The vaccine industry recognized the potential of mRNA vaccines as far back as the 1980s.1 It anticipated that mRNA molecules could be synthesized in large quantities more quickly and cheaply than proteins.2 And it also knew that mRNA vaccines would help patients avoid infection risks of the sort posed by live attenuated viral vaccines. Eventually, experimental mRNA vaccines advanced to preclinical studies. For example, mRNA vaccines were evaluated in animal models of rabies,3 influenza,4 Ebola, and Zika.5 Until recently, however, challenges associated with delivery and stability hindered development.6

Then, last year, COVID-19 changed everything. The disease inspired so much collaboration and lent such urgency to development that longstanding obstacles to development were swept aside.

“COVID-19 drove innovation, academic and industrial collaborations, and new ways of working,” says Katarina Stenklo, enterprise solutions commercial activation leader, Cytiva. “Significant funding made it possible to develop new vaccine technologies such as mRNA, to run phases of clinical trials in parallel, and to accelerate regulatory approvals.

“Regulatory bodies created a fast lane for COVID-19 vaccines, enabling the acceleration of their processes. They didn’t have any less rigor around review and approvals, but they found ways to reduce timelines through the parallelization of activities. For example, regulators started reviewing results periodically from clinical trials as they became available, instead of waiting for the completion of the full report.”

Infrastructure efforts

COVID-19 also helped create the infrastructure needed to work with mRNA. Moderna and Pfizer/BioNtech started planning for large-scale mRNA vaccine production last year. The companies began adding internal capacity7 and arranging deals with contractors. Behind the scenes, significant efforts were initiated to standardize and modularize production platforms and facilities.

“Investments have been made in building manufacturing capacity in parallel with product development and clinical trials, resulting in rapid and deployable access to vaccine manufacturing capacity,” Stenklo observes. “COVID-19 challenged the materials sourcing for vaccine suppliers and manufacturers. Manufacturers wanted large quantities of the same products at the same time, so suppliers ramped up their manufacturing capacity or built new capacity to meet the demand.

“This is where the vaccine manufacturers must consider speed and flexibility. Continuous planning, which calls for close relationships and regular communications between suppliers and manufacturers, is critical to delivering for customers.”

Besides offering encouragement to the mRNA vaccine sector, the successes seen with mRNA vaccines auger well for the wider vaccine industry. “Given the efficacy of these new vaccines,” Stenklo remarks, “we will likely see the new modalities such as mRNA being studied in other disease categories.”

Manufacturing changes

The COVID-19 response has proved to patients, governments, and the vaccine industry that mRNA-based shots are effective and have commercial potential. But the rush to develop and supply vaccines to slow and potentially stop the pandemic did not give the industry time to optimize production methods, which is what must happen now.

“For the first approved vaccines, manufacturers likely used a process that had worked before and scaled up what was good enough,” Stenklo suggests. “Not much time was spent on optimizing the processes for manufacturability. I think that with new generations of vaccines, we will see more optimized and intensified processes, and a focus on process economy.”

Stenklo adds that any changes in vaccine production that have occurred since the COVID-19 pandemic are mostly limited to the production of lipid-nanoparticle-encapsulated mRNA vaccines. For other vaccines, such as vaccines based on viral vectors and recombinant proteins, manufacturing processes remain much the same.

Wider lessons

For vaccine developers not directly involved in the fight against COVID-19, the pandemic’s main impact has been to highlight weaknesses in production methods and supply chains. For Damini Patel, a field application scientist at biotech instrument developer InDevR, the biggest lesson was the need for better analytical technologies.

“Time is of the essence when it comes to vaccine development and production,” Patel insists. “The coronavirus pandemic has shown everyone the importance of speed, but for those of us in the vaccine industry, the importance of speed is nothing new. For example, producers of influenza vaccines face short development timelines twice a year.” (The World Health Organization’s recommendations for the Northern Hemisphere’s vaccine are issued in February; those for the Southern Hemisphere’s vaccine are issued in September.)

“Slow, laborious, and often imprecise analytical techniques can be replaced by faster and better ones to help speed up the development and production process,” Patel argues. At present, techniques that could stand improvement include single radial immunodiffusion (SRID)—a common means of estimating antigen concentration. “SRID is not sensitive enough in work with low concentration ranges and some recombinant sample types,” she points out. “And it can take two to three days to complete an SRID run.”

