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Tuesday, May 14, 2024

The Last, ‘Ultra-Cold’ Mile for Covid-19 Vaccines

The pace of countering the coronavirus in the US is about to pick up. Two manufacturers, Pfizer and Moderna, have announced that their formulas are up to 95 percent effective at preventing Covid-19; Pfizer officials backed up their statement with a full report on their Phase III data, and one from Moderna should follow soon. On Friday, Pfizer announced that company officials are asking the Food and Drug Administration for an EUA—an emergency use authorization—a shortcut around the standard lengthy approval process. An advisory committee of the Centers for Disease Control and Prevention meets today, and another committee reporting to the FDA has scheduled a meeting to assess both formulas on December 10.

That means the trucks could be rolling soon. In fact, in a statement released on Friday, Pfizer officials announced that they expect to begin distributing a vaccine “within hours after authorization.” And last Wednesday, Francis Collins, director of the National Institutes of Health, told me in a video interview that he expects 20 million Americans to be vaccinated, with two doses each, by the end of December.

Coming at the end of this awful year, that is undeniably good news—and yet, looking at the last mile of the complex network that will distribute these vaccines, small and rural health departments are fretting. No matter how brilliant the science, a vaccine is useless unless it can be administered while it is potent. The logistics of delivery are as critical as the pharmacology. (“People are talking about the scientific conundrum of coming forward with a vaccine that works,” Merck CEO Kenneth Frazier told Bloomberg in July. “Maybe even a harder problem is … distribution.”)

Both vaccines have strict storage requirements, necessitating the kind of equipment usually found in big-city medical centers. But the people who will need to be vaccinated in small and rural jurisdictions live far from those facilities, and from each other too. That creates a potentially profound mismatch between what's needed and what’s possible, made worse by public health planners in these jurisdictions still not knowing which vaccine formula they will receive, and which storage and transport restrictions they will need to observe.

What such areas need, in truth, is a vaccine that is easier to handle: one that can be held at refrigerator or room temperatures, and one that only requires a single dose. Formulas that might do that are in the pipeline, but they aren’t expected to debut until sometime next year. Given the nationwide surge in cases, it isn’t responsible to wait.

“They can’t give this one a pass, because it’s just unknown when there might be another vaccine coming on,” says Claire Hannan, executive director of the Association of Immunization Managers, whose members lead state vaccination programs and are expecting to handle Covid-19 vaccination too. “They are really struggling with how they are going to do this.”

A few details, to make the problems more clear: Under normal circumstances, vaccine manufacturers do their best to optimize their products’ stability across a range of transport and storage conditions. And even in the best of times, pharmaceuticals can be tricky: The International Air Transport Association estimates that in 2019, $34 billion worth of vaccines were wasted because they were subjected to unsafe temperature fluctuations while being shipped.

But in this year’s sprint to achieve a vaccine as quickly as possible, safety and efficacy were the priorities, and stability tinkering got put to the side. That means there is no margin of error on the storage requirements of the first formulas now reaching approval.

Pfizer’s candidate has to be held at a punishing temperature whose technical description is “ultra-cold”—60 to 80 degrees below zero Celsius, or minus 112 Fahrenheit, far lower than any vaccine now used in the US. Moderna’s also has to be held below zero: at -20 Celsius or -4 degrees Fahrenheit. To put those in context: In storage, Moderna’s formula requires a freezer that gets below the temperature of the one in your kitchen, and stays there consistently with no freeze-thaw cycles. Pfizer’s requires the kind of deep-freeze found only in hospitals and academic microbiology labs.

At the far end of the vaccine distribution network, ultra-cold freezers—which can cost $15,000—are in short supply. Hannan estimates that a third of the states in her organization’s membership have purchased or leased them. Those states are mostly affluent and urban. “That cold storage does not exist in rural America,” says Alan Morgan, CEO of the National Rural Health Association. “It simply does not. And rural hospitals purchasing it is not under consideration.” Almost half of the rural hospitals in the United States, he says, run in the red.

Yet it’s rural areas where the vaccine will be most needed. “Rural America is older, sicker, poorer. Rural America has a much higher percentage of individuals with multiple chronic health issues,” Morgan says. “The rates of Covid incidence, hospitalizations, and mortality are all increasing, per population, at a greater rate in rural areas than in urban ones. These hundreds of small towns, those populations really should be on the front end of receiving this vaccine.”

Pfizer is expected to solve some of the problems of distributing an ultra-cold vaccine with special packaging—the Department of Health and Human Services has referred to the box as a “thermal shipper”—that can hold the product at storage temperature for 10 days, using dry ice, as long as it remains sealed. Once it has been opened, the box can serve as a table-top freezer for up to 15 days more, as long as it is opened infrequently and quickly and the dry ice is replenished regularly.

