mRNA to the Rescue

mRNA-based vaccines against the novel coronavirus are promising but difficult to produce. Can their production be accelerated using new methods?

The best way out of the pandemic has already been much discussed. Only one thing seems certain: Without a vaccine, it will be difficult. More than 150 candidates are currently being developed globally. As soon as one or more of them have been tested and approved, they must be produced as quickly as possible and distributed fairly. Experts all over the world are therefore currently preparing for the rapid production, distribution, and administration of an unprecedented number of vaccine doses. The World Health Organization’s (WHO) COVAX initiative alone aims to purchase around two billion vaccine units by the end of 2021.

As to which of the candidates could ultimately prevail, one keyword often comes up: “mRNA vaccine.” The German enterprise CureVac is one of the companies researching such a vaccine and has attracted global media interest in recent months. Among others, the German Federal Government supports their research. CureVac’s activities have also aroused the curiosity of Tesla CEO Elon Musk and prompted him to visit Tübingen. Fraunhofer IPK is now cooperating with the Tübingen-based company to advance the development and production of the vaccine.

How do mRNA vaccinations work?

Even though companies such as CureVac have been researching mRNA technologies for two decades, there are still no approved vaccines based on these technologies. The urgency of a global pandemic with the prospect of paralyzing entire economies for years to come could now help this technology make a breakthrough. Because unlike known viruses such as measles, diphtheria, or influenza, there is no »traditional« vaccine for the coronavirus that could replace the costly research into mRNA vaccines.

To date, most vaccines have been based on the idea of supplying the body with what are called antigens. These are either attenuated or dead versions of the virus against which the vaccine is administered, or what are called vectors: harmless vaccine viruses that are »disguised« with fragments of the harmful virus’ genetic information, thus feigning an infection. Although these antigens cannot cause disease, they can stimulate the body to react as if they did. The body can »remember« this defensive reaction for a certain period of time and add it to its immune defense arsenal. It can then be called up immediately if the real virus is ever detected.

In contrast, mRNA vaccines do not contain any components of the virus against which the vaccine is administered. With single-stranded mRNA, short for messenger RNA, it is merely a genetic construction manual that is introduced into the body of the vaccinated person. This is able to stimulate the body’s own cells to produce viral protein building blocks that are recognized as components of the virus and trigger a corresponding immune defense reaction. In other words: Based on the mRNA information, the body produces the antigens itself and then reacts to them.

As reported in the Deutsches Ärzteblatt, this type of vaccination offers »a significantly better safety profile and fewer side effects.« So why is there not even a single approved mRNA vaccine yet? The journal writes: »Development using mRNA as a vaccine was initially halting. This was mainly due to the fact that RNA molecules are degraded very quickly enzymatically.« This means that without special protection, the mRNA molecules cannot remain in the body long enough to bring about their intended effect in the right place.


Molecular protection

So how can the mRNA molecules be made suitable for vaccination and transport in the body? The German Federal Institute for Vaccines and Biomedicines, the Paul-Ehrlich-Institut, summarizes the principle as follows: »mRNA/DNA vaccines do not require a vector for vaccination, i.e. no carrier virus, but rather liquid nanoparticles (droplets of fat) so that they can enter certain body cells.«

The mRNA molecules must therefore be encapsulated in a protective lipid envelope. However, currently available technologies for generating such lipid nanoparticles and encapsulating the molecules are not yet very advanced. The SARS-CoV-2 vaccine candidates currently in development can therefore only be replicated and tested slowly. In particular, with the current state of the art, these difficulties also affect vaccine production once development is completed. This is how the collaborative project HeLiMol to produce lipid nanoformulations for the encapsulation of mRNA molecules with Fraunhofer IPK came about.

In this project, which is funded by the Fraunhofer-Gesellschaft within the »Fraunhofer vs. Corona« campaign, two possible approaches are being researched almost in parallel. The two approaches differ in the method of mixing the mRNA molecules and the lipid phase for fast and uniform encapsulation. This will allow microfluidic encapsulation technologies to be developed that allow for GMP-compliant encapsulation and scaling of production capacities at the same time. In addition, an entirely new approach to macroscopic high-throughput encapsulation of mRNA molecules is being researched, which will allow the required production capacities to be achieved even without the complex parallelization of microfluidic structures.