COVID-19 vaccine safety monitoring: The J&J vaccine and blood clots

Long ago (seemingly, at least, when in this pandemic months can seem like years), I—and many other vaccine advocates—warned that when safe and effective COVID-19 vaccines finally rolled out there would be adverse reactions and even deaths reported after the vaccines, that these events would be sensationalized by the news media, and that they would be weaponized by the antivaccine movement. This has come to pass even beyond what I had anticipated. Examples abound, ranging from Bell’s palsy to cardiac events to immune thrombocytopenia purpura (ITP) to, yes, deaths, with antivaxxers like Robert F. Kennedy, Jr. regularly mining the Vaccine Adverse Event Reporting System (VAERS) in order to make it seem as though COVID-19 vaccines are dangerous and that “they” are covering it up, even though, as I and others have pointed out, these adverse events were not occurring above the expected baseline rate and have not been shown to be related causally to the vaccines. Our message was that, any time tens or hundreds of millions of doses of a vaccine are administered, the law of very large numbers dictates that there will be deaths and adverse events that occur after that vaccine by random chance alone, because coincidence is far more common than people believe. We also warned that it will take time to disentangle whether any given adverse event observed after COVID-19 vaccines could plausibly be causally related, particularly for rare adverse events, which brings us to the announcement yesterday from the FDA and CDC about the decision to pause the rollout of the Johnson & Johnson COVID-19 vaccine due to the reporting of rare instances of blood clots after the administration of this vaccine.

Let’s look at the press release yesterday from the FDA and CDC:

As of April 12, more than 6.8 million doses of the Johnson & Johnson (Janssen) vaccine have been administered in the U.S. CDC and FDA are reviewing data involving six reported U.S. cases of a rare and severe type of blood clot in individuals after receiving the J&J vaccine. 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. Treatment of this specific type of blood clot is different from the treatment that might typically be administered. Usually, an anticoagulant drug called heparin is used to treat blood clots. In this setting, administration of heparin may be dangerous, and alternative treatments need to be given.

CDC will convene a meeting of the Advisory Committee on Immunization Practices (ACIP) on Wednesday to further review these cases and assess their potential significance. FDA will review that analysis as it also investigates these cases. Until that process is complete, we are recommending a pause in the use of this vaccine out of an abundance of caution. This is important, in part, to ensure that the health care provider community is aware of the potential for these adverse events and can plan for proper recognition and management due to the unique treatment required with this type of blood clot.

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. People who have received the J&J vaccine who develop severe headache, abdominal pain, leg pain, or shortness of breath within three weeks after vaccination should contact their health care provider. Health care providers are asked to report adverse events to the Vaccine Adverse Event Reporting System at https://vaers.hhs.gov/reportevent.html.

I had a couple of reaction to the news stories about this, and my reaction evolved as the day went on. You see, I had a busy operating room day yesterday, which, fortunately, meant that I didn’t obsess over this story because I couldn’t. I had to concentrate on the operations at hand. Unfortunately, though, the turnaround time in our particular operating room can sometimes be…suboptimal. That meant that, even after I had time to talk to patients’ families, make sure that each patient was doing alright in the recovery room, and talk to the next patient, there was still plenty of time to peruse Twitter between cases for new developments, particularly in the afternoon, when, due to a backup of patients in the recovery room, there was a rather long delay of my last case.

