COVID Transmissions for 10-15-2021
What does mixing vaccine doses do? Also, third doses of Moderna.
Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.
It has been 698 days since the first documented human case of COVID-19. In 698, there was an outbreak of bubonic plague in the Byzantine Empire and Arab Caliphate, spreading across Constantinople, Syria, and Mesopotamia. People even in this medieval era were wise to the existence of zoonotic illnesses like bubonic plague, and realized that this entered their population through animals. Emperor Leontios, acting on advice that identified the source of the plague in Constantinople as an animal market in a nearby trade port that does business through Syria, orders that market destroyed. I think we have all heard this story before; at the time, I don’t think anyone suggested that this plague originated in a laboratory, for some reason.
In today’s issue, we’ll discuss additional booster doses of the Moderna vaccine, and then we will discuss a new study looking at booster doses of every vaccine. By that I mean, the study looked at what happens when your first dose is with one vaccine brand, and your second dose is with any of the others currently available in the US.
Have a great weekend!
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.
Moderna vaccine boosters recommended by FDA panel, for specific at-risk populations
This is not a really big shock, but the FDA advisory committee made a recommendation yesterday that Moderna vaccines should have an additional booster dose given for specific at-risk patients: https://www.cnn.com/2021/10/14/health/fda-vaccine-advisers-moderna-thursday/index.html
The case to do this was less clear-cut than for the Pfizer vaccine, since Moderna had higher antibody responses in patients from the outset and these levels remained high in patients for quite some time. However, the company suggested that a half-strength booster dose might be warranted, and they were able to demonstrate that such a booster can improve the immune response. There were some questions as to whether the boost is necessary, but given the risks of COVID-19, the panel ultimately made a unanimous recommendation to authorize third doses of the Moderna vaccine 6 months after the first two doses, for people:
Age 65 or older
Ages 18-64 who have high risk of severe COVID-19
Ages 18-64 whose jobs put them at high risk of exposure to COVID-19 or at high risk for complications or severe illness
This is pretty similar to the recommendation made for the Pfizer vaccine, with the exception that the third Moderna dose is, as mentioned, half-strength relative to the first two doses.
This is just the first step. The FDA will need to officially issue a decision here, and then the CDC will make recommendations as to how clinicians should deploy these third doses. If you received the Moderna vaccination and are (or think you might be) in one of these groups, pay attention to the news—and this newsletter—to find out what the CDC ends up recommending you do.
Boosting with a different vaccine brand has…effects
The study that I mentioned in the last issue, covering the mixing of different vaccine brands as prime-boost series, has now been released as a preprint: https://www.medrxiv.org/content/10.1101/2021.10.10.21264827v1.full.pdf
I have to say that I’m a little disappointed with what this study turned out to be. It doesn’t contain any information on vaccine efficacy, which is what I really wanted to see. It is all molecular analysis of antibody levels for every combination of prime-boost for the Pfizer, Moderna, and J&J vaccines. The authors looked at general binding antibodies, as well as neutralizing antibodies, which are currently a candidate for consideration as a correlate of protection. The problem is, these values are extremely hard to interpret, because it is clear that there is a difference between the immune responses that are generated by the mRNA (Moderna and Pfizer) vaccines vs the viral vector (J&J) vaccine. While Moderna and Pfizer’s vaccines appear to create immunity that is indeed driven by high levels of neutralizing antibodies, the J&J vaccine seems to be doing something a bit different. The protection that it generates is still high, especially with two doses, but the antibody levels seen with that vaccine are typically lower than what we see with the mRNA vaccines.
This is probably because antibodies are not the whole story when it comes to antiviral immunity. T cells, particularly ones called CD8+ T cells which seek out and kill virus-infected cells, are an example of an entirely non-antibody manifestation of adaptive immunity. They are often involved in antiviral protective immunity, and they may be involved in the immune response that the J&J vaccine generates.
I’m saying all this at the beginning because the results show that really good antibody levels, both of neutralizing antibodies as well as generalized anti-spike antibodies, are increased when you boost any of the vaccines in question with any of the mRNA vaccines. In fact, any prime-boost combination that contained at least one mRNA vaccine dose yielded really nice antibody responses.
