Changing the status quo of vaccine production

When the rapid spread of SARS-CoV-2 suddenly led to a global pandemic, devastating effects on health, education, and economies followed all over the world. The pandemic also enhanced existing regional disparities in wealth and resources. Higher-income countries have, in some cases, over 200% immunization coverage while, developing countries have struggled to gain access to vaccine supply ― even with the COVID-19 Vaccines Global Access Facility (COVAX Facility) working to facilitate equitable global distribution [1]. The focus on self-recovery has overshadowed the role of global immunization in overcoming this health crisis.

Despite early failures in the response to SARS-CoV-2, retrospective reports applaud the unprecedented speed at which COVID-19 vaccines were developed and deployed ― a critical element in getting the spread of the virus under control. 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. Investment in the vaccine industry has been reinvigorated, with aims to replace outdated technologies and embrace new innovations to better prepare for future pandemics and democratize global access to vaccines.

The mRNA technology behind some of the COVID-19 vaccines is poised to disrupt the status quo where speed, versatility, and flexible platform production represent significant advantages over traditional vaccine methods in improving global manufacturing capabilities.

Convergence of innovative technologies

Decades of mRNA research have been brought to fruition by the development of COVID-19 vaccines that rely on mRNA to deliver genetic instructions encoding the SARS-CoV-2 spike protein to cells [4]. In contrast to traditional vaccines, RNA technology leverages the cells' own translational machinery to produce viral proteins that activate the immune system.

A technology that was essential to the mRNA vaccines' success was their lipid nanoparticle (LNP) delivery system. These carriers encapsulate and protect the mRNA to facilitate its entry into cells, where it’s translated and presented as a membrane-bound spike protein antigen that can elicit an immune response.

The modularity of mRNA and LNP technology production can provide agility for rapid, iterative prototyping of vaccine variants without the need for process modification or re-validation since common manufacturing processes can be leveraged [5]. This disease-agnostic platform can be easily adapted to produce a wide range of RNA-based treatments, expanding the scope of the technology beyond infectious diseases to broader disease targets and making 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, increase in vivo efficacy, and reduce dosing requirements will benefit next-generation RNA-based vaccines and provide efficiencies allowing for more flexible manufacturing designs.

The success of mRNA vaccines has driven an acceleration of other RNA-enabled treatments that will only put further strains on existing capacity limitations; 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 critical to successfully 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 vaccine production ― is inherently inflexible, making it difficult to pivot quickly in response to a pandemic [6]. This model also presents single points of failure in the supply chain that are vulnerable to material and personnel shortages, export bottlenecks, and complex cold chain logistics, all of which impact production and distribution and can result 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 one-twentieth to one-thirty-fifths of 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 align with the desire of many countries to establish their own domestic vaccine manufacturing. In the face of vaccine shortages, localized manufacturing can support national vaccine requirements as well as offer the capability to handle emerging regional virus variants.

Additionally, the modular, disease-agnostic nature of RNA-LNP production means integrated manufacturing facilities could be used to produce a range of RNA therapeutics, with shared resources (i.e., equipment, personnel) making the decentralized model more economical. Modularized GMP production suites and advancements in bioproduction technologies ― like microfluidics, digital or “4.0” automated bioprocess capabilities, and the inclusion of single-use equipment ― comprise key components for such manufacturing designs. And, once processes are established and validated, the technology can be adopted by other facilities to form a network of manufacturing sites with harmonized workflows to grow global vaccine production capabilities [5].

A report by the World Economic Forum lists the establishment of a consortium of bio-foundries to foster accelerated development and large-scale vaccine production as a critical element in combating pandemics [7]. 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 shift is evidenced by initiatives such as R3 ― a $60 million project jointly funded by The Coalition for Epidemic Preparedness Innovations (CEPI) and Wellcome Leap ― which aims to establish a global network of bio foundries to democratize access to state-of-the-art manufacturing centers that will accelerate the pace and diversity of RNA biologics [8].

These efforts could open up a new era of biomanufacturing with the ability to pivot quickly and create the capacity needed to respond rapidly to emergent situations, such as pandemics. Of course, continued collaboration and communication among all stakeholders from researchers, developers, manufacturers, and regulatory agencies will be paramount to support these endeavors. It’s clear that investment in these innovations is needed to ensure preparedness in the event of future outbreaks and pandemics.