Barely a year ago few people outside of a small network of scientists and companies had heard of mRNA vaccines. Today millions are pinning their hopes on these genetics-based immunizations, which have taken center stage in the fight against COVID. But deficiencies in needed supplies and materials for making the vaccines could lead to widespread shortages, some scientists say.

The first doses of mRNA COVID vaccines began arriving at hospitals in the U.S. and several other countries in December. An overarching question is how fast companies making them can scale up production to meet global demand. This is the first time mRNA vaccines have been authorized for use outside of clinical trials. They work by tricking the body’s own cells into making a viral protein that prompts immune reactions against infection. The U.S. has granted emergency authorization to two COVID vaccines so far—made by the pharmaceutical companies Pfizer and BioNTech and the biotechnology firm Moderna, respectively—and both rely on mRNA. A third company called CureVac, headquartered in Tübingen, Germany, currently has an mRNA vaccine in late-stage clinical trials. The Trump administration reached a deal with Pfizer in late December to provide 100 million additional doses to the U.S. by the end of July—resulting in twice the amount the government originally ordered. Together with its partner BioNTech, Pfizer plans to produce and distribute 1.3 billion doses globally next year. And Moderna intends to produce 500 million to one billion doses, of which 200 million have already been allocated to the U.S.

Meeting these targets will be no easy feat. “There aren’t any facilities in the world that have manufactured mRNA at such a large scale before,” says Maria Elena Bottazzi, a virologist at Baylor College of Medicine and Texas Children’s Hospital in Houston. Pfizer and Moderna have been building supply networks to shift from clinical to large-scale production. But each step in the manufacturing process requires raw materials that, before COVID, were only produced in the amounts needed for clinical research—“not sustained production of billions of doses,” says Patrick Boyle, an executive responsible for research and development at the Boston-based synthetic biology company Ginkgo Bioworks.

Such mRNA vaccines are created using much faster chemical processes than traditional vaccines made by growing weakened viruses in chicken eggs. Manufacturers start with a digital sequence of genetic building blocks for the novel coronavirus’s “spike” protein, which the pathogen uses to enter and infect cells. Robotic assembly lines transform that sequence first into a DNA template and then into the mRNA vaccine substance. To protect the mRNA, which is highly unstable, vaccine producers pack it within an oily lipid nanoparticle that also facilitates uptake by human cells. Inoculated cells will then make and display the viral spike on their surface so that the immune system learns to recognize and fight off the virus later.

According to a November report by the U.S. Government Accountability Office (GAO), much of what is needed to produce these vaccines is in short supply. During interviews with GOA staff, manufacturing plant personnel described challenges in obtaining reagents and certain chemicals, as well as glass vials, syringes and other hardware. They also cited a shortage of “fill and finish” facilities where vaccine doses are loaded into sterile containers and a dearth of workers with the specialized skills needed to run mRNA production processes. Such resource scarcities, GAO concluded, could lead to production backlogs.

Boyle singles out polymerases, a type of enzyme, that convert DNA to mRNA and ingredients used for making lipid nanoparticles as some of the most critical raw materials for the vaccines. He also says manufacturers need better access to a rare substance called vaccinia capping enzyme (VCE), which helps keep the mRNA from degrading and gives it a deceptively human appearance to prevent cells’ protein-making machinery from rejecting it. Boyle’s team has calculated that making the 10 pounds of VCE needed to generate 100 million mRNA vaccine doses would overwhelm the limited capacity of bioreactors (containers used to carry out biochemical reactions) and cost $1.4 billion. VCE prices should fall as manufacturing processes and efforts to increase production improve, however, Boyle says.

The impact of these shortages was evident in November, when Pfizer and BioNTech halved the number of doses they said could produce globally in 2020 from 100 million to 50 million. Pfizer did not say which shortfalls had affected production. But Tanya Alcorn, vice president of the company’s biopharmaceutical global supply chain, acknowledges there was “a bit of a scale-up issue in early fall” that she says has since been resolved. “When you’re running at this pace, everyone needs to scale up at the same time,” Alcorn says. “We need more from our suppliers, and our sites need to optimize operational performance as well.” The New York Times has reported that Pfizer’s new deal with the U.S. government hinges on better access to specialized materials that were not publicly disclosed by the company. But Alcorn tells Scientific American that the “new and unique components needed for lipid nanoparticles” are a limiting factor. Moderna did not respond to requests for comment.

A wild card in the needed manufacturing scale-up is how long mRNA vaccine protection lasts. Corey Casper, chief executive officer of the Infectious Disease Research Institute in Seattle, says experts were hoping the vaccines would stimulate antibody levels four to 10 times higher than those induced by natural infections. “That didn’t happen,” he says. “The mRNA vaccines work great: [about] 95 percent protection from disease [in clinical trials]. But if the antibodies drop quickly below a protective threshold, then people might need a booster,” which would require manufacturing more vaccine. It is possible that a broader array of immune cells, including T cells, will prolong and sustain mRNA-induced protection, but that scenario remains an open question.

Fortunately, mRNA vaccines are not the only game in town. Other companies—such as Johnson & Johnson and AstraZeneca—are taking COVID vaccines made using different approaches through late-stage clinical trials. And ideally, these efforts will contribute millions of additional doses—not just for the richer nations that so far have been hoarding the near-term supply but also for low- and middle-income countries. The latter category includes 67 nations where only one in 10 people may be immunized next year, according to an analysis by the People’s Vaccine Alliance, an organization that includes Amnesty International and Oxfam International. “It’s been said many times before, but we need multiple shots on goal,” Casper says.

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