She also says that vaccine developers need better enzyme-linked immunosorbent assays (ELISAs). According to Patel, ELISA problems include variability, long preparation times, and the need for large sample volumes.

“High variability can result in erroneous data or require that tests be repeated, taking up extra time,” she continues. “Older, single-plex techniques simply require more tests to be run, and that requires more trained personnel, which is hard to come by and adds cost.”

Investment decisions

The pandemic has also impacted how investors approach decisions over manufacturing capacity. Usually, large-scale manufacturing capacity is established during late-stage development when the risk of failure is low. Developers calculate capacity based on forecasted demand, building in flexibility to cope with fluctuations.

COVID-19 prompted organizations like the WHO,8 the EMA,9 and CEPI10 to reconsider how investment decisions are made. They suggested that instead of following the usual approach, the industry could invest in idle capacity. Then the industry would have capacity that could be brought online when needed. It would be better positioned to fight future pandemics and improve access to vaccines in general.

The advantages of idle capacity are clear, even though there are obvious economic difficulties. In addition, there are serious technological challenges.

Stenklo puts these challenges in the form of questions: “How do you invest in uncertainty? How do you know what’s coming next? What’s the product that will be manufactured? What will be the appropriate manufacturing scale, and how does a company make the correct manufacturing investments? What will be the size of the market for the next product? What scales are needed to support that market, and how urgent will this need be?”

“One specific challenge is knowing what manufacturing processes to invest in given the different types of vaccines,” she continues. “Companies must have an ear to the ground, and they must keep their scientists informed and engaged. They must consider material suitability and product quality attributes early in the development stage. And they must always be thinking about scalability and manufacturability.”

Stenklo suggests a flexible approach, specifically, the use of modular manufacturing technologies that can be reconfigured for each run or project. She explains that this approach would make it “easy to scale up and have a plan for expansion when it is needed.”

Vaccine developers seeking flexibility are likely to outsource production. Outsourcing, Stenklo says, usually makes the most sense for smaller companies. “For a small or start-up company, it can be a challenge to get through the clinical trials,” she elaborates. “This is where the large, established actors can be helpful. They already have experienced regulatory teams that can support clients throughout the trial process.”

According to Stenklo, factors favoring the use of contract development and manufacturing organizations (CDMOs) in vaccine production include the global impact of COVID-19 and the likelihood that future disease outbreaks will affect multiple countries. “I think the CDMOs will definitely play a role going forward,” she says. “They can be engaged for clinical-phase manufacturing but can also provide extra capacity when needed. A global CDMO will be able to support manufacturing in different parts of the world if the originator is a manufacturer without a global presence.”

 

References

  1. Dolgin E. The tangled history of mRNA vaccines. Nature 2021; 597(7876): 318–324.
  2. Harvard Health Blog. Why are mRNA vaccines so exciting? Published December 10, 2021.
  3. Armbruster N, Jasny E, Petsch B. Advances in RNA Vaccines for Preventive Indications: A Case Study of a Vaccine against Rabies. Vaccines (Basel) 2019; 7(4): 132.
  4. Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 2019; 37(25): 3326–3334.
  5. Richner JM, Himansu S, Dowd KA, et al. Modified mRNA vaccines protect against Zika virus infection. Cell 2017; 168(6): 1114–1125.e10.
  6. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines—a new era in vaccinology. Nat. Rev. Drug Discov. 2018; 17(4): 261–279.
  7. European Medicines Agency. Increase in vaccine manufacturing capacity for COVID-19 vaccines from BioNTech / Pfizer and Moderna. Published August 24, 2021.
  8. Georgieva K, Ghebreyesus TA, Malpass D, Okonjo-Iweala N. A New Commitment for Vaccine Equity and Defeating the Pandemic. World Health Organization. Published May 31, 2021.
  9. European Commission. EU Vaccines Strategy.
  10. Coalition for Epidemic Preparedness Innovations (CEPI). Enabling Equitable Access to COVID-19 Vaccines. https://cepi.net/wp-content/uploads/2020/12/Enabling-equitable-access-to-COVID19-vaccines-v5-10June2021.pdf. Published June 10, 2021.