In 2000, Ingmar Hoerr and colleagues founded CureVac, a biopharmaceutical company that develops therapies based on mRNA, in Tübingen, Germany. The basis for that was his discovery during his Ph.D. thesis that naked mRNA can be expressed in vivo without being rapidly degraded and that it generates a strong specific immune response. This was in contrast to the current state of research at the time.

Here, Ingmar Hoerr talks with Vera Koester for ChemistryViews about his research, mRNA COVID-19 vaccines, and inspiring entrepreneurs and pioneers.

 

What sparked your interest in mRNA research and what motivated you to do your Ph.D. with an immunologist and an organic chemist as supervisors?

I had already completed my diploma thesis with Günther Jung, a chemist in Tübingen, and he was collaborating with Hans-Georg Rammensee, an immunologist. I wanted to have this access to both scientists.

Günther was officially my Ph.D. supervisor, but I also collaborated with Hans-Georg. That was also very important. I had access to all the knowledge and skills about immunology there, and could use the mice from Hans-Georg, so it was a really good collaboration.

 

How then did your attention fall on mRNA?

It was actually an idea of Hans-Georg’s. Hans-Georg went to a conference in the US where he heard a talk by Eli Gilboa. Eli is also an immunologist, and he used RNA-transfected cells. [RNA transfection refers to the deliberate introduction of RNA into a living cell.] He didn’t actually inject the RNA anywhere, but he loaded RNA onto immune cells from mice, and then he re-injected those cells into mice. Hans-Georg asked me to figure out whether we could use RNA directly. So that was my Ph.D. project from the beginning.

Of course, I was interested in learning more about RNA. But I was also quite afraid because RNA is very unstable. So I used the packaging reagents from Günther Jung. Günther Jung was developing DNA liposomes at that time. I tried to package the RNA into these liposomes. I also used DNA, and I also used naked or unprotected RNA. I was wondering whether this unprotected RNA would be degraded within a few seconds …

 

… unprotected means that no packaging is present?

… yes, no lipids, no package, just natural RNA. There are a lot of RNA-degrading enzymes around, so I was sure that the RNA would be degraded within seconds. However, that was not the case. The RNA went into the cells and was expressed in the protein. I could see the immune response in the mice. I could also see the color because I was using a color encoded on the RNA. So the RNA was translated.

Those were quite interesting experiments at that time. I said, well, it’s not that difficult to use RNA. You can use RNA, and you do not have to package the RNA. You can use it because it’s stable enough and it can give you whatever you want: immune responses, but also protein therapies like insulin, and things like that. These results were the birth of CureVac.

I originally wanted to go to pharmaceutical companies with it, but they were not interested.

 

Because the time was not right?

Yes, exactly.

 

What motivated you to continue this research?

Because I was sure. I really wanted to bring these results into drug development. That was the reason why I wanted to commercialize this as soon as possible.

When you want to start clinical trials, you need to have good manufacturing practices (GMP) [GMP ensures that products are consistently produced and controlled according to quality standards.] That was a really high bar. I had never done that before. We did not have enough money for a clean room area and comparable things. Somehow, we still managed to have the first GMP mRNA. We also managed with CureVac to have the first patient injected with RNA, a melanoma patient in 2007.

 

I read that you did the first clinical human trials in mRNA and this is seen as the foundation for the whole mRNA industry.

So what makes your COVID-19 vaccine candidate different from the BioNTech and Modena vaccines?

Well, I only know the BioNTech stuff from the literature. With CureVac, the crucial point from the beginning is that we stabilize the RNA. We do a kind of sequence stabilization using the so-called 5’ and 3’ untranslated regions, which are regions that are not coding for any genes. They are at both ends of the RNA to stabilize the RNA. This was first published for β-globin because β-globin RNA is a very stable RNA in nature [1]. We just adopted the β-globin sequence elements and fused them to our RNA construct.

