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With over 63 million confirmed cases and over 1.4 million deaths worldwide as of the start of December, the COVID-19 pandemic has certainly lit a fire under the pharmaceutical industry in the pursuit of therapeutics. In the process, with the recent emergency use authorisation in the UK for Pfizer and BioNTech’s BNT-162b2 vaccine, and the 94.5% efficacy reported by Moderna for its mRNA-1273 vaccine, a new technology has shot to the forefront: the mRNA vaccine. This technology works  by introducing mRNA coding for a pathogenic antigen into a host, which then manufactures the immunogenic protein, subsequently training the host’s immune system to recognise it upon secondary further infection, thus inducing protection. In the case of COVID-19, the mRNA sequence typically encodes the spike protein, although like many platform technologies, the concept can be validated and stretched to numerous different therapeutic applications. This therefore begs the questions: what is the current state of the mRNA vaccine field, and how far can the technology go?

It is clear this is a new field. Out of 74 mRNA vaccine programs currently in the global pipeline, 67% are in preclinical development, with mRNA-1273 and BNT-162b2 being the only two programs to produce pivotal clinical trial data. While mRNA vaccine development is rapidly emerging, spanning 35 companies, 51 countries and 39 diseases, this is a field dominated by the few. Just three companies – Moderna, CureVac and BioNTech – are involved in the development of half of the entire mRNA vaccine pipeline. The “plug-and-play” nature of mRNA vaccine production, which unlike traditional vaccines does not require unique infrastructure for each development program [1],  means the technology is viable for smaller biotech players in the field to expand their presence. Figure 1 below shows a tally of the number of assets in development by each of the leading companies – where an asset is being developed by more than one company, it is counted against each.

Figure 1: Companies with >1 mRNA vaccine program, by stage of development 

To infinity and beyond: how far can mRNA vaccine technology go?

Source: Pharmaprojects®, December 2020

It is perhaps not surprising that Moderna, BioNTech and CureVac are so prominent in this area as mRNA technology is a focal point for all three companies. CureVac was the first to enter the space with a program in 2008, with BioNTech and Moderna following in 2012 and 2013. The earliest move to clinical trials for a drug which is still in active development was in 2013 for CureVac’s CV9202 oncology program, which is now in a Phase I/II clinical trial.

Attention on COVID does not distract from wider therapeutic application
Despite COVID-19 only arriving on the scene at the end of 2019, 28% of mRNA vaccines across all stages of development are targeting SARS-CoV-2 (including both prophylaxis and treatment). This reflects both the unique potential of mRNA technology to be rapidly pivoted and deployed to new emergent pandemic threats, but also the immediacy of the threat the virus poses. This has led to considerable funding to support clinical trials and manufacturing scale-up, led primarily by governments seeking to create national immunisation strategies, but also by healthcare investors responding to early therapeutic promise.
Besides COVID-19, other viruses are being considered as targets, the most advanced of which are a cytomegalovirus prophylaxis program in development by Moderna, and an HPV vaccine by BioNTech (BNT-113), both of which are in Phase II clinical trials for these indications. Infectious disease remains the primary interest for mRNA vaccine development, accounting for 76% of all candidates, with additional research investigating non-viral pathogens. For example, CureVac has a preclinical/discovery-stage mRNA vaccine project for malaria prophylaxis, and Translate Bio, in collaboration with Sanofi, has a preclinical program directed at bacterial infections.

