12/5/2020 Temperature concerns could slow the rollout of new coronavirus vaccines | Science | AAAS

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Arktek containers, which kept Ebola vaccines at –80°C in sub-Saharan Africa, could be used to transport COVID-19vaccines that require similar temperatures. WORLD HEALTH ORGANIZATION/S. HAWKEY

Temperature concerns could slow the rollout of new coronavirus vaccinesBy Jocelyn Kaiser Nov. 16, 2020 , 5:55 PM

Science’s COVID-19 reporting is supported by the Pulitzer Center and the Heising-SimonsFoundation.

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12/5/2020 Temperature concerns could slow the rollout of new coronavirus vaccines | Science | AAAS

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Today’s dramatic news that Moderna’s COVID-19 vaccine might work as well as one made by P�zerand BioNTech means the world could have two powerful weapons to �ght the COVID-19 pandemic.Now, the next hot vaccine topic is, well, heat. Both vaccines use a novel technology—strands ofmessenger RNA (mRNA), held within lipid particles—that is vulnerable to degradation at roomtemperature and requires doses to be frozen for transportation, then thawed for use.

That’s where the Moderna vaccine may have an edge: Unlike P�zer’s and BioNTech’s offering, it doesnot have to be stored at –70°C, but can tolerate a much warmer –20°C, which is standard for mosthospital and pharmacy freezers. That difference means Moderna’s vaccine should be easier todistribute and store, particularly in the rural United States and developing countries that lackultracold freezers. Moderna says years of development work enabled its vaccine to be stored athigher temperatures, but last week another mRNA vaccine company announced it is testing aCOVID-19 vaccine that early studies suggest can survive at the even warmer temperatures of 2°C to8°C found in refrigerators.  

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Many types of vaccines must be stored and transported frozen, via a cold supply chain. Publichealth o�cials have even found ways to keep a vaccine ultracold, between –60°C to –80°C, inplaces like sub-Saharan Africa. There, for the past 5 years, a high-tech thermos called Arktek hashelped distribute Ebola vaccines that must be kept ultracold. “In all likelihood, we’ll need a widerange of supply chain tools” to distribute COVID-19 vaccines, says Daniel Lieberman, a mechanicalengineer with Global Health Labs in Seattle, a nonpro�t created by the Bill & Melinda GatesFoundation and by the private o�ce of Bill Gates (who also funded Arktek’s development). Still,relying on an ultracold chain is expensive, and in some places it may make more sense to distributea vaccine that can tolerate warmer temperatures even if it’s less effective.

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12/5/2020 Temperature concerns could slow the rollout of new coronavirus vaccines | Science | AAAS

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Both the Moderna and P�zer/BioNTech vaccines give the body’s cells an mRNA template for makingthe spike protein of SARS-CoV-2, the virus that causes COVID-19. The protein then moves to thecell’s surface and triggers an immune response. This mRNA is relatively fragile compared with theproteins or protein fragments that often make up conventional vaccines, and it cleaves easily atroom temperature, says Alana Gerhardt, who studies vaccine product development at the nonpro�tInfectious Disease Research Institute (IDRI) in Seattle. Also, enzymes called ribonucleases thatchew up mRNAs “are everywhere, even in the controlled environment of the lab,” from sources suchas lab workers’ breath and skin, Gerhardt says.

The companies give the mRNA some protection during production and storage by inserting it into acarrier, a fatlike substance called a lipid nanoparticle. The lipid also shields the mRNA fromenzymes in the blood once it has been injected. But the nanoparticle is deliberately designed toslowly degrade, so it won’t build up in the liver and cause harm, says Massachusetts Institute ofTechnology geneticist and chemical engineer Daniel Anderson.

V. ALTOUNIAN/SCIENCE

Although the companies’ exact formulations are proprietary, P�zer and BioNTech have so far saidtheir vaccine has to be kept ultracold. But Barney Graham, a vaccine researcher at the U.S. NationalInstitute of Allergy and Infectious Diseases who designed the mRNA used by both Moderna andP�zer/BioNTech, says the temperature requirements are actually unclear. P�zer and BioNtechstarted with –70°C when they �rst asked regulators to test their vaccine in humans, and Graham

Some don’t like it hotVarious vaccine types have different temperature requirements for storage and transport. The new messenger RNA (mRNA) vaccines, which wrap lipids around a snippet of genetic material that encodes a protein, degrade at room temperature and need to be frozen, some at ultracold temperatures. The COVID-19 vaccine versions deliver into cells an mRNA that makes a coronavirus protein, stimulating immunity.

