Can a COVID-19 vaccine’s second dose be delayed? It’s complicated

Within a couple weeks after a first vaccine dose, people are well protected against severe COVID-19, new data suggest. With demand for shots far outpacing supply, that’s sparked a debate among scientists and policy makers: Is it OK to hold off giving the second dose?

Delaying the dose could make way for more people to get their first shots and stem the coronavirus’s spread, proponents say. Opponents say there’s not enough data to show if that one-shot protection is long-lasting enough. And they worry that changing timing now could confuse people, undermine trust and lead to more widespread hesitancy to get the vaccine. 

Here’s a closer look at the issues involved.

Data on dosing

In clinical trials, the second dose of the Pfizer/BioNTech vaccine was given 21 days after the first. Moderna’s second shot followed the first jab after 28 days. Both vaccines were about 94 percent to 95 percent effective after two doses (SN: 12/18/20).

AstraZeneca and the University of Oxford spaced doses of their vaccine four to 12 weeks apart in four separate trials. That vaccine’s efficacy ranged from 62 percent to about 90 percent depending on dosing schedules and amounts (SN: 11/23/20).

The U.S. Food and Drug Administration gave emergency authorization for the Pfizer and Moderna vaccines to be given on the same schedule tested in the trials. (The AstraZeneca vaccine is not approved for use yet in the United States.)

The United Kingdom took a different approach, deciding in late December to delay giving booster shots of coronavirus vaccines for 12 weeks after the initial dose. The goal: to stretch vaccine supplies to cover as many people as possible. The decision drew criticism. After all, scientists said, that timing had never been tested for efficacy against the coronavirus.

But now, some new data seem to justify the decision to delay.

A reanalysis of the Pfizer clinical trial data found that the mRNA vaccine has an efficacy of 92.6 percent starting two weeks after the first shot, two Canadian researchers write in a letter to the editor published February 17 in the New England Journal of Medicine. That’s similar to the 92.1 percent efficacy Moderna reported after one shot of its mRNA vaccine.

Pfizer had initially calculated that the first shot’s efficacy was 52.4 percent, but that included cases that emerged in the first two weeks after vaccination when immunity was still ramping up. Those early cases aren’t a fair test of a vaccine’s efficacy, says Danuta Skowronski, epidemiology lead for Influenza & Emerging Respiratory Pathogens at the British Columbia Centre for Disease Control in Vancouver. It takes a couple of weeks to build antibodies and train immune cells to attack a virus. The new estimate is similar that of Public Health England’s assessment of the data.

Here’s how first-shot efficacy has played out both in the real world and when real-world problems have thrown wrinkles into trials:

• Among health care workers at Sheba Medical Centre in Israel, rates of infection dropped by 75 percent 15 to 28 days after the first dose of the Pfizer vaccine compared with unvaccinated health care workers, researchers report February 18 in the Lancet. And rates of cases with symptoms were reduced by 85 percent.
• Among nearly 600,000 people who got the Pfizer vaccine through Israel’s largest health care system, the vaccine was 46 percent effective at preventing infections, 62 percent effective at preventing severe disease and 72 percent effective at preventing death two or more weeks after the first dose, researchers report February 24 in the New England Journal of Medicine.
• In Scotland, the Pfizer vaccine was 85 percent effective at preventing hospitalizations 28 to 34 days after the first shot, researcher report February 19 in a preprint in the Lancet. That study also found that the AstraZeneca vaccine was 94 percent effective at keeping people out of the hospital a month out from the first shot. Those preliminary data have not been thoroughly vetted by other scientists yet.
• And when manufacturing delays postponed giving the second dose of the AstraZeneca vaccine in trials in United Kingdom, Brazil and South Africa, efficacy went up. When people got the second shot less than six weeks from the first, the vaccine’s efficacy was about 55 percent, but waiting 12 weeks or more to give the booster shot produced about 81 percent efficacy, researchers reported February 19 in the Lancet. Antibody levels in the study participants’ blood did not drop in the three months after the first shot, the researchers also found, suggesting the first shot provides some lasting protection against the coronavirus.

