Don’t panic! J&J vaccine pause and rare blood clots: One-in-a-million risk

In “pausing” use of the Janssen vaccine, one of only three COVID-19 vaccines currently authorized for use in the US, RI is following national guidance from the federal Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC), the RI Department of Health (DoH) said in an early morning statement on Tuesday, April 13. The Janssen vaccine is also known as the Johnson and Johnson vaccine after the parent company.

The national pause results from cases of an unusual combination of blood clots and decreased platelet counts seen in six women, age 18 to 48, with onset 6 to 13 days after vaccine injection, three senior federal government doctors explained in a telephone conference call with press later Tuesday morning. One of the women died, apparently because she was given the standard treatment for blood clots, an anticoagulant or blood thinner, which in this unusual situation is likely to make the patient worse, they said, and one major reason for the pause is to get information out to the healthcare community how to treat this unusual condition if encountered; that is, blood thinners such as heparin or even aspirin, should not be given.

In a Tuesday afternoon press briefing, Nicole Alexander-Scott, director of RI DoH, said that 31,500 doses of Janssen had been administered in the state prior to the pause, which RI COVID-19 czar Tom McCarthy said represented about 5% of the total. Alexander-Scott emphasized that the adverse reaction is extremely rare and that it had been detected quickly. “It’s important to be able to relay to Rhode Islanders that the robust monitoring system that we have talked about from the beginning is demonstrating its full effect here in our ability to do this with access to data among millions of individuals who have been vaccinated. Because, again, this is a result of six cases out of 6.85 million doses nationally that have been administered.”

Alexander-Scott distinguished the mild flu-like symptoms that often occur in the first few days after vaccination from the more severe symptoms of the rare blood clotting problem that can occur at least six days and up to three weeks after vaccination, with a median onset of nine days. “It’s a combination of the clotting, the low platelets, and the symptoms that patients would watch for: of severe headache, abdominal pain, leg pain or shortness of breath,” she said. “It’s also important to note that the symptoms that I’ve mentioned as a part of this presentation are very different from the mild flu-like symptoms that people experience within a few days after receiving vaccine… Usually the the mild flu-like symptoms that can occur are within that very short window, those few days right after vaccination.

“We would not want to have everyone who’s had Johnson and Johnson just rushing to their provider to be evaluated because of how rare this seems to be. However, we do want to ensure that both patients and providers are informed and equipped with the information of what to monitor for,” said Alexander-Scott, cautioning against public alarm especially among those recently receiving the Janssen vaccine.

Anyone already given the Janssen vaccine, Alexander-Scott said, should not panic. “If you were vaccinated with the Johnson and Johnson vaccine more than a month ago, that’s before March 13, your risk is extremely low for having any sort of complications or challenges… The time frame of six days to 13 days after vaccination makes it such that if you are significantly past that, more than a month ago, of getting vaccinated, your risk is extremely low. If you have been vaccinated with Johnson and Johnson vaccine in the last three weeks, your risk is also very low, given that overall data point, one for every million vaccinated.”

Both Alexander-Scott and McCarthy agreed that the pause would have little practical effect in RI. In response to a question from Motif whether even the temporary loss of the only authorized single-dose vaccine would make it harder to vaccinate people for whom getting them to the second dose might be challenging, especially those in lower socio-economic strata, in hard-hit communities, prisoners, home-bound individuals and the homeless, “We anticipate and certainly look forward to this pause being brief so that it has minimal impact on how valuable Johnson and Johnson is for being able to provide some of the protections in, across the board, the individuals that have had very allergic reactions to vaccines in the past and just want one [dose] or those who are home-bound or hospitalized, or otherwise. We are anticipating that, in the long term, we’ll be able to continue with the appropriate safety mechanisms in place, but, if that were to not be the case, we would be prepared to adjust as we needed to and as we were planning to prior to Johnson and Johnson being available, working with our partners and determining ways that would allow us to ensure that would help ensure that people are able to return to get their second dose,” Alexander-Scott said. “Whether it’s Johnson and Johnson, Moderna or Pfizer, we will make it work.”