The FDA and CDC: Between a rock and a hard place

I’ll get to the science and whether the reaction of the FDA and CDC was appropriate in a moment. First, I must admit that I had a negative reaction when I saw the news stories in the morning and kept seeing the phrase “abundance of caution.” Does anyone remember that phrase? Those who’ve followed the antivaccine movement for a while might remember that phrase being used when the CDC and American Academy of Pediatrics recommended removing mercury from vaccines two decades ago out of an “abundance of caution” and to make “safe vaccines even safer.” At the time some childhood vaccines contained the antimicrobial preservative thimerosal (which contained mercury), and antivaxxers were claiming that thimerosal caused autism. (Indeed, RFK Jr.’s whole early shtick was conspiracy mongering about how the CDC had “covered up” the alleged link between thimerosal in vaccines and autism.) Unsurprisingly, the removal of mercury from all childhood vaccines had exactly the opposite effect, sending the unintentional message to antivaxxers that they had been right all along about mercury and leading parents to wonder, not at all unreasonably, why the CDC had removed thimerosal if, as it claimed, thimerosal was safe, it had removed it from childhood vaccines. It was the precautionary principle run amok, given that there was not then and is not now any good evidence linking thimerosal-containing vaccines to autism and plenty of evidence showing no association, the best of which is the observation that, even after the removal of thimerosal from childhood vaccines, autism prevalence kept increasing for 20 years, leading some wags to suggest sarcastically that maybe thimerosal prevents autism. In any event, in a pandemic, one has to weigh the question of how many more might die unnecessarily of COVID-19 due to not being able to access the J&J COVID-19 vaccine versus, even if the association ends up being found to be causative, the less than one-in-a-million risk of cerebral venous sinus thrombosis (CVST).

Here’s the problem. Most people see “abundance of caution” and interpret it to mean: “Danger, Will Robinson!” Certainly that’s what happened 20 years ago with thimerosal, and that’s what’s likely to happen now, particularly given that the vaccines are new, are being distributed under an emergency use authorization (EUA), and haven’t yet been fully FDA-approved. That’s why my next reaction was sympathy for the CDC and FDA. They truly are between a rock and a hard place on this. They called a pause based on these reports, and antivaxxers are predictably doing what antivaxxers always do, weaponizing the decision in order to portray the J&J vaccine as dangerous. If they hadn’t called a pause, antivaxxers would have weaponized that decision in order to portray the CDC and FDA as “covering up” or “ignoring” the adverse events. Basically, the FDA and CDC are damned if they do, damned if they don’t, and I now admit that I don’t know what the right call is.

This is also basically the same dilemma European regulators found themselves in a month ago after eerily similar rare reports of CVST after the AstraZeneca COVID-19 vaccine. Similar to the reports after the J&J vaccine, the patients experiencing CVST after the AstraZeneca vaccine were more common in women under the age of 55. Ultimately, the European Medicines Agency concluded:

• the benefits of the vaccine in combating the still widespread threat of COVID-19 (which itself results in clotting problems and may be fatal) continue to outweigh the risk of side effects;
• the vaccine is not associated with an increase in the overall risk of blood clots (thromboembolic events) in those who receive it;
• there is no evidence of a problem related to specific batches of the vaccine or to particular manufacturing sites;
• however, the vaccine may be associated with very rare cases of blood clots associated with thrombocytopenia, i.e. low levels of blood platelets (elements in the blood that help it to clot) with or without bleeding, including rare cases of clots in the vessels draining blood from the brain (CVST).

These are rare cases – around 20 million people in the UK and EEA had received the vaccine as of March 16 and EMA had reviewed only 7 cases of blood clots in multiple blood vessels (disseminated intravascular coagulation, DIC) and 18 cases of CVST. A causal link with the vaccine is not proven, but is possible and deserves further analysis.

Again, this was not unreasonable in terms of a risk-benefit analysis. Even if CVST were linked to the AstraZeneca (or J&J) vaccine, in the middle of a pandemic the risk of these very rare events needs to be weighed against the risk of serious illness and death from COVID-19. However, the human brain is not good at thinking this way, weighing very small risks against much larger risks, particularly when those very small risks come from an intervention used in people with no disease designed to prevent something that hasn’t happened yet. Contrast this to cancer chemotherapy, for instance. People can accept the serious adverse events and even the risk of death from chemotherapy when it is weighed against the risk of certain death from cancer. They have a much harder problem accepting even a one-in-a-million chance of a serious adverse event from a preventative treatment like a vaccine.

