Our public health agencies should follow the science

On dose-spacing, testing, and treatment recommendations, we’re behind the curve

Today my kid’s elementary school is hosting a pop-up vaccination clinic for 5 to 11-year-olds to get their second dose of the Pfizer vaccine, exactly three weeks after a pop-up clinic for first shots. It’s organized that way because of the CDC-recommended dosing schedule which, in turn, is in line with the Emergency Use Authorization the FDA granted the kiddie vaccine, which followed an EUA and eventual standard licensure for adults.

And that, in turn, was based on the dosing regime that Pfizer opted to use during its Phase III clinical trial to demonstrate the safety and efficacy of the vaccine when used in a large population that was randomly assigned either the vaccine or the placebo.

So everyone is following procedure and doing things by the book.

But unfortunately, the best available evidence suggests that this three-week spacing is not optimal and that the vaccine would be more potent if the doses were spaced further apart. There is not a gold standard Phase III clinical trial to demonstrate that, in part because Pfizer has no particular financial incentive to organize such a trial. But even though those kinds of randomization studies are the ideal form of evidence, they’re not the only kind of evidence that exists. And based on other evidence, it seems like we are sticking with a non-optimal dosing scheduling for arbitrary reasons of path-dependency.

Unfortunately, that is not the only area in which the United States is currently “following the procedural path of least resistance” rather than the science. The good news is that the majority of 5 to 11-year-olds would almost certainly be fine even unvaccinated, so sub-optimal dosing isn’t a huge deal in practice. The bad news is that with omicron bearing down on us, there is a very high chance that the pandemic — which continued to be quite deadly during the fall lull — is going to get quite a bit worse soon. And the country could really use its public health institutions firing on all cylinders.

Longer gaps between Pfizer doses work better

The way drug approvals work is that a company’s scientists spend a bunch of time working in a lab and doing experiments on animal models to try to come up with something that they are pretty sure will work in humans. But once you have the thing that you think will work, you need to test it — eventually on a large sample of humans. And at this point, scientists have to make some judgment calls about what kind of experiment they want to run.

For example, the folks at Pfizer decided they wanted to test a 30-microgram dose, while Moderna scientists decided to test a 100-microgram dose. We learned from those experiments that 30-micrograms of Pfizer work but 100-micrograms of Moderna work better. But is it actually true that the Moderna vaccine is “more effective,” or are they just giving you triple the dose? An ibuprofen gel tab is no more effective than a normal ibuprofen pill, but if you take 3x the dosage of the gel tab that will have a stronger effect.

By the same token, the pharmaceutical companies also needed to come up with a timing strategy on which to run the clinical trial.

One consideration was that they wanted to come up with a schedule that would show high efficacy in the trial and get the medicine approved. But another consideration was that they wanted to run the trial quickly and get approval. So if some guy in a lab coat came to you and said “our best guess is that with a three-week gap we’ll get 90% efficacy but with a 12-week gap it’ll go up to 95%,” I think the right answer might be to say “fuck it, let’s do the three-week gap and get approval faster — that will both save more lives and make us more money.”

But once the vaccine was approved, many countries found themselves dealing with a shortfall of vaccine supply. A few countries responded to that by adopting a “first doses first” strategy of trying to give everyone one shot and then looping back around with second shots once all the first doses had been given. The theory was that this would maximize population-level protection because, as you can read in this extensive document from Canada’s National Advisory Council on Immunization, the first dose does offer meaningful protection.

To be clear, the motivation for the various different dose-timing strategies that different countries adopted was about stretching supply, not maximizing efficacy. But because different places tried different things, we ended up with what the clinical trial didn’t do — experimentation that lets us draw conclusions about the efficacy of different schedules. And a team of researchers out of Oxford found that an eight-week gap is optimal.

Since the United States continues to be newly vaccinating some people and certainly is officially encouraging the unvaccinated to get vaccinated, we ought to update our guidance to be in line with evidence about best practices — an idea that, frankly, we’d be well-advised to take in other areas too.

