LP Vol. 31 - The COVID Endgame
If it hasn't been clear for the past year, the strategy of "ending" COVID through mass vaccinations is dead. The virus will be with us for the foreseeable future - turning into an annual fact of life no more surprising, but far more disruptive and deadly, than the annual flu been (1918 notwithstanding). Sadly, the majority of our institutions have failed to accept and prepare for this reality.
What is clear, however, is that case numbers, the metric that has guided much of our pandemic thinking and still underlies CDC’s indoor-masking recommendation for vaccinated people, are becoming less and less useful. Even when we reach endemicity—when nearly everyone has baseline immunity from either infection or vaccination—the U.S. could be facing tens of millions of infections from the coronavirus every year, thanks to waning immunity and viral evolution.
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On the ground, the U.S. is now running an uncontrolled experiment with every strategy all at once. COVID-19 policies differ wildly by state, county, university, workplace, and school district. And because of polarization, they have also settled into the most illogical pattern possible: The least vaccinated communities have some of the laxest restrictions, while highly vaccinated communities—which is to say those most protected from COVID-19—tend to have some of the most aggressive measures aimed at driving down cases. “We’re sleepwalking into policy because we’re not setting goals,” says Joseph Allen, a Harvard professor of public health. We will never get the risk of COVID-19 down to absolute zero, and we need to define a level of risk we can live with.
Our constant coverage of case rates is madness! The implicit assumption is that COVID infection in late 2021 is on par with what it was in early 2020. It makes it seem like zero covid is the goal, with no acknowledgement that for the vaccinated population, this is a very different disease. Here's David Leonhardt (emphasis mine):
For most people, the vaccines remain remarkably effective at turning Covid into a manageable illness that’s less dangerous than some everyday activities. The main dividing line is age. In Minnesota, which publishes detailed Covid data, the death rate for fully vaccinated people under 50 during the Delta surge this year was 0.0 per 100,000 — meaning, so few people died that the rate rounds to zero. Washington State is another place that publishes statistics by age and vaccination status. In its most recent report, Washington did not even include a death rate for fully vaccinated residents under 65. It was too low to be meaningful. Hospitalization rates are also very low for vaccinated people under 65. In Minnesota during the Delta surge, the average weekly hospitalization rate for vaccinated residents between 18 and 49 was about 1 per 100,000.
To put that in perspective, I looked up data for some other medical problems. During a typical week in the U.S., nearly 3 people per 100,000 visit an emergency room because of a bicycle crash. The rate for vehicle crashes is about 20 per 100,000. Covid is the threat on many of our minds. But for most people under 65, the virus may present less risk than a car trip to visit relatives this week. “The vaccination, I think, changes everything,” Dustin Johnston, 40, a photographer in Michigan who plans to gather with family, told The Times. The situation is more frightening for older people, especially those in their 80s and 90s. For the oldest age groups, Covid presents a real risk even after vaccination. It appears to be more dangerous than a typical flu and much more dangerous than time spent riding in a vehicle, based on C.D.C. data.
I'm not saying catching COVID is a benign experience for those who are vaccinated/boostered, especially for those of us with small children or family members who cannot be vaccinated for legitimate medical reasons, but our societal source code needs to be upgraded for a base case that assumes some level of coronavirus is an OK thing to tolerate.
We need a strategy that quickly detects the emergence of new variants that render our current vaccines impotent at preventing death, hospitalization or chronic symptoms (Omicron is looking relatively benign at the moment); and limits uncontrolled spread among the mainly unvaccinated that will overload, burnout and collapse local hospital systems To get super prescriptive, my ideal policy and investment looks something like this:
1/ Make it as convenient, cheap, and easy as possible for a lazy person to know whether they are currently infectious with COVID via rapid testing
Our goal with testing is to acknowledge and expect breakthrough infections to happen, and we should seek to minimize their collateral damage to the community. The consensus on the duration of vaccine efficacy is a flaming hot mess right now (somewhere between 6-10 months, but the UK just approved boosters after 3 months as a somewhat precautionary response to the higher potential virility of Omicron), but the continued mutations and periodic waning of immunity just further highlight the need for pervasive rapid testing as a key component of our endgame infrastructure.