SARS-CoV-2 spike protein

Presented to stimulate immune response

Lipid nanoparticle containing mRNA

Ribosome

mRNA

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says the companies might ultimately be able to document that the mRNA survives warmertemperatures.

In the meantime, at sites in Kalamazoo, Michigan, and Puurs, Belgium, P�zer will pack shipmentsof 200 to 1000 vials each containing �ve doses in insulated boxes with thermal sensors on dry iceto provide the necessary chill. Pharmacies and doctor’s o�ces that lack $15,000 ultracold freezerscan store it in the thermal box for about 2 weeks by re�lling the dry ice every 5 days; once removed,the vaccine can be refrigerated for 5 days. Moderna’s vaccine, however, is stable for 6 months at –20°C, or in a standard freezer, and the company announced today its product can be kept at normalrefrigerator temperatures for up to 30 days, longer than the 7 days initially expected.

The German company CureVac is lagging behind in the mRNA COVID-19 vaccine race, butannounced last week that its candidate is stable for 3 months at 5°C. Unlike the Moderna andP�zer/BioNTech vaccines, CureVac’s mRNA does not have a modi�cation to one of its four buildingblocks, a nucleoside called uridine, which the company says allows it to pack more tightly inside thenanoparticle. “Our hypothesis is that the more compact the mRNA is, the less susceptible it is todegradation,” CureVac spokesperson Sarah Fakih says. The company expects to launch a 30,000-person trial to test the vaccine’s e�cacy by the end of this year.

Even a vaccine shipped and stored at –20°C, like Moderna’s, poses challenges in developingcountries, where electricity for freezers can be unreliable and dry ice scarce. But frozen vaccinesdon’t have to be a deal breaker, as shown by the Ebola vaccine, which has been shipped in Arktekcontainers to different sites in the Democratic Republic of the Congo to vaccinate about 400,000people. Ultracold freezers in large cities were still needed to store the vaccine before it wasdistributed and to chill the cold packs used to keep Arkteks cooled, notes Prashant Yadav of theCenter for Global Development. That meant there remained a requirement for reliable electricity withbackup sources. “The key thing is to have a cold chain primary storage point,” Yadav says.

The Arkteks are expensive—about $2000 each—but they’re reusable and can keep vaccines and dryice or alcohol or salt-based cold packs chilled for much longer than an insulated box, Liebermannotes. “I see the Arktek being valuable anywhere where you want the vaccines to stay cold for daysor weeks without a freezer,” Lieberman says. The Gates Foundation’s global delivery program isreadying to ramp up production of the Arktek by the Chinese company that makes it, if needed forCOVID-19 vaccines, Global Health Labs says.

Another option is to freeze-dry the mRNA vaccines; they would then be reconstituted with water atthe delivery point. (Other vaccines already do this.) P�zer says it is working on a such a powderizedform of its vaccine. Regulators would likely require evidence to show the reconstituted vaccineworks as well as the liquid vaccine, says IDRI’s Corey Casper.

Several other COVID-19 vaccines now in e�cacy trials won’t require freezer storage either. If theywork as well as the mRNA vaccines, there will be no need for a –20°C or –70°C cold chain inresource-restrained settings, Yadav says. But if these vaccines aren’t as effective—say only 70%,

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12/5/2020 Temperature concerns could slow the rollout of new coronavirus vaccines | Science | AAAS

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compared with 90% for an mRNA vaccine—Yadav says that might tip the scale toward deployingmRNA vaccines, despite the costs and challenges.

With reporting by Jon Cohen.

Posted in: Health, Coronavirusdoi:10.1126/science.abf7422

Jocelyn KaiserJocelyn is a staff writer for Science magazine.

Email Jocelyn

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