A vision becomes reality

Like many other biotechnology companies, CureVac is a spin-off of an academic research project. In the mid-1990s, researcher Ingmar Hoerr focused his doctoral thesis on the question of whether RNA, which is typically unstable, could be used in vaccines. In 1998, he was the first scientist to discover that mRNA could induce a T-cell response in mice – a key finding suggesting that it could someday be administered directly to the body if its biological properties were appropriately modulated inducing an immune response.

This could open up new possibilities for prophylactic vaccines and therapies to treat infectious diseases based on the body’s internal biochemical machinery rather than external agents.

The name CureVac is composed of the words “Cure” and “Vac (cine).” In the early 2000s, the idea of healing through RNA-based vaccination was viewed with skepticism in scientific circles. The prevailing doctrine at the time was that mRNA was not stable enough as a carrier for a vaccine and would degrade too quickly to have a pharmaceutical effect. However, the researchers around Ingmar Hoerr and Florian von der Mülbe were committed to the idea and to their goal of exploiting the potential of mRNA and opening up new therapeutic opportunities across indications.

Over several years, the team developed further insights and a large knowledge base on the function and use of mRNA. Their initial goal was not to work on a product, but to build a novel technology platform that could be used to develop prophylactic vaccines against infectious diseases such as the flu, rotavirus and rabies, as well as therapies targeting different types of cancer.

The RNA People® were the first to enter this new medical territory.

In the year 2000, Dr. Hoerr founded CureVac together with Dr. Florian von der Mülbe, Dr. Steve Pascolo, Prof. Dr. Hans-Georg Rammensee and Prof. Günther Jung to develop RNA-based vaccines and therapies in therapeutic quality. Their vision became a reality.

The discovery of mRNA’s potential for use in vaccines

Discovery of DNA

The prehistory of CureVac began in Tübingen in the 1800s. In 1869, the Swiss physician and biochemist Johann Friedrich Miescher discovered a molecule unknown to him when he was studying proteins in cells at Hohentübingen Castle. The substance did not behave like other proteins and contained phosphorus. Miescher called it a nucleus; he had unknowingly discovered deoxyribonucleic acid (DNA).

The laboratory where Miescher worked was actually the castle kitchen, but well equipped as a laboratory by the standards of the time. Today, the entire castle is a museum. A test tube from the 19th century still bears witness to Miescher’s early research that led the fundamentals of drug development.

Function of RNA molecules

Ribonucleic acid (RNA) is closely related to deoxyribonucleic acid (DNA), from which our genes are built, and consists of a long chain of chemical building blocks called nucleotides. Similar to letters in a book, the sequence of these nucleotides stores information about all processes in our cells. Whereas in DNA two molecular strands – the familiar double helix – form a twisted rope ladder, RNA is generally a single-stranded molecule. RNA performs a variety of functions in the human body and is rapidly degraded by certain enzymes. One of its central functions is the conversion of genetic information into proteins. Messenger RNA (mRNA) acts as the messenger, providing exact instructions for building those proteins.

Short-lived RNA

The medical use of DNA and RNA did not take off until 150 years after their discovery. In exploring medical applications, the initial focus was on DNA, a very large double-stranded molecule that was very stable but somewhat cumbersome. To work with a single-stranded mRNA instead seemed like it might be an easier and safer option, as RNA would decay without leaving any traces once the mRNA did its job, eliminating concerns that it could integrate with DNA and cause genome alteration. However, developing mRNA therapies remained a difficult challenge, and many researchers abandoned mRNA as a medical opportunity in the late 1990s.

Potential of RNA

In 1995, a research group led by Prof. Günther Jung at the Institute of Organic Chemistry at the University of Tübingen and Prof. Dr. Hans-Georg Rammensee, head of the Department of Immunology at the University of Tübingen’s Faculty of Medicine, wanted to test whether messenger RNA (mRNA) could be administered as a vaccine. Doctoral student Ingmar Hoerr, in collaboration with a research group that also included Florian von der Mülbe and Reinhard Obst, tested this theory by trying to immunize the mRNA directly. After injection, the mRNA had to be kept stable to be able to stimulate the cells to produce proteins, allowing the immune system to establish defense mechanisms in order to be prepared for the actual virus. One measure the researchers explored for stabilization was a protective lipid capsule that would keep the mRNA from being naturally degraded by enzymes.

