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The rapid onset and spread of SARS-CoV-2 resulting in the global COVID-19 pandemic has had devastating effects on global health, education, and economies. The long-term fallout of this truly catastrophic event has yet to be fully realized as many countries are still battling rising infection rates, the emergence of more infectious variants, vaccine supply and distribution issues, and more.

COVID-19 has enhanced existing disparities in wealth and resources where high-income countries have over 200% population coverage of vaccine doses, leaving developing countries struggling to gain access to supply even with efforts by the COVID-19 Vaccines Global Access Facility (COVAX Facility) to facilitate equitable global distribution.1 The focus on self-recovery has overshadowed the need for global immunization to overcome this pandemic.

Despite the admitted early failures in the response to SARS-CoV-2, retrospective reports applaud the unprecedented speed at which COVID-19 vaccines were developed and deployed—speed to clinic had never been more important. The Moderna vaccine (mRNA-1273) went from sequence selection to preclinical evaluation in 63 days and was in commercial production in just 10 months.2 By comparison, the development of the mumps vaccine, which previously held the fastest record, took four years from the initial isolation of the virus to regulatory approval in 1967.2,3

Lessons learned during the development of COVID-19 vaccines underscore the need to reimagine the current paradigm of vaccine production from design to manufacturing methods, which has lagged severely behind. Reinvigorated investment in the vaccine industry to replace outdated technologies and embrace new innovations can help better prepare the world for future pandemics and democratize global access to vaccines.

The mRNA technology behind COVID-19 vaccines is poised to disrupt the status quo where speed, versatility, and flexible platform production represent significant advantages to improve global vaccine manufacturing capabilities.

Convergence of innovative technologies

Decades of mRNA research have been brought to fruition by the Moderna and BioNTech/Pfizer COVID-19 vaccines, which rely on mRNA to deliver the genetic instructions encoding the SARS-CoV-2 spike protein to cells.4 In contrast to classical vaccines, RNA technology leverages the cells’ own translational machinery to produce the viral proteins that will activate the immune system.

A critical technology that was essential to the successes of the mRNA vaccines is the lipid nanoparticle (LNP) delivery system used to get the mRNA inside cells. LNPs encapsulate and protect the mRNA to facilitate its entry into cells where it is translated and presented as a membrane-bound spike protein antigen that can elicit an immune response.

The modularity of mRNA and LNP technologies can provide the agility for rapid, iterative prototyping of vaccine variants without the need for process modification or revalidation since common manufacturing processes can be leveraged.5 The disease-agnostic platform can be easily adapted to produce a wide range of RNA-based treatments that can expand the scope of the technology beyond infectious diseases to broader disease targets, which could make alternate manufacturing models more economically feasible.

As RNA-LNP technology continues to mature, better mRNA constructs and modifications to the LNP carrier system to improve stability, increase in vivo efficacy, and reduce dosing requirements will undoubtedly benefit next-generation RNA-based vaccines and provide efficiencies that will allow for more flexible manufacturing designs.

The success of mRNA vaccines has driven an acceleration of other RNA-enabled treatments that will only exacerbate the already strained capacity to produce the COVID-19 vaccines; therefore, new solutions to address bottlenecks in development and manufacturing are needed. A manufacturing technology that scales easily and practically from the bench to commercial manufacturing is a critical issue in translating RNA medicines.

Next-generation microfluidic mixing devices that easily integrate into existing workflows and rapidly scale across all stages of development and manufacturing are improving vaccine time to market, formulation robustness, and repeatability. Innovative technologies like these are helping address uncertainties related to both the development and operation of large-scale production processes as RNA-LNP technology becomes more widespread and readily adopted.

NanoAssemblr
Precision NanoSystems has developed a microfluidic-based continuous flow manufacturing platform for the development and manufacture of nanoparticle drug delivery systems. The platform, called NanoAssemblr, includes Blaze (shown here), a system that allows nanoparticle formulations to be scaled rapidly in late preclinical development.

Decentralized and integrated manufacturing pave the way forward

Centralized, single-product, single-facility manufacturing, while providing economies of scale for classical and current COVID-19 mRNA vaccine production, is inherently inflexible and difficult to pivot quickly in pandemic responses.6 This model presents single points of failure in the supply chain that are vulnerable to materials and personnel shortages, export bottlenecks, and complex cold chain logistics, which impact production and distribution, resulting in incomplete geographical coverage.

