— Growing body of research suggests robust immune response with extended dosing interval

by Martin Makary MD, MPH

When most Americans showed up to get their first dose of an mRNA vaccine, they were sternly warned that they must schedule a second dose within a month. In my case, I politely explained that I would come back for my second dose at 3 months. The scheduler got flustered and treated me like I was a fugitive of the law. But a growing body of evidence over the last several months has shown that a longer interval provides better immunity in the long-term. It may even eliminate the need for a booster shot that’s now being recommended.

In May, researchers at the University of Birmingham found that delaying the second Pfizer dose to 12 weeks after the first resulted in a 3.5 times greater antibody response in older people. The increase is likely even greater in a younger cohort. Hematologist Paul Moss, MBBS, PhD, a co-author of the study, concluded that it’s a good idea to extend the time between the first and second doses of the vaccine. “An extended interval may help to sustain immunity against COVID-19 over the longer term and further improve the clinical efficacy of this powerful vaccine platform,” he wrote.

Similarly, data showed delaying the second Oxford/AstraZeneca vaccine by 12 weeks resulted in a stronger antibody response. That became the U.K.’s recommendation, which not only conferred better immune protection but also enabled the U.K. to ration its limited vaccine supply in a way that saved more lives. It was a winning strategy.

The U.S. basis for designing the 2-dose regimen with a short interval was that the pandemic was raging and there was an urgency to getting the trial done quickly. It was also believed that a short interval could more rapidly address a spike in cases. Based on the thinking at the time, the short interval may have made sense. But some vaccinologists have pointed out that the two doses were so close together that they functioned as a single primer dose.

Given the current data, it appears that if we had spaced the two doses farther apart, we would have had two benefits: 1) We would have had more first doses on hand to protect Americans from January through March when we were supply constrained and 2) We might not be calling for boosters for the general population so quickly.

While we can’t go back in time, we should consider where this growing body of data leaves us today.

Some may be concerned with studies showing that one dose is less effective than two doses against the Delta variant, even with the U.K.’s 12-week spacing approach. However, efficacy against simply infection is not the best endpoint. Instead, we need to look at death and hospitalizations.

Beyond only better immunity in the long-term, other considerations contribute to the present-day case for spacing the two doses. There are numerous anecdotal experiences suggesting that the typical vaccine side effects such as fatigue and malaise may be less common when the second dose is spaced at 3 months. The current short interval between vaccine doses may contribute to the rash of myocarditis cases we have seen in children. The heart complications are clustered after the second vaccine dose. (Incidentally, a Tel Aviv study found that a single dose of the Pfizer vaccine alone was 100% effective in children 12-15 years of age.) Such preliminary observations merit further study.

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