On the day that a COVID-19 vaccine is approved, a vast logistics operation will need to awaken. Millions of doses must travel hundreds of miles from manufacturers to hospitals, doctor’s offices, and pharmacies, which in turn must store, track, and eventually get the vaccines to people all across the country. The Centers for Disease Control and Prevention, along with state and local health departments, coordinates this process. These agencies distributed flu vaccines during the 2009 H1N1 pandemic this way, and they manage childhood vaccines every day. But the COVID-19 vaccine will be a whole new challenge.
The leading vaccine candidates both deploy a new, long-promised technology. Their core is a piece of mRNA, genetic material that in this case encodes for the spike protein—the bit of the coronavirus that helps it enter human cells. The vaccine induces cells to take up the mRNA and make the spike protein and, hopefully, stimulates an immune response.
By using mRNA, vaccine makers do not need to produce viral proteins or grow viruses, methods that are used in more traditional vaccines and that add time to the manufacturing process. This is why Moderna and Pfizer/BioNTech have been able to get their vaccines into clinical trials so quickly. Moderna went from a genetic sequence of the coronavirus to the first shot in an arm in a record 63 days.
To get a naked strand of mRNA inside a cell, scientists have learned to encase it in a package called a lipid nanoparticle. mRNA itself is an inherently unstable molecule, but it’s the lipid nanoparticles that are most sensitive to heat. If you get the vaccine cold enough, “there’s a temperature at which lipids and the lipid structure stop moving, essentially. And you have to be below that for it to be stable,” says Drew Weissman, who studies mRNA vaccines at the University of Pennsylvania and whose lab works with BioNTech. Keep the vaccine at too high a temperature for too long, and these lipid nanoparticles simply degrade. Moderna’s and Pfizer/BioNTech’s vaccines have to be shipped frozen at –4 degrees and –94 degrees Fahrenheit, respectively. Once thawed, Moderna’s vaccine can then last for 14 days at normal fridge temperatures; Pfizer’s, for five days.
The freezer temperature required by Moderna’s vaccine makes it difficult to ship; the ultracold temperature required by Pfizer and BioNTech’s vaccine is nearly impossible to maintain outside of a large hospital or academic center with specialized freezers. For this reason, Pfizer has devised “thermal shippers” that, unopened, can keep the vaccines frozen for up to 10 days; once opened for the first time, they have to be replenished with dry ice within 24 hours, then every five days. These shippers are supposed to be opened no more than twice a day to take out vials, and must be closed within one minute. The real catch, though, is that these shippers hold, at a minimum, 975 doses of the COVID-19 vaccine.
A large hospital in a city could deal with that volume, but in rural areas, a 975-dose shipment will need to be broken up into smaller ones—all while making sure the vials stay ultracold. “The other potential would be only shipping that vaccine to our more urban areas,” says Molly Howell, North Dakota’s immunization program manager, “but then we’re leaving out a lot of people who are health-care workers in rural areas or at high risk in rural areas.” To get the vaccine out to those places, her department is looking into buying frozen-transport coolers and potentially a dry-ice machine. If North Dakota is allocated, for example, 2,000 doses, the state will have to open the thermal shipper, repackage smaller allotments in dry ice, and physically drive them to rural clinics across the state. The vaccines are too precious to risk shipping conventionally.
Another worry for hospitals: having to juggle multiple vaccines that are not interchangeable, especially after more become available in the future. “What they’re concerned about is: I get a vaccine now in November, and then another manufacturer launches in January, and then another manufacturer in March, and three more launch in May,” Behlim says. Immunization registries can record who got which vaccine, but hospitals and clinics will still have to decide which ones to stock and how much of each. One vaccine might be more effective, but another one easier to store. A third might be most effective in older people, while a fourth could have the advantage of requiring only a single dose. The more vaccines there are on the market, the harder vaccine management becomes.
In fact, with dozens of vaccines currently in clinical trials, the U.S. will very likely have multiple COVID-19 vaccines from multiple manufacturers next year. Two other vaccines are just behind Moderna’s and Pfizer/BioNTech’s mRNA vaccines, in Phase III clinical trials in the U.S. One of those is made by AstraZeneca and the other by Johnson & Johnson; both insert the genetic code for the coronavirus spike protein into a harmless virus.
These vaccines take slightly longer to manufacture, because they require growing viruses, and they are also a relatively new technology. But they do not have to be frozen, and Johnson & Johnson’s can be given in just a single dose. Close behind these two are more traditional vaccines that use proteins purified from the virus, which will likely have traditional storage requirements. Of course, clinical trials still need to be completed before scientists will know whether any of these vaccines are safe and effective. “Which vaccine or vaccines will prove the safest and the most effective and the most deployable? I think we don’t know yet. And that’s why having redundancy is good,” says Dan Barouch, a vaccine researcher at Harvard. (His lab is a collaborator on Johnson & Johnson’s vaccine.)