The rollout of Covid-19 vaccines developed by AstraZeneca Plc and the University of Oxford and Johnson & Johnson has been marred by rare but serious blood-clotting side effects that resulted in some deaths. Now, scientists in Germany say they have uncovered the cause of the clotting condition and can fix it. Sam Fazeli, a Bloomberg Opinion contributor who covers the pharmaceutical industry for Bloomberg Intelligence, answers questions about the new findings. The conversation has been edited and condensed.
Can you explain this latest development and how it may further our understanding of these side effects?
Everyone is keen to understand what is causing the very rare blood clotting issues seen with the so-called adenoviral-vectored vaccines developed by Astra-Oxford and J&J. What is unusual about these issues is that they are blood clots that form in odd parts of the body, such as the cerebral sinus vein, at the same time as a reduction in platelets, which normally leads to bleeding. If we know why they occur, maybe we can find a way to prevent them. To this end, we already know that some Astra and J&J vaccine recipients develop an antibody directed against what's known as platelet-factor 4, which then leads to a reduction in the number of platelets. But what about the blood clots? That is what this study tries to answer. And I am afraid some people have taken the results of these experiments as suggesting a solution. But that is not the case. They are a very interesting set of experiments, but that's what they are. Their laboratory analysis seems to suggest that the vaccines from Astra and J&J — which target the “spike protein,” or rod-like structures that are stuck on the outside of the virus — could produce soluble pieces of this protein. They then hypothesize that these soluble spike proteins could bind to what are known as ACE2 receptors on the inside of human blood vessels and set off an inflammatory cascade which leads to blood clotting.
How credible is this report? Does it seem like a plausible explanation for the blood clots we're seeing if confirmed by additional research?
From an experimental perspective, it looks fine. The issue is that the authors, in my view, have gone a bit too far, even in naming their finding “vaccine-induced Covid-19 mimicry” syndrome. They don't show actual evidence to support their hypothesis. Some key steps are required to prove that this is actually the way the vaccines induce blood clots, known as thromboses.
What would the process of confirming this hypothesis look like, and if it proves valid, of remediating the vaccines? Is there any regulatory or scientific precedent?
Several things can be done. The first is to prove that those vaccinated with the adenoviral vaccines actually have soluble spike protein in their blood stream and that it is higher than those who have been inoculated with shots based on messenger RNA (Pfizer Inc.-BioNTech SE and Moderna Inc.). Then they need to show that there is indeed inflammation at the site of blood clots involving immune complexes with soluble spike protein and anti-spike antibodies. Additionally, if there is indeed soluble spike protein produced in sufficient quantities to matter, we need data on the time course of this and how it relates to the evolution of neutralizing antibodies. The authors hypothesize that the reason the clotting problem is rare is because neutralizing antibodies generally tend to form in time to bind to the soluble spike protein and stop it from sticking to the ACE2 receptors on the inside of blood vessels, and “neutralize” them. All this has yet to be proved.
But if after taking these steps the hypothesis is found to be correct, it would be relatively good news, right? Rather than a fundamental problem with this whole category of vaccines, the solution may just be tweaking the spike protein?
That would be great, wouldn't it? The companies could go back and modify their vaccines. But then they would have to prove that the modified vaccines are equally effective and, more importantly, that they don't cause the side effect. This would involve vaccinating hundreds of thousands of individuals to test this. I am not sure how feasible that is.
Does the fact that J&J's vaccine seemingly has a lower rate of these events than Astra's give any additional credence to the theory?
The operative word here is “seemingly.” We have to wait for much more data. I won’t be convinced that the J&J vaccine has a lower rate of such events until I see data from about the same number of vaccinations that Astra's vaccine has had. It is possible that’s the case, though, given that the two use different adenoviruses, spike sequences and manufacturing processes. The authors do try and use that as potential evidence in support of their hypothesis, but given how immature the data is, I don't think it’s a given.
What happens with the existing vaccines and existing production if the hypothesis proves true?
Countries are still using the vaccines, so it is unlikely that this study alone would change anything. As I said, we need a lot more clinical data before anyone actually accepts this as a cause-and-effect situation. But if the hypothesis were proved to be true, then indeed those existing vaccines would have to be replaced with new ones that have the modification. All of this would take time. That’s not to say it wouldn’t be desirable to find a solution. These shots are seen as key in the race to vaccinate the world and tame the virus, so if we were able to remove the threat of these rare but possible deadly side effects from the equation, that would be a big step forward. But we’re not there yet.
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