Figure 2: Indications with >1 mRNA vaccine development program

To infinity and beyond: how far can mRNA vaccine technology go?
Source: Pharmaprojects®, December 2020

Cancer is an equally promising target for mRNA vaccines, following the success of immuno-oncology treatments over the past decade (and minimal overlap of carcinogenic viruses). Currently, there are 11 specific cancer types in which mRNA vaccines are being tested, predominantly focusing on high-prevalence solid tumors (Figure 2). For the majority of these assets, the underlying principle is the same as that for anti-infective vaccines; however, the mRNA component codes for epitopes from tumor-associated antigens; that is, proteins found on the surface of tumor cells that are accessible to an immune response. [2]  The particularly exciting prospect here is that this nucleic acid-based tool lends itself well to highly personalised therapeutics, potentially to the level of individual patients. BioNTech, for example, has validated its proprietary “Individualized Neoantigen Specific Immunotherapy” (iNeST) platform in collaboration with Genentech, which uses the unique mutational profile of each patient to predict the resulting neoantigens, thus producing tailored, optimised mRNA as an immuno-oncology vaccine. [3]

Next-gen platform developments look towards stability and self-amplification

As with any form of development, mRNA vaccines are likely to have many iterations moving forward, giving way to “next-generation” versions. Many of these are likely to focus on improving mRNA stability, a concern as the Pfizer/BioNTech BNT-162b2 vaccine requires storage at around -70°C, placing a high logistical barrier for vaccine distribution. As such, developing new delivery platforms for the mRNA is key. Delivery of mRNA vaccines via nanoparticles, particularly lipid nanoparticles, is common and often a favourite; however, novel twists on this are emerging. One such mechanism is in development by pHion Therapeutics and utilises positively charged proprietary “RALA” peptides that interact with the negatively charged mRNA load to form highly stable nanoparticles with the additional benefit of low toxicity and immunogenicity [4].  Similarly, Gennova Bio has a proprietary “lipid organic nanoparticle (LION)” technology which is able to act as an adjuvant [5].  Further research is yet to determine how far these early-stage developments will progress.

In another vein, self-amplifying mRNA is also considered a promising technology. Here, the mRNA being delivered codes for both the relevant antigen as well as the necessary viral replication machinery, which is often based on viruses such as alphaviruses or flaviviruses thanks to their RNA replication efficiency  [6]. Developing mRNA which is capable of intracellular self-replication increases the quantity of antigen that can be delivered per dose. Two examples of this technology are GSK3903133A, a rabies vaccine currently in Phase I development by GlaxoSmithKline using its cationic nanoemulsion (CNE) platform for delivery, while CSL is progressing a self-amplifying mRNA vaccine through preclinical development against influenza.

Considering the incredible attention on mRNA vaccine technology for COVID-19, it is worth taking into account the potential and progress that is occurring elsewhere in R&D. With clinical proof of concept now well established, pioneers such as Moderna, CureVac, and BioNTech can capitalise on their momentum to look beyond COVID-19, tackling other infectious diseases, building pandemic preparedness, and even expanding into oncology. Backed by considerable COVID-19 vaccine funding and likely blockbuster commercial revenue streams, these disruptive innovators will be able to advance multiple new programs beyond clinical trials and onto the market. With the rapid deployment of manufacturing infrastructure removing further risk, there will be no shortage of potential partners from within Big Pharma to accelerate and further diversify this new technology.

 1. Jackson NAC, Kester KE, Casimiro D,
Gurunathan S, DeRosa F (2020) The promise of mRNA vaccines: a biotech and industrial perspective. NPJ Vaccines, 5(11). Available from: [Accessed 3 December 2020].
 2. Pardi N, Hogan MJ, Porter FW, Weissman D (2018) mRNA vaccines – a new era in vaccinology. Nature Reviews Drug Discovery, 17, 261–279. Available from: [Accessed 3 December 2020].
 3. BioNTech (2020) Platforms. Available from: [Accessed 3 December 2020].
 4.  pHion Therapeutics (2020) How Does RALA Work? Available from: [Accessed 3 December 2020].
 5.  Gennova Bio (2020) mRNA Vaccines. Available from: [Accessed 3 December 2020].
 6. Lundstrom K (2018) Self-Replicating RNA Viruses for RNA Therapeutics. Molecules, 23(12), 3310. Available from: [Accessed 3 December 2020].