When Molly Howell talks about the two-shot regimen needed to vaccinate residents of North Dakota’s 210 long-term-care facilities against the coronavirus, she sounds like a general mobilizing a massive air lift without knowing how many planes she will have.

As the state’s immunization program manager, Howell is on top of mass vaccinations for seasonal flu, essentially a one-stop shot. And she is well versed in serial immunizations, like the two-step shingles shots. But for the current coronavirus vaccines, which require two injections spaced either three or four weeks apart, she anticipates clinicians having to make many more than two visits to facilities. Will health-care workers be considered a high-priority group and thus scheduled for vaccination sooner than at-risk residents? How should shift workers be accommodated? And what about the many people who move in or out of facilities in the window between shots?

“It definitely will be an iterative process,” Howell said, as she multiplied those problems through jails, group homes and homeless shelters, wondering how not to waste precious doses if somebody doesn’t show up as expected for their second shot, leaving a precious vial in the refrigerator.

“Do you use second doses for first doses?” Howell speculated.

As the nation gears up to vaccinate tens of millions of Americans against the novel coronavirus, public health officials like her are facing novel dilemmas, driven by the urgency of the pandemic, the fact that only a small minority may have immunity from prior exposure and by the vaccine available at each site, with the differing intervals between shots depending on the manufacturer.

They will need to keep track of people who have received one dose in order to send a reminder about the need to return a few weeks later. They worry that the first vaccine may make people feel just sick enough that they won’t want to go through the ordeal again. And they foresee hitches if people get their first dose at, say, Walgreens and go to CVS for their second, or, worse still, if they cross state borders, moving from one health department’s registration system to another.

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“Two doses more than doubles the logistical challenges of administering the vaccines,” said Jeffrey Duchin, health officer for public health in Seattle and King County, Wash. “The moving parts have to align.”

A two- or three-dose dose regimen is routine for building immunity against many illnesses, but it is unprecedented in a pandemic when the public-health goal is to vaccinate 60% to 70% of the population within months to reach herd immunity and stop the virus’ spread.

“This is the only time we’ve faced a serious, immediate threat to the entire population that requires a two-dose vaccine,” said Kelly Moore of the Immunization Action Coalition, who was director of Tennessee’s program in 2009 during the H1N1 pandemic and recalls her relief when she learned everyone but young children would need only one shot.

That was possible because unlike COVID-19, which is caused by a novel virus, an influenza similar to H1N1 had previously circulated in humans giving many people partial immunity. Clinical trials showed that protection was afforded with only one injection.

With Ebola, Moore said, both single- and two-dose vaccines exist and experts have been figuring out how best to deploy them both in and around outbreaks, depending on the availability of supplies.

It’s not unusual for a vaccine to require re-upping in order to provoke the immune system to respond more effectively. The classic schedule for vaccines that target proteins like the spike protein on the surface of this coronavirus, Moore said, is three shots — “prime, prime, boost” — with the second and third shots coming one and six months after the first injection. Each of the first two shots primes the immune system and is typically followed by a modest drop-off in antibodies. The third shot, usually at least six months after the first one, can give long-term protection by boosting the immune system’s memory cells, which by that point have matured and are ready to respond.

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It’s not yet clear whether any of the new coronavirus vaccines in the pipeline will ultimately work best with a third shot capable of boosting long-term protection.

“Memory cells increase stepwise during at least six months,” said Claire-Anne Siegrist, a professor of vaccinology at the University of Geneva and head of the World Health Organization’s Collaborating Center for Vaccine Immunology. The urgency of the increasing infection rates and death tolls has led to the promotion of an immediate two-shot solution.

“In a ramping pandemic, where efficacy should be elicited as rapidly as possible, giving two primary vaccine doses and following to see whether and when a booster might be needed is a most reasonable choice,” she said.

It’s also possible that fewer doses may prove sufficient.

“For all we know, all these two-dose vaccines may work in one dose,” Duchin said.

Data will be gathered as populations are immunized, providing further information about how best to vanquish this particular disease.

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“I think we have to learn what is needed to keep immunity,” said Bruce Gellin, president of global immunization at the Sabin Vaccine Institute, fine-tuning strategies and policies based on the evolving science, with the potential for revaccination in the future, as with the annual flu vaccine.

“There are a lot of missing data points,” said John Brownstein, chief innovation officer at Boston Children’s Hospital, who runs Vaccine Finder, a system developed by Google a decade ago to help deploy the H1N1 vaccine.

The Vaccine Finder is designed to help people find providers of vaccines, from flu to shingles, close to where they live. The system doesn’t collect personal data, however, which would be necessary to send out reminders to individuals about a second coronavirus shot, for example.

“Right now, it’s a one-way push,” said Brownstein, who described his ambitions to rebuild the infrastructure so people could receive updates and information about scheduled vaccines.

The challenges of registering individuals and reminding them electronically about their second shots are daunting, said Sacramento County Health Director Peter Beilenson, who like Howell is concerned about the potential inefficiency of staggered staff and residents’ immunizations in long-term-care and other residential facilities.

The two-shot emergency schedule will upend the way many health departments have organized mass vaccination programs in recent years. For a decade, the Vanderbilt University School of Medicine has developed a program to immunize students, faculty, staff and volunteers against the flu — a one-shot-and-you’re-done deal that has succeeded in immunizing as many as 15,000 people in a single day.

Many of those efficiencies won’t be possible with the two-shot regimen.

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“It does impact staffing resources” at a time when health-care workers are already stretched thin, said Vanderbilt infectious-disease chief Thomas Talbot.

The coronavirus vaccines may give headaches, fevers and other unpleasant symptoms — all good signs of the body’s immune system getting to work — but Talbot is concerned they may prevent people from returning for their second dose.

Moore, who has studied another painful vaccine — two-dose shingles shots — says she is heartened by the way a vast majority of people who are educated about what to expect come back for their second doses despite the discomfort.

“I am very encouraged that our experience with Shingrix is that motivated people will come back as long as they are properly prepared to do so,” Moore said.

And while the challenges ahead are daunting, Howell said she is glad to be able to think them through with other experts.

“It’s comforting that we are all in same position,” she said. “All of us are going to figure this out.”