by Öner Tulum, William Lazonick, and Ken Jacobson
This is the final installment of a three-part series on the scalability of mRNA vaccine production. The current article focuses on explaining the process of selecting vaccine candidates based on dosing, stability, and optimization studies carried out during the clinical development of mRNA vaccines.
The success of an mRNA-based vaccine depends on the formulation of lipid nanoparticles (LNPs), which enable the delivery of genetic information to cells. While a company considers its process for assembling LNPs from lipids and mRNA to be proprietary information, the similarity of the two approved mRNA vaccines’ efficacy ratios, as shown in the table below, raises the question of whether the way lipids are assembled really matters.The three vaccines included in the table above use the same types of lipids in their LNP formulations. But the concentrations of lipids and mRNA in the LPNs vary significantly across these vaccines. This variation has major implications for the manufacturing, storage, and distribution of the vaccines. The BioNTech and Moderna vaccines, which have emergency use authorization (EUA) in a number of countries, offer similar rates of protection against SARS-COV-2, notwithstanding their use of different amounts of mRNA in each dose (see table above).
Why do mRNA concentrations differ in COVID vaccines?
Prior to regulatory approval, the clinical development of a vaccine involves three distinct phases, in which the vaccine is being tested on voluntary participants in the clinical trials. The first two phases seek to affirm the safety of the vaccine, while the purpose of the third phase is to establish the vaccine’s efficacy.
In the first phase of the trials, investigators attempt to identify potential side effects among 20 to 30 volunteers. In the second phase, investigations remain focused on vaccine safety, but now there are several hundred trial participants. The BioNTech/Pfizer phase III trials had 44,000 people, while the Moderna trials had 30,000. The early-phase trials include dose-toxicity studies, which allow investigators to understand participants’ tolerance of different dosage levels. Based on the results of these studies, researchers select the vaccine candidate with the best safety profile for the double-blind, placebo-controlled efficacy trials of phase III.
Carrying out the three phases of clinical trials usually takes years, but with the pandemic upon us, the vaccine developers had to accelerate the process. BioNTech/Pfizer combined the clinical trials into just two phases, whereas Moderna carried out the trials in the usual three phases.
The extreme haste with which each company’s scientists had to choose its candidate for phase III testing–at both BioNTech/Pfizer and Moderna they were given less than three months–had major implications for the transition from small-scale vaccine manufacturing for clinical trials to the mass manufacturing of doses for commercial use.
In March 2020, shortly after signing a partnership agreement for the manufacture and distribution of BioNTech’s COVID vaccine, Pfizer embarked on an ambitious production plan that entailed preparing several facilities to start mass manufacturing vaccines. The goal was to begin mass production in mid-August of 2020, while phase III trials were still being carried out.
Pfizer and BioNTech had designed the production process based on their lead candidate, but at the last minute switched to what had been their second choice, BNT162b2, which appeared to be somewhat inferior in efficacy but superior in safety. This change impacted production plans because candidate #2 required a larger volume of vaccine per dose. That meant, among other things, producing greater amounts of vaccine and procuring more vials for a given target number of doses. As can be seen in the table above, the BioNTech/Pfizer target for 2021 is 2.5 billion doses.
Moderna was the first company to start human clinical trials of an mRNA vaccine. Rushing to embark on phase III trials, Moderna chose to develop a vaccine with a much higher mRNA concentration per dose (100 mcg) than the one developed by BioNTech (30 mcg). As a result, Moderna has faced much greater capacity and scaling challenges than Pfizer. At the manufacturing facilities of its partner CDMO, Lonza, Moderna plans to produce 700 million doses of its vaccine in 2021–less than one-third of the BioNTech/Pfizer target for the year.
Stability and optimization
The vaccine developer conducts studies of the stability of LPNs under different thermal conditions to determine the optimal temperature at which to store them. As is well known, a drawback of both the BioNTech/Pfizer and Moderna COVID vaccines is the need for low-temperature storage after they are shipped from fill-and-finish operations to the clinics at which vaccination takes place. If there had been more time available for developing the vaccines, scientists might have been able to find ways to store them safely at higher temperatures.
Vaccine developers must get approval from the Food and Drug Administration (FDA) of all excipients contained in a vaccine that will be used in the clinical trials. Therefore, to avoid regulatory delays in commencing clinical trials, as well as unforeseen toxicity issues, Moderna and BioNTech formulated LNPs using lipid components that were already proven to be safe.
While the BioNTech/Pfizer vaccine has a scaling advantage over Moderna because of its much lower mRNA concentration per shot, the Moderna vaccine’s higher concentration appears to offer storage and logistical advantages. The Moderna vaccine can be safely stored in an industrial freezer at minus 20°C for up to 180 days or in an ordinary refrigerator between 2°C and 8°C for up to 30 days. BioNTech’s vaccine needs to be stored in ultra-cold freezers at no higher than minus 70°C for up to 180 days or for no more than 5 days in a refrigerator.
The optimal temperature level for a vaccine to remain stable depends on the particular formulation of mRNA within LNPs as well as the vaccine’s lipid and non-lipid ingredients. There is scientific debate about whether this Moderna advantage arises from its distinct LNP properties and structure or its higher concentration of mRNA, both of which make the vaccine more stable. LNPs can become highly unstable when the lipid ingredients used in their assembly fail to bind together. The safest solution is to store a vaccine at a very low temperature, which varies with the formulation of the particular vaccine.
The CureVac COVID vaccine has not yet attained EUA, but, when it does, it may benefit from “late mover” advantages as the scientific community learns from studying the mRNA vaccines that have been authorized. CureVac’s mRNA-based COVID vaccine appears to have both scaling and storage advantages over the two approved mRNA vaccines. It contains only 12 mcg of mRNA, which can be safely stored in the refrigerator up to 90 days. CureVac anticipates that its vaccine will have a safety and efficacy profile comparable to those of the two already-approved mRNA vaccines. The company says that the announcement of the results of its late-stage clinical trials is imminent. It hopes to receive EUA in June.
In a future post, we will analyze how the different developers of mRNA vaccines may change the innovation landscape for these products, both in competition with each other and in response to mutations of SARS-CoV-2.