McCarthy said, “As we’ve shared over the last few weeks, the amount of Johnson and Johnson vaccine coming into Rhode Island has decreased significantly. Two weeks ago we received 16,000 doses, last week that number decreased to about 6,000, and this week we’re only receiving 2,000 doses of Johnson and Johnson. Now those 2,000 doses are in addition to 1,400 of the Johnson and Johnson vaccine that we’ve carried over from last week for a total of 3,400 doses that are currently in the state.” Most of the patients scheduled for the Janssen vaccine would be switched to one of the others at the same time and place, McCarthy said, with the exception of about 300 appointments at three local pharmacies or clinics without the cold storage and other facilities needed for the other vaccines, naming the Rhode Island Free Clinic, Green Line Pharmacy, and White Cross Pharmacy; those patients were being contacted individually. He said he had no concern about waste of vaccine as a result of the pause: “No, none at all. The team has done a fantastic job. Our waste is well below even one-tenth of a percent at this point.”

Janet Woodcock, acting FDA commissioner, said on the morning call that she expected the pause to be brief. “The time frame will depend obviously, on what we learn in the next few days. However, we expect it to be a matter of days for this pause.”

Although only six individual cases have been reported in the US out of nearly 7 million doses administered of the Janssen vaccine, fewer than one per million, US regulators are recommending the national pause because the unusual adverse reaction essentially never occurs naturally and appears to be similar to an adverse reaction to the AstraZeneca-Oxford (AZ-O) vaccine observed in 222 cases out of 34 million dose administrations as of April 4, a rate of about one per 100,000 recipients; the AZ-O vaccine is not yet authorized for use in the US, but as of March 22 European regulators had conducted reviews of 86 of the cases, of which 18 were fatal.

“The combination here, that’s the real thing that is so notable here,” said Peter Marks, the director of the FDA Center for Biologics Evaluation and Research, on the call. “Those two things [blood clots and low platelet counts] can occur. It’s their occurrence together that makes a pattern, and that pattern is very, very similar to what was seen in Europe with another vaccine. So I think we have to take the time to make sure we understand this complication, and we address it properly.” He emphasized that it was critical to avoid the use of blood thinners in treating the unusual adverse reaction: “Together, the CDC and the FDA are reviewing data involving six reports of a rare type of blood clot called cerebral venous sinus thrombosis, or CVST, in combination with low levels of platelets in the blood, called thrombocytopenia… Treatment of this specific type of blood clot is different from typical treatments for other types of blood clots, which usually involve an anticoagulant called heparin. With cerebral venous sinus thrombosis, heparin may be dangerous and alternative treatments need to be given, preferably under the guidance of physicians experienced in the treatment of blood clots.”

In fact, before the emergence of what is coming to be called “vaccine-induced immune thrombotic thrombocytopenia” or “VITT,” almost all previously observed cases of the same unusual combination of blood clotting and low platelet count was caused by heparin, a rare autoimmune syndrome known as “heparin-induced thrombocytopenia” or “HIT.”

Alexander-Scott was even more emphatic about the need for the pause to allow reaching out to patient-facing health care providers: “One of the elements that is different about the thrombosis that has been identified in these six cases is, clinically, we would usually treat thrombosis with the medication referred to as heparin. Being able to pause with just the six that we have to get the message out to all providers that this presentation is leading to not using heparin as a treatment option. Being able to get that message to providers has been a critical element of this and warranted the pause so that we could make that clear, because that is a definitive shift from how we would usually treat such a condition identified.”

None of the worldwide cases occurred in anyone age 50 or older, and many countries have resumed use of the AZ-O vaccine with an age floor between 50 and 60 depending upon the country, based upon an assessment of risks versus benefits, taking into consideration that older people are more vulnerable to hospitalization and death from COVID-19 as well as apparently less susceptible to the particular adverse reaction.

The CDC will convene its Advisory Committee on Immunization Practices (ACIP), an independent panel of outside experts, on Wednesday, April 14, said Anne Schuchat, principal deputy director of the CDC, on the morning call, and they could choose to recommend age or other restrictions for the Janssen vaccine as other countries have done for the AZ-O vaccine. The meeting will be broadcast live on the web – ustream.tv/channel/VWBXKBR8af4 – 1:30-4:30pm ET. [UPDATE: After running long by an hour, at 5:30pm the ACIP reached a consensus that there was insufficient data to vote on any recommendation, and so decided to allow the pause to continue until they could schedule another meeting to be held in 7 to 10 days, hoping that clearer quantitative evidence of risks would develop.]

“We are committed to an expeditious review of the available information and to an aggressive outreach to clinicians so that they know how to diagnose, treat and report. One of the things that the ACIP deliberation will do is review the data on the cases and the context of risks, benefits and possible subsets of the population that may be in a different category. So I think our intent is, in the days ahead, to provide an update regularly and that the pause provides us time for deliberation and assuring appropriate diagnosis and treatment,” she said.

