Stability Modelling of mRNA Vaccine Quality: History
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Zoltan Kis

The vaccine distribution chains in several low- and middle-income countries are not adequate to facilitate the rapid delivery of high volumes of thermosensitive COVID-19 mRNA vaccines at the required low and ultra-low temperatures. COVID-19 mRNA vaccines are currently distributed along with temperature monitoring devices to track and identify deviations from predefined conditions throughout the distribution chain. These temperature readings can feed into computational models to quantify mRNA vaccine critical quality attributes (CQAs) and the remaining vaccine shelf life more accurately. Here, a kinetic modelling approach is proposed to quantify the stability-related CQAs and the remaining shelf life of mRNA vaccines. The CQA and shelf-life values can be computed based on the conditions under which the vaccines have been distributed from the manufacturing facilities via the distribution network to the vaccination centres.

  • mRNA vaccines
  • LNP-mRNA
  • COVID-19
  • stability modelling
  • quality by design
  • stability related CQAs
  • supply chain

1. Introduction

The detrimental impact of pandemics, such as the COVID-19 pandemic, can be reduced by rapidly mass-vaccinating the population against the pandemic pathogen. The successful COVID-19 mRNA vaccines were developed based on the persistent groundwork laid by devoted scientists such as Dr. Katalin Karikó and many more. However, as of October 2021, COVID-19 vaccines have been administered predominantly in high- and middle-income countries, while low-income countries are left behind [1]. This difference between countries of varying income level is even more pronounced with regards to the use of mRNA vaccines [1]. The deployment of current thermolabile mRNA COVID-19 vaccines in low-income countries is hindered by the high mRNA COVID-19 vaccine selling prices. In addition, distribution challenges can also be expected due to the lack of adequate cold chain infrastructure in low-income countries.
These thermolabile COVID-19 mRNA vaccines require distribution and storage under cold and ultra-cold conditions. However, these cold and ultra-cold chains are prone to faults and failure [2,3,4,5]. Cold chain faults and failures are even more frequent and severe in low- and middle-income countries (LMICs) [5,6,7]. Moreover, vaccine cold chain equipment in LMICs is frequently exposed to harsh environmental conditions, such as extreme temperatures, high humidity and dust, in addition to occasional substandard installation, intermittent power supply, insufficient maintenance capacity and inadequate supplies of replacement/maintenance parts [5,7]. In fact, according to a joint statement from the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF) in 55 LMICs in 2014, 20% of health facilities did not have cold chain equipment, 14% had non-functional cold chain equipment, 41% had poorly performing equipment, 23% had outdated cold chain technologies, while only 2% had a functional cold chain with optimal technology [5,6]. Besides lacking the adequate infrastructure and physical equipment, cold chain failures in LMICs can also be attributed to: (1) information gaps and the lack of ability to manage flawed information, (2) inadequate training and low knowledge on cold chain management, (3) underfunding and understaffing, (4) lack of vigilance, and (5) failures in decision making, coordination and planning [3,8,9,10,11]. Taken together, these issues have led to the wastage of up to 50% of the vaccines annually [12,13,14]. It is possible that the situation has slightly improved in the past few years, however cold chain issues are likely to cause problems and delays when sending these thermolabile mRNA COVID-19 vaccines to LMICs.
Given these strict COVID-19 mRNA vaccine cold chain requirements (see Section 2 below), temperature monitoring devices are included in each vaccine shipment, such as the TagAlert Temperature Monitors which accompany Moderna’s COVID-19 mRNA vaccine [15,16,17] and the GPS-enabled thermal sensors that monitor Pfizer’s COVID-19 mRNA vaccine [18,19,20]. These devices track the temperature of the vaccines and indicate whether the temperature of the vaccines during distribution was maintained within the range specified by the vaccine manufacturer. However, these monitoring devices do not provide information about the remaining shelf-life of the vaccine in function of the temperature exposure profiles. Neither do these monitoring devices assess the status of the vaccine critical quality attributes (CQAs) which can be affected during mRNA vaccine distribution. However, the temperature reading from these monitoring devices can feed into computational degradation kinetic models. Therefore, modelling of mRNA degradation kinetics can be feasible [21,22,23,24,25] and with further investigation the impact of temperature exposure profiles on CQAs can be assessed [26,27,28]. Therefore, here solutions are conceptualised to quantify the impact of the distribution conditions, including temperature excursions, on the remaining shelf life and on the stability-related CQAs of these thermolabile mRNA vaccines. The computed values of these stability-related CQAs can be used to determine the overall stability and remaining shelf-life of mRNA vaccines.

