COVID Transmissions for 4-20-2021
Vaccines now available to all US adults; more on clotting
Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.
It has been 519 days since the first documented human case of COVID-19. “The 519” is a community center in Toronto that primarily focuses on the LGBTQ community but also offers services for groups like refugees. I don’t know very much about their work, but when I check in on the current day count and one of the search results is a seemingly-worthy nonprofit, I think it’s nice to let people know about the organization. More information is available here: https://www.the519.org/
Speaking of the provision of essential support services, my first headline today deals with the universal adult availability of COVID-19 vaccines in the US. Then, I share an interesting case series about vaccine-associated blood clotting.
As usual, bolded terms are linked to the running newsletter glossary.
Keep COVID Transmissions growing by sharing it! Share the newsletter, not the virus. I love talking about science and explaining important concepts in human health, but I rely on all of you to grow the audience for this, which you can do by using this button here:
Now, let’s talk COVID.
Every adult in the US is now eligible for vaccination
Almost two weeks ahead of the planned original date of May 1st, and right on the revised date of April 19th, the Biden Administration announced yesterday that the US has reached full vaccine eligibility for adults.
The next step will be to extend that to all ages, pending the results of clinical trials.
I am hopeful that the prediction I made yesterday—that we would begin to see plummeting case numbers in the US by a month or two from now—will be fulfilled.
Case series claims “thrombotic thrombocytopenia” caused by AstraZeneca vaccine
A case series—in other words, a series of patient cases collected without intentional scientific study design—reported in the New England Journal of Medicine (NEJM) documents patients in Germany who were diagnosed with “thrombotic thrombocytopenia” after receiving the AstraZeneca COVID-19 vaccine. Thrombotic thrombocytopenia is the side effect that has dominated this headlines space for some time now—where patients are observed to have an increase in blood clots while also showing a drop in platelets, the cells that allow blood clots to form.
This case series covers 11 patients, 9 of whom were women. The median age was 36 years with a range from 22 to 49. This is an extremely small sample by comparison to the number of people who received the vaccine (about 20 million). In terms of specific clotting disorders, 9 of 11 had CVST, the specific clotting disorder that has attracted attention with regard to these vaccines. Some of these patients also had other types of clots. In this group, 6 of the 11 patients ultimately died.
I still believe that the risk of these clots is quite low compared to the number of vaccine doses administered, and the risk of death from them is even lower. I am sharing this case series not because I think this safety event is a matter to be tremendously concerned about for the average person. Instead, I think this is an important development in vaccinology that may impact the future of adenovirus vectors, and also I think that this case series may drive a better understanding of how to treat this safety event, or how to avoid it.
Something that jumps out immediately at me is that the age range in this case series is extremely close to the range seen with the J&J vaccine; 22-49 here, 18-48 there. Also, both skewed heavily to women, something that is interesting given something that we will learn from this case series.
What is really special about this case series is that the researchers looked into the specific factors that might be responsible for the disorder. They performed platelet-activation assays, using blood serum from these patients, to try to understand what may be present in patient serum that could cause the clotting syndrome observed.
In these platelet activation assays, they added various supplemental factors, and one stuck out as intensely activating platelets when present along with patient serum: platelet factor 4 (PF4). PF4 is a small signaling protein that normally mediates coagulation, but interestingly, it also counteracts the anticoagulant effects of heparin. PF4 and heparin can bind to one another.
In some people, the PF4-heparin complex can be targeted by specific antibodies. The complex of PF4-heparin-and-antibody itself can activate platelets. This leads to a condition known as heparin-induced thrombocytopenia (HIT), where platelet levels drop because of increased activation. This is a serious situation where major clots can develop due to increased platelet activation, but also the patient is at risk of bleeding because of the heparin treatment.
