I’ve had two fun things happen back-to-back recently. One of them was being chosen as “Tar Heel of the Month” by our state newspaper based in Raleigh, the News and Observer.
The other was that my university, UNC-Chapel Hill, is now running many vaccination clinics, and I had the chance to contribute. I don’t think I’ll ever stop being amazed by vaccines in general, but these ones in particular are incredible. Without a doubt, this has felt like the happiest, most positive turning point in the pandemic for me. I feel a palpable sense that the end is in sight, even if the path there is still full of grim twists and turns. I had never really thought one could take a selfie wearing a mask, goggles (mandated by the clinic), my own mask underneath (yes, an N95), plus my own glasses, and still be so visibly happy. While I think the ventilation we have is probably not that terrible, I’m not that sure. It’s a sealed building. We are running this clinic in the community, not in a hospital, and we’re vaccinating mostly the elderly—who are not just more susceptible but tend to transmit a lot, an unfortunate fact that has devastated long-term care facilities and similar congregate living. I believe in precaution and then hope, and that picture is me at peak for both.
The very first person I helped get vaccinated as part of this clinic was a 92-year old woman who had driven herself to the clinic. She was carrying a giant purse and pausing to catch her breath after every few steps she took. But she had made it! She was African-American and North Carolinian, so think of all that she had lived through in her many years: being born right before the Depression era, being a teenager during World War II, the Civil Rights movement, and the rest. It’s easy to forget how much medicine has advanced just in one lifetime. When she was a child, if she got a strep throat—something that is a mere inconvenience for us now—her parents would have been justified to be scared that they might lose their child. We didn’t have effective antibiotics until after World War II. We didn’t have widespread vaccination for polio and smallpox either. There is much detail to this history, of course, but it is truly a wonder and, if you will, a miracle of its kind, how far we’ve come, how quickly, including with these vaccines.
With the COVID vaccines, we have clearly hit a home run, on all of them. They are all tested thoroughly. There were no shortcuts, just due speed. We had all the requisite trials conducted. Part of the reason that the clinical results from the trials are so clear is that these vaccines are amazing—when something works this well, their effectiveness is easy to observe. (The sad counterpart is that their efficacy is easier to observe during such a raging epidemic: the more cases there are, the more chances for the vaccine to demonstrate how well it works).
But what about the variants? That six-fold drop in neutralizing antibodies? The scary headlines warning about immune escape and vaccine resistant variants? There are things to worry about there, but not necessarily in the way they are being reported.
The news is concerning, but not really because the variants are knocking out our vaccines—more on that in a bit. First, the real and current problems.
As I wrote last December, a more transmissible variant is terribly worrisome—more so than one that was lethal at a similar percentage, because lethality is a linear measure, while transmissibility is an exponential threat. One of my favorite quotes from this year is from Dylan H. Morris: “You cannot finesse the steep part of the exponential.” Exponential dynamics are huge threats (or, if you are trying to grow a social network online, a huge opportunity) and cause for massive concern.
Second, there is the problem of convergent evolution we appear to be observing around the world, where mutations generate similar consequences, a big sign of adaptive evolution. Rather than random drift, this is the virus successfully evolving into a more transmissible version. (Some of these variants may or may not also be causing more severe disease or even be more lethal. The lethality of the virus and its peak contagious period are separated by about four to six weeks, so those things are not under a huge evolutionary pressure to evolve together at this time scale).
All this means that we may well need boosters—in the future. The good news is that manufacturers are already looking into boosters that better cover the variants, “out of abundance of caution.” That’s the right approach.
Here’s the other real and current problem. We don’t have enough vaccines in this country, and we don’t have enough for the world. We are racing against the more transmissible variants taking hold, and when they do eventually take hold, it will be even harder to contain them. Speeding up vaccination is even more urgent when one considers this.
Using non-pharmaceutical interventions as best we can to drive down transmission is also crucial. However, at this point, the messaging can’t just be telling people to “mask up” or “stay home.” Those who are wearing masks are doing so already—they need better, certified masks. And for most of the victims of this pandemic, “stay home” is a function of privilege. In most countries where we have research, we find that the younger victims are those we call “essential” frontline workers: the people who cannot work from home but who make our society run. They cannot just stay home, because we all depend on them to keep our society functioning. And besides, they cannot afford to stay home.
Other than those issues, however, I’m not worried about the variants and the current vaccines for now. We have a problem here with analogies: the so-called “vaccine resistance” is not like antibiotic resistance. Our mental models of “resistance” come mostly from antibiotics, but this analogy isn’t applicable here in the same way. Vaccines aren’t drugs; they are tools to give our immune system test practice so that when the real thing shows up, our body knows what to do. When antibiotics don’t work, they don’t work. Not so here. If the test practice isn’t as precise because the variant is a little different around the spike protein, the conclusion isn’t necessarily that the immune system won’t be able to do its job and stave off illness.
