COVID Transmissions for 5-11-2021

Pfizer vaccine approved for 12-15 year olds in the US, which matters

May 11, 2021

Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.

It has been 540 days since the first documented human case of COVID-19. In 540, the Eastern Roman Empire—the Byzantines—reconquered Italy and much of Northern Africa. Something was coming around the corner, though. More on that tomorrow.

Today, in 2021, we’ll talk about the expansion of the Pfizer vaccine authorization to a wider group of adolescents in the US, something that I think is fantastic news but raises some questions.

Also, I go through a paper that was referred to me by a reader.

As usual, bolded terms are linked to the running newsletter glossary.

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FDA authorization of Pfizer vaccine in adolescents

Yesterday the FDA authorized the use of the Pfizer COVID-19 vaccine in children as young as 12, as was expected this week: https://www.cnn.com/2021/05/10/health/pfizer-vaccine-eua-12-15-teens/index.html

This means that potentially, 17 million more people in the US will be vaccine-eligible. However, the vaccine still needs to be recommended for use in this group by the American Committee on Immunization Practices in order to actually get used. Vaccination programs are complicated, and in order for a vaccine to get used, authorization or approval is not always sufficient. Most countries have some kind of vaccine technology committee that must also recommend how a new vaccine should be implemented within the healthcare system. ACIP handles that here in the US.

I do not expect any huge problems with ACIP, but it is an additional step that must be taken.

I do expect some amount of debate in the popular press about the expansion of the vaccine to this group, though. For one thing, there are currently healthcare workers in various countries around the world with zero access to COVID-19 vaccines. I anticipate there will be a debate over whether it is better to vaccinate teenagers in the US, or ship the doses they would use to countries that desperately need those doses. I am not sure what the right answer is, here. The more people who we vaccinate in the US, the closer we get to disease control here. Without a doubt, that saves lives. But having more vaccines for healthcare workers around the world also saves lives. It is a hard question to answer.

Additionally, I think that people will be talking about whether children actually need the vaccine, and I want to take a moment to clear something up about children and COVID-19: they can die from it. In the US, there is only one group of people that was extremely well-protected from COVID-19—children. Children’s primary centers for interaction with other people were largely closed for much of the worst portions of the pandemic. When they were opened, strict protocols for disease control were recommended and frequently actually enforced. This wasn’t universal, but frankly, if there’s anyone the US protected from COVID-19, it was children.

Consequently, we have a very distorted view in the US of how serious COVID-19 can be in children. Yes, it does appear to be generally less severe in the young, but it is not harmless. It can kill, and we are seeing potentially thousands of child deaths in Brazil (more on this, with a very sad specific story, here: https://www.bbc.com/news/world-latin-america-56696907). The situation in Brazil is motivated by factors that are not entirely clear at this time, but it does make it evident to me that there is genuine risk to children from this virus. While the specific focus of that article is on an age group that cannot yet be vaccinated in the US, it serves to underscore that COVID-19 can kill or harm anyone of any age, and that vaccines are worthwhile for everyone of every age.

I share this not to terrify, but hopefully to make a clear and convincing argument that it is better to get the vaccine and be much more certain of increased safety than to play the odds and take a chance with the virus. For that reason, I am very glad that the eligible age group for COVID-19 vaccination in the US will soon expand.

What am I doing to cope with the pandemic? This:

Starting my new job

As it turns out, I got the job that I interviewed for last week. I started yesterday, and there is a lot of onboarding to be done. In my new position, I manage the training of our company’s medical field force, in addition to continuing to work on the development of publications regarding my company’s clinical trial results. It’s going to be a very interesting growth opportunity, with a lot of added responsibilities. I’m excited to face the challenges that it will bring.

Reader Sam left a comment, noting that they (I don’t know Sam’s pronouns) were the author of the deleted comment I made reference to yesterday, and then asking a further question:

Sorry to delete that comment re: vascular effects in children. After posting it, I did some more reading on the topic, reaching the same conclusion that you do here, and I didn't want to waste your time with it. Thanks for addressing it regardless.
Totally unrelated, but I'd love to read your thoughts on this paper, which seems to suggest (though much of it is frankly over my head) that mRNA vaccination might diminish certain kinds of innate immune response: https://www.medrxiv.org/content/10.1101/2021.05.03.21256520v1

This paper presents some interesting and bold claims, and I’m glad you’ve asked about it because I think it illustrates the problems with accepting the conclusions made in preprints. I don’t think this paper would make it through peer review with a lot of its conclusions intact, and here’s why in my response, which gets quite technical, I’m afraid:

No worries, I just thought that comment would be interesting to discuss.
Anyway, this new piece is interesting to discuss too. You've stepped into a fun area for me, since my PhD dealt specifically with induction of immune responses by RNA.
What this paper has done is, mostly, reported results on the cytokine response of peripheral blood mononuclear cells (PBMCs) from Pfizer-vaccinated patients, comparing cells collected before vaccination, during the time between doses, and 2 weeks after the final dose. To induce a cytokine response, they have used a variety of different innate immune stimuli, some of which I don't think are very good choices. Others are very standard choices but represent quite artificial stimuli; one I would call out is polyI:C, an artificial double-stranded RNA molecule. I would also call out R848, which is actually a drug that directly activates the same receptors that natural RNA activates, but itself is not RNA nor is it a molecule found naturally in the body.
The odd ones that I don't understand are a host of inactivated viruses that they seem to have thrown at these cells. I am not sure that inactivated virus particles are the best stimuli of cytokine response in a tissue culture setting, and their experiments don't contain the necessary controls to convince me that these were a good choice.
I therefore paid the closest attention to the results involving ligands that I know should induce a response. The results are not very convincing of anything. Yes, there are some apparently statistically-significant changes, but they appear to be extremely small changes in various cytokines that are normally quite potent in small doses. I see what looks like vanishingly small changes in production of very specific cytokines in very specific cell types, in response to very specific artificial stimuli. Appropriate controls are not included to help me believe these results, either. Everything is shown relative to a baseline value that is not well-characterized, and there is no placebo-vaccinated control used.
There is only one experiment where they show raw values, where they suggest that interferon alpha responses to the artificial ligands polyI:C and R848 are slightly diminished. There's nothing that says to me that these diminished responses are clinically meaningful, because they didn't show the levels of any of these relative to an unstimulated control.
Generally, if I were to design experiments looking at cytokine levels, as I did routinely for my doctorate, they would always include controls that show what happens in the unstimulated case. I see nothing of the kind here. I would also want control experiments performed in patients who did not receive the vaccine or who received some other vaccine recently. And, finally, I would like to see more follow-up, to determine if these small supposed effects are transient or long-lasting.
However, let's suppose that there is a genuine effect here, albeit small. I can think of a couple of reasons that this might be the case. First of all, the vaccine should affect the PBMC population. PBMCs are a very broad class of cells, containing things like T cells and B cells as well as other cells we don't often talk about in this newsletter, like macrophages, natural killer cells, and dendritic cells. These cells all have very different functions that are tightly controlled by cytokine signals, and in different ways. They are often examined as a broad class, but the results can be hard to interpret. Usually they are not examined by taking them out of an organism that has been given some kind of immune stimulus, because immune stimuli (like vaccines) have systemic effects. Usually, one would prefer to sample PBMCs from organisms or patients that have not recently had anything done to their immune systems.
The reason for this is that immune stimuli change where these cells go in the body. Macrophages and dendritic cells, for example, can be called to lymph nodes and sites of infection in response to immune stimuli. T cells and B cells can begin to proliferate wildly, expanding their populations far beyond normal and also migrating through the body to lymph nodes and sites of infection. It would not surprise me at all if these events distort slightly the types of PBMCs that can be collected from patients by standard techniques. It is possible that those PBMCs which are most likely to respond to RNA stimuli have been depleted somewhat from the general blood circulation because they are involved in responding to the vaccine. This could lead to slightly different cytokine responses being measured from the now-biased sample population.
Given the small effect size and absence of appropriate controls, I'm really skeptical that what's reported here is a meaningful or even real effect, but I think if there is something genuine being detected, it is a sign that the vaccine very slightly disturbs the distribution of immune cells in the body, slightly changing the composition of PBMC populations that the researchers were able to sample. Since the vaccine is supposed to induce an immune response, I think this is probably a good thing. Given the apparent size of the effect, which is quite small, I don't think it would make any difference to the ability of a patient to mount another immune response against a different stimulus. I also seriously doubt that this effect, if real, would persist for more than a month or so after the second vaccination.
If there's something here, I think it is perhaps a picture of how immune cells redistribute themselves through the body in response to vaccination. That is interesting from a basic science perspective. But to really tell us something about that, there would need to be many more experiments done here and much better controls included. As it stands, all I can really say is that the authors make bold conclusions about impacts on innate immunity that are not supported by the data they present.

All in all, I believe these authors have quite a lot more work to do to have something that would pass peer review. Perhaps they have stumbled onto something interesting, but I do not believe they have a complete or meaningful scientific story here. They have much more to do to make this convincing and establish what, if any, impact there is of what they report.

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