In a patient with HIT, we might expect that the addition of heparin or the addition of PF4 to these patient samples would increase platelet activation due to the immune reaction. This is what was actually seen in these postvaccination patients:
We can learn a few things from this figure. Firstly, heparin in all of its forms is acting as an anticoagulant in these patients, as it would be expected to do typically. The reason this is interesting is that it indicates these patients do not have typical HIT; if they did, addition of heparin might have increased platelet activation (at least as I understand the condition to work; we are straining my expertise here a little bit, so if anyone is a physician or nurse and wants to chime in, please do!). These patients have something else; the paper calls it vaccine-induced thromobotic thrombocytopenia, VITT.
Another thing we can learn from this figure is that PF4 is part of the profile that activates these patients’ platelets. However, we need the final piece of the puzzle to understand how: the IVIG section. The addition of IVIG, intravenous immune globulin, inhibits antibody-mediated activation of platelets. IVIG provides a competitive signal that prevents platelet-activating antibodies from getting to the platelets and activating them. So from the fact that IVIG does something here, we know that antibodies are somehow involved. The effect of PF4 here also shows us that PF4 is involved.
Ultimately, the authors went on to identify that these patients have produced anti-PF4 antibodies, which are capable of activating platelets and thus causing clots while reducing platelet levels. This causes a syndrome similar to HIT with thrombosis (called HITT), but because heparin was not involved, we get the name VITT as mentioned before. That’s if you believe, as these authors do, that the vaccine is the cause. I am beginning to agree with these authors, by the way.
It appears that in certain very rare patients, vaccination with the AstraZeneca product is leading to the creation of anti-PF4 antibodies, which then can go on to cause a clotting syndrome with thrombocytopenia. This is, in a sense, an autoimmune disorder that seems to be triggered in a very small proportion of people by vaccination.
Here is where it becomes relevant that these patients are predominantly (but not exclusively) women. As it turns out, autoimmune disorders are substantially more common in women. One of the conditions that my day-job company works on is an autoimmune disorder that is most frequently found in women as well, so this is a pattern I’m very familiar with. This is something you can read more about here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292717/. For this reason, the overrepresentation of women in these cases leaves me even more convinced that the mechanism here is an autoimmune one.
So it would appear that some kind of autoimmune reaction occurs—again very rarely—in response to vaccination. This autoimmune condition may be forming in one of several ways. One option is that there is an antibody being generated against a vaccine component which also happens to recognize PF4. Another possibility is that the immune stimulus provided by the vaccine strongly activates preexisting anti-PF4 antibodies in these patients. That will need to be studied further.
So through this case series we start to learn a lot about the potential contours of this rare syndrome, but we of course need to be cautious since this is a very small study.
However, there is another benefit to the work here: it suggests a potential treatment algorithm in patients who experience this. First, we know that existing screening tools for anti-PF4 antibodies can detect this pattern, making it easier to positively identify cases. Second, it seems likely that administration of IVIG to patients could improve their condition (this will require further work). Third and finally, it demonstrates some laboratory tests that could be performed that would tell a clinician whether it is safe to give their VITT patient a dose of heparin, something that was previously unclear.
While there is not yet a smoking gun connecting this adverse event with any vaccine, the fact that is has appeared rarely in two adenovirus-vectored vaccines with different designs and the presence of the potential immune-mediated component leaves me feeling there is strong circumstantial evidence that this rare effect is a genuine vaccine reaction.
At the same time, the results here leave me feeling that it will be possible to redirect the most at-risk patients (looking like women who are under the age of 50 so far) to other vaccines, and potentially to easily recognize and effectively treat this reaction when it does occur. That’s very good news, since we’re going to need every vaccine we can get in order to end this pandemic.
