Ingmar Hoerr, PhD
Ingmar Hoerr, PhD

The first “International mRNA Health Conference” was held in Tübingen, Germany, in 2013, initiated by mRNA (messenger RNA) platform companies CureVac, Moderna, and BioNTech. The leaders of the then-young field formed an alliance at the conference with the goal of increasing awareness of the technology. The competitors agreed to accept each other as development engines, communicate with one another, and recognize the field’s co-development responsibility. Ultimately, the goal was to make a disruptive technology available to patients as quickly as possible, yet responsibly.

Now, only six years later, data is being collected in more than 25 clinical studies across numerous modalities, other companies are entering the mRNA space, the first mRNA companies are publicly listed (Translate Bio and Moderna), and “proof of concept” clinical studies are being initiated. Today, many eyes are on the mRNA space as the race for the first product on the market is fully underway.

What hurdles remain?

The first hurdle is the application (delivery) of mRNA. Encapsulation through packaging in lipid nanoparticles (LNPs) is currently the method of choice for most product developers. The LNP technology originates from a few companies (Acuitas, Arbutus, and Arcturus) and research groups (such as one composed of MIT researchers), which provided the field with licenses to bring the first mRNA projects to clinical trials. Now, some mRNA companies are developing these delivery technologies in-house. Different applications require custom LNP optimization. LNP toxicity remains a risk for multiple dosing regimens.

The second hurdle is mRNA optimization. Nature has finely regulated the half-life and expression levels of mRNA. These factors heavily influence the availability of therapeutic proteins or vaccines. It is important for vaccines to generate a high peak expression to give rise to T-cell responses and antibodies. Protein therapies, like enzyme replacement, require a high and steady expression for longer-term therapeutic benefit.

Various factors influence the expression level and half-life of mRNA, including untranslated regions (UTRs), polyA tails, cap structures, and open reading frames (ORFs). One view is that chemical modifications to the mRNA can exercise a decisive influence on the stability, immunogenicity, and expression level; another view focuses on remaining as close as possible to the natural system. As there exists a ratio of LNP required to deliver the mRNA payload, it is a significant benefit to maximize the mRNA expression levels to keep the concentration of the LNPs low for customized, highly engineered mRNA to prevent or reduce unwanted side effects.

The final hurdle is the production of mRNA. CureVac was the first company to receive GMP certification in 2005. Subsequently, other mRNA companies established production, and there are now several CMOs that offer mRNA production as a service. The quantity and quality of the mRNA is still a bottleneck. The upscaling of an industrial process with high throughput and the lowest possible production costs is a significant challenge.
Molecular therapy uses, such as mRNA-coded antibodies, require large quantities, up to gram levels. The costs in the conventional production process still exceed the production costs of customary recombinant antibodies; therefore, advances in the reduction of mRNA production cost is critical.

The first product to market

The first approved mRNA product will gain a market advantage. For nearly all developers, one of the challenges is to define a product development strategy that hits big markets and exhibits the unique benefit of the mRNA application. The most lucrative markets and the greatest benefits lie in the expression of therapeutic proteins.

Often, mRNA-based therapies require systemic application, excellent safety, and high concentrations of the therapeutic protein, meaning high quantities of mRNA. That is why almost all developers initially chose to develop mRNA prophylactic vaccines, because small quantities of formulated mRNA via local administration is sufficient to induce an immune response. Also, the read-out based on antibody titers in the blood is standardized and quick.

Many mRNA companies have entered into partnerships to advance their broader vaccine development programs: CureVac with Bill & Melinda Gates Foundation, Translate Bio with Sanofi, Moderna with Merck, and BioNTech with Pfizer. The excellent properties of the mRNA technology enable administration of the different antigens as a cocktail. One can envision developing a broader protective vaccine including not only the most prevalent strains but multiple antigenic drifted viral isolates of one subtype. This process might be assisted by AI prediction algorithms including machine learning to better match future circulating strains. Those vaccines could be further enhanced by equipping them with conserved antigens that activate a cellular immune response.

Even if the universal vaccine remains a dream of the future, one can envision achieving at least an improved protection that lasts two to three years, which is still better than conventional market seasonal vaccines.

The second candidate for the first product to market is an enzyme replacement therapy. An in vivo bioreactor (organ) which can be efficiently loaded with mRNA, and which expresses this mRNA without causing undesired immune responses or side effects, is required. The liver is an excellent candidate for a bioreactor. It is accessible via intravenous injection of LNP-encapsulated mRNA, and LNPs effectively transfect hepatocytes.

It is only natural to turn toward liver diseases, including ornithine transcarbamylase deficiency (OTC). Many companies are already exploring this area, including CureVac/Arcturus, Moderna, Roivant, and Translate Bio. Local delivery to the lung is also currently under development by companies like Translate Bio, Moderna, and Ethris, for conditions like cystic fibrosis. Pulmonary therapies require a tight safety profile since the lung is prone to allergic and immunotoxic reactions.

The third promising candidate for the first product to market lies in oncology. Companies like CureVac, Moderna, and BioNTech are utilizing mRNA-encoded neoantigens or individual, patient-specific tumor antigens to induce systemic immune responses that target primarily metastases. Often these approaches are combined with checkpoint inhibitors.

Another approach to generate a local effect of RNA is the direct application of RNA in the tumor. The aim is to put pressure on the tumor by injecting immunostimulating RNA- or mRNA-encoded immunomudulators. This process turns “cold” tumors “hot,” introduces apoptotic cell death, leads to a release of tumor-associated antigens, and triggers a systemic immune response, which can target even nontreated tumor lesions.

The ultimate goal of this approach is to have cancerous cells act as their own vaccine. In the field of intratumoral application, there is currently a gold-rush atmosphere; there are several other technologies, such as oncolytic virus constructs, which make use of a similar principle of action. CureVac, Moderna, and BioNTech are exploring various mRNA compositions.

CureVac notes that its mRNA therapeutics follow the same functional principles found in nature. When supplied the right mRNA, the body can produce its own medicinal proteins.


There is an exciting race to bring the first mRNA therapy to market. All mRNA competitors know that this product will have a signaling effect on all future product developments. This effect is needed to develop new disruptive approaches that include completely new mechanisms of action. For example, mRNA technology can be used to influence intracellular pathways or to express membrane receptors, opening new therapeutic possibilities. Therein lies the real magic and power of mRNA technology: It creates a universe of new treatment options. Once one mRNA medicine enters the market, many more will enter the clinic. The possibilities are truly limitless.


Ingmar Hoerr, PhD, serves as chairman of the supervisory board at CureVac.

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