Once the vaccines are taken out of the box, they can be held thawed in a refrigerator for several days; they expire quickly, within a few hours, at room temperature. Those short amounts of time create a profound logistical problem once they are layered over another reality of vaccine distribution: The Pfizer vaccine will be shipped as a “minimum order” of 975 doses per box. Then add in a third requirement: Before the shots go into arms, states will first have had to prioritize who receives them.

The CDC has recommended that the first recipients be health care workers. A major urban medical center with multiple hospitals and many health care personnel might not find it difficult to use up 975 doses, especially if personnel from nearby long-term care hospitals and rehab clinics are called in to be vaccinated. In rural areas, it’s a different story. Even if a local health department casts a wide geographic net, there may not be 975 workers to give the shot to.

“I think about one county that I work with: They have a local health department with maybe 10 employees; they have a local hospital with a few hundred maybe; and they have a satellite clinic with 20 employees and another satellite clinic with 20 employees and a local pharmacy that has three,” says Ann Lewandowski, who is program manager for the Southern Wisconsin Immunization Consortium, where she oversees immunizations for seven rural counties. “Places like those are the most difficult to plan for.”

It is likely that, to get vaccines into these areas, the ultra-cold shipments will have to be taken out of their special packaging, broken up into smaller lots, and transported various distances—maybe a few miles, maybe a few hundred. That will start a countdown clock ticking on the vaccine’s viability. The recipients might be small clinics that possess only normal refrigerators. Or they might be local pharmacies or individual doctors’ offices, if they exist—218 of the 3,141 counties in the US have no doctor at all. Two nationwide pharmacy chains have contracted with HHS to administer Covid-19 vaccines in nursing homes.

“Some of this is going to be received by a clerk at a CVS or a Walgreens pharmacy, somewhere in rural America, who’s had very little cold-chain training or expertise,” predicts Joseph Battoe, CEO of Varcode, a Chicago-based company making barcodes that record when a medical package’s cold chain has been broken. “The challenges are extraordinary.”

(No doubt taking note of this, Moderna announced in its preliminary data release that its vaccine formula can remain stable at 2 to 8 degrees Celsius, or 36 to 46 degrees Fahrenheit, for up to 30 days. “The temperature of a standard home or medical refrigerator,” the company noted in its statement, in a tone inches away from smug.)

There may be a tech fix coming. AeroSafe Global, based in Rochester, New York, manufactures complex frozen and refrigerated packaging for biologics and tissues, and it also made packaging for delivery of some Covid-19 vaccine formulas to some trial sites in the US. (The company declined to identify which vaccine companies it worked with.) Temperature-controlled boxes can be customized, according to Jay McHarg, AeroSafe’s CEO. “We ship heart valves in a container the size of a jewelry box,” he says.

One solution for the problem of breaking a large frozen shipment into smaller tranches, he said, might be as simple as a smaller container that holds the vaccine at the same low temperature. Another might be a less complex container, similar to a tote bag or a suitcase, that holds 100 or so doses at the refrigerator temperature in which the vaccine lasts a few days. “You tell the box what temperature it is going to be held at, by the coolants you use,” he said. “The box doesn’t care what temperature you specify.”

The challenge, of course, is that customization costs money. AeroSafe’s thermal shippers are complex—they incorporate internal data loggers that report whether the package stayed frozen throughout transport, and also link to cloud-based demonstration and training videos for workers at the locations receiving the vaccine—and thus are not disposable. Once whatever product they contain has been removed or used up, the company’s staff picks up the boxes, reconditions them, and deploys them again. If AeroSafe’s containers became part of the pandemic-vaccine supply chain, it is not clear who would pay for their customization.

States are already running short of money: They’ve received $200 million so far in Covid-19 federal stimulus funds, yet Hannan’s organization and the Association of State and Territorial Health Officials estimate that deploying vaccines across the US will require more than $3 billion. (Companies making vaccines have received $10 billion through the government’s Operation Warp Speed.) Further Covid-19 funding is hung up in congressional negotiations that have been delayed by the election chaos; any potential agreement is receding further into the lame-duck session.

Yet boxes of vaccine could be on the move shortly, and some of the product they contain will be headed for the rural areas where health care authorities feel they are not equipped to receive it. At this point, no jurisdiction’s health officials know which vaccine will arrive, nor how much, nor exactly when. “It’s like we’re trying to build a house when we haven’t been given the architectural plans,” Lewandowski says. “And when I go to grab for a hammer, maybe I come up with pliers instead.”

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