Modification

The Tübingen research group worked further to overcome limitations in the stability of mRNA. It found out that the biomolecule mRNA, which is considered to be very unstable, can be administered directly into the tissue as a therapeutic agent and vaccine if its biological properties are appropriately modulated. Elaborate formulation or molecular packaging are not required for this. These difficult questions were precisely the incentive for Ingmar Hoerr to pursue the intriguing concept of mRNA-based medicines and develop it further for medical applications, including the production of vaccines.

Discovery of mRNA as a vaccine

In his experiments, Ingmar Hoerr wanted to find out whether mRNA could be optimized so a vaccine could prepare the immune system to protect against pathogens. In 1998, as part of his doctoral research, Hoerr injected both RNA protected by a liposome capsule and naked RNA (without a protective sheath) into mice.

The results were unprecedented. While the RNA that was protected showed hardly any reaction, the naked RNA had, contrary to expectations, triggered a strong immune response, activating T and B cells and producing antibodies. Through the experiment, Hoerr was able to demonstrate that RNA can remain relatively stable – a finding that indicated exciting potential for future vaccine research.

A vaccine based on RNA

mRNA offered a near-ideal therapeutic option: it was shown to be stable over a sufficiently long period of time and to decay after protein synthesis without leaving any long-term traces. It could also be produced easily and in large quantities. In his thesis research, CureVac co-founder Ingmar Hoerr laid an experimental foundation for the development of mRNA-based vaccines by demonstrating that mRNA could be optimized and used as a therapeutic vaccine or agent when administered directly into tissue. Thus, Hoerr recognized the potential of mRNA and its future medical applications.

A century and a half after the discovery of DNA and RNA by Friedrich Miescher, Tübingen was once again the starting point for innovative developments in biotechnology and perhaps even for a revolution in medicine.

Doctor thesis of Ingmar Hoerr

In his 1999 dissertation entitled “RNA vaccines for the induction of specific cytotoxic T lymphocytes (CTL) and antibodies” Ingmar Hoerr described the basics of his discovery of the principle of mRNA vaccination. That same year, he presented the results of his doctoral work publicly for the first time on a poster at a congress in India and patented the use of RNA as a vaccine agent. In January 2000, Hoerr and his research colleagues published the discovery under the title “In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies” in the European Journal of Immunology. In the publication, Hoerr and his colleagues explained how specially stabilized and protected mRNA could have applicability not only for vaccines but also for tumor therapy.

Vision of a broad medical application

The wide range of applications of mRNA in medicine motivated the research group around Ingmar Hoerr to further develop the possibilities for mRNA vaccines to treat a variety of diseases. The researchers aimed to develop a well-tolerated, safe and effective mRNA vaccine that could be administered in small doses and ideally could be stored and transported at refrigerator temperature to enable access for developing countries.

To advance the vision of treating people with mRNA vaccines to a reality, it would be essential to confirm the research results and test the safety and efficacy in human clinical trials. The vision was there, but the conditions for it had to be created.

Prerequisites

Soon after the decision was made to harness the potential of mRNA technology and further develop and eventually produce mRNA-based vaccines and drugs, Dr. Ingmar Hoerr, Dr. Florian von der Mülbe and Dr. Steve Pascolo founded CureVac. In collaboration with Prof. Hans-Georg Rammensee and Prof. Günther Jung, the founders registered the company on February 4, 2000 and called themselves the RNA people®. Drs. Hoerr and von der Mülbe received funding from the Baden-Württemberg Ministry of Science, which included the opportunity to use laboratory space at the university and employ doctoral students. The company quickly moved to the neighboring chemistry building and converted existing rooms into a laboratory with clean room conditions for the production of pure RNA.

