【AI Explained】Addressing the Cold Reality of mRNA Vaccine Stability.

Literature Information

TL;DR

This commentary highlights the challenges of formulation and stability of mRNA vaccines, particularly in the context of the COVID-19 pandemic, and emphasizes the need for systematic approaches to identify degradation mechanisms and improve storage conditions. The findings suggest that enhancing the stability of mRNA vaccines is crucial for their effective deployment and adaptability in future infectious disease outbreaks, urging proactive measures rather than reactive solutions.

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COVID-19 · Cold chain · Formulation · Lipid nanoparticles · Shelf life

Abstract

As mRNA vaccines became the frontrunners in late-stage clinical trials to fight the COVID-19 pandemic, challenges surrounding their formulation and stability became readily apparent. In this commentary, we first describe company proposals, based on available public information, for the (frozen) storage of mRNA vaccine drug products across the vaccine supply chain. We then review the literature on the pharmaceutical stability of mRNA vaccine candidates, including attempts to improve their stability, analytical techniques to monitor their stability, and regulatory guidelines covering product characterization and storage stability. We conclude that systematic approaches to identify the key physicochemical degradation mechanism(s) of formulated mRNA vaccine candidates are currently lacking. Rational design of optimally stabilized mRNA vaccine formulations during storage, transport, and administration at refrigerated or ambient temperatures should thus have top priority in the pharmaceutical development community. In addition to evidence of human immunogenicity against multiple viral pathogens, including compelling efficacy results against COVID-19, another key strength of the mRNA vaccine approach is that it is readily adaptable to rapidly address future outbreaks of new emerging infectious diseases. Consequently, we should not wait for the next pandemic to address and solve the challenges associated with the stability and storage of formulated mRNA vaccines.

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Primary Questions Addressed

1. What specific physicochemical degradation mechanisms have been identified in mRNA vaccine formulations?
2. How do different storage temperatures impact the stability of mRNA vaccines during transportation?
3. What analytical techniques are most effective for monitoring the stability of mRNA vaccines in real-time?
4. How can the formulation of mRNA vaccines be optimized to enhance their stability at ambient temperatures?
5. What regulatory guidelines exist for the characterization and stability testing of mRNA vaccine products?

Key Findings

Research Summary: Addressing the Cold Reality of mRNA Vaccine Stability

Background and Objective

The emergence of mRNA vaccines as a leading strategy to combat the COVID-19 pandemic has highlighted significant challenges related to their formulation and stability. This commentary aims to discuss current storage proposals for mRNA vaccines, review existing literature on their stability, and identify critical gaps in knowledge and practice concerning the stability of these vaccines.

Main Methods/Materials/Experimental Design

The authors conducted a thorough review of publicly available information regarding mRNA vaccine storage conditions, focusing on data from major manufacturers such as Moderna, Pfizer-BioNTech, and CureVac. They also analyzed the existing literature on the stability of mRNA vaccines, including efforts to enhance stability, analytical techniques for monitoring, and relevant regulatory guidelines.

Key Results and Findings

1. Storage Proposals: Current recommendations for the storage of mRNA vaccines include:

   • Moderna: Frozen at -80°C to -60°C for up to 6 months.
   • Pfizer-BioNTech: Frozen at -80°C to -60°C for up to 6 months, with stability at 2-8°C for up to 5 days.
   • CureVac: -60°C for at least 3 months, with room temperature stability for up to 24 hours.

2. Stability Literature: The literature reveals a lack of comprehensive studies specifically addressing the stability of formulated mRNA vaccines. Existing research primarily focuses on stabilizing the mRNA molecule itself rather than the complete drug product.

3. Regulatory Guidelines: The FDA and EMA have established guidelines for vaccine development, but specific criteria for mRNA vaccine stability testing remain underdeveloped. Key stability parameters include mRNA integrity, potency, and other physicochemical properties.

Main Conclusions/Significance/Innovation

The authors conclude that there is an urgent need for systematic approaches to understand the degradation mechanisms of mRNA vaccines and to develop stable formulations that can withstand varied storage conditions. They emphasize that the pharmaceutical community must prioritize rational design and formulation strategies to enhance the stability of mRNA vaccines, enabling their effective distribution and use in future pandemics.

Research Limitations and Future Directions

The commentary identifies several limitations, including:

• Insufficient data on the stability of formulated mRNA vaccines compared to the stability of naked mRNA.
• Lack of mechanistic understanding of degradation pathways.
• Limited public access to detailed quality control information regarding mRNA vaccines.

Future research should focus on:

• Developing second-generation mRNA vaccine formulations that can be stored at refrigerated or ambient temperatures.
• Conducting in-depth stability assessments to inform regulatory practices and enhance the global distribution of mRNA vaccines.

In conclusion, addressing the stability of mRNA vaccines is crucial not only for the current COVID-19 pandemic but also for preparing for future infectious disease outbreaks.

