Rare Side Effects of Adenovirus Vaccines Call for Careful Surveillance

Clinical trials have given us a wealth of information about the effectiveness, and safety profile, of vaccines for COVID-19. But the work of gathering evidence, and weighing the results in the context of an ongoing pandemic, isn’t done.

The importance of developing population-based effectiveness and safety profiles associated with a mass vaccination campaign — the sort of deep datasets that go far beyond what’s possible in a controlled clinical trial — has been urgently demonstrated over the past three weeks.

Extraordinarily uncommon, but severe, adverse events have occurred with the administration of the AstraZeneca vaccine in Europe and the Johnson and Johnson (J&J) vaccine rollout here in the United States. Intense public scrutiny of these rare adverse events in adenoviral vector vaccines prompted a brief “pause” in administration of the J&J vaccine, after about 7 million doses were given in the US.

When a mass vaccination campaign is rolled out, adverse events are observed more acutely and more accurately than the slow trickle rollout that goes with any other kind of vaccine or drug distribution. The infrequent becomes more frequent because the number of people vaccinated is so large—a one-in-a-million problem becomes one per day rather than one every 2 to 6 months.

Critics of mass vaccination argue that these campaigns are fraught with difficulties. In some ways, this is true. Beyond the safety and efficacy profiles, there are logistical issues in mass production, quality control, and distribution. There are also the ongoing issues we’ve seen with limited access and certain populations being left out and feeling a continued sense of separation from the vaccination process, reinforcing a distrust of the entire vaccine effort and the people leading it.

It is also true that from a historical perspective mass vaccination campaigns have brought real risks: Guillain-Barré syndrome was associated with the swine influenza vaccination campaign in the mid-to-late 1970s.

Today, we have a new disease to study called vaccine-induced thrombotic thrombocytopenia (VITT). It’s sometimes called Thrombosis with Thrombocytopenia Syndrome (TTS). This phenomenon has now been linked to both COVID-19 adenovirus vaccines—AstraZeneca’s and to a lesser extent the J&J vaccine.

This rare event was detected because it was unusual, like Guillain-Barré syndrome with Swine influenza vaccine. The persons affected by VITT had presented with severe clots in their head, and when surgeons were looking at this and trying to treat it, these clots would reoccur right in front of their eyes. In addition, the blood cells that were involved that were usually high in clotting disorders were low and beside the clots, there was bleeding.

Rare as it may be, physicians and scientists have seen something like this before. This observation was similar to an unusual immune response to the anticoagulant heparin. Immediately, investigators in Europe—mainly in Germany and the UK—described this phenomenon in recipients of the AstraZeneca vaccine. They detected an antibody in the blood of people that activated the platelets (platelet factor-4) that causes blood to clot. This antibody seems to put the platelets in one’s body into overdrive, which then results in a simultaneous clotting of the blood and depletion of the platelets, which causes bleeding.

Clotting and bleeding at the same time—this is a very difficult condition and highly unusual.

It is a clinical condition that’s so unusual, it was instantly recognized and now it seems clear that it’s a rare side effect of the adenovirus vaccines. VITT seems to appear after the first dose, generally in younger people, mostly but not exclusively in women and usually within 4 and 14 days but as far out as 28 days post vaccination.

We’ve now learned how to diagnose this disease by doing a blood test of anti-platelet factor-4, using the sensitive ELISA assay. We can treat it by giving high doses of IV immune globulin to neutralize the autoantibody; and (sometimes) administering steroids. It can also be managed by giving other kinds of blood thinners. Crucially, patients with this syndrome can’t be given heparin, which has shown to worsen the disease.

The disease is rare but sobering; about 30% of the persons with intracranial thromboses and bleeds have died.

To date, in the United States, there are 15 cases of VITT among the 7.5 million persons receiving the J&J vaccine; 14 of the 15 cases are in women and almost all are under the age of 50, which equates to a case rate of about two cases per million vaccinated persons. A thorough review of the risk benefit of the vaccines was performed by both the CDC and the FDA and both of these organizations advised that people should be alerted about the possibility of VITT and to seek medical evaluation if they experience prolonged abdominal pain, worsening headache, or shortness of breath in the days post vaccination.

Further, the FDA and the CDC made the determination that the enormous number of lives saved by the J&J vaccine outweighed the risk of developing VITT and hence restarted the Emergency Use Authorization vaccination program.

To give you a real-world example of the kind of personal risk benefit ratio we’re considering, the data out of the CDC estimate that here in the United States, the odds of being struck by a car is about 1 in 4,292. And the odds of dying as the result of being struck by a car are about 1 in 47,273. And yet, this is a risk we all manage most every day, usually without even thinking about it. VITT, of course, is a new risk related to a new vaccine, so yes, we are all understandably cautious, but it’s important to keep the risk in perspective.

The advantage we have at this point is that we know how to diagnose and treat it, so there’s at least a potential to lessen the impact of the disease. With this knowledge in hand, is it worth it? I think at the moment we have to look at the number of deaths in our country and globally from COVID-19 and weigh the risk of this rare and serious side effect with the overwhelming benefit of the J&J vaccine to fight COVID-19 symptomatic disease, keep people out of the hospital and alive.

And at the same time, we should continue to weigh the risk versus benefit as we learn more. The regulatory authorities, and the scientific community, should continue to communicate the risks and benefits of the vaccine in real-time as we gather more evidence.

We should, and I think will, continue to use the science to drive policy. There are clear benefits for the one-dose J&J vaccine during this ongoing pandemic. Given its less stringent cold-storage requirements, the J&J vaccine is often the only viable option for hard-to-reach communities, and it’s important to remember its effectiveness has been demonstrated in a well-controlled global clinical trial. It works not only against severe disease, but against a wide variety of variants. We also have an effective adverse event surveillance system set up—and the wherewithal—to rapidly diagnose and treat people who develop VITT.

This is an ongoing and important conversation, and there is much work to be done. The blood samples from the 44,000-person Phase III clinical trial need to be evaluated and we need to determine whether a large percentage of people actually develop antiplatelet factor-4.

If so, is it just a few who get such high levels that it sets this cascade off? If it’s uniform, then we’ll have to look at it more closely and determine what really is the risk benefit ratio? Is it good news because that means we can detect it early? Or bad news because it will mean we’re going to need to continue careful monitoring? Or both?

One thing is certain: we need to spend the time, energy, and resources to continue to ensure we do good surveillance.

Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health to respond to the global pandemic, and the Chair of the ACTIV COVID-19 Vaccine Clinical Trials Working Group. He was intimately involved in the planning of the phase 3 vaccine studies conducted under the funding auspices of Operation Warp Speed. He is past President and Director and Professor in the Vaccine and Infectious Disease Division of Fred Hutchinson Cancer Research Center, and Professor of Medicine and Virology at University of Washington.