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Curated Papers > High-impact authoritative literature on "mRNA vaccines"

mRNA vaccines manufacturing: Challenges and bottlenecks. ​

Literature Information ​

DOI10.1016/j.vaccine.2021.03.038
PMID33771389
JournalVaccine
Impact Factor3.5
JCR QuartileQ2
Publication Year2021
Times Cited205
KeywordsVaccination, mRNA applications, mRNA manufacturing, mRNA vaccines
Literature TypeJournal Article, Research Support, Non-U.S. Gov't, Review
ISSN0264-410X
Pages2190-2200
Issue39(16)
AuthorsSara Sousa Rosa, Duarte M F Prazeres, Ana M Azevedo, Marco P C Marques

TL;DR ​

This review highlights the growing significance of mRNA vaccines in public health, particularly as a response to infectious diseases like Covid-19, and emphasizes their potential for treating various conditions, including cancer and genetic disorders. It addresses the challenges in their large-scale manufacturing processes, advocating for improved technology platforms and cost-effective methods to enhance their effectiveness and accessibility during health crises.

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Vaccination · mRNA applications · mRNA manufacturing · mRNA vaccines

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.

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Primary Questions Addressed ​

  1. What are the specific technological challenges faced in the large-scale production of mRNA vaccines?
  2. How do the manufacturing bottlenecks of mRNA vaccines compare to those of traditional vaccine production methods?
  3. What innovations in purification techniques could potentially streamline the manufacturing process of mRNA vaccines?
  4. How can the cost-effectiveness of mRNA vaccine production be improved while maintaining product quality?
  5. What role do regulatory frameworks play in the development and manufacturing of mRNA vaccines, particularly in addressing challenges?

Key Findings ​

Research Background and Objectives ​

Vaccines are critical tools in public health for preventing infectious diseases. Traditional vaccines have limitations, prompting the exploration of novel approaches. mRNA vaccines emerged as a promising alternative, particularly highlighted during the COVID-19 pandemic. This review aims to address the challenges and bottlenecks in the manufacturing of mRNA vaccines, focusing on the necessary advancements to facilitate rapid and cost-effective production.

Main Methods/Materials/Experimental Design ​

The review details the manufacturing process of mRNA vaccines, which consists of upstream processing (mRNA synthesis) and downstream processing (purification). The manufacturing steps can be visualized in the following flowchart:

Mermaid diagram

Key Results and Findings ​

  • mRNA vaccines are characterized by their ability to induce both humoral and cellular immune responses with a safety profile that minimizes risks associated with traditional vaccines.
  • The manufacturing process involves a one or two-step IVT followed by multiple purification techniques, including DNase digestion, chromatography, and filtration.
  • Challenges identified include high production costs, scalability issues, and the need for stringent quality control measures.

Main Conclusions/Significance/Innovation ​

The review concludes that mRNA vaccines represent a significant advancement in vaccine technology, offering flexibility, safety, and rapid production capabilities. However, for mRNA vaccines to be a reliable response to emerging health crises, improvements in manufacturing processes are essential. This includes the development of continuous manufacturing techniques to reduce costs and enhance efficiency.

Research Limitations and Future Directions ​

While mRNA technology has shown promise, several limitations remain:

  • The dependency on expensive raw materials and complex purification processes.
  • Current manufacturing methods are not fully scalable for large-scale production.

Future directions should focus on:

  • Implementing continuous processing to enhance production efficiency.
  • Exploring alternative purification techniques that are cost-effective and scalable.
  • Developing regulatory frameworks for quality assurance in mRNA vaccine production.

This comprehensive understanding of mRNA vaccine manufacturing can facilitate the development of more effective responses to public health emergencies.