Arguing for delay

Those numbers justify temporarily postponing second doses to ensure that more people get their first shots, says Robert Wachter, who heads the Department of Medicine at the University of California, San Francisco.

“That’s not a hard math question,” he says. “You’ll save far, far more lives — on the order of tens of thousands more lives — giving those extra vaccine doses to people for their first shot, getting them from zero to 85 percent protected, than using that same capacity [for] giving people their second shot and getting them from 85 to 95 [percent efficacy].”

The real driving force behind proposals to delay the second shots is that there just isn’t enough vaccine to go around. It’s all about getting jabs into as many arms as possible, Skowronski says.

Postponing the second dose doesn’t mean cancelling it, she says. It’s just a delay that could allow for more widespread distribution of the vaccine, especially to people at high risk of hospitalization and death from COVID-19.

Even though no one knows how long protection from a single shot will last, immunity doesn’t disappear overnight. That buys time, she says.

“We should be ensuring as many people as possible, by whatever means possible, get the first dose before we double back and try to top up with a second dose,” Skowronski says. “Every second dose we administer is essentially depriving someone else of the substantial protection they could have got from that vaccine supply as a first dose.”

Arguing against delay

Yes, the data overall suggest the first doses work pretty well, but scientists don’t know how durable that protection is, says virologist Onyema Ogbuagu. That may not be as much of a problem in countries like Israel and the United Kingdom, which have been vaccinating people pretty quickly. But in the United States, the vaccine rollout has been creeping and crawling, Ogbuagu says. Because of that slow progress, “you could be six months or 10 months into vaccination and the first people you vaccinated could become vulnerable again.”

The second shot should make immunity last longer. “The role of the second dose is, without question, an advantage,” he says. “It optimizes the efficacy and durability.” Ogbuagu, who oversees COVID-19 clinical trials at Yale School of Medicine, was involved in testing the Pfizer vaccine’s efficacy.

Earlier Phase I and II safety trials also tested people’s immune responses to the mRNA vaccines. Those data showed that antibody levels after the first shot are respectable but often don’t get close to matching levels seen in people who have recovered from COVID-19, Ogbuagu says. “But the pattern after the second dose is just so striking, antibody levels just skyrocket,” often exceeding levels from recovered patients, he says.

He also notes that the dosing data from the AstraZeneca trial came from a part of the study wasn’t planned and other unknown things might be influencing the outcome, A new clinical trial mixing the Pfizer and AstraZeneca vaccines will test in which order the shots should be given, and whether a four- or 12-week interval between doses produces better efficacy. That trial will produce more reliable data on which to base a decision about shot schedules. For now, though, “we have to deal with the unknowns,” he says, “and I think the benefits of giving that second shot outweigh giving just the first one and hoping for the best.”

There’s another big worry: Even under a best case scenario, some people are bound to get sick after getting vaccinated. The vaccines aren’t perfect and some new variants of the coronavirus can evade antibodies generated by the jabs. Some researchers are concerned that delaying a second dose could help produce new variants (SN: 1/14/21).

And if infections happen while monkeying with untried dosing intervals, it could undermine public confidence in the shots, worries Nicole Lurie, a strategic adviser for the Coalition for Epidemic Preparedness Innovations, an organization that funds vaccine development.

It may feed a narrative that health officials didn’t fully follow the science as promised, Lurie says. If public confidence erodes to the point that people turn down vaccines, “then in the long run, you’re doing the nation a disservice.”

It’s fine to provide a little wiggle room for people to get the second shot when circumstances — such as the winter storms in Texas, or other problems — prevent getting it on time, she says. But sticking as closely to the schedule as possible should be the policy.

She and Wachter laid out their counterarguments on delaying doses February 17 in the New England Journal of Medicine. And while they came to different conclusions, they don’t necessarily disagree on the challenges, including the concern that some people will interpret the data to mean they don’t need a second shot at all. Says Watcher: “We have to decide if the uncertainty is too great to do what, mathematically makes, to me, a ton of sense.”