Covid-19 Vaccines: Delays and Doses

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WITH EFFORTS underway across the country to expand access to Covid-19 vaccines, new questions have arisen about what happens if the supply is insufficient for everyone to get a second dose: about how long protection might last after just one dose or how long a delay might be possible before getting the second dose without risking Covid-19 infection.

As January 15 marks one year since the first confirmed U.S. case of Covid-19, numbers of cases and deaths continue to increase, and more contagious variants of the vaccines continue to spread.

Because drug companies did not study what happens to people if the second dose is delayed—past 21 days for the Pfizer vaccine, and 28 for the Moderna—some experts say that’s a reason any delay is too risky, while others point to the same lack of evidence as support for their position that delay could pose little or no risk.

The U.K. recently changed the timing of the Pfizer vaccine’s second doses to 12 weeks—based on the absence of any evidence to suggest the vaccine’s effectiveness was beginning to decline toward the end of the 21-day period following the first dose.

In the U.S.—along with increasing access to the vaccine for younger ages and different health groups—the current administration has promised second doses to everyone who has the first one. But having a sufficient supply of vaccines to provide second doses on the prescribed schedules would require an exponential expansion in production and delivery, which seems unlikely given ongoing supply-chain bottlenecks.

Of 300 million doses promised by Operation Warp Speed by January, only about 1/10^th of those vaccines were available; and Pfizer recently announced lower production targets for its vaccine. On the other hand, delays in providing second doses could buy extra time to ramp up production, which in turn could provide enough doses in enough time to avoid compromising immunity.

Also, the long-awaited Johnson and Johnson vaccine—which requires only one shot and less extreme refrigeration, and is thus less expensive—could win approval by late March, although manufacturing difficulties have already delayed the company’s delivery schedule by about two months.

The AstraZeneca vaccine, available in the U.K., also faces at least a two-month delay in the U.S., with approval held up by questions about efficacy—for one, among elderly people, which is “effectively unknown,” according to Operation Warp Speed head Moncef Slaoui. In addition, while combined results from different trials add up to 70% efficacy, the AstraZeneca vaccine showed 90% effectiveness in one group that mistakenly received a half dose in the first shot.

“We need a clear and concrete number more than a number that is accumulated by adding together different trials with different schedules and different materials,” Slaoui told Politico. On the question of delaying second doses, Slaoui stands firmly on the need-more-research side of the debate, saying, “It’s important, I think, to use the vaccine based on how you studied it.”

All Covid-19 vaccines approved to date require two doses—similar to many current vaccines, such as those for tetanus, hepatitis B, measles, polio and HPV, as well as the newer shingles vaccine. After the first dose, immunity builds slowly, creates significant protection in anywhere from one to two weeks and may peak at around four weeks. After that, for Covid-19 vaccines, researchers have no data.

The WHO currently recommends that the interval between doses for the Pfizer vaccine might be extended up to six weeks “on the basis of currently available clinical trial data.”

And testing of the vaccines’ efficacy done by both Pfizer and Moderna throughout the trials showed “robust immune response four weeks after the first shot, and most experts believe it is extremely unlikely immunity would somehow plummet by week eight or even week 12 following a single shot,” write UCSF Department of Medicine Chair Robert Wachter and Brown School of Public Health Dean Ashish Jha in a Washington Post Op-ed.

Giving a single shot that is 80 to 90% effective to 100 million people will save “far more lives than giving 50 million people two shots that are 95% effective,” write Wachter and Jha. In people who have suffered the coronavirus infection, immunity also declines over time—to below 85% in one recent British study of more than 20,000 healthcare workers.

Another concern with a second-dose delay is the risk that, in those with weakening immunity, the virus might develop resistance —leading to the spread of vaccine-resistant virus variants through the population.

On the other hand, if single doses of the vaccine reduce natural infection, they might cut the risk of resistance evolving, according to University of Chicago virologist Sarah Cobey, who told Nature: “It’s a very serious thing to be sacrificing people now because you’re afraid that you won’t be able to handle a strain in the future…If I were to place a bet I would be doing what the UK is doing.”

Conducting large studies that compare the efficacy of one dose alone versus two could help answer the questions and, if started now, could produce preliminary data by March, suggests Memorial Sloan Kettering’s Peter Bach on STAT.

Another possibility: Although numbers are unavailable, a few participants in the original trials who didn’t receive a second dose—usually because they didn’t show up—“were generally only followed for a short period of time,” according to an FDA statement. Now some are wondering about tracking these patients down.

Finally, according to Moncef Slaoui, the administration is considering allowing half-doses of the Moderna vaccine—despite lack of research on this option, although missing data is exactly the reason that Slaoui firmly resists altering current vaccine dose schedules.

—Mary Carpenter

Well-Being Editor Mary Carpenter keeps us updated on Covid-19. To read more of her posts, click here.