mRNA to the Rescue

mRNA-based vaccines against the novel coronavirus are one of the most important steps on the way out of the COVID-19 pandemic. Can the production of mRNA-based vaccines 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. A successful, rapid vaccination campaign is essential. Some vaccines have already been approved and administered by the millions. Many others are still in various stages of development, and the World Health Organization (WHO) is aware of nearly 300 vaccine projects. All over the world, people are striving for the rapid production, distribution, and administration of an unprecedented number of vaccine doses. The novel mRNA vaccines are in especially high demand on a global scale. Not only do they show high efficacy and very low side effects, but they are also relatively easy to adjust. In principle, they could be engineered to generate a robust immune response even to mutated variants of Sars-CoV-2.

The German enterprise CureVac is one of the companies researching such a vaccine and has attracted global interest. The German government, among others, supports their research. Tesla CEO Elon Musk has been working on a »vaccine printer« with CureVac since earlier this year. Fraunhofer IPK is 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, until recently there had not been any approved vaccines based on these technologies. The urgency of a global pandemic with the prospect of paralyzing entire economies for years to come has now helped this technology make a breakthrough. Because unlike known viruses such as measles, diphtheria, or influenza, there was no »traditional« vaccine for the coronavirus.

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. It 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 did it take so long for mRNA vaccines to break through? 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 supported by CureVac in the form of equipment, material, and expertise and 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.