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 in human history has yet to be fully realized as many countries are still battling rising infection rates, 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 distribution1. 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 months2. 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 19672,3.  

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 Reinvigorated investment in the vaccine industry to replace outdated technologies and embrace new innovations can help better prepare the world for future pandemics and democratize global access to vaccines.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 has 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 cells4. 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 re-validation since common manufacturing processes can be leveraged5. 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 improvements to the LNP carrier system to improve stability, 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. 

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, are inherently inflexible and difficult to pivot quickly in pandemic responses6. 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 impacts 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 1/20 to 1/35 of the upfront capital investment5. 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. In the face of current COVID-19 vaccine shortages, localized manufacturing can support national vaccine requirements as well as offering 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 (i.e., equipment, personnel) and cost 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, comprise 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 capabilities5.  

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 pandemics7. The concept of foundries has revolutionized manufacturing in other industrial sectors (i.e., semiconductor foundries) and is a logical path forward for RNA vaccine production. Support for this is evidenced by initiatives such as R3 ($60M 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 biologics8. 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’ years of experience in LNP formulation, vaccine manufacturing platform development and industry know-how is ushering in the new frontier of vaccine production. Through their 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 https://www.precisionnanosystems.com/  

References