The data on breakthrough infections for vaccinated individuals is still surprisingly thin, but the takeaway from one study from the spring of 2021 is that breakthrough infections happened roughly 0.05% of the time (64 per 100k individuals), with virtually no hospitalizations. The study found that vaccinated individuals were "almost always" symptomatic (e.g. no silent spreaders, you would have obvious symptoms), and perhaps more importantly, viral load diminished much more quickly.
2/ Approve and ramp production of promising new anti-viral treatments as quickly as possible to relegate COVID to a disease you can ride out in the comfort of your own home instead of taking up a hospital bed and a ventilator
The FDA is currently expected to approve two anti-viral treatments (Molnupiravir and Paxlovid) that sound pretty fucking amazing (again, yay science!):
Molnupiravir and Paxlovid are particularly exciting because antivirals that effectively target viruses at specific points in their life cycle are the “holy grail” of viral therapeutics—as past experience with other viruses has shown. Infection with HIV was fatal for nearly all patients until antivirals were developed against enzymes crucial to viral replication and researchers figured out how to combine those drugs to maximize their effectiveness and limit the emergence of resistant viral strains. These changes revolutionized HIV treatment, massively improving the prognosis for people who had access to antivirals. Instead of developing severe illness, treated patients could live healthily and expect normal life spans.
The development of these highly active oral antivirals for HIV infection took a decade and a half after the disease first came to light; the incredible progress in COVID-19 therapeutics took 18 months. Intriguingly, the COVID-19-treatment research borrowed many ideas from the HIV field; the two new COVID-19 drugs focus on similar pathways in the viral life cycle that HIV drugs target. In essence, these drugs prevent the target virus from reproducing itself. Because they work differently from the majority of COVID-19 vaccines, which teach the immune system to identify and attack the coronavirus’s characteristic spike protein, the antivirals remain effective against mutant variants whose spike proteins are harder for immune cells to recognize**. Designing, manufacturing, and distributing vaccines updated for new variants will take time, so the availability of antivirals will be all the more essential.
These drugs can be prescribed as outpatient medications and drastically reduce symptoms and viral load in vaccinated individuals experiencing breakthroughs. The data for Paxlovid shows it decreased hospitalizations and death in unvaccinated individuals by an order of magnitude with no apparent side effects. - There's been some interesting discourse from Scott Alexander and Matt Yglesias ($) on how crazy it is the trials for both drugs were stopped early on ethical grounds (the drugs worked so well it was unethical to continue giving trial participants a placebo), yet the FDA continues to take their sweet ass time on approval.
Here's Yglesias:
One piece of good news about Omicron is that two recently developed anti-viral drugs — the somewhat effective Molnupiravir and the highly effective Pavloxid — will likely be just as effective against Omicron as they seem to be against previous variants. The bad news is that these drugs are not actually available. In the immediate term, this is because we’re in the annoying wait-and-see period during which experts fully expect the drugs to be approved by the FDA, but they have not yet been approved. As has consistently been the case throughout this crisis, there are questions about why the FDA can’t do a review of this kind on a more rapid basis given the urgency of the situation. And it continues to rankle that over a year after Election Day, Biden does not have a confirmed FDA commissioner. As of today, there is — at last — a nominee, but months and months of hand-wringing and searching only to come up with the guy who was FDA commissioner in 2016 suggests a real lack of thought during the campaign about a critical role.
And Alexander:
[I]t’s pretty weird that the FDA agrees Paxlovid is so great that it’s unethical to study it further because it would be unconscionable to design a study with a no-Paxlovid control group - but also, the FDA has not approved Paxlovid, it remains illegal, and nobody is allowed to use it. One would hope this is because the FDA plans to approve Paxlovid immediately. But the prediction market expects it to take six weeks - during which time we expect about 50,000 more Americans to die of COVID
Perhaps that 10% chance of it not getting approved is very important, because that’s a world in which it’s discovered to have terrible side effects? But discovered how? There was one trial, it found no side effects at all, and Pfizer stopped it early. And it’s hard to imagine what rare side effect could turn up in poring over the trial data again and again that’s serious enough to mean we should reject a drug with a 90% COVID cure rate.
