“Just a few kilograms are enough to vaccinate millions”

All over the world, researchers are searching for a vaccine against SARS-CoV-2. They are counting on mRNA vaccines. What is so special about this type of vaccine?

There are three major challenges when developing vaccines in a pandemic situation: First, the vaccine must be produced quickly. Second, the vaccine must be clinically tested to prove that it works and is safe. Third, the vaccine must be made available to millions of people within a short period of time after it has been approved. An mRNA vaccine has clear advantages in all three areas. An mRNA can be produced very quickly. It has an advantage in clinical testing in that it is a pure and biochemically very well characterized substance produced in the laboratory without animal additives. And we only need small amounts, just micrograms. This means that just a few kilograms of the mRNA agent might be sufficient to vaccinate many millions of people.

How does the concept work?

The mRNA (messenger RNA) is a naturally occurring substance in every cell that transports the genetic code from the cell nucleus to the areas of the cell where the proteins are made. In theory we have known that these molecules can act as vaccines for over 30 years. However, a great deal of scientific and technological progress was needed to bring this concept into pharmaceutical use and optimize it. The operating principle has already been tested and matured in many clinical studies. However, no mRNA vaccines have been approved thus far.

So you put the pathogen mRNA into the human body and the cells produce the protein that triggers the immune response?

Exactly. In the case of SARS-CoV-2, we have targeted the RNA for the protein (called spike protein) that is used by the virus to bind to the cells and allows it to penetrate the cell. We have now produced variations of the mRNA for this protein in the laboratory and tested whether it can work as a vaccine. We started the project mid-January. In addition to the experiments, we contacted the regulatory authorities, the Paul Ehrlich Institute in Germany, and coordinated our development plan. We have also been in communication with the Chinese drug authorities and the American Food and Drug Administration (FDA) over the past few weeks. We plan to start a clinical trial in Germany at the end of April to test the vaccine in humans.

If we have known for years that the concept works, why are there still no approved mRNA vaccines?

Preapproval studies are extremely expensive and cannot be shouldered by biotechnology companies alone. Pharmaceutical companies have only become aware of this innovative technology in recent years.

Naked RNA rapidly degrades in the body. How can they ensure that the RNA is absorbed into the body’s cells?

The RNA is packed into lipid nanoparticles ranging in size from 60 to 80 nanometers. These are small, spherical capsules that fuse with the cell membrane. This is how the RNA enters the cell. Then it is translated into protein by the cell machinery like any mRNA. This is how the cells form the antigen. The foreign RNA itself also stimulates the immune system.

Isn't there a possibility that the immune response will be too strong or too weak?

This is of course extremely significant and has been one of the main focuses of our research over the last 10 years. The RNA must be designed in such a way that, even if it enters the body in small quantities, it can be translated into protein in sufficient quantities. This research is now paying off. We only need one millionth of a gram of mRNA to achieve the desired effect. And this is particularly important now because we need a vaccine for a great many people very quickly.

The second challenge is the clinical trial. This step is necessary to ensure the effectiveness and safety of the vaccine. We often hear that this cannot be done before 2021.

The question is not whether we can accelerate the process, but how. And when you work with the experts and authorities on this, you can always find a way. Nor would it be the first time in medical history that substances are urgently needed and approved through an expedited procedure. Drug approval laws are designed to balance potential risks and benefits and to mitigate risks through appropriate measures. A drug is approved if the benefits outweigh the risks. The benefits of a vaccine against SARS-CoV-2 can be enormous. Therefore, a risk-benefit analysis appropriate to the situation must be conducted.

From your discussions with the authorities, do you get the impression that this is happening?

Definitely yes. But it is only possible with the legislature. They must grant the authorities the required leeway, otherwise their hands are tied.

How can the process be accelerated in practical terms?

First of all, we are trying to speed up the preclinical phase, which is everything that happens before the tests on humans. We can get a lot of data on tolerability and efficacy from animal models alone. The planned clinical trials will provide us with information on the tolerability and activity of the vaccine. We can use suitable methods to test whether vaccinated individuals produce antibodies that deactivate the SARS-CoV-2 virus. It is therefore a matter of constructing a conclusive data packet. If approved, I assume that the vaccine will not be approved for everyone immediately. Instead, it may initially be approved for certain risk groups, such as medical staff or the elderly with pre-existing conditions.

About 50 projects worldwide are trying to develop a vaccine. Do you think that several different preparations will ultimately make it to the market?

A handful will make it. It certainly won’t be just one. RNA vaccines could be among the first, then conventional vaccines. The biggest unknown at the moment is how quickly the virus will spread and whether our priority will continue to be to protect the population through appropriate measures, as it has been until now.

How do you think things will continue in this regard?

I see two possible scenarios. One is that the pandemic progresses rapidly and we see a very high rate of infection of the population in a relatively short time. Then of course vaccines will only be used for those who are not yet infected. The second option is that the spread of the virus can be slowed down until vaccines are available. Then a large proportion can benefit from immunization.

The dramatic developments in recent weeks have certainly caused immense disruption for you and your company too.

Absolutely. But we assessed the situation quite thoroughly back in January. The spread of the virus in China quickly showed that it cannot be contained locally. We also knew there was no basic immunity to this virus. We then started a four-step program and got things going. We are now transitioning from step 3 to step 4. Over the last few weeks, many of our employees have also been working weekends and coordinating with each other so that the project can be implemented without interruption. We have also experienced incredible support from outside of the company. But of course we are trying to maintain social distancing. Many of us are coordinating the work from home. No more than one or two people are active at the same time in a laboratory. The office spaces are already separated. And yet we are pushing ahead with the project with all our might. It is important to all of us who are working on it to provide help in time.

Thank you for the interview and good luck!

Prof. Ugur Sahin, M.D. is the Managing Director of Translational Oncology (TRON) at the Mainz University Medical Center as well as the co-founder and CEO of BioNTech (Biopharmaceutical New Technologies). The biotechnology company based in Mainz specializes in the development and production of immune therapies for the treatment of cancer, infectious diseases, and other serious illnesses. The German Cancer Research Center (DKFZ) collaborates with the Research Institute for Translational Oncology at the Helmholtz Institute “HI-TRON”.