The complexity of the supply chain has some questioning whether a coronavirus vaccine could be produced quickly at the scale needed.
A vaccine supply chain involves a long list of ingredients, including some that seem odd, such as a derivative of horseshoe crab blood called “limulus amebocyte lysate,” or LAL, and a substance extracted from shark liver oil known as squalene. And a COVID-19 vaccine might also contain messenger ribonucleic acid, or mRNA.
Whether the companies involved can scale up production of those materials by early 2021 is a major challenge facing the distribution of a vaccine, one that extends beyond the process of discovering and proving the efficacy of a vaccine — a task that the Trump administration and drugmakers are trying to complete at record speed.
The demand is enormous. Preorders of COVID-19 vaccines have topped 5 billion. The U.S. government has ordered 300 million doses from AstraZeneca and Oxford and 100 million from both Moderna and the partnership of Pfizer and BioNTech, all of which are currently in phase three of testing a COVID-19 vaccine.
“As soon as a vaccine is approved, safe and effective, we want to have millions of doses available immediately,” said Alex Tabarrok, an economist at George Mason University who has written extensively about the economics of vaccines. “We want the factories to be warmed up and ready to go … and we want different types of factories ready to go since the vaccines are different. You want all your cars at the starting line.”
The problem is there are numerous cars.
“Vaccines are pretty complicated,” Tabarrok said. “The supply chains are long, global, and complex … One break in the chain can destroy the value of the entire process.”
Additionally, there has been limited innovation in the vaccine production process in recent decades, according to Dr. Felipe Tapia, a bioprocess engineering researcher at Max Planck Institute in Germany. He says that vaccines are still produced in “batches” instead of on a continuous production line.
“If vaccines were produced on continuous production lines, production would be twice as fast and 10-fold cheaper,” Tapia said. That’s not likely to change. “It does not make sense for companies to install 10 production lines in parallel to produce 10 times faster if those 10 production lines are abandoned after the pandemic,” Tapia noted.
Tabarrok is most concerned with the production of mRNA. The vaccine produced by Moderna will use mRNA. mRNA is a nucleic acid present in all living cells that sends instructions from a cell’s DNA to its proteinmaking machinery. This would be the first use of mRNA in a human vaccine.
“For a variety of reasons, the Moderna vaccine and similar types are most likely to fail because this supply chain has never been tested,” Tabarrok said. “This supply chain has never been put under pressure. It’s all entirely new … the factories are having to be built, the supply chain has to be built.”
One reason new factories have to be built is that mRNA often degrades quickly. To fix this, the mRNA must be “capped” with a “vaccinia capping enzyme.” Producing vaccinia capping enzymes requires enormous amounts of bioreactor capacity, so much so that producing just 10 pounds costs $1.4 billion. Ten pounds would be enough to cap about 100 million doses of the vaccine, but, according to Tabarrok, there is not enough bioreactor capacity worldwide to produce both enough vaccinia capping enzymes and other vaccines.
Luckily, producing sufficient LAL and squalene may prove less difficult. LAL is produced from the milky-blue blood of the American horseshoe crab that lives off the coasts from Maine to Mexico. The blood is highly sensitive to bacteria, making it an ideal substance for the LAL needed to test vaccine vials for contamination. Squalene is used to create an adjuvant, which helps a vaccine produce a strong immune response. Many vaccines today use only a portion of a virus, which can elicit weaker immune system responses. Thus, it becomes necessary to add an adjuvant such as squalene. Vaccines with adjuvants have more side effects, such as redness and swelling at the injection site and fever and chills.
Makers of LAL and squalene say their part of the supply chain is in good shape.
Vann Jones, senior manager of marketing at LAL producer Associates of Cape Cod, said, “There are four naturally sourced LAL manufacturers in the U.S., and between them, they can manufacture enough … tests to satisfy the testing need of the 5 billion doses in a day or two of production activities.”
Environmentalists are concerned that the American horseshoe crab is near threatened, but Jones doubts that concern.
“The concept of an insufficiency of natural-sourced [LAL] to meet public safety needs is simply not true,” Jones said.
Amyris, a maker of squalene, uses a process involving sugarcane instead of sharks.
“We can produce enough squalene for 1 billion vaccines in one month or less,” said Beth Bannerman, chief engagement and sustainability officer at Amyris. “As you might imagine, we are talking to a number of companies who are interested in sourcing their squalene from Amyris for their COVID vaccines. Those companies are working with the federal government.”
