FAU physicist is investigating the inner workings of the Covid-19 vaccine
Since the end of 2020, a great many people worldwide have been vaccinated against Covid-19, but until now the exact structure of these vaccines was not known. Prof. Dr. Tobias Unruh from the Chair of Crystallography at FAU and his team have now begun to rectify this. The results of these elaborate analyses differ, in some cases significantly, from previous assumptions. For example, the active ingredients and excipients inside these mRNA vaccines do not appear to be solid, as previously assumed, but instead consist of many liquid nanodroplets.
Liquid nanospheres
“Size and internal structure strongly influence how the active ingredient is absorbed by the organism, how it is distributed there, and thus also how it works and what side effects may occur,” explains Tobias Unruh. If you know the structure of such a drug or vaccine, you have a better chance of optimizing its effect and can more easily analyze possible side effects. This also increases the chances of mitigating or preventing them. Even though the chemical composition of the Covid-19 vaccines is, of course, known, structural investigations remain difficult in practice.
This is also due to the fact that modern active ingredients are often unstable in water or are only very poorly soluble in it and are therefore difficult to introduce into the bloodstream. Instead, such substances are often encapsulated with so-called lipids. These often have a fat-like structure on one side, which effectively encapsulates such active ingredients, while the other end dissolves well in water. This can be used to produce dispersions in which fat-like droplets containing the active ingredient swim inside, while their outer areas can easily cope with water. Since such lipid droplets with a diameter of less than a thousandth of a millimeter are already in the nanometer range, they are called “lipid nanoparticles” or LNP for short.
Since the structure of such dispersions and thus also their effect in the human organism is very complex and can only be determined with great effort, such LNP-encapsulated active ingredients were only used for very serious diseases such as cancer until 2020 and therefore only given to relatively few people. With Covid-19 and the vaccines developed by various companies against this infection, this situation changed abruptly.
These vaccines contain a completely new type of active ingredient called “mRNA”, such as that used in the Comirnaty preparation marketed by the companies BioNTech and Pfizer. In biochemistry, “mRNA” refers to relatively small nucleic acids that are a copy of the genetic material and thus transport an operating manual for the construction of certain proteins. In the Comirnaty vaccine that Tobias Unruh and his team are studying, this mRNA contains all the information for producing a protein that is almost identical to the spike protein that protrudes from the surface of the SARS-CoV-2 virus. This protein, in turn, attaches itself to certain surface structures of cells in the human body, thus starting the infection with this pathogen.
When the vaccine is injected into the muscle of the upper arm, some of these mRNAs are taken up by cells of the body, which then begin to produce the spike protein in the cells of the affected person according to the instructions contained in the mRNA. The immune cells of the organism recognize this protein as a potentially dangerous intruder and activate the body’s defense system. In this way, the organism builds up an immune response that, in the event of a subsequent real infection, gives the body’s immune system a head start that can be crucial for the health and life of those affected.
However, the exact structure of the vaccine, which is important for its effect and possible side effects, has been unknown until now. Tobias Unruh and his team have therefore used a range of modern analytical methods to get to the bottom of it. The small group developed a method that combines the results of measurements using small-angle X-ray scattering and dynamic light scattering, both of which can determine the size of LNPs. The result of this calculation brought some surprises: “It showed that the internal structure of the lipid nanoparticles in the Comirnaty preparation looks significantly different than BioNTech had previously assumed,” says Tobias Unruh. For example, the largely spherical lipid droplets with the active ingredient have a diameter of just 55 nanometers, with only very slight deviations, where one nanometer is one millionth of a millimeter.
However, as Unruh and his team discovered, in addition to these very uniform nano-droplets, there are also very few giants that have a diameter of around 1000 nanometers and are thus around 20 times larger than the vast majority of other globules.
One test in particular, which Unruh’s cooperation partner Frank Steiniger carried out at the University Hospital of Jena, looks spectacular: In this process, a vaccine sample is shot into liquid ethane, which, at a temperature of minus 180 degrees Celsius, is only 93 degrees warmer than absolute zero. “The sample cools extremely quickly at around a million degrees per second, and the water it contains does not even have time to form crystals when it freezes,” says Tobias Unruh, describing the method. The frozen mass can then be analyzed in the transmission electron microscope. There, the tiny droplets can be seen as discs, the diameter of which can be counted. This direct measurement produces the same results as the newly developed combination method – and can thus confirm the results.
“Under the light microscope, we were even able to see the very few giant droplets directly,” Tobias Unruh recalls. After a few more measurements with Raman and nuclear magnetic resonance spectrometers, the FAU group was finally able to determine that the lipid nanoparticles inside are liquid and not solid, as had been assumed in the approval process for the Comirnaty vaccine. In doing so, Tobias Unruh and his team have created an important basis for a much better understanding of the effects and side effects of the Covid-19 mRNA vaccine.
Further information
https://doi.org/10.1021/acsnano.4c02610
Prof. Dr. Tobias Unruh
tobias.unruh@fau.de