Global vaccines shortages are pushing scientists to revolutionize manufacturing practices and shift from growing viruses in giant vats to cultivating them in long, thin tubes.
By some estimates, only around 1 percent of people in low-income countries have received one COVID-19 shot and each year only 5 billion doses of vaccines of every type are produced worldwide, according experts convened by the London-based think tank Chatham House. They noted that scaling up shots for COVID-19 is proving difficult. That is a grave concern, because the pandemic has underscored the need for technology that can dramatically boost global vaccine manufacturing capacity.
There are different kinds of COVID-19 vaccines that have proven to work. Some consist of genetic material called mRNA that contains the instructions to build just part of the virus (the spike protein). Others use inactivated coronavirus to provide the immune system with a preview of the pathogen. Another variety of vaccine uses a harmless version of a cold virus as a vehicle to deliver the immunizing bits of coronavirus material. Each technology requires a different manufacturing process. “There's no one standardized method of making a vaccine,” says Tarit Mukhopadhyay, head of vaccine process development at Merck. However, the latter two vaccine technologies require producing the inoculating viruses in large batches.
But viruses can’t be grown on their own. They need host cells in which to grow and multiply. In many cases, companies use cells as tiny factories to churn out the vaccine product: such as viral particles they will inactivate or viral proteins used in the jab. But growing enough cells, in the giant steel tanks can take weeks compared to just couple of days required to process the virus and make the actual vaccine. “The problem is that about 80 percent of the time you're just sitting on your hands. You're not actually making a virus because you're just growing up host cells,” explains Richard Braatz, a chemical engineering professor at the Massachusetts Institute of Technology.
Also, once the batches are done, time is lost to cleaning and prepping the tanks for the next round. When vats aren't properly cleaned and reset, millions of doses can go to waste, as recently happened with 60 million doses of Johnson & Johnson vaccine. For reasons such as this, groups of scientists are looking to move away from making vaccines in batches toward a continuous way of manufacturing them.
One team of scientists believes they’ve found a solution by manufacturing vaccines in a 300-meter-long tube rather than a vat. The tube is narrow—just 1.5 millimeters in diameter—but they say their prototype demonstrates that true continuous vaccine manufacturing is possible.
Oil refinery inspires vaccine manufacturing
The idea was developed in part by Felipe Tapia, a bioprocess engineer at the Max Planck Institute for Dynamics of Complex Technical Systems in Magdeburg, Germany. As a university student in Chile, Tapia used to pass an oil refinery every day. The oil industry typically pumps its product through tubes to remove impurities, and this design inspired Tapia to think differently about vaccine production when he moved to Germany in 2012.
Over the last decade he and his Max Planck colleagues have adapted that tubular approach to vaccines as a way to replace large batch bioreactors.
The tubular design is suited to manufacture vaccines based on viral components, such as those used for the AstraZeneca and Johnson & Johnson COVID-19 vaccines; it cannot be used to make mRNA-based vaccines such as the ones offered by Pfizer and Moderna.
There are quality-control advantages to continuous vaccine manufacturing, explains Keith Roper, who heads the department of biomedical engineering at the Utah State University. A giant vat of cells can only make good vaccine product for a defined period before it begins to peter out and make subpar product.
But continuous vaccine manufacturing is fueled by a constant supply of cells, growth ingredients, and viral material. He likens batch-based vaccine manufacturing to plugging into a battery, which loses power over time, whereas continuous manufacturing is akin to hooking into the power outlet. “If you plug your electronic device into an outlet, our distributed national power grid is a continuous source of electricity, whether you plug it in at 8 a.m. or 5 p.m., whether you plug it in yesterday or tomorrow, you expect that that source of electricity will be steady and continuous and operate within a pretty well-defined range,” Roper says.
In the batch bioreactor vats, which sometimes measure 2,000 liters in volume, the viruses grown to be either live-attenuated, killed-vaccine or viral vector vaccines eventually kill off the cells in the vats that are allowing them to multiply. But the tubular continuous design aims to avert that massive die-off. Instead, fresh cells are continuously grown in a small tank and fed into the opening of the tube along with fresh cell culture media. Another tube feeds into the primary tube and allows small quantities of virus to be added to the cells, which they infect. A peristaltic pump keeps the fluid moving forward to flow through the 300-meter tube where the virus replicates over the course of 48 hours until it is harvested.
Eventually, a liquid containing virus and cell debris exits the primary tube via a harvest pipe. The virus is separated from the other components and processed into a vaccine. “It’s a simple idea but it was not very easy at the beginning to be convinced that actually it would work,” Tapia says.
One concern was that the pump used to move materials through the tube would malfunction or somehow harm the cells as they churned out vaccine materials. “We thought it would be too much pressure for the cells,” he explains. But it worked. Tapia and his colleagues demonstrated a proof of concept of this design for making influenza vaccine in a 2019 PLoS One study. They've launched a company, called ContiVir, to get the technology off the ground and are talking to pharmaceutical companies interested in this new form of manufacturing.
“It's a good idea,” says Rahul Singhvi, cofounder and CEO of National Resilience, who has been working on elements of continuous vaccine manufacturing for decades. If companies could get a completely continuous process to work for commercially-sold vaccines it would be a game-changer, he says. “End-to-end continuous manufacturing is the holy grail.”
Getting to real-world implementation
Scientists have been trying to come up with a way to continuously manufacture viral products since 1965. “Continuous manufacturing is certainly not a new concept,” Roper says. But implementing it has not been easy, he adds: “I think it's safe to say that there are no end-to-end continuous vaccine manufacturing processes currently.”
Merck is collaborating with Braatz at MIT and others to try to incorporate some elements of continuous manufacturing into their vaccine production. One feature they are testing is a filter that attaches to the side of their production tanks to continuously extract vaccine material, rather than harvesting it in bulk. The feature is still in development. Other vaccine manufacturers, such as the Japanese pharmaceutical giant Takeda, also have explored shifting toward continuous vaccine manufacturing.
Tapia emphasizes that the continuous system such as the tubular reactor he helped develop has the advantage of being small, obviating the need for giant tanks that are housed in massive manufacturing facilities, which are difficult to build, staff, and maintain—especially given the rapid scale-up of production needed. Space is a major constraint that currently holds back traditional vaccine manufacturers from increasing production. "The problem comes when you have a pandemic, and you need to increase your manufacturing capacity by a factor of 10 or more," Tapia says.
Singhvi agrees that building large facilities to house the traditional vat-based process is a limiting factor in global vaccine production capacity. But creating these facilities is costly, and not possible with the limited financial and personnel resources in many places. Moreover, it’s not very feasible to invest the large resources in creating these giant manufacturing sites and just abandoning them for years until the next pandemic. “You can't put a tarp on something,” Singhvi says, because the buildings require maintenance.
Smaller, more affordable vaccine production machinery could mean more countries could have local vaccine production plants, he says: “It gives countries more agency to control their own destiny.” Resilience co-founder Singhvi hopes that his company can make production more efficient by setting up continuous manufacturing factories around the world which pharmaceutical companies turn to when they want to outsource their vaccine production.
Engineers and developers say that efficient manufacturing would eventually benefit all vaccines. The world witnessed a flurry of innovation in creating COVID-19 vaccines, and now there’s a push to carry that innovation into the manufacturing process. “I think we're really at a turning point,” Mukhopadhyay says, “both in terms of vaccine discovery, but also vaccine manufacturing itself.”