Understanding mRNA vaccine thermal stability

por Natalia Markova, Wednesday, 19th January 2022

mRNA vaccines are an exciting development in vaccine technology. While hundreds of scientists have worked on mRNA vaccines over decades, the success of the SARS-CoV-2 mRNA vaccine has propelled this modality from a niche industry into a run-away success. In less than two years, many billions of doses of these vaccines have been administered across 184 countries, making this the most successful vaccine campaign in history.

The importance of thermal stability in mRNA-based vaccines

Whilst mRNA-based vaccines have great potential, there are still big challenges to overcome when working with this type of vaccine. For one, these vaccines are highly temperature-sensitive.

The thermal instability of mRNA vaccines could be due to the mRNA itself and/or its delivery vector. Current evidence points to the inherent instability of mRNA molecules, which readily cleave at room temperature. When this occurs, the mRNA degrades, drastically reducing the efficacy of the vaccine. The Moderna and BioNTech/Pfizer SARS-CoV-2 vaccines are kept at -20°C or -80°C, throughout their lifecycle.

This cold storage requirement adds challenges to the supply chain and administration of a global vaccine program. Not only does it add high costs to vaccine transport and storage, it severely limits the reach and distribution of vaccines in areas that lack adequate transport and electrical infrastructure. Thermal stability is therefore of the most significant challenges to overcome with mRNA-based vaccines.

But that’s not all. As well as measuring the stability of the vaccine under different conditions, thermal stability data is also essential in monitoring key manufacturing steps like formulation and buffer exchange (helping to ensure consistency) and in comparing the quality of different production lots.

So what tools are there to address the thermal instability of mRNA-based vaccines?

Monitoring vaccine stability with differential scanning calorimetry testing

Differential Scanning Calorimetry (DSC) is a well-established technique for structural characterization and stability profiling of biomolecules and viruses in solution. It works by measuring the enthalpy (ΔH), temperature (Tm) and thermal stability of a vaccine.   

DSC testing is useful for a wide variety of applications within vaccine research, development and manufacturing. Applying DSC helps de-risk vaccine development by building a clearer picture of the vaccine’s stability profile and, together with other analytical methods, supporting the development of stability-indicating assays. When you repeat these measurements through shipping and storage, you can identify factors affecting the structural stability of the vaccine. For example, DSC can analyze the effects of different storage conditions on the higher-order structure of the lipid nanoparticles encapsulating mRNA molecules. (Read our recently published, peer-reviewed paper to learn more.)

DSC offers several advantages that make it an ideal method for testing vaccine stability. For one, it is a label-free technology that reports on the stability of samples. Label-free technologies are particularly useful because they allow you to study samples without the use of fluorescent labels and dedicated reagents. Moreover, DSC readout is non-spectroscopic, meaning it is not affected by optical artefacts like solution turbidity and background fluorescence. This adds to the reliability of DSC as a method to test the thermal stability of vaccines.

Putting ice on mRNA-based vaccine instability

mRNA-based vaccines are a real breakthrough in vaccines against infectious diseases and immunotherapies for multiple diseases. But as we’ve seen with the SARS-CoV-2 vaccine rollout, global adoption of mRNA-based vaccines requires highly orchestrated cold storage infrastructures. Assessing the heat stability of mRNA-based vaccines is therefore critical to progress their development and widespread use.

DSC is an effective method that is helping vaccine developers and manufacturers to create more stable vaccines. When applied early, it can help overcome the thermal instability challenges of mRNA-based vaccines, helping to realize their potential as vaccines that protect entire communities.

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