We also learned that we can enrich G/C or guanine-cytosine in the RNA to stabilize the molecule. This coding optimization is possible, because there are many codons for the base that code for the same amino acid. For example, for the coding of the amino acid glycine, the codons GGU or GGA can be replaced by GGG or GGC. We programmed a computer program to get a G/C-rich construct.

Besides this G/C inversion and the untranslated regions, another thing is very important: ribosome binding sites. Ribosomes, the translational machinery of the body, bind to specific sequences of RNA. Protein production is controlled by the binding of the ribosome to the mRNA. This is determined in part by the binding affinity between the ribosome and the ribosome binding sequence on the mRNA. We also use this to make the mRNA molecule more stable and effective for protein biosynthesis.

All of this is natural. So, unlike Moderna and BioNTech, we do not chemically modify the RNA, it is all done through optimization of natural processes.

 

When you look at the longer-term vision, how do you think the development of these vaccines will continue? Will they replace other vaccines or maybe the way we administer them will change?

Yeah, for sure. It only took BioNTech and Moderna one year to develop the COVID-19 vaccine and get it to market. That is the fastest process ever. So I think now when new mutations come up and the old vaccines are no longer efficient, you can just adapt the vaccine. For us, it is always the same RNA production, no matter what the sequence is.

You can also think in different directions towards other diseases. Think about the seasonal flu. We have a seasonal vaccine, but maybe a flu vaccine that protects for ten years or longer is also feasible if you have some kind of library, some kind of algorithm that maps where you think the flu virus is going to mutate in the next few years, and then you can also incorporate those sequences. So you have a longer protection. That is also interesting and doable.

But the most important thing for me is that you have really high speed. If there is any outbreak scenario in the world, in a few months at most the first product can be in clinical trials.

 

How much can you change a vaccine so that it does not have to go through all the trials again?

Here, I can only share my personal assumption: If there is already trial data from the same sequence more or less and only minor changes have been made to the sequence, then I think you can do it like you do with the flu vaccines every year. So you do not have to do all these clinical trials, you just have to prove that it works. Safety will always be important. So I can assume that you will always have to do some kind of phase-one trial where you check the safety before you get approval. But I do not represent any regulatory authority with whom this needs to be discussed in detail.

 

What about other diseases where this mRNA technology can be used?

Well, the sky’s the limit. It is very open to many things. We were very interested in cancer from the beginning, but cancer is quite complicated because you only have access to patients with a low immune response, that is, the late-stage cancer patients. They cannot build up an immune response properly. It is hard to get access to healthier patients because those patients need normal treatments like radiation or chemotherapy. I do not know how to really get around that, how to ethically do a research trial without interfering with the other therapies that are already granted. So cancer is one of the big issues.

Of course, you can also think about many other things, such as how to stay healthy in old age, how to prevent the degeneration of the brain in Alzheimer’s disease, for example, and things like that. So there are many directions in which you can go.

And again, it is always the same molecule – just the sequence is different. That allows you to be really fast in clinical trials, with the same product process, no adaptation is required.

You can also use libraries, different genes in a cocktail. CureVac also has some experience with making cocktails of different RNAs. So the more science-based information we have, the more we can do with RNA.

 

So I guess we will see more of this then in the coming years.

For sure.

 

Your Ph.D. supervisor wrote in a letter to the editor of Nachrichten aus der Chemie that Katalin Karikó and Drew Weissman are being treated by some in the U.S. as potential future Nobel Prize winners and that your pioneering work is not getting enough attention. What do you say to that?

Well, nobody can nominate themselves. [laughs] You know, I am grateful that mRNA has become popular now. Karikó and Weissmann have done great work and BioNTech and Moderna are using their work. They are using modified RNA, not natural RNA as CureVac does. Using modified RNA is possible, but there is no real need for this, as shown by CureVac. That is the main difference, as mentioned earlier.