Techno-economic assessments suggest that the facility footprint required to produce RNA vaccines could be two to three orders of magnitude smaller than conventional vaccine production processes with 1/20th to 1/35th the upfront capital investment.5 This could make a geographically distributed, decentralized manufacturing model more feasible. Moreover, integrated manufacturing designs where RNA drug substance production, LNP formulation, analytical testing, and fill/finish operations are localized in a single facility aligns with the desire of many countries to establish their own domestic vaccine manufacturing capabilities.

In the face of current COVID-19 vaccine shortages, localized manufacturing can support national vaccine requirements as well as offer the capability to handle emerging regional variants.

Additionally, the modular, disease-agnostic nature of RNA-LNP means integrated manufacturing facilities could be used to produce a number of RNA therapeutics where shared resources (such as equipment and personnel) and costs could make decentralized facilities more economical. The availability of modularized GMP production suites and advancements in bioproduction technologies like microfluidics, digital or “4.0” automated bioprocess capabilities, and inclusion of single-use equipment, constitute key components to build out such manufacturing designs. As well, once production processes are established and validated, the technology could be adopted by other facilities to form a network of manufacturing sites with harmonized processes to grow the global vaccine production capabilities.5

A report by the World Economic Forum lists the establishment of a consortium of biofoundries to foster accelerated development and large-scale vaccine production as a critical element to combating pandemics.7 The concept of foundries has revolutionized manufacturing in other industrial sectors (such as the semiconductor sector) and is a logical path forward for RNA vaccine production. Support for this is evidenced by initiatives such as R3 (a $60 million project jointly funded by CEPI and Wellcome Leap), which aims to establish a global network of biofoundries to democratize access to state-of-the-art manufacturing centers that will accelerate the pace and diversity of RNA biologics.8 This could open up a new era of biomanufacturing with the agility to pivot rapidly for the emergency capacity needed for rapid pandemic responses.

Of course, continued collaboration and communication among all stakeholders from researchers, developers, manufacturers, and regulatory agencies will be paramount to support these endeavors. It is clear that investment in these innovations is needed to ensure preparedness in the event of future outbreaks and pandemics.

Precision NanoSystems is leveraging years of experience in LNP formulation, vaccine manufacturing platform development, and industry know-how to usher in the new frontier of vaccine production. Through the company’s active involvement in the novel COVID-19 mRNA vaccines, this specialized knowledge and expertise, paired with highly scalable instrument platforms and LNP reagents, can be leveraged by researchers, developers, and manufacturers alike.

 

Learn more about Precision NanoSystems at www.precisionnanosystems.com.

 

References

  1. The Independent Panel for Pandemic Preparedness and Response. COVID-19: Make It the Last Pandemic. Published: May 12, 2021. Accessed: November 5, 2021.
  2. Bloom DE, Cadarette D, Ferranna M, Hyer RN, Tortorice DL. How New Models Of Vaccine Development For COVID-19 Have Helped Address An Epic Public Health Crisis. Health Aff. (Millwood). 2021; 40(3): 410–418. DOI: 10.1377/hlthaff.2020.02012.
  3. Ball P. The lightning-fast quest for COVID vaccines—and what it means for other diseases. Nature 2021; 589(7840): 16–18. DOI: 10.1038/d41586-020-03626-1.
  4. Dolgin E. The tangled history of mRNA vaccines. Nature 2021; 597(7876): 318–324. DOI: 10.1038/d41586-021-02483-w.
  5. Kis Z, Kontoravdi C, Dey AK, Shattock R, Shah N. Rapid development and deployment of high-volume vaccines for pandemic response. J. Adv. Manuf. Process. 2020; 2(3): e10060. DOI: 10.1002/amp2.10060.
  6. Sell TK, Gastfriend D, Watson M, et al. Building the global vaccine manufacturing capacity needed to respond to pandemics. Vaccine 2021; 39(12): 1667-1669. DOI: 10.1016/j.vaccine.2021.02.017.
  7. Freemont P, Curach N, Friedman D, Lee SY. These ‘biofoundries’ use DNA to make natural products we need. World Economic Forum. Published October 28, 2019. Accessed: October 20, 2021.
  8. R3: RNA Readiness & Response Program. Wellcome Leap. Published July 14, 2020. Accessed November 5, 2021.