References ​

  1. Process mapping of vaccines: Understanding the limitations in current response to emerging epidemic threats. - Georgina Drury;Siobhan Jolliffe;Tarit K Mukhopadhyay - Vaccine (2019)
  2. History of vaccination. - Stanley Plotkin - Proceedings of the National Academy of Sciences of the United States of America (2014)
  3. Induction of HIV-1 gag specific immune responses by cationic micelles mediated delivery of gag mRNA. - Mengnan Zhao;Man Li;Zhirong Zhang;Tao Gong;Xun Sun - Drug delivery (2016)
  4. A guide to large-scale RNA sample preparation. - Lorenzo Baronti;Hampus Karlsson;Maja Marušič;Katja Petzold - Analytical and bioanalytical chemistry (2018)
  5. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. - D Boczkowski;S K Nair;D Snyder;E Gilboa - The Journal of experimental medicine (1996)
  6. Conscious coupling: The challenges and opportunities of cascading enzymatic microreactors. - Pia Gruber;Marco P C Marques;Brian O'Sullivan;Frank Baganz;Roland Wohlgemuth;Nicolas Szita - Biotechnology journal (2017)
  7. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. - Ugur Sahin;Petra Oehm;Evelyna Derhovanessian;Robert A Jabulowsky;Mathias Vormehr;Maike Gold;Daniel Maurus;Doreen Schwarck-Kokarakis;Andreas N Kuhn;Tana Omokoko;Lena M Kranz;Mustafa Diken;Sebastian Kreiter;Heinrich Haas;Sebastian Attig;Richard Rae;Katarina Cuk;Alexandra Kemmer-Brück;Andrea Breitkreuz;Claudia Tolliver;Janina Caspar;Juliane Quinkhardt;Lisa Hebich;Malte Stein;Alexander Hohberger;Isabel Vogler;Inga Liebig;Stephanie Renken;Julian Sikorski;Melanie Leierer;Verena Müller;Heidrun Mitzel-Rink;Matthias Miederer;Christoph Huber;Stephan Grabbe;Jochen Utikal;Andreas Pinter;Roland Kaufmann;Jessica C Hassel;Carmen Loquai;Özlem Türeci - Nature (2020)
  8. Challenges and advances towards the rational design of mRNA vaccines. - Charlotte Pollard;Stefaan De Koker;Xavier Saelens;Guido Vanham;Johan Grooten - Trends in molecular medicine (2013)
  9. Toll-like receptor 7/8-matured RNA-transduced dendritic cells as post-remission therapy in acute myeloid leukaemia: results of a phase I trial. - Felix S Lichtenegger;Frauke M Schnorfeil;Maurine Rothe;Katrin Deiser;Torben Altmann;Veit L Bücklein;Thomas Köhnke;Christian Augsberger;Nikola P Konstandin;Karsten Spiekermann;Andreas Moosmann;Stephan Boehm;Melanie Boxberg;Mirjam Hm Heemskerk;Dennis Goerlich;Georg Wittmann;Beate Wagner;Wolfgang Hiddemann;Dolores J Schendel;Gunnar Kvalheim;Iris Bigalke;Marion Subklewe - Clinical & translational immunology (2020)
  10. A novel, disruptive vaccination technology: self-adjuvanted RNActive(®) vaccines. - Karl-Josef Kallen;Regina Heidenreich;Margit Schnee;Benjamin Petsch;Thomas Schlake;Andreas Thess;Patrick Baumhof;Birgit Scheel;Sven D Koch;Mariola Fotin-Mleczek - Human vaccines & immunotherapeutics (2013)

Literatures Citing This Work ​

  1. PEGylation of mRNA by Hybridization of Complementary PEG-RNA Oligonucleotides Stabilizes mRNA without Using Cationic Materials. - Naoto Yoshinaga;Mitsuru Naito;Yoshihiro Tachihara;Eger Boonstra;Kensuke Osada;Horacio Cabral;Satoshi Uchida - Pharmaceutics (2021)
  2. Emerging antibody-based products for infectious diseases: Planning for metric ton manufacturing. - Kevin J Whaley;Larry Zeitlin - Human vaccines & immunotherapeutics (2022)
  3. Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action. - Franz X Heinz;Karin Stiasny - NPJ vaccines (2021)
  4. Therapeutic cancer vaccines revamping: technology advancements and pitfalls. - G Antonarelli;C Corti;P Tarantino;L Ascione;J Cortes;P Romero;E A Mittendorf;M L Disis;G Curigliano - Annals of oncology : official journal of the European Society for Medical Oncology (2021)
  5. The use of nanobodies in a sensitive ELISA test for SARS-CoV-2 Spike 1 protein. - Georgina C Girt;Abirami Lakshminarayanan;Jiandong Huo;Joshua Dormon;Chelsea Norman;Babak Afrough;Adam Harding;William James;Raymond J Owens;James H Naismith - Royal Society open science (2021)
  6. Nano-carriers of COVID-19 vaccines: the main pillars of efficacy. - Carolina Constantin;Anissa Pisani;Giuseppe Bardi;Monica Neagu - Nanomedicine (London, England) (2021)
  7. The nano delivery systems and applications of mRNA. - Mingyuan Li;Yuan Li;Shiqin Li;Lin Jia;Haomeng Wang;Meng Li;Jie Deng;Ali Zhu;Liqiao Ma;Weihong Li;Peng Yu;Tao Zhu - European journal of medicinal chemistry (2022)
  8. A Single Dose of a Hybrid hAdV5-Based Anti-COVID-19 Vaccine Induces a Long-Lasting Immune Response and Broad Coverage against VOC. - M Verónica López;Sabrina E Vinzón;Eduardo G A Cafferata;Felipe J Núñez;Ariadna Soto;Maximiliano Sanchez-Lamas;M Jimena Afonso;Diana Aguilar-Cortes;Gregorio D Ríos;Juliana T Maricato;Carla T Braconi;Vanessa B Silveira;Tatiane M Andrad;Tatiana C S Bonetti;Luiz M Ramos Janini;Manoel J B C Girão;Andrea S Llera;Karina A Gomez;Hugo H Ortega;Paula M Berguer;Osvaldo L Podhajcer - Vaccines (2021)
  9. Development of a microchip capillary electrophoresis method for determination of the purity and integrity of mRNA in lipid nanoparticle vaccines. - Jessica Raffaele;John W Loughney;Richard R Rustandi - Electrophoresis (2022)
  10. Structural Biology of Nanobodies against the Spike Protein of SARS-CoV-2. - Qilong Tang;Raymond J Owens;James H Naismith - Viruses (2021)

... (195 more literatures)

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