by Kevin Schofield

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Earlier this week Carolyn Bick wrote an excellent article on the CDC’s decision to “pause” use of the COVID vaccine developed by Johnson & Johnson after reports of a handful of cases of blood clots in the several days following vaccination. This week’s Long Reads dives into the science of why the CDC made that controversial move, and what happens next.

A quick refresher: vaccines don’t fight viruses directly; rather, they train our own immune system to recognize a particular virus and be prepared to attack it quickly if it ever sees the real thing in the future. There are currently three methods in common use for creating a vaccine.

1. Create a weakened or dead version of the virus that won’t have the harmful side-effects but will still train up our immune system to recognize it;
2. Graft part of the target virus onto another harmless virus, such as an adenovirus, so that our immune system trains up on the new virus as it fights off the harmless one;
3. The newest technology: an mRNA vaccine, which has a chunk of “messenger RNA” that infects our cells and instructs the cell machinery to reproduce just a small part of the virus so that our immune system can train up on it.

The Pfizer and Moderna vaccines are of the new “mRNA” type. The AstraZeneca and J&J vaccines are the second type: modified adenoviruses. All four focus on the “spike” protein in COVID, a protein that contains the magic sequence that allows the virus to unlock and enter our cells. Moderna and Pfizer have mRNA that tells our cells to create copies of the spike protein, while AstraZeneca and J&J graft the spike protein onto an adenovirus.

Two months ago, after tens of millions of doses of the AstraZeneca vaccine were administered in Europe, 11 cases were identified in which patients developed unusual blood clots within three weeks of receiving the vaccine. Those patients all also had very low platelet counts at the time they were diagnosed with the blood clots.

A word about platelets: they are a component of our blood that, when activated, can quickly bunch up together and form clots to stop bleeding when a vein or artery is broken. But there are also many ways in which the function of platelets can go wrong, leading to clots inside our bloodstream. This can be dangerous, even life-threatening: blood clots can cut off the circulation to an arm or leg (known as “deep vein thrombosis” or DVT), a portion of a lung (called a pulmonary embolism) or other organ, or part of the brain (one form of stroke).

Some drugs can cause clotting as a side effect by unnecessarily activating platelets. One very rare but well-documented instance of this is with the drug heparin, which is normally a blood-thinning agent (i.e. it inhibits platelet activation) but in some cases it can join up with an important protein in our bodies called PF4, and the heparin-PF4 chemical combination triggers antibodies that both activate platelets and cause the overall platelet count to drop. It should be noted that most drugs that cause clotting don’t also cause the platelet count to drop; that combination is fairly unique to the heparin-PF4 interaction and is one key to the puzzle of the COVID vaccines.

Eleven cases of blood clots among the 82 million people who have received the AstaZeneca vaccine in Europe is an incredibly small sample, so small that it could easily just be random coincidence – though the fact that nine of the eleven are women strongly suggests it may not be.  Our immune systems are quirky and there is a long list of known auto-immune diseases (not to mention the unknown ones) that cause the body to start attacking itself. Or the 11 cases could have been caused by some drug interaction. The scientists looking at those 11 cases needed to evaluate all the possible causes before concluding that they were related to the vaccine. All 11 patients showed the same two symptoms as if they were heparin-induced blood clots, but none of them had received heparin in advance of its onset. Further testing found the same antibodies in the eleven patients as had previously been found in cases of heparin-induced clots, as well as the presence of high levels of PF4. Same symptoms, same antibodies, same PF4 protein present – but no heparin. This led the scientists to conclude that something in the AstraZeneca vaccine (either in the adenovirus being used or the spike protein grafted on) was triggering the same auto-immune reaction that the heparin was, causing the blood clots and the low platelet count in those eleven patients.

And that brings us to the Johnson and Johnson vaccine, which is just starting this same process. At this point, there are six known cases of blood clots and low platelet counts after receiving the J&J vaccine, out of 6.8 million doses administered. Again, it is an incredibly small number; on the other hand, all six are women, which suggests that it isn’t just random coincidence. It’s certainly reasonable to guess that it’s the same issue as with the AstraZeneca vaccine since both are adenovirus-based, but all the lab tests aren’t done yet to confirm that belief. That’s why earlier this week an advisory panel convened by the CDC punted on making a decision until April 23: so the lab work can catch up and they can then make an informed decision about what is really happening with these six cases. It also gives the CDC time to scour the data and find any additional cases that may have been overlooked or misclassified.

Even if the panel concludes that the J&J vaccine is causing this extremely rare autoimmune side effect that leads to blood clots, that doesn’t mean the CDC will permanently pull the vaccine from use. But it does mean that they will issue (and in fact already have) specific guidance on how to treat blood clots if they appear. One of the most common treatments for blood clots is heparin, but in this case there are very good reasons to believe that using heparin could make the problem even worse. Fortunately, there are several other blood thinners available and well-informed doctors can use them instead, out of an abundance of caution.

That said, pulling the J&J vaccine, even temporarily, creates other headaches. Unlike the two-dose mRNA vaccines, the J&J and AstraZeneca vaccines only require a single dose. “One and done” is a huge advantage in efforts to vaccinate individuals who are much less likely to come into contact with the public health system twice in a three-week period, such as the homeless, those with mobility issues, and individuals without regular healthcare. 

We can do our part to help the CDC quickly get to the bottom of this by using the v-safe app to report any side effects we have after vaccination. That will give scientists more data to understand the scope and scale of these and any other issues with the vaccines.

CDC Health Alert on Johnson & Johnson COVID-19 Vaccine

New England Journal of Medicine analysis of blot clot cases after receiving the AstraZeneca vaccine

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📸 A vial of the Johnson & Johnson vaccine. (Photo: Alex Garland)

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