CureVac was the first company to use naked RNA in organisms, and the first one to implement a GMP protocol, and a clinical trial. So that is groundbreaking, but it is not on me to valuate the scientific importance.

 

So do you think they were lucky to be the first to develop a vaccine with their mRNA technology?

Of course, it is always good to be the first. It has been proven that their method works in humans; CureVac still has to prove that. But once that is proven, we can compare Karikó’s and CureVac’s technology.

So far, it seems that CureVac’s dose is lower than the ones from its competitors. It seems that CureVac’s stability is higher, because CureVac does not need deep freezing like the others. But since BioNTech and Moderna are on the market and CureVac is not, I think we really have to wait for the market approval of CureVac.

 

And you are aiming for May?

I do not have that data in my hands. So, I can only repeat the company’s statement: the second quarter of this year.

 

Starting a company in Germany is not easy. We do not have support programs at universities like MIT in the US, for example, and biotech startups, in particular, need a lot of money at the beginning. So what other skills besides having a great idea are important, and how do you get to talk to a Dietmar Hopp or Bill Gates, for example, who supported CureVac?

Of course, that was not planned from the beginning. I could not approach Dietmar Hopp and say, “Hi, I am Ingmar, and we’re doing something interesting.” It is always a question of networking. You talk to a lot of people without really knowing where it is going to lead.

With regard to Dietmar Hopp, the contact came about through a lawyer, Sven Riethmüller, from Lion Bioscience, Friedrich von Bohlen’s company in Heidelberg. We spoke to Sven at a conference in the US. He is a US-based lawyer and he told us about Friedrich and that he is interested in ventures and likes to get involved in the founding of a company. So we reached out to Friedrich. At that time, Friedrich managed to put us in contact with Dietmar Hopp. When we got the funding from Dietmar Hopp, that also opened up doors to the Bill Gates Foundation. So it always starts somewhere small and you have to be really active, meet a lot of people, and make people aware of what you’re doing.

Of course, it is crucial to have solid data. In terms of CureVac, we had data from animal studies that showed that the principle works, that there is an immune response, that it is not just fiction. Bill Gates, in particular, was very interested in this.

 

If you were to give advice to younger scientists, would you say they need to be outgoing and stick to their goal?

I do not know if what happened with CureVac can be easily replicated. We were also lucky. We had the right experiments, we had the right people on board, we had the right network and the right connections.

I think the most important thing is to really believe in what you see, in the vision. You cannot pretend to do this; you are not an actor, you are a founder. People have to see that you really believe in the vision, that you really engage with it, that you know a lot about what you need, what the market surrounding looks like, so you know about the competition, if there is any, and also about the development – what the next steps and milestones are. How much investment do you need in total to get a product to the market? But you also have to stay humble. You have to stay open for advice and thoughts.

For us, for example, there was this GMP issue, as I told you. The GMP certificate was our biggest hurdle. Nobody had a clue what they wanted us to do, how we could do it. It is extremely expensive. You have to invest a lot of money in these clean room areas, the processes, the documentation. It was a huge hurdle to go from a lab to a real pharmaceutical production process, and we were aware of that. We told Dietmar that this was the next step that we had to achieve, and only then could we start with the trials. It was not possible before that.

 

That is a great success story. What do you enjoy most about your job?

Well, I really enjoyed building up this company. That I have been able to see that this technology is really robust, and that we are able to drive it forward in projects, in clinical trials, in production. Seeing the results gives you a lot.

That was always an inspiration for me. I am a scientist, so I believe in the scientific results and I do not think so much about business plans. That is maybe one of our advantages compared to other founders who are not in the scientific field. My strong belief in our vision was always data-driven.

 

Who inspired you most during your career?

I was always inspired by entrepreneurs or pioneers. For example, Hans Hass, an underwater diving pioneer who dived during World War II. There are a lot of books and movies about him. As a schoolboy, I came across his books in a public library in my village and was inspired by his adventures, such as diving with sharks. For me, it is always important to look beyond boundaries and not see borders as immovable.

