During the spring of 2020, when squabbles erupted in grocery stores over basic necessities like water, food, hand sanitizer, and toilet paper, it became apparent that the eventual release of billions of vaccines would be necessary to combat the domestic and international reaction to the COVID-19 pandemic.
As mRNA-based vaccines gained momentum, a new modality that had not previously existed globally had to be assembled, along with an exceedingly complicated supply chain. Even pioneers in mRNA production, such as Maravai Life Sciences’ TriLink BioTechnologies, were caught off guard by the magnitude and quality of production needed for preclinical and phase one trials.
“This was a popular technology in the then relatively small universe of mRNA therapeutic programs because it’s very enabling for efficiency and yield,” Trey Martin, CEO of Maravai LifeSciences, told Inside Precision Medicine. “That all shifted very quickly when we went from preclinical programs and smaller preclinical and phase one programs to needing to make enough reagents for billions of doses of vaccines. It was a thousandfold scale up from normal activity.”
The production of a critical ingredient in TriLink’s final drug substance went from grams for research to kilograms for medical use in a remarkable scale-up project that fully complies with Good Manufacturing Practices (GMP) standards. And that scaling up hasn’t stopped.
On August 13, 2024, Inside Precision Medicine was invited to a ribbon-cutting ceremony to celebrate the completion of its new manufacturing facility dedicated to GMP nucleic acid raw materials. An essential component of one of the COVID-19 vaccines, TriLink’s proprietary mRNA capping technology, CleanCap, is among the many reagents manufactured in the new cGMP facility.
“The response will be mRNA because the reality is you can go from sequence to vile in 90 days—there’s just no other technology that exists like that,” said Martin. “Think about the fact that we still make influenza shots with chicken eggs. The configurability of this is going to really revolutionize rapid response for vaccines.”
Made in the USA
Following the announcement of a partnership with the U.S. Department of Defense (DOD) and Health and Human Services (HHS) in May 2022, TriLink’s efforts to scale up domestic production capacity for products essential to creating mRNA vaccines and therapeutics reached a fever pitch.
“BARDA focuses on creating, developing, and utilizing adaptable public-private partnerships,” said Bob Huffman, program director for the Manufacturability and Resilience Program at BARDA. “To implement our advanced research and development agenda for medical countermeasures, we have to work really closely with industry.”
According to Huffman, the supply chain problems discovered in the early stages of the COVID-19 pandemic caught everyone off guard. A portion of the funds allocated to BARDA were to increase vaccine production capacity and cover other necessary expenses to address the supply chain risks that the COVID-19 pandemic brought to light. The entire process of generating the mRNA for therapeutics, including using raw materials, at this facility will be completely domestic, which will be increasingly important to secure the U.S. public health supply chain.
“It (the facility) is here in America; it greatly shortens supply lines and response time, and it also provides those mRNA precursors in the required amounts on the timeline that’s needed for vaccine manufacturers,” said Huffman. “BARDA invests in facilities like this to be prepared to rapidly respond to future public health emergencies, when demand increases on these types of raw materials. That’s the importance of having facilities like this in the U.S.”
Huffman maintains that this is not a one-off arrangement. As a component of the agreement with the U.S. government, funding was allocated to TriLink to enhance its nucleic acid production capabilities in San Diego, California. This will aid in advancing medical countermeasures to safeguard the nation and address contemporary health security threats, like pandemic prevention. According to the original agreement, BARDA would have an ongoing and renewable 10-year engagement with TriLink after the project is finished.
“We’ll continue to understand what challenges TriLink sees coming up because we want to be able to fold in—to the extent that companies can share that knowledge and that understanding—the advanced research and development pipeline of national medical countermeasures that we’re supporting across BARDA,” said Huffman. “So it’s a very important relationship that we established three years ago. It’s very important to us and frankly, it’s very important to the American people during the next public health crisis or emergency that we make the most of these types of partnerships going forward.”
The facility that TriLink originally used for the COVID-19 response in collaboration with the newly unveiled facilities is strictly for nucleic acid reagents—there is zero focus on the lipid supply chain needed for the lipid nanoparticles (LNPs) that deliver the mRNA technology. The facility will manufacture various mRNA caps and all nucleic acid bases at the cGMP scale to be included in the final product. TriLink’s facility has expanded from one suite to four, and each can now produce over 25 times the capacity that TriLink had during the pandemic response.
“Operation Warp Speed was a big risk, and it worked,” said Martin. “That in itself is pretty amazing, but it was a testament to the 20 years of work that had happened in relative obscurity before that. We just had to close the last mile and, on the first try, went from an idea to billions of vaccine doses that completely changed the immunity profile for most of the world. And the scale up during the difficulties and shortages of the pandemic was an incredible feat. So, we will be in a position completely different now to respond with facilities like this—ready to go along with others in the BARDA network.”
A configurable medicine
Maravai and TriLink intend to continue developing nucleic acid technology to push the boundaries of configurable medicines, as Martin defines them.
Martin said, “I think it will all evolve quickly because this is a programmable platform. Think of mRNA as the software of the human cell. That configuration is just the code, and we have the ability then to express any protein by essentially changing the base configuration of the mRNA message. The reality is whether it’s a spike protein neo-antigen for COVID, a personalized new vaccine for oncology, a protein replacement therapy, or part of the CRISPR gene editing platform—in all of those cases, you’re making essentially the same molecule, which is very different than traditional pharmaceuticals.”
Unlike small and large molecules used in pharmaceuticals and biologics, the building blocks of messenger RNA technology are essentially only a few conventional nucleic acid bases plus pseudo-uridine. The team of Katalin Karikó and Drew Weissman was honored with the Nobel Prize in Medicine in 2023 for their discovery of a nucleoside base modification that effectively reduced the immune response and made it possible to develop mRNA vaccines against COVID-19.
Maravai and TriLink’s primary goals are more effective dosing, targeting of additional cell types, and process optimization for the realization of each drug substance. To illustrate this point, Martin mentioned the use of self-amplifying RNA, which boosts antigen production significantly—a major boon to effectiveness and dose requirements.
Along with the ribbon cutting, TriLink also unveiled a second facility that was self-funded and serves a variety of end uses and program needs, each of which has its own preferences when it comes to lipid or non-lipid delivery options.
“I think there will be quite a bit of innovation in the delivery side, just as there has been in nucleic acid medicines for the last 30-plus years,” said Martin. “We have not delved into all the different ways you can deliver mRNA, which formulates the drug product. There will be various variants, and they’ll probably evolve toward use cases for target tissue and others, like delivery. We want to help as much as possible and be in the middle of all that.”