2. mRNA Vaccine Formulations and Storage Requirements

The active ingredient or drug substance of Moderna’s and BioNTech/Pfizer’s COVID-19 vaccine is the mRNA which encodes the prefusion stabilized full-length spike glycoprotein of the Wuhan-Hu-1 isolate of SARS-CoV-2 [25,29,30]. This mRNA is single-stranded, 5’-capped and codon optimised. Importantly, the uridine nucleosides are replaced by N1-methylpseudouridine nucleosides [25,29,30]. N1-methylpseudouridine is used because Dr. Katalin Karikó and Drew Weissman has demonstrated that it reduces the level of the innate immune response and at the same time increases protein translation levels [31,32,33]. The Moderna mRNA-1273 vaccine contains 100 µg of mRNA per dose, while the BioNTech/Pfizer BNT162b2 vaccine contains 30 µg of mRNA per dose.
These mRNA molecules are encapsulated into lipid nanoparticles (LNPs) which are placed in an aqueous cryoprotectant buffer [25,29,30]. The composition of these two mRNA vaccine formulations is shown below in Table 1. The ionisable lipids SM-102 and ALC-0315, together with the PEGylated lipids ALC-0159 and PEG2000-DMG are the novel excipients. Since the BioNTech/Pfizer COVID-19 mRNA vaccine obtained emergency use authorisation, its formulation buffer has been updated from the old phosphate buffered saline (PBS) formulation to the new Tris buffer formulation [34]. The new Tris buffer formulation does not contain sodium chloride and potassium chloride, while maintaining the same target pH of 7.4 [34]. Additionally, this new Tris buffer formulation of the BioNTech/Pfizer vaccine comes in two formats to be used with or without dilution for administration at the vaccination centres [35,36]. The vaccine solutions are filled into borosilicate or aluminosilicate glass multidose vials with bromobutyl or chlorobutyl rubber stoppers and aluminium seals. The new BioNTech/Pfizer mRNA vaccine that does not require dilution contains 2.25 mL solution intended for 6 doses, with 0.3 mL per dose. On the other hand, the Moderna mRNA vaccine contains 6.3 mL for 10 doses, with 0.5 mL per dose. These vials are then placed into secondary and tertiary packaging for distribution and low or ultra-low temperatures.
Table 1. Composition of the Moderna and BioNTech/Pfizer COVID-19 mRNA vaccine [25,29,30,34,35,36].
Component Moderna COVID-19 mRNA Vaccine BioNTech/Pfizer COVID-19 mRNA Vaccine–Original PBS Formulation BioNTech/Pfizer COVID-19 mRNA Vaccine–Updated Tris Formulation
Active ingredient nucleoside-modified mRNA-1273 * nucleoside-modified BNT162b2 mRNA * nucleoside-modified BNT162b2 mRNA *
Functional, ionisable lipid SM-102 (heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate) ALC-0315 (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) ALC-0315 (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate)
Functional lipid PEG2000-DMG (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000) ALC-0159 (2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide) ALC-0159 (2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide)
Structural lipid DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) DSPC (1,2-Distearoyl-sn-glycero-3-phosphocholine) DSPC (1,2-Distearoyl-sn-glycero-3-phosphocholine)
Structural lipid Cholesterol Cholesterol Cholesterol
Cryoprotectant Sucrose Sucrose Sucrose
Buffer component Tris (Tromethamine) Phosphate-Buffered Saline (PBS) Tris (Tromethamine)
Buffer component (s) Tris-HCL (tris(hydroxymethyl)aminomethane-hydrochloride), sodium acetate, acetic acid Disodium phosphate dihydrate, Potassium dihydrogen phosphate, potassium chloride, sodium chloride Tris-HCL (tris(hydroxymethyl)aminomethane-hydrochloride)
Buffer component water for injections water for injections water for injections
pH 7.5 6.9–7.9 7.4
In order to facilitate distribution of its COVID-19 mRNA vaccine, Pfizer has designed special thermal shipping containers that utilise dry ice [18,20,37]. This original PBS formulation of this vaccine requires ultra-cold temperatures of between −90 °C and −60 °C, commonly −80 °C for shipment and longer term storage for up to 6 months, cf. Table 2 [18,20,37,38]. Alternatively, the PBS formulated BioNTech/Pfizer COVID-19 mRNA vaccine can also be transported between −25 °C and −15 °C, commonly −20 °C, and the unpunctured vials can be stored at this temperature for up to 2 weeks [18,20,37,38]. Transportation of this vaccine between 2 °C and 8 °C is also possible, however this should be completed within 12 h [18,20,37,38]. Unpunctured PBS formulated BioNTech/Pfizer COVID-19 mRNA vaccine vials can be kept at 2 °C and 8 °C for up to 1 month, however once punctured and mixed with the diluent these vials need to be used within 6 h at room temperature (8 °C to 25 °C) [18,20,37,38]. Once the vaccine is thawed it should not be frozen again and exposure to sunlight should be avoided [18,20,37,38]. The updated Tris formulation of the BioNTech/Pfizer COVID-19 mRNA vaccine has an enhanced stability profile and can be stored for 9 months at −90 °C to −60 °C, commonly at −80 °C. In addition, this updated formulation can be stored for up to 10 weeks at temperatures between 2 °C and 8 °C, commonly at 4 °C. Punctured vials containing the Tris formulation of the BioNTech/Pfizer mRNA vaccine can be kept at temperatures between 2 °C and 30 °C for 12 hours, thus doubling the time available for administration compared to the original PBS formulation.
Table 2. Storage and transportation condition comparison for the regulatory-approved COVID-19 mRNA vaccines [4,15,17,18,20,36,37,38,39].
Condition Moderna COVID-19 mRNA Vaccine BioNTech/Pfizer COVID-19 mRNA Vaccine–Original PBS Formulation BioNTech/Pfizer COVID-19 mRNA Vaccine–Updated Tris Formulation
Ultra-cold frozen
unopened vials		 Not required −90 °C to −60 °C, commonly −80 °C
for six months		 −90 °C to −60 °C, commonly −80 °C
for nine months
Cold frozen
unopened vials		 −50 °C to −15 °C, commonly −20 °C
for six months		 −25 °C to −15 °C, commonly −20 °C, single period of two weeks −25 °C to −15 °C, commonly −20 °C, single period of two weeks
Thawed unopened vials 2 °C to 8 °C,
commonly 4 °C
for 30 days *		 2 °C to 8 °C,
Commonly 4 °C
for one month		 2 °C to 8 °C,
commonly 4 °C
for 10 weeks
Thawed punctured vials 2 °C to 25 °C,
within 12 h		 8 °C to 25 °C,
within 6 h		 2 °C to 30 °C,
within 12 h
On the other hand, Moderna’s COVID-19 mRNA vaccine does not require ultra-cold temperatures for long term storage and transportation. This vaccines is distributed and stored frozen for 6 months at temperatures between −50 °C and −15 °C, commonly at −20 °C [4,15,17,39]. Unpunctured vials may be stored in the refrigerator between 2 °C to 8 °C for up to 30 days and between 8 °C to 25 °C for a total of 24 h [4,15,17,39]. Punctured vials may be stored between 2 °C and 25 °C for up to 12 h [15,17,39]. Moderna’s COVID-19 mRNA vaccine vials cannot be frozen again once thawed, should not be placed on dry ice and prior puncturing vials should not be exposed to sunlight [15,17,39].

