Delay Second Doses? A Guide To The Latest COVID-19 Vaccine Debate

Sometimes “following the science” is a simple matter of listening to the authorities you trust, like Anthony Fauci, and ignoring the ones you don’t, like pretty much anybody who was working inside former President Donald Trump’s White House.

But sometimes it’s more difficult, because the trustworthy scientists don’t agree with one another and because the arguments on both sides sound compelling ― and because the debate is taking place against the backdrop of a pandemic that seems to be spinning off new, more dangerous versions of the pathogen every day. 

Such is the case with the debate over whether to delay second doses of the COVID-19 vaccine and focus on getting first doses to as many people as possible. It’s the strategy that British officials have chosen and, increasingly, the notion is getting serious consideration here in the U.S. ― although some of the most high-profile, most trusted authorities on the subject, including Fauci, remain opposed.

Here’s a breakdown of the situation and the arguments, and why so many well-informed people are coming to different conclusions:

Right now, the two vaccines authorized for use in the U.S. come from Pfizer and Moderna. They are the first-ever approved vaccines to use messenger RNA (mRNA) technology. Their development, less than a year after the virus first started spreading across the globe, is nothing short of miraculous.

Both companies designed the shots to come with two doses, spaced three weeks apart for Pfizer’s and four for Moderna’s. Many vaccines require boosters to provide full protection, and both company’s scientists estimated that those intervals were most likely to be effective, based on specialized studies they conducted earlier in the year.

Clinical trials for both showed that the two-dose regimen is around 95% effective at preventing illness, relative to a placebo, with protection against severe disease and death that is near total. The U.S. Food and Drug Administration (FDA) quickly gave the vaccines emergency authorization and they are now going into the arms of Americans at a pace of more than 1 million shots a day.

But buried in the research that the vaccine makers submitted to the FDA was another intriguing finding: evidence of some protection from just one shot. 

Initially it looked like the efficacy after that one dose ― and before the second ― was about 50%. But that figure included everybody who got sick during that three- or four-week interval, and most had gotten sick in the first few days. Most likely, they encountered the virus either right before or right after getting the vaccine, before it had time to take effect. 

Within 10 to 12 days after vaccination, enough time for the immune system to respond to the vaccine, incidence of disease fell sharply. Extrapolating from that, researchers concluded that efficacy from one dose was a lot higher than 50% after a few weeks, once the immune system had time to react.

That got some experts wondering: Why don’t we just give first shots to as many people as possible now, and then circle back to the second shots at a later date, when the supply is more plentiful? 

The idea of delaying a second dose quickly got attention in the United Kingdom, where government officials were already dealing with one of the new, faster-spreading coronavirus variants. British regulators also had at their disposal data from AstraZeneca, which had developed a two-dose vaccine with Oxford University researchers. That data showed a similarly strong response following one dose..

Given the limited supply of vaccines, officials announced a new protocol in January under which second doses could wait for up to 12 weeks.

A chorus of experts in the U.S. and  European Union called the move reckless, as nobody had actually studied the effects of delaying the dosage explicitly. The findings were based on retroactively pulling out and comparing relatively small subsets of data from the clinical trials. That’s not the kind of evidence that regulators would normally accept to make such a decision.

Nor, critically, did the trial results say anything about how long the effects of a single dose last. “While we think that single shot could give protection for more than four weeks, we just don’t know that,” John Mascola, director of the Vaccine Research Center at the National Institute for Allergy and Infectious Diseases, told STAT News. “We don’t know when it’s going to drop off.”

Another unknown was whether the effects of a single dose could vary based on age. Immune systems of elderly patients are known to respond more sluggishly to vaccines. Delaying second shots for them could leave them a lot more vulnerable, which would be especially troubling given that they are also the most susceptible to severe, fatal versions of the disease.

“I can’t be quite as certain they don’t need that second dose for protection,” Kathleen Neuzil, an epidemiologist at the University of Maryland School of Medicine, told Science magazine.

There were other issues too, like the fact that “neutralizing antibodies,” a key part of the immune response, don’t seem to increase significantly until after the second dose. And then there’s the inherent risk of extrapolating from the AstraZeneca trials to make judgments about Moderna and Pfizer. All three shots target the virus’s widely recognizable protein spikes, but they work differently. AstraZeneca’s uses DNA, not mRNA, and delivers it to cells by using a disabled virus rather than a lipid as the Pfizer and Moderna shots do. 

Those things might not matter. Or they might. As of early January, the public consensus among experts in the U.S. and much of the European Union seemed pretty clearly against changing the dose timetable.

A few things have changed since then, starting with the production of more data from the both U.K. and Israel, which is vaccinating its population faster than anybody on the planet. 