The FDA needs to approve more tests

Last week the Biden team rolled out a rapid testing strategy that included the Byzantine idea of requiring health insurance companies to reimburse households for the cost of Covid tests. Since this intersects with a lot of people’s longstanding complaints about the whole organization of American healthcare financing, we got a lot of commentary about how this is dumb (I’ll recommend Natalie Shure’s version in The New Republic) and how we should be subsidizing more directly.

That eventually led to a confrontation in the White House Briefing Room with press secretary Jen Psaki that left a lot of people shaking their heads and saying that, yes, the government should send everyone free rapid tests.

Matt Karolian @mkarolian

Jen Psaki somewhat mockingly asks reporter at the White House Daily Press Briefing if the US should be sending out rapid #COVID19 tests to every household. In the UK you can order 1 pack (containing 7 tests) everyday. gov.uk/order-coronavi…

Not to defend the testing status quo, but I do think the “just make the tests all free” discourse skips a key step. Right now, in addition to being expensive, rapid tests are somewhat rare. My household has amassed a small stockpile in dribs and drabs over the past few months — using them when appropriate and giving tests to friends who need them. They’re sometimes in stock at local stores, but often not. There weren’t any for sale on Amazon when I checked earlier, but when I checked just now there are some; however, they’re taking a week or more to deliver.

If we want people to be using tests liberally, in other words, we actually need more tests.

A key bottleneck here, as David Leonhardt wrote for the New York Times on October 6, is that the FDA has been slow to approve rapid tests for home use in the United States. For a long time, basically the only approved one was the Binax Now test from Abbott, and since it was an uncompetitive market, the prices were high and supply was low. But in October, the FDA did approve some other tests, so the thesis of Leonhardt’s piece was that the bottleneck was about to ease. But it didn’t really, according to Lydia DePillis and Eric Umansky, and one reason seems to be that the FDA still hasn’t approved enough tests:

So why are at-home tests still so pricey and hard to find in the United States?

The answer appears to be a confounding combination of overzealous regulation and anemic government support — issues that have characterized America’s testing response from the beginning of the pandemic.

Companies trying to get the Food and Drug Administration’s approval for rapid COVID-19 tests describe an arbitrary, opaque process that meanders on, sometimes long after their products have been approved in other countries that prioritize accessibility and affordability over perfect accuracy.

We even have American companies like California’s WHPM selling rapid tests in Europe but not the United States.

I would say the philosophical issue here is that the American regulators are underrating the value of test abundance and overrating the problems of letting people use flawed tests.

The value of testing

The Trump White House tried to make frequent use of rapid tests a substitute for other social distancing measures back in the summer and fall of 2020 and ended up turning Amy Barrett’s confirmation party into a super-spreader event.

This sort of behavior seems to be the animating concern behind U.S. regulators’ approach to instant tests. They believe that they are useful in a limited sense as a diagnostic tool to supplement the more accurate but slower PCR tests, but dangerous in the hands of the mass public, which may use them to rationalize irresponsible behavior. In particular, a false negative could encourage a false sense of security.

I have never agreed with this logic, which was founded on the public health community’s unrealistic view that indefinite prolongation of strict social distancing was a viable strategy. I used to harbor the fantasy that we might embrace Paul Romer’s vision of frequent national surveillance testing instead. The idea was everyone might test themselves once or twice a week, then quarantine if positive. He demonstrated mathematically that even if tests gave a reasonably large number of false negatives, this would still serve to strongly suppress the virus even in the absence of any other measures. Combined with masks and a little prudence, we really could have kept the death toll much much lower until vaccines became widely available in spring 2021.

Today it’s clear there isn’t going to be a mass testing strategy, but it’s also clear that there’s no need to worry about a false sense of security — we’re now divided between cautious vaccinated people who want to live their lives as normal and unvaccinated people who don’t care about the virus at all.