The Janssen and AZ-O vaccines use similar delivery vectors to produce immune response in the body, although using different carrier adenoviruses. The Pfizer-BioNTech and Moderna vaccines, the only remaining COVID-19 vaccines currently authorized for use in the US, both use a messenger RNA (mRNA) delivery vector and not an adenovirus. Marks said that the adverse reaction was strongly likely to be induced by vaccine rather than coincidence, given its near-zero occurrence naturally. “It’s plainly obvious to us already that what we’re seeing with the Janssen vaccines looks very similar to what was being seen with the AstraZeneca vaccines. The AstraZeneca is a chimpanzee adenoviral-vectored vaccine. The Janssen is a human adenoviral-vectored vaccine. So I think we can’t make some broad statement yet. But obviously, they are from the same general class of viral vectors.”

There are hypotheses about the cause of the unusual adverse reaction but little is known with confidence. Marks said, “We don’t have a definitive cause, but the probable cause that we believe may be involved here that we can speculate is a similar mechanism that may be going on with the other adenoviral-vectored vaccine [AZ-O] is that this is an immune response that occurs very, very rarely after some people receive the vaccine, and that immune response leads to activation of the platelets and these extremely rare blood clots.” Woodcock agreed, “The person being vaccinated makes an immune response potentially that actually involves their own platelets or other parts of the coagulation system, and can cause this problem. And that’s the sort of leading theory or hypothesis about what’s going on here.”

“Just to remind clinicians and the public that 121 million people have been vaccinated with at least one dose of one of the three vaccines, and the vast majority of the doses were of the other two products, the Pfizer and Moderna products. With our intensive safety monitoring, we have not detected this type of syndrome with the low platelets among the other vaccines” authorized in the US, Schuchat said.

Despite all of the US cases so far occurring in women of child-bearing age, Marks said, the vaccine-induced adverse reaction is unlikely to be associated with that, because the type of blood clots sometimes seen as side effects from oral contraceptives are substantially different in both loci and absence of correlation with low platelet count. “It’s not clear that there’s any association with the oral contraceptive pill, birth control, in the individuals who had these blood clots,” Marks said, pointing out that generalizing from only six cases was impossible. “Additionally, I think it’s too early to make any speculation on how many cases will come out.”

Schuchat agreed with Marks, “We’re working right now from a small number, from the six events that have been reported here in the US, and so while we’re seeing them in women under 50, I think we are going to need to take some time and have our Advisory Committee on Immunization Practices take additional time to review. My understanding is that there weren’t predisposing conditions for these events in at least some of those individuals.” Asked to clarify, she said, “What I tried to say is there were not [predisposing conditions] in all of them. So not to say that there may have been in some, but I think my main point is that review of six is difficult to make generalizations from. We’re going to have our expert committee take a careful look, and we’re, of course, trying to assure that providers will report suspect episodes so that they can be further investigated, because the numbers are quite small, small enough that it’s hard to generalize, but large enough that we wanted to take the action with the pause.”

In response to a question from Motif whether the Janssen pause could increase vaccine hesitancy, even if fears were irrational and unfounded given the one-in-a-million risk, and what effect that might have in RI on his previously stated goal of reaching 70% of everybody eligible to be vaccinated by May 15 and 70% of the entire population by June 5, especially because in order to reach 70% of the entire population of the state we have to reach about 84-85% vaccine take-up in those eligible to be vaccinated, McCarthy said, “Absolutely, and that’s something that’s top of mind for me. It’s ambitious but it’s absolutely achievable, and why I am confident in it is that among those groups of Rhode Islanders that are currently eligible, we have seen uptake rates around that mid-80th percentile. So I think it’s absolutely doable and achievable, but the important thing is we all have a part to play, whether it be getting vaccinated, having conversations with your loved ones, your neighbors, folks in the community, to make sure that people are educated, they have the facts, I find that there’s a tremendous amount. It’s something we’ve seen throughout the pandemic, just based on how dynamic it is and how quickly things change. There is a lot of information out there, making sure we get the right information, the facts to build that confidence, is going to be important. Again, before even this consideration, we knew that it was going to have to take a deliberate intentional community effort to achieve those goals. I don’t think that has changed. I do think though this gives us an opportunity to focus some of our conversations even more about some of the specific safety and impacts of the different vaccines.”