So what’s with the clots, anyway?

What makes the reports of CVST after the J&J and AstraZeneca COVID-19 vaccines a bit more plausible as being related to the vaccines has to do with the type of vaccines they are and the fact that, after 180millions of doses, there have been no reports of CVST after the Moderna and Pfizer/BioNTech vaccines. Why is that important? The Moderna and Pfizer/BioNTech vaccines use a different method to generate SARS-CoV-2 spike protein as an antigen than these vaccines. You’ll recall that the Moderna and Pfizer/BioNTech vaccines use messenger RNA (mRNA) encoding the SARS-CoV-2 spike protein encapsulated in lipid nanoparticles in deliver the “message” that induces cells to make the protein to generate an immune response. The J&J and AstraZeneca vaccines also induce the recipients’ cells to make the spike protein to generate an immune response, but they use the DNA encoding the spike protein inserted into a replication-deficient adenovirus vector. Adenoviral vectors have long been used as tools to get cells to make various proteins and have been tested as gene therapy and vaccine vectors. AstraZeneca uses a chimpanzee adenovirus base, while J&J uses a human adenovirus, but the technology is very similar. So the fact that these rare clotting events have been observed after the use of two vaccines using an adenovirus vector and not at all after the use of mRNA-based vaccines is one factor constituting a safety signal for adenovirus-based vaccines.

Another worrisome aspect of these reports is the presence of thrombocytopenia (low platelet count) along with the clotting disorder, as described in this joint media call:

From the transcript, here’s Dr. Peter Marks, director of the FDA Center for Biologics Evaluation and Research:

Thank you, Dr. Woodcock. 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 CBST in combination with low levels of platelets in the blood called thrombocytopenia in women ages 18 to 48 who presented with symptoms between six and 13 days after receiving the Johnson and Johnson or Janssen COVID-19 vaccine. 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. Of the clots seen in the United States, one case was fatal and one patient is in critical condition. While we review the available data out of an abundance of caution, the FDA and CDC are recommending a pause in the use of this vaccine in the United States.

Later in the call, Dr. Marks elaborates:

So the issue of cerebral venous veins, cerebral venous sinus thrombosis, the background rate of that is probably somewhere between two and 14 per million people, but that’s in the setting of a normal platelet count. The combination here, 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. 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.

The important things to note here are (1) this particular type of clotting should not be treated with heparin, as acute clotting normally is and (2) the association between this particular kind of clot plus a low platelet count could suggest an immune mechanism.

Interestingly, last week a paper was published in the New England Journal of Medicine by a group of German and Austrian researchers about this phenomenon observed after the AstraZeneca vaccine. The investigators assessed the clinical and laboratory features of who developed thrombosis or thrombocytopenia after vaccination with ChAdOx1 nCov-19 (the AstraZeneca vaccine) and found the development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. They even suggested naming this novel entity vaccine-induced immune thrombotic thrombocytopenia (VITT), in order to avoid confusion with heparin-induced thrombocytopenia, while suggesting:

Since vaccination of millions of persons will be complicated by a background of thrombotic events unrelated to vaccination, a PF4-dependent ELISA or a PF4-enhanced platelet-activation assay may be used to confirm the diagnosis of vaccine-induced immune thrombotic thrombocytopenia through this novel mechanism of postvaccination formation of platelet-activating antibodies against PF4.

As I was saying, the background rate of adverse events matters, and it’s still not entirely clear whether we’re observing this phenomenon at a higher than background rate. As I like to say, the more you look for something, the more of it you will find, and the unprecedented vaccine safety monitoring after the rollout of COVID-19 vaccines guarantees that rare events that might not have been noticed before will be found. That being said, this association is more suggestive of vaccine causality than previous adverse reactions that have been reported.

