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Review
. 2021 Apr 15;39(16):2190-2200.
doi: 10.1016/j.vaccine.2021.03.038. Epub 2021 Mar 24.

mRNA vaccines manufacturing: Challenges and bottlenecks

Sara Sousa Rosa  1 , Duarte M F Prazeres  1 , Ana M Azevedo  2 , Marco P C Marques  3
Affiliations
Review

mRNA vaccines manufacturing: Challenges and bottlenecks

Sara Sousa Rosa et al. Vaccine. .

Abstract

Vaccines are one of the most important tools in public health and play an important role in infectious diseases control. Owing to its precision, safe profile and flexible manufacturing, mRNA vaccines are reaching the stoplight as a new alternative to conventional vaccines. In fact, mRNA vaccines were the technology of choice for many companies to combat the Covid-19 pandemic, and it was the first technology to be approved in both United States and in Europe Union as a prophylactic treatment. Additionally, mRNA vaccines are being studied in the clinic to treat a number of diseases including cancer, HIV, influenza and even genetic disorders. The increased demand for mRNA vaccines requires a technology platform and cost-effective manufacturing process with a well-defined product characterisation. Large scale production of mRNA vaccines consists in a 1 or 2-step in vitro reaction followed by a purification platform with multiple steps that can include Dnase digestion, precipitation, chromatography or tangential flow filtration. In this review we describe the current state-of-art of mRNA vaccines, focusing on the challenges and bottlenecks of manufacturing that need to be addressed to turn this new vaccination technology into an effective, fast and cost-effective response to emerging health crises.

Keywords: Vaccination; mRNA applications; mRNA manufacturing; mRNA vaccines.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All authors attest they meet the ICMJE criteria for authorship.

Figures

Fig. 1
Fig. 1
Vaccination targets and milestones adapted from , .
Fig. 2
Fig. 2
Breakdown of mRNA vaccines clinical trials filed per year according to disease type (left) and delivery system (right).
Fig. 3
Fig. 3
Distribution of clinical trials from https://clinicaltrials.gov/ and http://www.isrctn.com/ using mRNA vaccines per condition and phase (A), types of cancer (B), other disease types, and (D) infectious diseases.
Fig. 4
Fig. 4
Schematic representation of the production and purification steps of a mRNA vaccines manufacturing process. mRNA production can be performed in a one-step enzymatic reaction, where a capping analog is used, or in a two-step reaction, where the capping is performed using vaccinia capping enzyme. mRNA purification process at lab scale consists of Dnase I digestion followed by LiCl precipitation. Purification at a larger scale is obtained using well-established chromatographic strategies coupled with tangential flow filtration. Alternatively, new types of chromatography can be used to complement the standard purification.
Fig. 5
Fig. 5
Conceptual design of a continuous manufacturing process for the production of mRNA vaccines. The process is composed of a 2-step enzymatic reaction in continuous form, followed by enzyme recycling using tangential flow filtration strategies and two multimodal chromatography steps, one in bind-elute mode for the intermediate purification, and a second in flowthrough mode for polishing. Formulation is achieved using a third tangential flow filtration module.
See this image and copyright information in PMC

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