Giving more vaccinated people the ability to test more frequently when someone in their circle gets sick would tamp down the spread somewhat and give people peace of mind. It could also be a very useful tool in school settings as an alternative to blunt quarantines that hurt learning. I think ideally, we’d also be testing people before they get on airplanes and at other high risk locations, but that may be infeasible. The point is that testing abundance would be good, even if the test quality is less than stellar. Abundance would make the tests cheap, and when the tests are cheap it’s possible to subsidize the price down to $0 or maybe $1 just so people don’t waste them.

We should also be maximizing our use of anti-Covid tools that are already cheap and widely available.

The government should be recommending Fluvoxamine

It never got the hype of ivermectin or hydroxychloroquine, but back in the early “throw shit against the wall and see what sticks” phase of the pandemic, another old generic drug that some clinicians thought might help was fluvoxamine.

Fluvoxamine (marketed as Luvox) is an SSRI normally prescribed as an antidepressant. It’s similar to Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac), etc. I think it’s not normally psychiatrists’ go-to choice because the gastrointestinal side effects that you see with all SSRIs are somewhat more common with fluvoxamine. But it is used for depression, and to some extent for OCD and social anxiety. Apparently compared to other SSRIs, it also has a more potent anti-inflammatory impact. According to an article in Frontiers of Pharmacology, this is because it “has been shown to have the strongest activity of all SSRIs at the sigma-1 receptor (S1R) with low-nanomolar affinity,” but I’m not a doctor and I don’t know what that means.

What I do know is that some doctors thought this meant it might help with Covid, so they tried it, and some of them thought it was helping their patients. That’s exactly the HCL/dewormer zone and is not convincing on its own, but when subjected to a rigorous RCT, fluvoxamine turns out to actually work and generates a 30% reduction in hospitalizations.

That’s the same efficacy as Merck reported for its much-hyped new antiviral candidate molnupiravir. But fluvoxamine is cheaper and more widely available. What’s more, some scientists are worried about molnupiravir because its mechanism of action is that it induces fatal mutations in the virus. The concern is that if people don’t complete the full course of treatment, this could end up inducing non-fatal mutations which might worsen the pandemic. Largely for this reason, the FDA advisory committee vote on molnupiravir was closely divided with 13 in favor of approval and 10 against.

I’d be inclined to side with the 13 on the grounds that the downsides here are pretty hypothetical, if not for the fact that an equally effective alternative treatment — fluvoxamine — is already available. That consideration, to me, tilts things in the direction of the 10. But I think it’s a tough call. What’s not a tough call is that we should be recommending fluvoxamine as a safe and somewhat effective treatment. Unfortunately, the federal government’s official treatment guidelines on this have not been updated since April so they don’t include the results of the big RCT and don’t recommend the treatment.

I don’t really know what to say about this. I am a generalist political pundit working with an editor, an intern, and a part-time copy editor, and I am apparently more up to speed on the scientific evidence about Covid-19 treatments than the official NIH document. I found out about it because I follow Kelsey Piper on Twitter. If you’re lucky, your doctor does, too.

There’s a lot of room for improvement on Covid

I think it’s pretty clear that Covid-19 is going to be with us as a fairly serious public health problem for a while before it eventually tamps down into something much less burdensome.

Unfortunately, this transition to endemicity could take a while if the trajectory of today’s common cold coronaviruses is any indication:

But if the Covid-1889 theory is true, I think that helps illustrate some themes we should think about going forward. Realization seems to be spreading that even with vaccines available, it is very unlikely that we are going to reach Covid Zero. For context, Mark Honigsbaum and Lakshmi Krishnan wrote in The Lancet that “although H. Franklin Parsons, the medical investigator for England's Local Government Board, completed his final report on the ‘1889–92 epidemic’ in 1893, further severe recrudescences were observed in 1893, 1895, 1898, and 1899–1900.”

The advantage we have relative to our predecessors in the 1890s is much better science and technology. With vaccines (including future variant-optimized boosters) and therapeutics and tests, we ought to be able to make Covid steadily less lethal even as it fades into endemic status. But to do that, we really need to be tackling the problem with alacrity, not just by being stuck in an endless culture war loop about low-cost, low-efficacy mask mandates.