Extension

Six RNA people pushed ahead with RNA development in 2002, supported by a financing round from a venture capitalist. To expand production in accordance with Good Manufacturing Practice (GMP) guidelines required for the manufacturing of pharmaceutical products regarding consistently high quality standard – additional larger laboratory space as well as a production facility became necessary. The team received an offer to move in as a tenant in the newly developing Technology Park in the north of Tübingen, where it did contract work for research and industry and produced short-chain ribonucleic acid molecules (siRNAs – small interfering RNA) for some years, which among other functions regulate the expression of genes.

Construction of the first GMP plant

With a further round of financing and the arrival of the biochemist Friedrich von Bohlen CureVac set the course for further research progress in 2004. In addition to vaccines (RNActive®), CureVac worked on RNA-based effect enhancers for protein or therapeutical mRNA vaccines. A year later, a new era began for CureVac when the company connected with SAP co-founder and investor Dietmar Hopp, who offered CureVac a long-term planning opportunity with a financial commitment of his investment company dievini Hopp BioTech holding GmbH & Co. KG. Following approval from the Tübingen Regional Council in 2006, CureVac put into operation the world’s first GMP-compliant production facility for the production of RNA for medical use.

2007–2013

In 2009, CureVac opened a new site in Frankfurt, from which employees planned and managed the company’s first clinical trials. In the same year, CureVac began initial studies of its mRNA-based vaccine in prostate and lung cancer. Two years later, data from both studies demonstrated that the vaccine was both safe and tolerable, and elicited the desired strong immune response. Data from a phase 1 study in 2013 for a rabies vaccination led to encouraging results as well. The mRNA technology had proven itself in a variety of ways and was coming to the attention of many scientists. Together with the University of Tübingen, CureVac hosted the first mRNA conference in 2013 for professional exchange and networking.

Partnerships and the 2014 Vaccine Prize

With Sanofi Pasteur SA in 2011, CureVac initiated the first major partnership with a pharmaceutical company for the development of mRNA-based vaccines against infectious diseases. This was followed in 2014 with an agreement with Boehringer Ingelheim Pharma GmbH & Co. KG for further development and commercialization of therapeutic vaccine for the treatment of lung cancer.

CureVac received further recognition in 2014, when the company was honored with the European Commission’s Vaccine Prize for a cold chain for the transport and storage of vaccines.

That same year, the first contact was made for a collaboration with the Bill & Melinda Gates Foundation to promote global health through international vaccination programs and new vaccine development. The common goal of the collaboration was to develop a platform to inexpensively produce, easily transport and store prophylactic vaccines for developing countries.

2015–2019

In 2015, CureVac opened an office in Boston, Massachusetts, USA, and founded the subsidiary CureVac Inc. The company then found its way into a vibrant biotechnology landscape where research and development horizons were expanding. Further rounds of financing followed.

Construction of a fourth production building for the manufacture of mRNA on an industrial scale began in 2017. In 2019, CureVac received manufacturing authorization from the Tübingen Regional Council for its GMP III production facility. Clinical trial material is produced there in accordance with Good Manufacturing Practice (GMP) requirements. Today, CureVac has EU GMP-certification for three production facilities, which represents the highest standard of pharmaceutical production worldwide.

Progress in 2020 and 2021

As the COVID-19 pandemic emerged in early 2020, CureVac made another important decision to develop an mRNA based vaccine against the virus. At this time, RNA technology rapidly moved into the public focus. CureVac’s existing partnerships were renewed and intensified and new partners were added. This was accompanied by financial support from partners and the German government. At the same time the company moved into a new laboratory and office building at Friedrich-Miescher-Strasse 15 in Tübingen.

The company’s evolution since then has included a successful NASDAQ IPO 20 years after its foundation and the start of a global clinical Phase 2b/3 trial of CureVac’s COVID-19 vaccine candidate, as well as partnerships with Bayer, GlaxoSmithKline and the British government. Furthermore, CureVac expanded its European production network with several contract manufacturers.

As CureVac advanced its vaccine into clinical studies, it also accelerated the growth and development of the broader company – the total of employees has increased from 450 at the beginning of 2020 to 600 as of February 2021. This rapid development marks a huge step in the transition from a research-based biotechnology company to an integrated biopharmaceutical company.