COVID Transmissions for 10-20-2021

What does Colin Powell's death say about vaccination? Also, mixed-brand vaccination.

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

It has been 703 days since the first documented human case of COVID-19. In 703, the Arab-Byzantine war was still ongoing, and the Arabs constructed a Mediterranean fleet to harass the Byzantine Navy. Using it, they were able to capture some key Iberian vacation destinations—the islands of Ibiza, Menorca, and Mallorca.

Today we’re going to talk about a high-profile breakthrough case: the death of fully-vaccinated famous person Colin Powell, and what it means for vaccine effectiveness.

We will also discuss mixed-brand vaccination, which is also being called “mix-and-match” vaccination, a term I don’t love.

Bolded terms are linked to the running newsletter glossary.

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Now, let’s talk COVID.


What does Colin Powell’s death say about vaccine effectiveness?

Nothing, really. But it’s worthwhile for us to understand the underlying science of why his death is not an indictment of COVID-19 vaccines.

If you are confused as to what I’m talking about, former US Secretary of State (and the first Black man to hold that position), as well as retired General, Colin Powell died of complications from COVID-19 this week. This was despite his being fully vaccinated.

Certain bad actors are using this event as a way to undermine confidence in vaccination, so I wanted to walk through why they are dead wrong to do this. We’ll begin by first managing expectations about vaccines.

Vaccines are a biologic medical intervention. They’re made in a biological system, and everyone’s body reacts to a specific vaccine differently. The complexities of the immune system are so great that we really don’t have a handle on how each individual will respond to a given vaccine yet. Science just isn’t there. So, when we give a vaccine, we expect there to be a variety of different responses among individual patients. This is also true of non-biologic interventions, but with biologics there’s even greater complexity, so the point applies even more.

In light of that, we can only conduct trials that look at the average response that people have to a vaccine, not the individual response. I cannot look at a patient’s medical records and tell you exactly what is going to happen to them when a specific vaccine is given—and that’s not just because I’m a scientist rather than a physician. It’s because there are too many variables.

This is why vaccine effectiveness and efficacy are never 100%. Even when the result appears to show 100% in a clinical trial, we know that this is not realistic and is likely to be the result of the trial being too small to capture the rare breakthrough event. No vaccine is perfectly protective. There are always subpopulations or even individuals where quirks of biology mean that protection will be incomplete or nonexistent.

For this reason, there will always be anecdotal cases where someone gets sick or dies from the disease that a given vaccine is expected to prevent. When you hear about those cases, the question to ask is whether their frequency is so great that it deviates from expectations based on experimental data, or whether it is not. In the case of COVID-19 vaccines, I can tell you that breakthrough deaths are in line with expectations based on what was seen in clinical trials. They are extremely rare, but that is different from saying that they do not happen. We simply expect them to happen more than 95% less frequently among vaccinated people compared to the rate that deaths from COVID-19 occur in unvaccinated people. The exact number varies a little from study to study.

Right now there are about 2000 COVID-19 deaths in the US every day, largely in unvaccinated people. If the population of vaccinated and unvaccinated people were roughly the same size (thankfully vaccinated people now outnumber unvaccinated people almost 3-to-2, though), then we might expect that about 20 of those deaths were among vaccinated people, every day, assuming that the risk of death for a vaccinated person is 1% that of an unvaccinated person. This is a very small number, and if everyone were vaccinated, we might see COVID-19 deaths drop to fewer than 15,000 annually in the US rather than the 730,000 who have died since 2020, but even with a small number it is noticeable. Please note that all the numbers in that paragraph are really rough estimates, I didn’t do any modeling off the cuff here.

Anyway, my point is that even with a highly effective vaccine, there are bound to be some breakthrough negative outcomes, and when one happens in an especially famous patient, it may seem like this means the vaccine doesn’t work. Except, anecdotes aren’t data. They’re just outlier stories that don’t tell us a lot. The epidemiology tells us that vaccination against COVID-19 is protecting people from death at a rate similar to what was expected, and that’s fantastic.

Now, that’s the generalized answer for any breakthrough death. In the case of Colin Powell, we know more about his medical history than we do about the typical breakthrough death, so I can tell you exactly why I think the vaccine might have failed in his case.

Powell was suffering from a disease called Multiple Myeloma (MM). MM is a blood cancer, specifically affecting B cells. B cells are the ones that make antibodies. In MM, cancerous B cells proliferate out of control—out of control cell proliferation being a hallmark of cancers in general. However, when B cells grow out of control, they don’t form a cancerous mass that presses on organs, like with “solid” tumors. Instead, in MM, these out of control B cells produce copious volumes of useless antibodies, specific for no invader, that flood the bloodstream with protein. This protein overload eventually does irreparable kidney damage, which can be fatal.

The treatment of MM is rather complicated, partly because the disease often occurs in older people and isn’t always too aggressive. Sometimes, treatment isn’t required right away. On the other hand, MM doesn’t have a great prognosis. Overall, there is about a 54% 5-year survival rate for the disease,1 which is skewed low by advanced patients who are in desperate need of treatment. However, there is one thing that unifies all MM treatments: since out of control B cell growth is the problem, the treatments are designed to stop B cell proliferation.