3. mRNA Vaccine Instability and Stability Modelling

mRNA molecules at neutral or slightly alkaline pH, such as in current mRNA vaccine formulations, degrade predominantly via the cleavage of the RNA phosphodiester bonds of the RNA backbone. This 3’, 5’ phosphodiester bond breaks via a transesterification reaction due to the close proximity of the adjacent 2′-hydroxyl group of the ribose moiety to the phosphorus center [21,26,40]. This transesterification reaction occurs via an SN2 nucleophilic substitution reaction mechanism, whereby the 2′ oxygen attacks the adjacent phosphorus center. Under alkaline conditions, base catalysis occurs, whereby the 2′-hydroxyl group of the ribose moiety is deprotonated by hydroxide to generate the more nucleophilic 2′-oxyanion group [21,26,40]. As a result of this transesterification reaction, a new bond between the 2′ oxygen and phosphorus is created and the bond between the same phosphorus and 5′ oxygen of the adjacent ribose is cleaved. Thus, the RNA backbone is cleaved and two new ends of the RNA polymer are created; one end has a cyclic 2′,3′- cyclic phosphate while the other end has a 5‘ alkoxide [21,26,40]. This transesterification reaction is also referred to as base-catalyzed hydrolysis or auto-hydrolysis.
Kinetic models describing mRNA degradation have been developed based on first-order kinetics at physiological pH ranges [21,22,23]. It was also shown that this mRNA degradation reaction follows the Arrhenius behavior [21,24]. Recently, Moderna also stated that the mRNA from their COVID-19 vaccine demonstrated Arrhenius behavior, with first order kinetics [25]. Moreover, the stability profiles from this Moderna mRNA vaccines were shown to be predictable and amenable to modelling [25].
Besides pH, higher order RNA structures (e.g., secondary structures, tertiary structures) can also contribute to the rate of the transesterification reaction [21,22,26,40]. Computational molecular modelling and molecular dynamics simulations are being used to predict RNA structure. These include various atomistic force field methods, broad spectrum of enhanced sampling methods, and coarse-grained modeling [22,26,41,42,43,44,45,46,47,48,49,50]. Single stranded RNA is more prone to hydrolysis than double stranded RNA, however RNAse A enzymes catalyze the cleavage of RNA molecules, including double-stranded RNA, using acid-base hydrolysis [26]. Thus, it is crucial to prevent the contact or interaction of RNAse A with the mRNA.
The encapsulation of mRNA into LNPs protects the mRNA of current COVID-19 vaccines from the action of RNAse A enzymes when the vaccine is injected into humans, and the LNPs also help the delivery of the RNA into the cells [25,29]. Therefore, the colloidal stability of the mRNA-LNP complexes is also crucial for the quality, safety and efficacy of mRNA vaccines. The LNPs are subject to both chemical and physical instability [27,28,51]. Chemical instability can be caused by oxidation, and temperature- and pH-dependent hydrolysis of the lipids [27,28,51]. Physical instability can occur in the following forms: aggregation, fusion, and leakage of the encapsulated RNA [27,28,51]. However, additional investigation is needed to fully understand the mechanisms of LNP instability [27,52]. Such a detailed mechanistic understanding of LNP instability or the availability of abundant data can support the development of mechanistic or data-driven models, respectively.

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This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14020430

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