I also appreciated Alexander's comparison of these anti-virals to the ivermectin debate:
PPS: I know I’m going to get asked: how is this different from the ivermectin situation? Last week I wrote a long post arguing that most of the early super-promising trials of ivermectin were garbage, and that despite the hype it probably doesn’t work against COVID. Shouldn’t I be equally skeptical of Paxlovid now that it’s having its own super-promising early trials? No. For one thing, this isn’t amateur hour anymore. The ivermectin trials were random people who bungled their experiments or just plain made them up. They had sample sizes of (going through the first few on my notes) 25, 116, and 66 people. The Paxlovid trial was run by the best scientists Pfizer’s money can buy, and had a sample size of 1,219 (it would have been 3,000 if they hadn’t stopped it early). Like everyone else, I hate the fact that pharmaceutical companies are the only people with enough resources to run high-quality studies, and that this controls what drugs we end up using. But while we’re working on that problem, pharmaceutical companies do have a lot of resources, and their studies are pretty good, and we don’t have to grade them by the same standards we use for amateur hour, especially when their studies are 20x bigger**. Just because this shouldn’t be true doesn’t mean that we have to pretend it isn’t, especially when that pretense could kill thousands of people unnecessarily.
I know I’m not going to convince many ivermectin supporters. So consider this: ivermectin is FDA approved. It’s approved against parasitic worms, but that’s fine: once a drug is approved for anything, any doctor can (more or less) use it for whatever they want. Doctors can absolutely prescribe ivermectin right now if they want, and many of them (like Pierre Kory) have. The ones who don’t prescribe it are avoiding it because they think it doesn’t work, not because the FDA is trying to prevent them. Heck, people can get ivermectin even without a prescription as long as they use the veterinary version.The medical regulatory system has made prescribing ivermectin legal and easy. All I’m ask is that they do the same for a drug which almost certainly works - before thousands more people die unnecessarily
3/ Re-orient our public health outreach and investment towards testing mandates versus vaccine mandates
Earlier this week, the Biden Administration announced new air travel guidance:
By the holiday season, flying will have changed dramatically for Americans returning to the United States from abroad. They will be asked to show proof that they are vaccinated, to commit to two coronavirus tests if they are not and to participate in a new contact tracing system. For Americans traveling within the United States, however, none of this applies. As airlines prepare for what’s expected to be the biggest travel rush of the past two years, domestic travel — aside from a mask mandate and some restrictions on alcohol — will be largely the same as it was before the pandemic: packed cabins and no testing or proof of vaccination required.
This reveals a lot about the state of our society to tackle hard and complex problems:
Though every room seemed to have at least four people flouting the conference’s mask mandate, no one queried seemed to object to the vaccine or testing requirement. When asked why domestic airlines should not also have these rules, Mr. Hayes of JetBlue Airways explained that it’s different because, while the conference had a few hundred attendees, roughly three million people are once again flying domestically every day. Though he supports encouraging vaccination, requiring proof from all those people involves too much “operational complexity,” he said. Unlike Israel and the European Union, the United States has not created a uniform digital proof of vaccination or coronavirus status system. That means that airlines and airports would potentially have to come up with a whole new way of reviewing and verifying results. Domestic travelers eager to check in online and whiz through security “would have to come earlier,” Mr. Hayes said. “There would be longer lines.” Doug Parker, the chief executive of American Airlines, made a similar comment in an interview on the Sway podcast in August.
Seriously fuck this energy.
Rapid tests should be available outside of all commercial buildings, airports and transportation centers like cough drops and hand sanitizer. Airlines should be selling $500 and $1000 travel vouchers that come with a 50-pack of tests for families and business travelers to use before they leave for the airport. There should have been a half dozen public challenges with multi-million dollar prizes to build test result integration into your travel app profile. There should be workplace protections and easy unemployment benefits to collect (jury duty, but better!) while you're waiting for your viral load to diminish.
We need to build cultural norms around proving you are not currently infectious, adding societal friction to engaging your community when you are, and funnel safety net funding to make it easy and correct to stay home until you are no longer a threat to the community.
We've had 18-months to get reps at this stuff and instead of creative approaches to accelerating our return to normal, we've let Zeroism rot our brains and render practical policymaking impotent.
You may look at that last one and think it's not that important, but I'm just going to leave this one here and let you go on with your weekend:
Thank you for coming to my TED Talk. I promise to return to lighter fare next week.
Xo,
W