Addressing the Cold Reality of mRNA Vaccine Stability
Open accessAbstract
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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mRNA instability is a major obstacle in storage and distribution of the vaccine, requiring cold-chain technologies that hinder use in developing countries.
“This instability has also become a major obstacle in the storage and distribution of the vaccine, requiring the use of cold-chain technologies that hinders its use in developing countries4.”
From Algorithm for optimized mRNA design improves stability and immunogenicity (2023) · cites this paper as [4]
The Introduction says frozen storage and transport pose a challenge when vaccines must be distributed worldwide. The Concluding Considerations call for more stable formulations to enable shipping and storage at refrigerated or ambient temperatures. These passages support the storage and distribution obstacle, but do not specifically say that cold-chain requirements hinder vaccine use in developing countries. (LLM, conf=0.84)
Experimental — accuracy not yet measuredmRNA vaccines still suffer from decreased efficacy due to poor RNA stability in solution and in vivo and to limited expression of the payload mRNA.
“mRNA vaccines still suffer from decreased efficacy due to poor RNA stability in solution and in vivo and to limited expression of the payload mRNA; these are all pivotal issues that need to be carefully optimized for preclinical and clinical applications3–6.”
From Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics (2022) · cites this paper as [6]
The Historical Perspective section (page unavailable) says mRNA degradation can reduce vaccine potency by slowing translation and limiting antigen expression; it also discusses degradation in solution. The Concluding Considerations section (page unavailable) links in vivo delivery and antigen production to immunogenicity, but our copy does not establish poor RNA stability in vivo as a cause of decreased vaccine efficacy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredRNA is inherently unstable due to its 2'-hydroxyl group, and degradation of the mRNA in solution by in-line nucleophilic attack, potentially aggravated by formulations, poses a major challenge.
“In particular, RNA is inherently unstable due its 2’-hydroxyl group, and degradation of the mRNA in solution by in-line nucleophilic attack, potentially aggravated by formulations, poses a major challenge6.”
From Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics (2022) · cites this paper as [6]
The Historical Perspective section (page not provided) describes mRNA degradation in solution, including phosphodiester-bond hydrolysis, and says cationic lipid formulations may increase cleavage rates. The Concluding Considerations section treats stability as a major formulation challenge. Our copy does not identify the 2′-hydroxyl group or in-line nucleophilic attack as the mechanism, so those specific parts are not supported. (LLM, conf=0.86)
Experimental — accuracy not yet measuredmRNA vaccines must be stored and carried at extremely low temperatures compared to protein-based vaccinations that can be stored and transported at lower temperatures.
“mRNA vaccines must be stored and carried at extremely low temperatures as compared to protein-based vaccinations that can be stored and transported at lower temperatures (Crommelin et al. 2020).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Crommelin et al. 2020
The Introduction describes mRNA vaccine candidates kept at −80 °C and the difficulty of transporting them under those conditions. The storage-conditions table lists frozen storage for three COVID-19 mRNA candidates, but also limited periods at 2–8 °C; the claim's unqualified “must” is too broad. Our copy does not provide the asserted comparison with protein-based vaccines. (LLM, conf=0.87)
Experimental — accuracy not yet measuredmRNA vaccines exhibit critical limitations caused by mRNA instability and degradation.
“Messenger RNA (mRNA) vaccines are being used to combat the spread of COVID-19 (refs. 1–3), but they still exhibit critical limitations caused by mRNA instability and degradation”
From Algorithm for optimized mRNA design improves stability and immunogenicity (2023) · cites this paper as [4]
mRNA instability and degradation are major obstacles for the storage, distribution and efficacy of mRNA vaccine products.
“which are major obstacles for the storage, distribution and efficacy of the vaccine products4”
From Algorithm for optimized mRNA design improves stability and immunogenicity (2023) · cites this paper as [4]
Much less attention has been paid to the stability of mRNA-LNP vaccines during storage than to their in vivo stability and efficacy.
“Although progress has been made to enhance the stability in vivo and efficacy of mRNA-LNP vaccines, much less attention has been paid to their stability during storage (Crommelin et al., 2021).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Crommelin et al., 2021
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- Authors
- Crommelin, D. J. A., Anchordoquy, T. J., Volkin, D. B., Jiskoot, W., & Mastrobattista, E.
- Affiliations
- Utrecht University (NL)
- University of Colorado Anschutz (US)
- University of Kansas (US)
- Leiden University (NL)
- Corresponding author
- Crommelin, Daan J.A.
- Mastrobattista, Enrico
- Venue
- Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 110
- Issue
- 3
- Pages
- 997-1001
- ISSN
- 0022-3549 (ISSN-L)
- PMC
- PMC7834447
- OpenAlex
- W3110973116
- Semantic Scholar
- c98a0b512285a4204ecbb2300188d059b291f6c5
- Cited by
- 517
- References
- 22
- Citations by year
- 2026: 65 · 2025: 74 · 2024: 79 · 2023: 111 · 2022: 119 · 2021: 67 · 2020: 1
- FWCI
- 9.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Pharmaceutical Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Keywords
- mRNA vaccines, vaccine stability, cold chain storage, frozen storage, COVID-19 vaccines, vaccine formulation, stability monitoring, regulatory guidelines, vaccine supply chain, cold storage
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, BNT162 Vaccine, 2019-nCoV Vaccine mRNA-1273, Cold Temperature, Drug Stability, Drug Storage, Humans, RNA, Messenger, Vaccines, Synthetic, RNA Stability, Vaccine Potency
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