Rüdiger Nehberg, another adventurer, was a survival expert and an activist for human rights. He too was constantly jumping over borders. For example, he sailed alone across the Atlantic Ocean in a ridiculously tiny, self-made boat, got seasick, but he made it. He was always inspired by going to the edge and looking beyond borders.

And Rollo Gebhard, a single-handed sailor [this means he sailed alone] who sailed around the world two or three times. For many years I looked up to these highly motivating personalities, they inspired me.

 

Your short-term and most important goal is probably to get the CureVac COVID-19 vaccine approved. However, where would you like to be in ten years?

I hope that I do not have to push forward as much as I did in the last 20 years and I know there is a great team at CureVac. I hope that there will be a lot of treatments based on RNA technology by then. That would be exciting.

I have a family, a wife and two sons, and they became more central to my life. It is not just about the company anymore; it is about my family. And I think they deserve it because they missed their husband and daddy for a few years.

 

Sounds great. Thank you for your time and the interview.

 

Reference

[1] Ingmar Hoerr, Reinhard Obst, Hans‐Georg Rammensee, Günther Jung, In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies, Eur. J. Immunol. 2000. https://doi.org/10.1002/1521-4141(200001)30:1<1::AID-IMMU1>3.0.CO;2-%23

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Ingmar Hoerr, born in 1968, studied biology at Eberhard Karls University in Tübingen, Germany, and spent one year studying at Madurai Kamaraj University, India. In 1999, he received his Ph.D. from Günther Jung, Institute of Organic Chemistry, in cooperation with Hans-Georg Rammensee, Institute of Immunology and Cell Biology, at the University of Tübingen on the topic of RNA vaccines for the induction of specific cytotoxic T lymphocytes (CTL) and antibodies.

In 2000, he co-founded the biopharmaceutical company CureVac with Florian von der Mülbe, Steve Pascalo, Hans-Georg Rammensee, and Günther Jung. Ingmar Hoerr served as CEO until 2018, when he moved to the Supervisory Board as Chairman before being re-elected CEO in 2020. Following an illness, Franz-Werner Haas took over Hoerr’s position as CEO in August 2020.

Ingmar Hoerr holds over 30 patents.

 

mRNA Vaccines CureVac’s, BioNTech’s, and Moderna’s COVID-19 vaccines contain an mRNA that is taken up by cells after injection into a muscle and used to form the spike protein of SARS-CoV-2. The protein, which is foreign to the body, then stimulates the formation of antibodies. CureVac uses a different technology to produce the vaccine than Moderna and BioNTech. One difference is that BioNTech and Moderna chemically modify the mRNA, whereas CureVac relies on the chemically unmodified mRNA. CureVac began development of mRNA-based COVID-19 vaccine candidates in January 2020. The vaccine candidate selected for initial clinical development, CVnCoV, is an optimized, non-chemically modified mRNA encoding the full-length SARS-CoV-2 virus prefusion-stabilized spike protein. It is formulated in lipid nanoparticles (LNPs). CVnCoV has been in Phase 2b/3 clinical trials since December 2020. In February 2021, CureVac initiated a rolling marketing authorization application for CVnCoV with the European Medicines Agency (EMA).

 

CureVac CureVac is a global biopharmaceutical company in the field of mRNA technology with expertise in the development and optimization of mRNA for medical purposes. The company uses non-chemically modified mRNA as a data carrier to instruct the human body to produce its own proteins that can fight a wide range of diseases. The company’s clinical pipeline includes prophylactic vaccines, cancer therapies, antibody therapies, and the treatment of rare diseases. CureVac had its initial public offering on the New York Nasdaq in August 2020. The company is headquartered in Tübingen, Germany, and employs more than 600 people in Tübingen, Frankfurt, both Germany, and Boston, USA. www.curevac.com