And immunology is a super complex field. It’s not yet clear that the things we can more easily measure, like neutralizing antibodies, are the best correlates of clinical protection from illness we seek that the vaccines confer. Plus, when those antibodies drop “six-fold” (or whatever the number), that doesn’t mean that the vaccine is six times less efficacious. It’s possible that the actual drop or effect may well be so little that, as far as disease burden is concerned, it’s hardly noticeable. That’s exactly why we do phase III trials—where we test the vaccine against the pathogen in the real world—because we can’t exactly predict how good a vaccine will be in reality on the basis of the things we can measure, like those neutralizing antibodies. Those are very good and valid discussions for immunologists and other specialists to have—amongst themselves. Yes, social media makes all that visible, and yes, lacking authoritative guidance that we trusted for most of last year has meant that it’s really tempting to try to interpret all that. It’s not necessarily wise.
What we should look at is the clinical outcomes of these trials, including against the variant. That’s something we should care about and we can interpret. And there, it’s been non-stop good news if you look at the right metric.
For most of these trials, our “endpoint” has been things like any disease, however minor, even sniffles. Even when we look at “severe” disease, it isn’t what most of us think of as severe: hospitalization, ICU, ventilation and such.
So what’s the news there? Since the beginning of the trials, all trials, there has not been a single death or hospitalization among people vaccinated. Not one. Zero. Not for Moderna, not for Pfizer/BioNTech, not for Oxford/AstraZeneca, not for Sputnik, not for J&J, not for Novavax.
The latter two have included trial components against various variants in the UK and South Africa. Not one person ended up in the hospital (while many in the placebo arm did end up, tragically, hospitalized and/or dead). Even the incidence of severe disease is very low. We’re waiting for more details on both J&J and Novavax. But in the earlier trials, there was a single “severe” disease in the vaccinated arm among both Pfizer and Moderna trials (approximately 30,000 people), and it was someone who had oxygen saturation of 93 percent. One more percent, and that case wouldn’t even be classified as severe. She didn’t need any medical care or hospitalization. So even “severe” in a trial isn’t necessarily severe the way we may think about it.
The reason I emphasize this is that there is a mismatch between what the trials measure, which is “any disease”—because it is a better metric to get us where we need to arrive quickly—and the metrics we should be concerned about for purposes of public health and ending this pandemic. The public conversation around it has been less than productive, comparing the “efficacy” numbers, as if they had much clinical significance. Is one vaccine better than the other? I’ve even seen doctors—with tens of thousands of social-media followers—advocate that a rich country should aim to procure one of the “more efficacious” ones, basically treating the others as inferior.
If anything, given the different trial periods, it’s quite plausible that there is no huge underlying difference in “efficacy” either. Maybe the variant increases the likelihood of someone having a fever rather than not even a fever, but it’s quite likely that that may apply to the earlier vaccines which were tested when these variants weren’t widespread.
Based on the existing data, and to the best of my understanding of having read every paper, authorization application and preprint on the efficacy of these vaccines, I can, without a hesitation, say that of the ones I know are being considered in various places in the US, UK and Europe—Moderna, Pfizer/BioNTech, J&J, Oxford/AstraZeneca, Novavax—I would be happy with receiving *any* of them. I would easily recommend *any* of them to anyone I know, whatever they were offered. (I have not yet read the Sputnik paper, but the numbers look excellent. I know there are issues of trust there, but I don’t have any a priori reason to think that it also wouldn’t work well). If we were to find real efficacy differences, we’d give the higher efficacy ones to the elderly (whose immune systems tend to work less well). But, as a country, and as the world, as things stand, all of these vaccines will do the job of eventually getting us out of this pandemic—once enough people are vaccinated.
So, what is the best way forward now? Do your best to get through this winter, and hopefully, we can offer the vaccine to as many people as possible, globally, as soon as possible.
And on that note, ICYMI: I had a conversation with Charlie Warzel of the New York Times on the hows of wearing and caring for high-filtration masks. It has a lot of practical advice, but also my reflection that it’s high time that people stop needing to turn to “civilians” for such advice. Meanwhile, I’ve become a fan of this vaccine shanty:
Soon may the vaccine come...
That table is a wonderful sight. Re: masks, I have seen recommendations to double-mask. I have had good luck with a KF94 (Korean) under a cloth mask with behind-the-head ties. The KF94 does the filtration, and the cloth mask holds it against my face much better than the ear loops, fixing the side leakage quite well.
Thanks for the optimistic article and the wonderful chart! And, I loved the N and O article naming you Tarheel of the Month. Congratulations!