The light at the end of the pandemic tunnel was marred by a worrying shadow. As the COVID-19 vaccines were rolled out, headlines fuelled anxiety: some people were developing life-threatening blood clots after receiving either the Johnson & Johnson vaccine (made by one of its subsidiaries, Janssen Vaccines) or the Oxford-AstraZeneca shot. This serious complication was almost only seen with these two vaccines, althoughĚýĚýwho received the Moderna vaccine andĚýĚýwho was vaccinated with the Pfizer shot also received the same diagnosis.
The anti-vaccine movement took this real observation and stretched it out of proportion, accusing all COVID vaccines of killing large swaths of the population throughĚýdeadly coagulation.
The actual issue was very rare and quite narrow, though still distressing. Based on a survey of what was reported in the scientific literature,ĚýĚýworldwide are known to have died from blood clots following COVID vaccine injection,ĚýĚýof whom died in Canada. Shortly after the problem was identified, health authorities revised their vaccine recommendations. Johnson & Johnson halted production of its vaccine inĚý; AstraZeneca withdrew its vaccine worldwide inĚý.
When the rare complication was first identified, science communicators like me, as well as doctors, nurses, and public health officials, did not have an explanation. All we could say was that we did not know why, in exceptional cases, these clots had developed. The vaccines were very safe; very rare injuries cannot be detected in a clinical trial because we can’t recruit millions of participants; and we needed people to get vaccinated in order to significantly slow down this wave of death and disability we had experienced since late 2019. But the brain abhors a vacuum, and this episode undoubtedly contributed to vaccine hesitancy. “We were promised safe vaccines,” someone likely thought, “but see what happened? And they don’t even know why.”
We do now.
I was on the edge of my seat last week readingĚýĚýjust published inĚýTheĚýNew England Journal of Medicine, where researchers used elegant experiments to track down exactly how these clots happened and who is susceptible to them. We already had part of the story back in July 2021; now, it looks like the entire molecular cascade has been delineated.
To the vaccine hesitant, who think scientists may be lured by pharmaceutical bribes to stop caring, I hope this story shows you that there are genuine efforts into making vaccines even safer and understanding what goes wrong when something like this happens.
If entering the world of molecular biology seems too daunting, here’s the lay summary. Because the AZ and J&J vaccines packaged their code for the spike protein inside of an adenovirus, those who received the vaccine developed antibodies not only against the spike protein but also against a specific protein present in the adenovirus. On its own, this is fine. But because of genetics—an immune gene they inherited from a parentĚýandĚýa mutation that arose in their body as it was making antibodies—the end result is that they produced theĚýwrongĚýantibody. It didn’t bind to that adenovirus protein; it mistakenly bound to and started agglomerating a similar molecule present in the body and involved in clotting. This clump activated platelets, and blood coagulated.
Thus, the people who developed blood clots following the AZ or J&J vaccine weren’t unlucky once. They weren’t unlucky twice. They got three doses of bad luck.
#1: The gene they inherited from a parent
The syndrome they developed has been referred to, in the manner of so many inelegant medical designations, as vaccine-induced immune thrombotic thrombocytopenia or VITT. Five to ten days after receiving the vaccine (on average), the unlucky few would develop a blood clot in a vein or artery (the “thrombotic” adjective in the name), and when their blood would be tested, the laboratory would detect low platelet levels (“thrombocytopenia”). This may sound counter-intuitive: if platelets are used in clotting, why are too few detected in the blood? That’s preciselyĚýbecauseĚýthese platelets are no longer circulating but are instead used up to form clots.
This clotting mess is not how vaccination is supposed to go. Normally, the vaccine is injected at the top of the arm and its content is taken up by cells in the area, especially dendritic cells which are part of our immune system. Inside these cells, the piece of genetic code present in the vaccine is treated the same as any other bit of DNA or RNA produced by these cells: it is read just like an architectural drawing at a construction site and it is used to build a protein, in this case the spike protein of the coronavirus.
What does the cell do with this spike protein? It breaks it down because it doesn’t need it. Bits and pieces from it migrate to the surface of this cell, displayed like a flag, and this is detected by another immune cell, a B cell, and it is this cell that produces a Y-shaped antibody against the spike protein. Making more of this antibody will help fight off the coronavirus when we later encounter it.
Antibodies are proteins: they too are encoded by genes.ĚýIn the paper that just came out, the researchers looked at 100 patients with VITT. Ninety-nine of them had a very specific version of a gene used to make antibodies. This version of the gene is not shared by everyone on Earth: 60% of white people have it and only 20% of Asians do, which helps explain why VITT was even more rare in Asia. Antibodies are like meals at a buffet, where a single meal is made up of different dishes put together. Antibodies are encoded by a grab bag of genes that get assembled together. This version of the gene found in people with VITT codes for one particular dish at the buffet, but having it is not enough to get VITT. It’s just the first instance of bad luck.
The antibody that results from carrying the instructions from this gene doesn’t target the spike protein of the coronavirus; it instead binds to something that the AZ and J&J vaccines have in common.
#2: The use of an adenovirus in the vaccine
ĚýYou see, these two vaccinesĚýrely on a virus, and I don’t mean the SARS-CoV-2 coronavirus.
