COVID Transmissions for 10-13-2021
Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.
It has been 696 days since the first documented human case of COVID-19. In 696, St Peter’s Abbey in Salzburg, Austria was founded. It is the oldest abbey in the world with a continuous history from foundation to the present.
It’s a pretty big issue today, covering:
An upcoming study on mix-and-match vaccination
A massive study of vaccination effectiveness, and declines therein, from New York State
A discussion of where we stand on the infection-induced vs vaccine-induced immunity debate—spoiler, there’s not debate, please get vaccinated
Have a great week!
Bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
A study of mixed-dose vaccination will appear later this week
Normally I try to wait for the news to happen before commenting, but today I saw this:
This refers to the use of one vaccine brand for the prime dose followed by some combination of the original brand plus other vaccine brands for booster doses. The logic of this is that different vaccine design strategies may interact with the immune system in different ways, so combining different designs may ultimately lead to a better-rounded and thus more robust immune response.
The results of such a study will be a very big deal, and I’d like to do that I can to prepare you to interpret them. I think that this piece from STAT news is a good primer: https://www.statnews.com/2021/10/12/a-primer-on-what-we-know-about-mixing-and-matching-covid-vaccines/
I’ll of course still write about the study results when they appear, but I wanted to help prepare you all in advance, given the opportunity.
New York releases analysis of why vaccine efficacy dropped
New York State has released a massive real-world analysis containing nearly 9 million people, looking at the effectiveness of the Pfizer, Moderna, and J&J vaccines against two major endpoints: infection and hospitalization. You can read the preprint of this here: https://www.medrxiv.org/content/10.1101/2021.10.08.21264595v1
There are a lot of numbers in this prospective study, so I’m not going to quote them all back at you, but there are a couple of broad conclusions that I’d like to review:
All of the vaccines display a drop in effectiveness against infection over time, of about 28% or less depending on recipient age and particular vaccine
Pfizer’s vaccine showed the largest drop in effectiveness, but not by much—Moderna and J&J also had declines
These declines correlated with increased prevalence of the Delta variant in NY, and with relaxation of pandemic control restrictions in the state
Declines in vaccine effectiveness were seen at similar calendar times in cohorts determined by age, brand of vaccine, and time of vaccination
Generally speaking effectiveness against hospitalization began high and remained high, with little or no decrease for the vaccine brands examined
The facts here fit with the narrative we have been exploring in previous discussions of vaccine effectiveness drops. We see effectiveness against any infection fall, but we do not see big drops in effectiveness against serious outcomes. However, with this massive study1 we have information that we did not see in previous work. Specifically, we have a comparison here of the time of vaccination against the timing of decline. This can tell us something about whether it is the patients’ internal immunity or external conditions that drive the decline. To illustrate what I mean, let’s look at an example figure from the paper:
In this figure, we see that all the effectiveness lines begin to drop right after the CDC mask guidance is changed and NY adopts the change. This is around the same time that Delta begins to expand in the state. All groups drop essentially simultaneously, and continue to drop as the Delta variant gets more and more dominance among infections in the state. The decline only stops—and to some degree, reverses, when the CDC changes mask guidance to recommend that vaccinated people start masking up indoors again. This is just an example figure. Similar figures appear, with basically the same patterns, for other age cohorts and other vaccine brands.
The authors of the NY study use this to make the argument that behavior and the Delta variant are the key drivers of the loss of vaccine effectiveness—not immunological decline on the part of the patients. They note that immunological decline is a phenomenon that should originate from the date of an individual patient’s vaccination, and so the different time-cohorts represented by the three lines here should each be separated in decline by at least a month if there is a change in immune response taking place. In other words, if the problem is people’s immune responses to the vaccines weakening, they should weaken at a comparable rate across all of the cohorts. It should take an average of X months. So if you got vaccinated in January, the waning would happen by month 1+X, and if you got vaccinated in April, the waning would happen by month 4+X. There would be a three-month gap between waning in these two patient groups, because they got vaccinated three months apart.
Instead, we see that there is no apparent time separation regardless of the month that the vaccine was delivered. This suggests that external factors are at play, and through correlation analysis, the authors propose that the emergence of the Delta variant is a key external factor in the loss of vaccine effectiveness. They also propose that the relaxation of restrictions played a role, but this is less well-supported by analyses (I’m not saying it isn’t a factor, I’m just saying they didn’t do enough work to prove to me that it is a big one).
I’m a little concerned about giving too much weight to this study, because it confirms something that I’ve been saying all along and I don’t want to be subject to that kind of confirmation bias. Still, I think this is the first study with a design that adequately attacks the question of immunological waning vs changes in external factors, and it suggests that external factors play a big role. I’ve thought so too.
Still, I’d be remiss if I didn’t mention that we do know there is a molecular decline taking place in the immune system. We know that antibody levels do go down. I shared a study about this recently. It’s not an imaginary effect. However, it is not definitively an effect that has real-world impact. Antibodies can be produced quickly in response to infection, and decline in serum antibody levels happens after vaccination and infection for pathogens where we know lifelong immunity is possible.
The NY study says to me that we don’t necessary have a clear-cut argument to say the vaccines are the problem. The vaccines work quite well, even with the declines. Our immunity is not necessarily the problem here, either. The problem is, as it has always been, people breathing in each other’s faces, aided by the emergence of a variant that is very good at taking advantage of people breathing in each other’s faces. The Delta variant may also have some ability to evade antibodies to previous variants, and that may play a role here too.