When only the J&J vaccine was used, the antibody levels of both types were lower. But, I cannot say that this means anything. The prime-boost schedule used in this study was very short (~2 weeks), and the efficacy results that we have seen for two doses of the J&J vaccine used a booster timeline of between 2 and 6 months for the second dose to be administered, which generated >90% efficacy against disease. It is hard to cross-compare, or indeed to at all reconcile, what is observed in this study with what was observed there.
The bottom line is that we know that these combinations of J&J’s viral vector vaccine with one dose of an mRNA vaccine did something in this study, but we do not know if that effect means anything of clinical significance. These results are going to make a lot more sense if this advances into a Phase 3 trial and we have some relative efficacy numbers to be able to compare with. There probably won’t be a placebo group in such a trial, so the efficacy results would be relative to prime-boost schedules that are not mixed-brand, most likely. This means we’ll be looking at a relative reduction in risk that will look quite different from what we’re used to seeing in the placebo-controlled context. In a trial where every arm gets something that we know works, even a 10% or 20% improvement over the active controls might be considered a meaningful, practice-changing result. Stay tuned to see if we end up with something like that; I think it’s possible we could.
If the viral vector vaccine indeed produces more T cell based immunity, but boosting it with an mRNA vaccine produces a reliable elevation of neutralizing antibodies to levels normally seen with 2 mRNA doses, it could mean that this combination yields a better-rounded immune response that has both T cells and antibodies working in unison. That might mean better vaccine efficacy compared to 2 doses of the same vaccine brand. But, I have no idea, because we haven’t seen that experiment yet.
Something else that the authors did was look at safety, and here I can be a lot more confident in the results:
Reactogenicity was similar to that described in prior evaluations of Ad26.COV2.S, mRNA-1273 and BNT162b2 vaccines and did not differ between heterologous and homologous boosts. No safety concerns were identified.
The safety profiles don’t look different between a mixed-brand vaccination course vs a same-brand prime-boost series. The figure is a little too dense for me to fully walk through, but here it is:
What I’m seeing here is that there is no particular combination of vaccine brands that leads to some sort of screwball safety problem that is unexpected and severe. Very few severe reactions at all are noted. The most frequent reactions were pain at the injection site (when you poke someone with a needle they might be sore in that spot afterwards, I know this is really a huge shock), aches, and fatigue. Nothing here is a surprise.
It does jump out at me that the lowest rate of severe reaction is seen when the booster dose given is Pfizer, but I suspect that has to do with the Pfizer vaccine containing the lowest dose of mRNA among the available mRNA vaccines.
At any rate, this is looking pretty good—as I said, there are no surprises here, and when you’re looking at safety data, you want there to be no surprises.
All told this study is a foundation for future work to assess the efficacy of mixed-dose regimens. I can’t tell you to take any actions based on the results here, and in fact, I would caution you against it. This isn’t enough to tell us what the best combination is. You might already have gotten vaccinated with the best combination.
What am I doing to cope with the pandemic? This:
Watching: For All Mankind
OK, I’m coming a little late to Apple TV here and catching up on shows that anyone who got it around launch time already burned through. Still, I’m impressed with the quality of the content there. For All Mankind is a fantastically-envisioned and subtle alternate history show. Instead of making a huge change to history, the show makes just one relatively small one: that the Soviet space program successfully completed the design and construction of the N1 heavy-lift rocket and thus was able to beat the United States to land on the Moon in 1969, but just a matter of weeks. Instead of the Space Race essentially ending with undisputed US dominance following the Apollo Moon landings, it continued and intensified in this alternate universe, and to interesting effect. It’s partly a period piece about NASA and the 1960s to 70s, and partly an envisioning of a past that never happened. We’re enjoying it.
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. And don’t forget to share the newsletter if you liked it.
Always,
JS
I always appreciate your newsletter for your clear communication of COVID science, but had to chime in that we are also late discoverers of the For All Mankind series. It's so good!