Pfizer’s and Moderna’s COVID-19 vaccines packaged their spike protein instructions inside a tiny bubble of fat; but AstraZeneca and Johnson & Johnson chose instead the shell of an adenovirus. You can think of it like a hollowed-out egg used to carry things inside of it. If you had a powerful enough microscope, you would see that inside this shell, bound to what is left of the adenovirus’ genetic code, is a protein. Using Roman numerals, the protein is named pVII (pronounced “p7”).Ěý
When people received either vaccine containing the adenovirus capsule, their bodies not only developed antibodies against the spike protein; they also developed antibodies against pVII, which is fine, but the presence of this protein will play a pivotal role in the final chapter of this story.
#3: The mutation that spontaneously occurred when antibodies were fine-tuned following vaccination
The last necessary element for VITT is something that is not inherited from the parents and doesn’t come from the vaccine. When we get vaccinated and our dendritic cells display part of the spike protein at its surface like a flag, a B cell will bind to it and recognize that this spiky thing shouldn’t be there. It’s not part of the self. It will start proliferating and making all sorts of changes to the antibodies it was already carrying. It isĚýfine-tuningĚýthem via mutations, and this process can lead to random errors. (To be clear, this isĚýnotĚýthe vaccine mutating our DNA; this is the normal way in which our bodies mount an immune response.)
The people with VITT all had a very specific mutation in B cells which arose through this process. It changed a single amino acid in their antibody—one building block in a long chain of them. The amino acid that should have been there had a netĚýpositiveĚýelectrical charge; but once mutated, the new amino acid had a netĚýnegativeelectrical charge. Believe it or not, this combination—the very specific immune gene they received from their parents and this one tiny mutation that arose by chance while their body was reacting to the vaccine—created some bad antibodies. They were meant to bind to pVII found in the adenovirus carrier. But these small genetic variations changed their affinity. Instead, they bound to a clotting protein.
It’s called protein platelet factor 4 or PF4. Our own platelets secrete it, and it turns out that PF4 has a segment thatĚýlooks a bit like part of the adenovirus pVII.
VITT happens because these rare, mutated antibodies bind to PF4 proteins in the blood and these complexes grow in size. Eventually, they bind to a platelet in such a way that it becomes the first domino in a cascade that encourages platelets to bind to each other and form a clot. A genetic predisposition combined with a genetic error after vaccination led to the creation of faulty antibodies that should have harmlessly targeted a protein found in the vaccine but instead bound to a clotting protein and led to the formation of a life-threatening clot.Ěý
How this discovery will change the future
When VITT was discovered following COVID-19 vaccination, doctors quickly put in place and later refinedĚýĚýfor these patients in order to reduce their odds of dying. It often involved giving patients antibodies intravenously, which in this situation appears toĚý, so to speak.Ěý
But our understanding of what was happening at the molecular level was limited. What scientists recently did to understand the molecular cascade leading to VITT is really elegant. They found the antibodies directed against PF4 in the blood of patients with VITT. They saw that almost all of them had been built in part using a very specific form of an immune gene. They also noticed this striking new mutation that changed the electrical charge of one single amino acid. They observed that some people had developed antibodies against PF4 after getting the vaccine but theirs did not lead to clotting, and it was because they didn’t have the genetic characteristics they found in the VITT patients.
They then created antibodies in the lab to test their theory in mice. They even “backmutated” them—changing that one amino acid back to what it should have been—and saw a drastic reduction in blood clotting. It became clear that these two genetic changes—one inherited and the other happening spontaneously after vaccination—were needed to misdirect antibodies to a coagulation protein.
What does this mean for the future? This is not something that we can easily test for, like those DNA kits that tell you if you have the gene variant that makes cilantro taste like soap. That second mutation, the one that changes a single amino acid, is not normally present in our DNA; it arises after vaccination in a tiny subset of people. And even after vaccination, you won’t find it in most of your cells. It is only present in a subset of B cells, and you won’t pass it along to your children. I can’t emphasize enough thatĚýthese vaccines are not altering your genetic code.ĚýB cells always generate a ton of mutations when fine-tuning their antibodies. It’s a process called somatic hypermutation. It’s a clever way our immune system has of adapting to new threats, and it does not change the DNA in your skin cells, heart cells, or brain cells.
However, that pVII protein in the adenovirus capsule? The lynchpin behind this whole series of unfortunate events? That can be modified or replaced, so that the body stops targeting it and thus stopsĚýmistargetingĚýit on rare occasions.
When we say that vaccination is safe, we never mean it is 100% safe because nothing is. Surgery isn’t, pills aren’t, eating isn’t, driving sure isn’t, and getting an infection is not. But in the rare instances where something goes wrong, we investigate. And sometimes, we discover exactly what went wrong, and we can use this knowledge to make sure it doesn’t happen again.Ěý
Take-home message:
- In very rare instances, the AstraZeneca and the Johnson & Johnson COVID-19 vaccines caused life-threatening (and in some cases deadly) blood clots.
- Scientists have figured out how these clots happened, which will help make similar vaccines even safer in the future.
- The clotting happened because of two genetic factors—one inherited from a parent and one occurring after vaccination—which created antibodies that instead of binding to a part found in the vaccine bound to a clotting factor and made blood coagulate.