References

1. 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)
2. Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines. - Kimberly J Hassett;Kerry E Benenato;Eric Jacquinet;Aisha Lee;Angela Woods;Olga Yuzhakov;Sunny Himansu;Jessica Deterling;Benjamin M Geilich;Tatiana Ketova;Cosmin Mihai;Andy Lynn;Iain McFadyen;Melissa J Moore;Joseph J Senn;Matthew G Stanton;Örn Almarsson;Giuseppe Ciaramella;Luis A Brito - Molecular therapy. Nucleic acids (2019)
3. Long-term storage of DNA-free RNA for use in vaccine studies. - Kathryn L Jones;Debbie Drane;Eric J Gowans - BioTechniques (2007)
4. A thermostable messenger RNA based vaccine against rabies. - Lothar Stitz;Annette Vogel;Margit Schnee;Daniel Voss;Susanne Rauch;Thorsten Mutzke;Thomas Ketterer;Thomas Kramps;Benjamin Petsch - PLoS neglected tropical diseases (2017)
5. mRNA vaccines - a new era in vaccinology. - Norbert Pardi;Michael J Hogan;Frederick W Porter;Drew Weissman - Nature reviews. Drug discovery (2018)
6. Chemical stability of nucleic acid-derived drugs. - D Pogocki;C Schöneich - Journal of pharmaceutical sciences (2000)
7. The effect of secondary structure on cleavage of the phosphodiester bonds of RNA. - S Mikkola;U Kaukinen;H Lönnberg - Cell biochemistry and biophysics (2001)
8. Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery. - Piotr S Kowalski;Arnab Rudra;Lei Miao;Daniel G Anderson - Molecular therapy : the journal of the American Society of Gene Therapy (2019)
9. Considerations for Producing mRNA Vaccines for Clinical Trials. - Andreas Schmid - Methods in molecular biology (Clifton, N.J.) (2017)
10. The European Regulatory Environment of RNA-Based Vaccines. - Thomas Hinz;Kajo Kallen;Cedrik M Britten;Bruno Flamion;Ulrich Granzer;Axel Hoos;Christoph Huber;Samir Khleif;Sebastian Kreiter;Hans-Georg Rammensee;Ugur Sahin;Harpreet Singh-Jasuja;Özlem Türeci;Ulrich Kalinke - Methods in molecular biology (Clifton, N.J.) (2017)

Literatures Citing This Work

1. Sterilizing Immunity against SARS-CoV-2 Infection in Mice by a Single-Shot and Lipid Amphiphile Imidazoquinoline TLR7/8 Agonist-Adjuvanted Recombinant Spike Protein Vaccine*. - Sonia Jangra;Jana De Vrieze;Angela Choi;Raveen Rathnasinghe;Gabriel Laghlali;Annemiek Uvyn;Simon Van Herck;Lutz Nuhn;Kim Deswarte;Zifu Zhong;Niek N Sanders;Stefan Lienenklaus;Sunil A David;Shirin Strohmeier;Fatima Amanat;Florian Krammer;Hamida Hammad;Bart N Lambrecht;Lynda Coughlan;Adolfo García-Sastre;Bruno G De Geest;Michael Schotsaert - Angewandte Chemie (International ed. in English) (2021)
2. Response to: Regarding the Article: Coronavirus Disease (COVID-19): Current Status and Prospects for Drug and Vaccine Development. - Kevin Ita - Archives of medical research (2021)
3. mRNA vaccine for cancer immunotherapy. - Lei Miao;Yu Zhang;Leaf Huang - Molecular cancer (2021)
4. International Collaboration to Ensure Equitable Access to Vaccines for COVID-19: The ACT-Accelerator and the COVAX Facility. - Mark Eccleston-Turner;Harry Upton - The Milbank quarterly (2021)
5. Development of thermostable vaccine adjuvants. - Yizhi Qi;Christopher B Fox - Expert review of vaccines (2021)
6. Tamper-Proof Time-Temperature Indicator for Inspecting Ultracold Supply Chain. - Lam Tan Hao;Minkyung Lee;Hyeonyeol Jeon;Jun Mo Koo;Sung Yeon Hwang;Dongyeop X Oh;Jeyoung Park - ACS omega (2021)
7. Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics. - Kathrin Leppek;Gun Woo Byeon;Wipapat Kladwang;Hannah K Wayment-Steele;Craig H Kerr;Adele F Xu;Do Soon Kim;Ved V Topkar;Christian Choe;Daphna Rothschild;Gerald C Tiu;Roger Wellington-Oguri;Kotaro Fujii;Eesha Sharma;Andrew M Watkins;John J Nicol;Jonathan Romano;Bojan Tunguz;Eterna Participants;Maria Barna;Rhiju Das - bioRxiv : the preprint server for biology (2021)
8. mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability. - Linde Schoenmaker;Dominik Witzigmann;Jayesh A Kulkarni;Rein Verbeke;Gideon Kersten;Wim Jiskoot;Daan J A Crommelin - International journal of pharmaceutics (2021)
9. Perspectives on RNA Vaccine Candidates for COVID-19. - Pobitra Borah;Pran Kishore Deb;Nizar A Al-Shar’i;Lina A Dahabiyeh;Katharigatta N Venugopala;Vinayak Singh;Pottathil Shinu;Snawar Hussain;Satyendra Deka;Balakumar Chandrasekaran;Da’san M M Jaradat - Frontiers in molecular biosciences (2021)
10. mRNA vaccines for COVID-19: what, why and how. - Jung Woo Park;Philip N P Lagniton;Yu Liu;Ren-He Xu - International journal of biological sciences (2021)

… (220 more literatures)

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