The Israeli data, which is preliminary, found disease incidence fell sharply after one dose of the Pfizer shot; in one cohort of people, infections fell by about 60% within 13 to 21 days. The U.K. data comes from AstraZeneca, which has been testing intervals of different lengths and found that the body’s immune response was actually stronger if the second dose came later, rather than earlier.

At the same time, frustration has grown with the pace of vaccination in the U.S. Although shots are getting into arms more quickly than in most peer countries, confusion and backlogs have plagued the rollout. Millions of doses appear to be just sitting in freezers, waiting to go into long-term care facilities where administration has been slow. 

And then there are the new variants, which have now arrived in the U.S. and are spreading just as quickly as they have overseas. While caseloads here are falling right now, many experts expect them to rise again. 

“Because of this surge, we have to call an audible,” Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, said on NBC’s “Meet the Press” last Sunday. “We still want to get two doses in everyone, but I think right now, in advance of this surge, we need to get as many one-doses in as many people over 65 as we possibly can, to reduce serious illness and death that is going to occur over the weeks ahead.”

That appearance came days after two written essays making the same essential case. One, a letter in the journal Clinical Infectious Disease, came from Neal Halsey and Stanley Plotkin, senior and venerated figures in the fields of infectious disease and vaccination. The other was a New York Times op-ed by specialists in pediatric immunology: Adam Finn from the Bristol Royal Hospital for Children in the U.K. and Richard Malley from Boston Children’s Hospital.

“More lives would be saved,” Finn and Malley wrote, by “just forgetting about any boosters for a while, maybe even a very long while.”

It’s not clear exactly when each of these researchers decided that delaying the second dose made sense. Some experts have been talking about the possibility for a while ― among them, Bob Wachter, professor of medicine at the University of California, San Francisco, and Ashish Jha, dean of Brown University’s School of Public Health, who co-wrote a Washington Post column raising the possibility back in early January.

Wachter still thinks it’s the right idea, and told HuffPost he isn’t surprised that it’s getting more attention now. “The growing threat of the variants that has turbo-charged the need for speed,” he said. 

Still, he acknowledged, it’s “not an easy call.” 

On the other side of the debate are experts who say the scientific evidence points in the same direction it always has: against delaying the second shot. Their primary concern remains the lack of knowledge about a single shot’s effect past the three-or-four-week period that the clinical trials tested. 

“I do not think this is a good idea,” Celine Gounder, an infectious disease specialist at the NYU Grossman School of Medicine, told HuffPost. “We don’t have good data on the durability or quality of the immune response to just one dose of Pfizer or Moderna. … I think this strategy could backfire.”

Advocates for delaying second doses note that it is bound to happen sometimes, no matter what the official recommendations say, because of unexpected supply or distribution problems or because people will simply miss appointments. CDC guidelines already allow for this, and recommend that people get their second doses even if it’s well beyond the preferred three- or four-week window.

But Fauci, arguably the nation’s most trusted infectious disease expert, warned during a White House press conference this week not to read too much into that allowance for occasional delays. “That doesn’t mean that we want to do it,” he said. “It means that under special circumstances, it’s better to delay that couple of weeks than not do it at all.” 

While Fauci said he respects the judgment of U.K. scientists and health officials, who are reacting both to the data before them and the situation in their country, he reiterated his belief that the U.S. should stick with the two-dose regimen because the evidence showing its efficacy is rock solid. “We feel strongly that we will go by the science,” Fauci said.

Even some experts who think the case for delaying second doses has gotten stronger think it’s too soon to make the switch.

“I think delaying the second dose would be something to consider if we had a bit more data, but it is not my first choice right now,” Nahid Bhadelia, director of the special pathogens unit at Boston Medical Center, told HuffPost. Her preference, she said, would be to try every reasonable way of vaccinating more people quickly, whether through better distribution, faster production or both.  

The pace of vaccination is actually picking up already and has been for a few weeks. The Biden administration is now trying to push things along even more quickly, through a variety of steps. Those include using the Defense Production Act to guarantee vaccine makers have raw materials, for example, and setting up mass clinics staffed by the military.

One of the biggest constraints right now is supply: The number of shots available is simply a lot lower than the number of people eligible. But supply is likely to increase over the next few months ― especially if, as expected, a one-dose vaccine from Johnson and Johnson gets emergency authorization following an FDA review at the end of February. The U.S. has already agreed to buy 100 million, most of which the company says it can deliver by the middle of the year.

In the meantime, there will be more data to consider, as researchers conduct more trials and see how vaccinations are playing out in the real world. The case for delaying a second dose could become stronger, just as surely as it could become weaker, forging more of a consensus or simply causing opinion to shift. 

“Following the science” means paying attention to the best available evidence. But the best available evidence can change and even qualified, trusted experts can weigh it differently.