As COVID-19 vaccine administration lags behind early projections and a new, more infectious variant circulates, many experts are calling for a change in plans. By extending the time between the two doses, or halving the dose, more people can be inoculated sooner without sacrificing broad efficacy, they argue.
Others, however, including FDA leadership, advocate staying the current course. The evidence for efficacy of single doses isn’t strong enough to delay the second dose, they say, and public health officials should focus on speeding up the distribution and administration processes instead.
“Suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature and not rooted solidly in the available evidence,” according to a statement released by FDA’s Stephen Hahn, MD, and Peter Marks, MD, PhD, on Monday. “Without appropriate data supporting such changes in vaccine administration, we run a significant risk of placing public health at risk.”
Both the Pfizer/BioNTech and Moderna vaccines exhibited about 95% efficacy for preventing illness in clinical trials when patients received two full doses within the companies’ specified intervals — 21 days for the Pfizer/BioNTech vaccine and 28 days for the Moderna version. Those estimates came from counting illnesses diagnosed beginning 7 days after the second dose.
But there’s little data to rely on for decision-making when it comes to doling out fewer doses, or extending the interval.
In its phase I data, Pfizer reported that serum binding antibody concentrations 21 days after the first dose were comparable to or better than levels from convalescent plasma two weeks post-infection. Those levels rose far higher a week after the second dose. Neutralizing antibody levels saw “small increases” 21 days after the first dose but rose “substantially” 7 days after the second shot.
In its early data, Moderna reported that binding antibody levels “increased rapidly” after the first vaccination, and were similar to median levels from convalescent plasma specimens. But after the second dose, levels were “in the upper quartile of values in the convalescent serum specimens.” For neutralizing antibodies, responses were far better after the second vaccination.
In phase III data, Pfizer reported efficacy of 52.4% within 21 days after the first dose, i.e., before the second dose. The company also reported an efficacy of 82% “after dose 1,” which appeared to be for participants receiving both doses and counting all infections, including those occurring prior to the second dose.
Nevertheless, Chris Gill, MD, an infectious diseases physician at Boston University, told WBUR that efficacy may be as high as 90% with a single injection. He pointed to the roughly 2,000 participants in the Moderna trial who had only one injection, in whom efficacy appeared to be 80% to 90%.
More support for delaying the second dose came from a modeling study published this week in the Annals of Internal Medicine, which estimated that a “flexible” dosing strategy could avert an additional 23% to 29% of COVID-19 cases compared with a “fixed” strategy where doses are given 3 weeks apart. That was based on the Pfizer/BioNTech estimate of 52% efficacy with a single dose.
Given these clues, some experts have called for a change in strategy. For example, Bob Wachter, MD, of the University of California San Francisco, recently advocated delaying second doses by a few weeks or more.
“Few credible scientists have argued that a 2-month delay in dose 2 will compromise the strength/durability of the ultimate immune response. In fact, some have argued that it might enhance it,” Wachter tweeted. “The possibility that immunity will wane between doses 1 and 2 … also doesn’t seem to be a major concern – particularly given the miniscule reinfection rate that we’ve seen from natural infection and the robust immune response seen after dose one.”
But “it may make sense,” Wachter added on Twitter, “to stick with the early 2nd dose to the most vulnerable (over 75, nursing home) or most exposed (frontline healthcare workers). The small drop in efficacy from the 2nd-dose-later strategy might be quite meaningful in these groups.”
“Given the enhanced transmission variants on the rise, we need a modified strategy,” tweeted Akiko Iwasaki, PhD, a biology professor at the Yale School of Medicine.
But even Iwasaki favors the two-dose approach in the long run, as data regarding single-dose efficacy are not robust enough. “Whether a single-dose vaccine provides protection from severe COVID is not clear due to small sample size and short follow-up duration,” she tweeted.
Changing course now could also undermine public confidence in the vaccine, some experts said, which is especially important because many people, including healthcare workers, have already declined it, citing trust issues.
Some experts are calling for clinical trials of the modified vaccination proposals — including Peter Bach, MD, of Memorial Sloan Kettering Cancer Center, who wrote in an editorial for STAT that hospitals are uniquely positioned to handle such trials, which could yield preliminary data as soon as March.
“There are two ways to resolve this question: We can debate it on social media or we can go get more data. I believe we should do the latter,” Bach wrote. “Clinical studies cost money. But if we can dole out billions to companies to develop vaccines, then we should be ready to dole out millions to study how they are best used to control the pandemic.”
The Infectious Diseases Society of America supports the FDA position, according to its own statement released Tuesday. Instead of deviating from the proven dosing intervals, the group said, efforts should be redoubled to “support successful vaccine administration strategies, including expanding staffing for planning and implementation, and working with healthcare providers, healthcare systems and workplaces to operate high-volume sites and ensure timely access.”
Other nations have already adjusted their policies. The U.K. recently extended the Pfizer/BioNTech and AstraZeneca intervals to 12 weeks. Some patients may be permitted to mix different vaccines, despite government officials acknowledging “no evidence on the interchangeability,” Reuters reported.
The E.U.’s European Medicines Agency (EMA) is permitting as long as six weeks between inoculations of the Pfizer/BioNTech vaccine, but Spanish and Irish health authorities recommend following Pfizer/BioNTech’s schedule.
Tweeted Wachter: “The debate is healthy. There are pros and cons to the current strategy and the alternative we present, and there are real uncertainties associated with them both…. The context for the debate is the near certainty that we’ll lose another 50-100K [sic] Americans this month, and we’re threatened by a mutation that may accelerate the tragedies. So time is a crucial variable…. Let’s put our best minds, data, and models to this question, so we can make the best choices.”
Operation Warp Speed aimed to administer 20 million doses by the end of December. As of Tuesday, only 17 million doses had been distributed and only 4.8 million doses had been administered, according to the CDC.