Deaths in the United States from covid-19 have been falling, but it would be premature to assume that trend will continue. The recent mutations discovered in Britain, South Africa and Brazil — which have spread to the United States — are more transmissible. “We’re in the eye of the hurricane,” warns Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine. Death rates could increase as we enter a fourth wave that could peak even higher than the first three. We are in a race against the virus to reach V-Day, when we have vaccinated enough people to achieve herd immunity.
Simply waiting for vaccine production to ramp up is inadequate. With thousands of people dying daily, there’s a strong case for stretching the doses we have now. A “first doses first” approach — that is, prioritizing first doses by delaying the second shot from three to four weeks (the period studied in clinical trials) to 12 weeks — would allow more people to get vaccinated quickly, for example. “Fractional” dosing, such as by giving half-doses, would instantly increase the vaccine supply and has been used successfully in previous epidemics. And, of course, we should authorize more vaccines, including Johnson & Johnson’s and AstraZeneca’s (despite one disappointing trial for the latter in South Africa), and the Novavax vaccine. We should take a closer look at Sputnik, the Russian formula, now that it has shown strong results in clinical trials. Finally, to get shots into arms we could ease up on prioritization rules, to streamline the process.
If vaccines weren’t scarce, we might abide by the trial protocols and in every case follow one shot with another a month later. But a pandemic forces trade-offs. The Pfizer and Moderna vaccines, the two approved for emergency use in the United States, are each estimated to be about 80 to 90 percent effective at stopping symptomatic covid-19 once the first dose has started to take effect, around 10 to 12 days after injection. And they are about 95 percent effective a week after the second dose.
Is it better to give a second dose to one person, boosting them from 80 percent to 95 percent protected, or to give a first dose to someone else, raising them from 0 percent to 80 percent protected? Ethics and efficiency both suggest that it’s better to protect two people well than one person maximally. It’s also a quicker route to herd immunity, a key part of any vaccine strategy.
Following this reasoning, the British government is prioritizing first doses to as many people in its high-risk categories as possible and delaying second doses to 12 weeks. The strategy appears to be working, as the British have now vaccinated close to 20 percent of their population with at least one dose, compared with only 10 percent in the United States. (The British health system’s centralization probably also helps distribution.) It is true that the drug-approval trials do not offer direct evidence of the efficacy of first doses beyond five weeks or so (assuming the second dose takes a week to kick in), but remember that the short intervals were a choice designed in part to hasten the trials and speed approval. There is little reason to think a trial protocol that gave the second shot at, say, 12 weeks would have been any less effective. One study of the AstraZeneca vaccine found that it was actually more effective with a 12-week or longer delay (82.4 percent) than when the second shot is given after three weeks (54.9 percent).
It’s not even clear that everyone benefits from a second dose. Three recent studies, as yet unpublished, found that people previously infected with the coronavirus had an antibody reaction to the first shot at least as strong as the reaction most people had to the second. Akiko Iwasaki, an immunologist at the Yale School of Medicine, told the New York Times that for someone who has been infected, one shot is probably “more than enough,” and a second shot may be “overkill.” Giving the Americans who have already been infected (up to 100 million people) only one shot would help doses go further.
Like any decision made amid uncertainty, a “first doses first” policy is not without risk. The evidence for the effectiveness of the first dose is not as compelling as for the second dose. There is a chance that the virus could mutate in people who have only first doses, as it adapts to partial vaccination. But Britain’s New and Emerging Respiratory Virus Threats Advisory Group concluded that the danger is probably far greater that the virus will mutate in the unvaccinated population. If that’s true, delaying the second dose to increase first doses would reduce mutation risk, by reducing the number of unvaccinated people.
Some experts worry that any deviation from the drug-trial regimens approved by the Food and Drug Administration would increase distrust of vaccines. But the hardcore anti-vaxxers are probably set in their opinions, regardless of how we proceed, and almost everyone else would welcome creative action to fight the virus. We need to address vaccine hesitancy, but we shouldn’t let U.S. vaccination policy be driven by the fearful and scientifically illiterate.
Another way to reach herd immunity faster is to use half-doses. Theory and data both indicate that a smaller dose of either the Moderna or the Pfizer vaccine could be as effective as a larger one. Clinical data for adults 18 to 55 from the Moderna Phase II trial, for instance, already suggests that quarter-doses produce a robust immune system response, which is why Operation Warp Speed chief scientific adviser Moncef Slaoui has advocated for half-doses (leaving plenty of margin). Halving the doses would have the same effect as instantly doubling the output of the Moderna and Pfizer factories — saving thousands of lives. (Partial doses of a yellow-fever vaccine were used to great effect in a 2018 outbreak in Brazil.)
It also makes no sense that we are not using all the vaccines we have. The Johnson & Johnson formula, a one-shot treatment, will probably get an emergency use authorization in a matter of weeks, and the AstraZeneca vaccine has been approved in Britain and in the European Union, two of the most stringent drug regulators in the world. The AstraZeneca shot is safe, and more than 1.5 million people have already taken it in Britain with very few serious side effects.
The AstraZeneca vaccine recently suffered a setback: A small-scale clinical trial suggested that it is less effective at preventing mild to moderate infections with the South African variant of the coronavirus, leading that country to stop distributing the vaccine. The subjects in the sample were not elderly, however, and the study was too small to speak to whether the vaccine prevents more-serious illness. The Johnson & Johnson vaccine is also less effective against the South African strain but appears to be highly effective at preventing severe cases and deaths, while Pfizer and Moderna have not been tested against it.
So caution is warranted, but the FDA could provisionally approve AstraZeneca based on information that British and European regulators have signed off on — as officials continue to monitor the studies. After all, Operation Warp Speed has optioned the use of a factory in Baltimore that is currently stockpiling doses. The sooner we tap those supplies, the better. Meanwhile, although Johnson & Johnson’s vaccine production is behind schedule, U.S. officials still say that doses in the “single-digit millions” will be available by late February, pending approval.
The limited supply of Pfizer and Moderna doses remains a challenge. But some people argue that adding a third (or fourth) vaccine might not help because of persistent delivery logjams at the state and local levels. But we know there is unused distributional capacity, even for the supply we do have. The United States is currently administering about 1.5 million coronavirus vaccine shots per day. While that sounds like a lot, for comparison consider that in September — during the pandemic, when social distancing measures were in full effect — we vaccinated for the seasonal flu in some weeks at the rate of 3 million people a day.
There are two main reasons the rollout has been so slow. First, the Moderna and especially the Pfizer vaccines require ultracold storage. (The Johnson & Johnson and AstraZeneca doses can be stored at ordinary refrigerator temperatures.) Second, we have tried to prioritize vaccinations using a confusing mishmash of age, health conditions and essential-worker status that differs by state and sometimes even by county. “Confirming such criteria is complicated at best, and it’s probably not even feasible to try under conditions of duress,” as Baylor’s Hotez puts it.
Arguments continue about prioritization lists, and the idea of tossing them entirely would cause a political fight. But there is a compromise at hand: Quickly approve the Johnson & Johnson and AstraZeneca vaccines and make them — and only them — available to anyone, anywhere. Keeping things simple is a sure way to increase total vaccinations. With no cold-storage requirement, the new vaccines could be administered by any of the 300,000 pharmacists and more than 1 million physicians in the United States authorized to deliver vaccines, most of whom are not now giving Pfizer or Moderna shots.
The United States has been playing catch-up to the virus since Day One, and the pathogen is still killing thousands of citizens a day. To get ahead of it we must be prepared to make decisions that we might be uncomfortable making in ordinary times.