The authors note that it’s known that adenovirus can bind to platelets and activate them, but even they seemed a bit puzzled that the vaccine could cause such a reaction:

Although we found enhanced reactivity of patient serum with platelets in the presence of ChAdOx1 nCov-19, this is likely to be an in vitro artifact. It is well known that adenovirus binds to platelets²² and causes platelet activation.^22,23 Furthermore, the amount of adenovirus in a 500-microliter vaccine injection administered 1 or 2 weeks earlier would seem unlikely to contribute to subsequent platelet activation observed in these patients. 

But they nonetheless speculated:

However, 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. We have previously shown that DNA and RNA form multimolecular complexes with PF4, which bind antibodies from patients with heparin-induced thrombocytopenia and also induce antibodies against PF4–heparin in a murine model.²⁴

This last bit strikes me as rather hand-wavey. Still, if this association is real, this could be the mechanism that explains it. The real question, though, is why such a rare reaction would be observed predominantly in premenopausal women. Given how rare this immune-mediated clotting is, even if it does turn out to be caused by the vaccines, it’s going to be really hard to figure out the mechanism and why women are more susceptible, and the CDC notes that there are still too few cases of this phenomenon to conclude it is due to adenovirus vectors or any other risk factors. Still, appropriately, scientists are all over it, looking to confirm causality and determine potential mechanisms.

Vaccine safety monitoring works

I can’t help but wrap up by pointing something out that seems to elude antivaxxers. If there’s one consistent theme in antivaccine disinformation, it’s the false claim that vaccine safety monitoring systems are inadequate and miss all the horrific adverse events that antivaxxers attribute to vaccines. Yet, right here, right now, in 2021 in real time, vaccine safety monitoring in Europe and the US have rapidly identified a potential complication of a specific type of COVID-19 vaccines that is rare. (Indeed, in the case of the J&J vaccine thus far, it’s less than one in a million doses.) As seen on Twitter:

Exactly.

In a rational world, the fact that regulators in Europe and the US identified, acted on, and investigated such a rare correlation should increase confidence in the COVID-19 vaccine (and, actually, all vaccines). Even if worry is increased about the AstraZeneca and J&J vaccines, this system should provide even more confidence in the Moderna and Pfizer/BioNTech vaccines, for which no such serious rare complications have been reported after 180 million doses. Moreover, scientists are all over this, investigating potential immune mechanisms by which these rare instances of CVST might be caused by the vaccine. No one is “ignoring” anything. No one is sweeping anything under the rug. Sadly, this is not a rational world, and it is likely that this pause in the use of the J&J vaccine, even if it’s only a few days to investigate, will likely contribute to vaccine hesitancy. Certainly the antivaccine movement is doing its best to see to that.

Also, as Steve Novella points out, there remains a serious dilemma that involves weighing the risk of these rare but serious events after vaccination with the risk of people dying of COVID-19:

The adenovirus vaccines are also safe and effective, but it increasingly seems like they can trigger a rare (about one in a million) autoimmune reaction in women less than 50. The medical community needs to know about this, how to recognize and treat it properly, and the general public needs to know in order to be vigilant about early symptoms. But the dilemma remains – in the middle of the COVID pandemic these vaccines will save thousands of lives for every one they take, and if we are careful we may be able to avoid any vaccine-related deaths. But we also know the public mostly does not make rational decisions based on math, and are more likely to avoid causing harm even if that passively allows a far greater harm to occur.

As Eric Topol noted:

Although it should be noted:

This problem is even more acute in Europe, which relies far more heavily on the AstraZeneca vaccine, while the J&J vaccine is thus far only a relatively small proportion of the COVID-19 vaccines being administered.

Again, I’m not sure what the right answer is, to do what the FDA and CDC have done and pause the J&J vaccine or to have continued to administer it with a black box warning. What I do know from this is that vaccine safety monitoring is very effective and that antivaxxers will capitalize no matter what the FDA and CDC do.