The world is months, if not years, away from a validated coronavirus vaccine. Small biotech firm Moderna, the first company to launch vaccine trials in humans, has barely begun its first safety study in a small group of 105 people. Yet the US government’s Biomedical Advanced Research and Development Authority (BARDA) has already invested $483 million to scale up the company’s vaccine production, along with hundreds of millions more for other vaccines that have yet to be tested.
These investments may well go to waste. But they’re also essential: In a sign of the complexity and urgency of creating vaccines, ramping up production now will help avoid delays in delivery if a vaccine is approved.
Moderna announced its contract from BARDA last week, which will support large-scale production of its vaccine along with clinical trial development. At the end of March, Johnson & Johnson announced it would commit $1 billion, of which $456 million will come from BARDA, into accelerating vaccine research and ramping up production. And in February, BARDA and Sanofi said they’d expand an earlier collaboration on a flu vaccine to focus on coronavirus; BARDA told Quartz it had granted an additional $30 million funding for this work.
Johnson & Johnson’s subsidiary Janssen Pharmaceuticals isn’t even in phase 1 safety trials yet—it’s aiming to start human trials by September 2020 at the latest. But the pharmaceutical company says it plans to be able to manufacture 600 to 900 million coronavirus vaccine doses by the first quarter of 2021, increasing to a billion over the year. It currently would have the ability to produce around 300 million coronavirus doses.
“This is unique,” says Phyllis Arthur, vice president for infectious diseases and diagnostic policy at Biotechnology Innovation Organization (BIO), a biotechnology industry group. “Normally, companies would not invest in their manufacturing scale-up until they were deep into phase 2 and starting phase 3. They’d have more clarity that a product was going to work.”
Such clarity takes months, though, and researchers don’t have that time to spare. Before any vaccine is approved, it must be tested on tens of thousands of people, and so a small company like Moderna, which has 830 employees compared to Janssen Pharmaceuticals’ 40,000, must significantly increase production abilities just to have enough vaccines for trials.
Moderna is hiring 150 staff and increasing manufacturing production to three shifts a day, seven days a week in order to increase production. This expansion is “orders of magnitude bigger” than current capabilities, says Ray Jordan, head of corporate affairs at Moderna. “You typically run tens of subjects in phase 1, tens in phase 2, and thousands in phase 3. We’ve talked about being able to manufacture millions of doses per month in 2020 and tens of millions of doses in 2021.”
Jordan says Moderna is able to scale up quicker than traditional manufacturers, as its vaccines are created by manipulating mRNA, the molecule that carries genetic instructions from DNA to a cell’s protein-making ribosome. Moderna manipulates mRNA so that it instructs human cells to produce certain viral proteins; the proteins themselves don’t cause infection, but they do invoke an immune response. “The RNA uses the human body as its bioreactor,” says Jordan, so Moderna itself doesn’t have manufacture the proteins. “To create a different vaccine candidate [for Moderna] is to trigger a different RNA sequence. We don’t need to build a different cell processing plant,” says Jordan.
Using its BARDA investment, Moderna is planning on getting more mRNA production machines and increasing the output of existing machines. It also plans to contract out parts of the process, though it hasn’t released details.
Such contracts are standard in vaccine production, says Chris Stanley, a biopharmaceutical consultant at Harmony Consulting who helps companies get BARDA contracts. There are a limited number of viral vector production facilities, for example, which have features such as single pass air, meaning that air doesn’t recirculate in the room. “There aren’t many of these specialized facilities. They can’t be built overnight,” says Stanley. These manufacturing facilities are getting booked up fast: One company recently told Stanley they’d get back to him about availability in 2022.
Janssen Pharmaceuticals currently has a lot more in-house vaccine production capability than Moderna. But it creates more traditional viral vector vaccines, which are slower than Moderna’s mRNA methods. Janssen must grow cell cultures for the virus to invade, which is a delicate process requiring enormous, 20,000-liter bioreactors. The process of developing safe levels of the virus in cells typically takes months.
For both Moderna and Janssen, each batch of vaccine created and the process of creating it must be overseen and approved by the US Food and Drug Administration, which is necessarily time-consuming. Then the process of packaging a vaccine so that it can be given to patients—known as “fill and finish”—is itself extremely complex. And, as a coronavirus vaccine is needed globally, the companies may have to plan for international production.
“If manufacturing is set up on several continents, so that they’re closer to where they’ll be used, that’s a great time saver,” says Nancy Connell, microbial geneticist and professor at Johns Hopkins Bloomberg School of Public Health.
Despite the immense costs, there’s every possibility that the vaccines won’t get past trial stages. “That’s why it’s such an extraordinary step,” says Gigi Gronvall, immunologist and professor at Johns Hopkins Bloomberg School of Public Health. Vaccine production is precisely tailored to each specific vaccine, meaning it’s unlikely that increased production at Janssen and Moderna could be repurposed for other coronavirus vaccines. There’s a general understanding that these investments could be a loss, she added: “This is what you do when you have the money and a lot of urgency.”
BARDA is well aware that its investments are far from guaranteed to deliver returns. “Planning later phases before the earlier phase data is analyzed is a business risk, but it’s a risk we believe American taxpayers expect based on the severe pandemic and the economic impact the pandemic is having on our economy,” a spokesperson wrote in an email to Quartz. “Large-scale manufacturing is much more complex than it sounds. By starting this work now, the next phase can begin as soon as data is analyzed from the previous phase.”
The government agency is juggling these investments with its own internal issues: The director of BARDA, Rick Bright, stepped down from the organization on April 21, reported STAT. His former deputy, Gary Disbrow, is now serving as acting director, and will have responsibility for the agency’s significantly expanded budget.
Moves to scale up production aren’t the only unusual feature of coronavirus vaccine trials. The National Institute of Health, which is conducting Moderna’s phase 1 trial, introduced at-risk populations of older adults (ages 56 to 70) and elderly adults (age 71 and above) to the trial; usually, such populations would be introduced in later phases. And Jordan said Moderna has already begun manufacturing the material for phase 2 trials. “As soon as we see clean safety data from stage 1, we can begin ramping up a phase 2 trial,” he says. “You don’t normally run trials like that.” The coronavirus vaccine trials, though, are far from normal.