that,” he replied. “I wouldn’t want to speculate as to what would happen. Often, when you see things like this, that you pause and come back. Whether or not that happens now, I can’t guarantee it. But I can tell you that’s exactly what the CDC and FDA people are going to be deciding on and looking at very carefully.”
At an FDA-CDC press briefing earlier that morning, FDA Acting Commissioner Janet Woodcock said how long the pause lasts will depend on what the government learns but she expects it “to be a matter of days.” She also commented that there were too few cases to determine if there is a subpopulation at more risk.
FDA’s handing of the situation was praised by White House officials later in the day. (See sidebar for story.)
At the morning briefing, Peter Marks, director of FDA’s Center for Biologics Evaluation and Research, said the agencies don’t know the definitive cause of the blood clots but the probable cause is a mechanism going on with other adenovirus vectors, in which an immune response occurs after vaccination leading to activation of platelets and blood clots. He noted that the background rate of cerebral venous sinus thrombosis is probably between two and 14 per million people in the setting of a normal platelet count.
“The real thing that is so notable here is not just the cerebral venous sinus thrombosis or the thrombocytopenia. Those two things can occur. It’s their occurrence together that makes a pattern," Marks said.
Are Adverse Events A Class Effect?
FDA and CDC officials noted that the recommendation for a pause in administration of J&J’s vaccine was made in part to ensure that the healthcare provider community is aware of the potential for this adverse event and can plan for proper management. Marks said that if one administers the standard treatment for blood clots, heparin, “one can actually cause tremendous harm or the outcome can be fatal.”
Asked whether the adverse event is a class effect with adenovirus vector vaccines, Marks said, “I hesitate to call it a class effect but it’s plainly obvious to us already that what we’re seeing with the Janssen vaccine looks very similar to what was being seen with the AstraZeneca vaccine.” AstraZeneca's vaccine is a chimpanzee adenoviral vector vaccine and J&J’s Janssen unit’s vaccine is a human adenoviral vector vaccine.
Marks also underscored that the pause is a recommendation, not a mandate. If an individual healthcare provider has a conversation with an individual patient and they determine the benefit-risk for that patient is appropriate, the government isn’t going to stop the provider from administering the vaccine, he said.
The CDC and FDA officials noted that cerebral venous sinus thrombosis has not been seen with Pfizer and Modern’s vaccines.
CDC principal deputy director Anne Schuchat said she understood that the women who had blood clots after taking J&J’s vaccine did not have a predisposed condition. Marks also said that at this time it is not clear that there is any association of the adverse event with oral contraceptive pills.
Possible EUA Review?
Arthur Caplan, professor of bioethics at New York University Grossman School of Medicine, said there is not enough information right now to call for restrictions on use of the vaccine in a subgroup, but he said that could be coming.
“In light of not knowing what is going on,” the agencies may recommend using other vaccines instead, he said. He noted that there also may be calls for reexamination of the emergency use authorization (EUA) for J&J’s vaccine.
He said there is a “very remote” possibility that the EUA may be withdrawn if questions about the vaccine cannot be answered, but it is more likely that the pause will come to an end and the association with blood clots will likely not hold.
The coronavirus pandemic has seen an eruption in the number of EUAs used compared to past public health crises. The vast expansion has lead to questions about how the mechanism might be adjusted based on the COVID experience, and how the profusion of the pathway might change the FDA’s baseline operations.
J&J Pauses European Rollout, Vaccine Trials
J&J issued a statement saying it had decided to proactively delay the rollout of its vaccine in Europe and pause vaccinations in all COVID-19 vaccine trials while it updates guidance for investigators and participants.
“We have been working closely with medical experts and health authorities, and we strongly support the open communication of this information to healthcare professionals and the public,” the company said.
In a 13 April note, SVB Leerink analysts said they expect ACIP will recommend a demographic-based restriction to the recommendation for use, e.g., not recommended for women under 50 years of age. They said there is likely to be a follow-up meeting of FDA’s Vaccines and Related Biological Products Advisory Committee where specific labeling and communications to providers is likely to be discussed.
They also said they believe that any finding of increased risk for J&J’s vaccine by the FDA makes US approval of AstraZeneca’s COVID-19 vaccine even less likely than they previously expected.
“Regardless of the outcome of the ACIP meeting and other labeling changes, we expect use of J&J’s vaccine to plummet, and be replaced with increased utilization of the two mRNA products” from Pfizer and Moderna, they stated.
Morningstar Equity Research analysts said in another note that they expect the pause to be temporary because of the rarity of the adverse events.
“Under the worst-cancer scenario, where the J&J vaccine is removed from the market, we believe enough alternative vaccines are available to only slightly delay herd immunity in the U.S. from early June to late June. However, globally, the potential loss of the vaccine would be more pronounced, given the ease of one-dose delivery and easier storage conditions,” they said.