Do you see the problem? B cells make antibodies in response to infection. Infections like the ones caused by SARS-CoV-2. They also make antibodies in response to vaccination, like the COVID-19 vaccines. B cells also produce memory populations that are able to rapidly proliferate and produce large numbers of antibodies when the body is exposed to an infectious agent that it has fought off before.

If you inhibit the ability of B cells to proliferate, you hurt all of those functions. In other words, if you’re undergoing active treatment for MM, you’re probably going to have problems with forming meaningful immunity to infectious diseases and also you might have trouble recovering from infections. This applies to COVID-19 as much as it does influenza.

Among patients with MM, COVID-19 mRNA vaccination has been documented to produce an adequate immune response in only 45% of patients: https://www.nature.com/articles/s41375-021-01354-7. Another study showed that even 10 days after the second vaccine dose, when antibodies should be at their highest, about 16% of patients undergoing a specific MM therapy had no detectable antibodies against SARS-CoV-2: https://www.medrxiv.org/content/10.1101/2021.05.15.21256814v1

The take-home of all of this is that our understanding of immunology suggests that MM patients will have highly impaired immune responses to COVID-19 vaccination, and that this theoretical prediction is confirmed by data observed in real patients.

So, really, it makes a lot of sense, intellectually, that Colin Powell was not adequately protected from COVID-19 by his vaccination. He was one of the people in the small percentage of patients who aren’t adequately protected against death from the disease, and once he was exposed to it, that inadequate protection couldn’t stand up to the infection.

But just because it makes sense doesn’t make it OK that this happens. Put aside any political feelings, positive or negative, you might have for the specific person in this case, please. See them as a patient who doesn’t want to die. We know they’re not protected adequately by vaccination. MM isn’t a secret here. These patients know they’re at risk and their doctors know they are at risk. They also know there is very little that can be done to protect them, because their bodies cannot mount an adequate immune response.

So how do we protect people with diseases like MM? We all have to get vaccinated. Even with imperfect protection against disease transmission, vaccination of everyone around an MM patient—or any other immunocompromised patient—reduces the chance that this high-risk person ever gets exposed to disease. Everyone should get vaccinated because it protects them personally from death and other negative outcomes, but everyone should also get vaccinated because it further protects vulnerable people. That’s the message we should take home from Colin Powell’s death, at least when it comes to vaccination. His death, and every COVID-19 death of a person with a compromised immune system, is a product of a society that hasn’t done enough to stop the spread of this disease. When we don’t do our part, people die. When we do our part and get vaccinated, we save lives.

FDA to allow mixed-brand vaccination for booster doses

You know I was expecting this, but reports are telling me that this is coming sooner rather than later, which I didn’t expect! The FDA is apparently set to formally recommend that patients be allowed to mix-and-match their vaccine brands for the administration of booster doses: https://www.nytimes.com/2021/10/18/us/politics/fda-mix-and-match-boosters.html

Based on the data available to me, I personally think that the best case for this approach is currently among patients who got two doses of the Pfizer vaccine but now wish to get a third dose (if indicated) of the Moderna vaccine, which has a slightly higher amount of RNA and might produce a really nice improvement to antibody numbers.

I have seen folks saying that this is especially good news for the J&J vaccinees, but I don’t know that I agree. I still haven’t seen any efficacy data on mixed-dose vaccination for J&J, only antibody numbers in the very short term, and I’m not completely convinced that mixing mRNA vaccines for one dose with a viral vector vaccine for another produces a durable immune response. The two vaccine strategies seem to elicit different types of immunity by different mechanisms, and I am not sure the degree to which they reinforce memory responses for one another when mixed. I would like to see more long-term data on this approach before saying that the second dose given to a J&J recipient should be from an mRNA vaccine. For now, there are great data suggesting that 90+% efficacy against disease can be achieved by getting 1 dose of the J&J vaccine and a second dose of the same vaccine 2 to 6 months later. I would personally stick with that. If I needed to get a third dose, I might then go for an mRNA vaccine. That said, if you already went out and got J&J as one dose and then an mRNA vaccine for another single dose? I bet you’re probably well protected. I’m just being cautious here because I don’t have a lot of data to go on.

Anyway, I overall think this is great news, if only because people will no longer need a clinic to be stocked with a specific brand of vaccine before they go out and get their recommended third dose. You got Pfizer but CVS only has Moderna that day? Don’t sweat it, the FDA—and soon the CDC—will be cool with that. This makes the supply of vaccines more flexible, which helps logistically for everyone.


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

Working on a new exercise plan

I know I shared something about exercise recently, and I try to keep those less frequent than other types of updates, but the bottom line is there is a professional goal I want to achieve in the next year, and if I want to do it, I need to lose about three inches off my waistline. So I’ve been working hard this week to make a plan to do that…in between caring for a newborn. Yeah, there is a lot on my plate.

It’s off to a good start, though! I’m finding time to work out when I can, and if that means something as simple as taking the kid for a walk in the park, that’s still calories burned.


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JS

1

This number is actually, gratifyingly, going up. There was a time not too long ago when the number was 30%. Less than 5 years ago, when I was actively involved in supporting medical education for a multiple myeloma treatment, the number was 47%. To see it jump by 7% in such a short time is pretty great news.