Is Choice Always Worth the Anxiety?

Vaccines and variants, part two.

This is a post that gets a bit “in the weeds”—partly because it’s a typical thorny example of making decisions under uncertainty, and also an example of a case when that uncertainty matters a lot less substantively than the anxiety it seems to be causing.

In the last post, I tried to explain a few things about the three vaccines that have been approved in the United States. 

To recap, the first thing to remember is why we chose the trial endpoints—symptomatic COVID—that we did. (tl;dr symptomatic COVID gave us the best intersection that was both indicative of important things and fast with a reasonable trial size—hence statistical power). If we had more time or the ability to conduct much, much bigger trials? We could have answered more or different questions. It’s not that those questions are irrelevant or unimportant, but there was really no feasible way to answer them quickly enough for our purposes. Such is life in a pandemic. 

The second thing to remember is that the immune system is not a seawall guaranteed to be overrun and progress to severe disease or worse if it fails to hold off any symptomatic disease. Instead, it’s a complicated, tiered system and also a really, really complex area of science. It’s exciting and interesting and amazing, but it also makes it a very tricky topic to report on and discuss. Most of us have nowhere near the kind of knowledge needed to interpret the intermediary studies on the question of variants and vaccines (again, myself very much included) beyond some basic results. Plus, the difficulty and the complexity of the field means that we don’t have anywhere near perfect knowledge—otherwise we could just rely on lab results or small phase I/II trials. We can’t do that because we can’t fully predict what will happen in our bodies, and at a population-scale, by just looking at the lab results or a few studies. And clinical trials and real-world applications at scale… take time. Hence, a lot of (yet) unknowns are inevitable. 

Where does this leave us? Not in any dire need to be vaccine-shopping as individuals.

There are some known differences between the vaccines, obviously. J&J has the advantage of currently being a single-shot, but the company is already studying to see if a booster makes things ever better. My working assumption is that we will have at least one more round of boosters, including perhaps for J&J—eventually. So even that difference is likely to even out over the intermediate to long-term. We know J&J has easier storage requirements, so that’s great for reaching populations that cannot travel to centralized sites, and for poorer countries. 

The other key difference, the one that’s leading to the  reporting that frames Johnson and Johnson’s as being an inferior or “less effective” vaccine is the the finding that, in the United States, the single-shot was 72% effective in preventing mild/moderate COVID compared to the other two vaccines that reported 95% efficacy (after two shots). 

That is a difference, but it’s not as easy to interpret as it may seem. First, as many have noted, it doesn’t mean a failure to prevent deaths or hospitalizations—all the vaccines are holding up there. But, of course, a slightly higher chance of developing milder symptoms is something people will notice and it is a question. But the comparison isn’t completely straightforward as it looks. 

Johnson and Johnson ran its trial after those pesky “variants-of-concern” had risen. On the one hand, that’s good. Johnson and Johnson is the only vaccine among the three in the United States that has been trialed against two crucial variants-of-concern — B.1.1.3.5 (South Africa) and P1 (Brazil) — and held up very well. Will the others do so as well, and to what degree? Some lab studies are encouraging but we don’t know for sure. Moderna and Pfizer both have variant-specific or multivalent (targeting multiple types) boosters in the works. FDA has declared that it is ready for a fast-turnaround approval for such modifications. On the other hand, the initial two seem to be slightly better for preventing breakthrough cases for the original wildtype virus that is being rapidly replaced by other variants. So where does this leave us for “vaccine-shopping”? Not clear that there is a straightforward answer.

But what about the rest of the important matters? Is one of vaccines better for preventing what we are calling long-COVID, or not? Which one will be stronger for preventing asymptomatic infection (and hence provide sterilizing immunity to more people) and/or transmission? Will the hospitalization/death prevention remain identical or near-identical (already very, very strong in that it was 100% in *all* the trials)? We don’t know. Not yet. And we may not know for a while.

Johnson and Johnson has other advantages: fewer reported adverse side effects than the other two vaccines, plus a single-shot means much easier storage. Will the booster for it (if it happens) match the higher side effects of the other two vaccines—reportedly higher in the second round? We don’t know that either. 

So the answer to many of the swirling questions is: we don’t yet know. We don’t know because the trials weren’t statistically powered to answer these questions. Or we don’t know because the trials are not completely comparable due to timing. Or we don’t know because we don’t understand the problem very well in the first place—like long COVID. 

And here’s the truth: we’re not going to know these details for sure for a while. We cannot conclusively compare things the trials didn’t and couldn’t measure with sufficient precision and confidence.

But the real world data is coming in for those and other vaccines, and so far it’s quite encouraging. 

For example, as noted in the previous newsletter, T cells matter, and there’s excellent news coming in on that front regarding the variants. T cells are able to recognize the (slightly) mutated spike protein better than the initial wave of neutralizing antibodies which may be less able to do so, and  hence cause an increase of breakthrough illness. Here’s (an actual) expert explaining this. 

A different vaccine, Oxford/AstraZeneca, or ChadOx1—not yet approved in the United States—seems to have drastically cut down COVID deaths and hospitalizations in Scotland even after just one dose. 

The elimination in deaths and hospitalizations among the vaccinated seems to be holding up very well in large-scale vaccinations. (We don’t expect this to be zero once scaled up to millions because there’s always people for whom something may go wrong—even common cold outbreaks can be potentially fatal among frail nursing home residents, for example). 

This is, of course, a difficult message to communicate, but here’s how I’ve been thinking about it—especially since I get asked about this all the time now. 

When I’m doing comparison shopping for something to purchase, if, after a little bit of research, one of the choices doesn’t stand out as obviously superior, I stop researching because at some point, that signals that the anxiety and time isn’t worth what the research is producing in terms of differences. That doesn’t mean I’m confident there’s nothing I don’t know, or they’re guaranteed to be equal if I had perfect knowledge. But deciding in the face of uncertainty can’t always be done with certainty, and sometimes, the differences aren’t big enough or known enough to keep worrying about them.

Sometimes, the answer is to concede the uncertainty, and just pick—especially when all the options have such great upsides. Flip a coin, take the first one offered, go on gut feeling, whatever. This is perfectly fine especially when there appears to be no wrong answer—and there appears to be no wrong answer between the vaccines we have in the United States and most of Europe.

This isn’t the same as saying those other questions about these vaccines don’t matter, or that everything will turn out to be equal. But there seems to be no data-driven, confident way to distinguish between the three in an obvious way that answers all the concerns and eases all the anxieties. Frankly, there doesn’t seem to be a need either—not that I can notice, yet.

I think that we can confidently tell people that all three vaccines are excellent, that they look equally likely to stave off hospitalization and death—to almost completely, if not completely eliminate the possibility of those fates—and it makes sense to take the first available one. 

Other than that, if there is a choice, I ask people if they are looking for one-shot-and-done, or are they ready for a booster in about a month? If they say the former, I do say they shouldn’t rule out a booster in the future. If they say the latter, I remind them to schedule the second shot for when they can take a few days off, as the booster seems to be resulting in a stronger side-effect profile in more people. 

Then I congratulate them.