Perhaps it seems like splitting hairs, but I think this study challenges the narrative that vaccine-induced immunity does not endure. In fact, it may well be enduring—but as we change our behavior and as the virus evolves, it may no longer be quite enough to prevent as large a number of infections. Since it still seems to be enough to prevent almost all hospitalizations and deaths, that may actually be OK. But it gives us another way to think about the phenomenon we are observing in the world.
That said, I—and the authors of this study—do not think it should be used to counter messaging recommending booster doses for at-risk people. At this time we believe that boosters restore effectiveness, and there are data to suggest this is the case. Whether the loss in effectiveness is due to one cause or another is not really material in the recommendation to get one.
For those of us who are not recommended to get boosters, this study has a different sort of advice—that we ought to strongly consider doing everything we can, including masking and social distancing, to avoid exposure to the Delta variant. While the vaccinated are still protected from the worst outcomes, if we take those measures we can help stop the spread and not be a contributor to someone else’s transmission chain.
Immunity from infection vs immunity from vaccination
A reader requested that I revisit the topic of whether infection-induced immunity2 or vaccine-induced immunity is more protective. I’ve written about this before:
I’ll build on that today, and also update you on another study that I discussed, just over a month ago:
In that second issue, I talked about an Israeli study that suggested that infection-induced immunity may be substantially more protective than vaccine-induced immunity. I made some points in writing about that study that indicated why I might be skeptical, but I need to revisit it with one key point: the rate of COVID-19 among people who got COVID-19 is 100 percent. The thing about infection-induced immunity is that, because of this statement, we are only measuring it in the survivors. There is a serious survivorship bias in these types of analyses. The people who didn’t develop protective immunity in response to infection died. They’re dead now. We can’t assess how well protected they are against future infection, because they will never be infected with any pathogen ever again—but not by virtue of immunity, by virtue of being dead. This may have led to imbalance observed in the Israeli study—among the infection-induced immunity group, we know there were fewer people with high-risk coexisting conditions than in the vaccinated group. That could be because among the infected, those people tend to die, while among the vaccinated, they tend to survive, or it could just be a random variation. Either way, it probably biased the results.
For these reasons, I find it pretty hard to make much out of the Israeli study.
Another important point is that a lot of the information we have about infection-induced immunity is at this point contradictory. For example, while some studies have suggested that infection-induced immunity is long-lasting, we have seen data from the CDC suggesting that infection-induced immunity to older variants is not very protective against, for example, the Delta variant. We have also seen evidence that antibodies against SARS-CoV-2 decline rapidly, to undetectable levels within about two months, in about 30% of patients who are recovering from infection: https://www.cdc.gov/mmwr/volumes/69/wr/mm6947a2.htm. It is hard to make conclusions based on antibody-decline data, but since I mentioned declining vaccine-induced antibodies in a previous item today, I think it’s worth mentioning that it happens with infection, too—and quite rapidly.
One thing we are really missing in all of this is a straight study that definitively looks at how likely a Delta variant-caused incidence of disease is in a person who previously recovered from disease caused by a different variant. Leaked data from the CDC once suggested that people in this situation are less than 50% protected against the Delta variant, but I do not believe I have seen this published anywhere. I would like to see some data I can really sink my teeth into before I comment on that.
Either way, though, I stand by what I said in the 7-9-2021 issue. There is a lot more variation in immune responses to infection than there is in responses to vaccination. Responses to vaccination appear to produce better levels of neutralizing antibodies that continue to work against future variants, too.3 And, the nice thing about vaccine-induced immunity is that you don’t need to risk death or disability from COVID-19 in order to get it. You just need to get the vaccine.
For what it’s worth, Apoorva Mandavilli of The New York Times appears to have been thinking along similar lines recently, and just released this piece: https://www.nytimes.com/2021/10/12/health/if-youve-had-covid-do-you-need-the-vaccine.html. It covers a lot of what I’ve just discussed, though does not always agree with my perspective. It also has a lot of expert quotes that help to interpret the results. I’d recommend giving that a read, too.
What am I doing to cope with the pandemic? This:
Getting back to exercising
Combine the schedule of the Jewish holidays with becoming a parent, and you’re bound to put on some extra pounds. I’ve gained a little weight back, and am working hard to lose it again. However, I’ve noticed that with all my missed workouts, my performance has suffered. Definitely much moreso with my cardio capabilities than with my weight lifting—that’s a well-known thing. Weight training declines less rapidly than cardio endurance. These declines are discouraging, but guess what? The only way to fix them is to get back out there and do what I can. Sure, I’m not happy with my mile pace, but I’m only going to be happy with it again if I get out there and run.
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.
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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 don’t want to skip over what an impressive feat this study is. They took vaccine registry data, testing reporting, and hospitalization data for 9 million people and matched the information across the databases to be able to perform this analysis. That is no small feat.
Often called “natural” immunity, but all immunity is natural, so I don’t use that term, because I think it is biasing language.
There is some debate over whether it is better to be vaccinated, or infected-then-vaccinated, for protection against future variants. While there do appear to be some advantages for those who were infected and then vaccinated in terms of the diversity of their antibody response, I think Russian Roulette is a stupid game. In my opinion it is better to be vaccinated fully, and then perhaps to later get either boosted against a new variant or become infected with a mild case of it and thusly update your immunity. Whatever happens, getting vaccinated before you get COVID-19 is the best way to reduce your risk of death or disability from COVID-19.