You can read this case series here: https://www.nejm.org/doi/full/10.1056/NEJMoa2104840
What am I doing to cope with the pandemic? This:
Mentoring
Over the course of the pandemic, I have sought out new opportunities to mentor young science communicators, and I’ve found it very rewarding. Yesterday, I had a call with one such person, and I am hoping that I set them in the right direction with regard to finding a career in pharmaceutical medical writing. Next week, I will meet with my more long-term mentee, who is a PhD student looking to get into medical communications after she completes her degree. It’s really rewarding to be able to help people out who are trying to break into a field that has been a source of a lot of success for me. I think it’s even more important in this pandemic crisis, because that’s making everything harder on everyone—and grad school is hard enough to start with.
I also learn a lot from my mentee. She is a better grad student than I was, but she still struggles in many of the ways that I did, emotionally. Giving her advice on these situations, based on my experience, has made me realize that there were a lot of positive, constructive lessons that I learned from going through those difficulties. And then, of course, there are times when my mentee is just smarter than me, and I learn things from that too.
I really recommend getting involved in mentoring if you can—either as a mentor or a mentee.
Today a reader named Chris Finch asked the following:
John,
I would very much appreciate it if you could comment on outbreaks of shingles that are occurring in persons who have been COVID-19 vaccinated.
I had to reject the premise of this question (not Chris’s fault; the premise did not originate with this comment). While there have been rumors spread online of shingles outbreaks after vaccination, there is no uptick in shingles cases happening associated with vaccination. See my answer here:
The incidence of shingles in people who have been COVID-19 vaccinated is no higher than the incidence of shingles in people who have not been vaccinated. About 25% to 33% of people will develop shingles at some point in their lifetime; it would be quite noticeable if this were being exceeded in people who received COVID-19 vaccination.
You can read more expert opinion on this in this article: https://www.webmd.com/vaccines/covid-19-vaccine/news/20210209/experts-debunk-covid-19-vaccine-shingles-link
And there's a little more here as well: https://www.weny.com/story/43623043/chances-of-getting-shingles-after-covid-19-vaccine-doctor-debunks-rumor
The reason it's expert opinion is that there are no data showing an uptick in shingles cases in vaccinated people, and it's hard to link to nothing.
There is some theoretical basis for the idea that an immune insult can lead to shingles reactivation. I have seen people suggest that COVID-19 itself can predispose a person to shingles reactivation also, a possibility that I consider more likely (but also have not seen any evidence to support) because an actual infection can have extremely disruptive systemic immune effects.
All of this having been said, there is a vaccine for shingles and it is now widely available for appropriate age groups. If you're in one of the appropriate age groups, it might be a good idea to seek out that vaccine.
Shingles is a painful neurological disease caused by the varicella zoster virus, which is also the virus that causes chicken pox. If you have had chicken pox at any point in your life, or otherwise been infected with this virus, you can get shingles. Shingles represents reactivation of virus that has been latent within your cells since you were first exposed—it is similar to how herpes viruses, like those that cause cold sores, can periodically reactivate. Shingles is awful. I’ve had several close family members and friends get it, and it just really sucks.
There is no exact science for predicting shingles reactivation likelihoods, but it seems to happen often in situations of high physical or emotional stress and is more likely as people get older. As I mentioned in my comment, there is an effective vaccine against shingles for people who are 50 years of age and older. Since I have had chicken pox in the past, I intend to seek out this vaccine as soon as I turn 50, because I never ever want to experience shingles.
I suspect that at least some anecdotes about an uptick in shingles lately are the result of the intense stress of the current global situation. This is a difficult world to live in right now, and people are feeling the strain, sometimes in extreme and unfortunate ways such as this.
You might have some questions or comments! Send them in. As several folks have figured out, you can also email me if you have a comment that you don’t want to share with the whole group.
Join the conversation, and what you say will impact what I talk about in the next issue.
Also, let me know any other thoughts you might have about the newsletter. I’d like to make sure you’re getting what you want out of this.
Part of science is identifying and correcting errors. If you find a mistake, please tell me about it.
Though I can’t correct the emailed version after it has been sent, I do update the online post of the newsletter every time a mistake is brought to my attention.
No corrections since last issue.
See you all next time.
Always,
JS