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’s doctoral thesis addressed the question of whether RNA, which is considered unstable, could be used in vaccines. He confirmed earlier findings that naked RNA injected into a mouse leads to gene expression in the living organism. This suggested that, with appropriate modulation of its biological properties, the molecule can be administered directly into the body to elicit an immune response.

This could open up new possibilities for cancer therapies as well as prophylactic vaccines against various infectious diseases in which humans produce the active ingredient in their own bodies based on the administered RNA.

The name CureVac is composed of the words “Cure” and “Vac(cine)”. In the early 2000s, the scientific community was skeptical of the idea of healing through RNA-based vaccination. 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 were committed to the idea and to their goal of exploiting the potential of mRNA and opening up new therapeutic opportunities across numerous indications.

Over the course of several years, the CureVac team developed further insights and a large knowledge base on the function and use of mRNA. The goal, first and foremost, was to develop a novel technology platform that could be used in oncology and later in infectious diseases and molecular therapy. CureVac’s RNA people® were the first to enter this new medical territory.

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

The discovery of mRNA’s potential for use in vaccines

Discovery of DNA

The prehistory of CureVac began in Tübingen in the 19th century. In 1869, the Swiss physician and biochemist Johann Friedrich Miescher discovered a molecule unknown to him while studying proteins in cells at Hohentübingen Castle. The substance did not behave like known proteins and contained phosphorus. Miescher called it a nucleus; he had unwittingly discovered deoxyribonucleic acid (DNA).

The laboratory where Miescher worked was actually the castle kitchen, but was well equipped as a laboratory by the standards of the time. Today, the entire castle is a museum. A 19th-century test tube there still bears witness to Miescher’s early research, which laid the foundations for the development of medicines.

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 the cells. Whereas in DNA two molecular strands – the well-known 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 of the exact building instructions for these proteins.

Short-lived RNA

The medical use of DNA and RNA did not take off until 150 years after their discovery. Research into medical applications initially focused on DNA, a larger double-stranded molecule. Single-stranded mRNA, by comparison, seemed easier and safer to handle because it decays and degrades after completing its messenger job, eliminating concerns that it would integrate with DNA and cause genome alteration. However, the development of mRNA therapies continued to be challenging due to ubiquitous degradation enzymes, causing many researchers to abandon mRNA as a medical opportunity in the late 1990s.

Potential of RNA

In 1995, a working 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 Medical Faculty of the University of Tübingen, also looked into the question of whether messenger RNA could be administered as a vaccine. The research group investigated the theory of immunizing directly with mRNA. After injection, the mRNA had to be kept stable until the cells were stimulated to produce proteins, thereby enabling the immune system to start defense mechanisms. The research team investigated ways to keep the mRNA from being naturally degraded by enzymes. They saw as an advantage that in vivo uptake of RNA did not require the use of additional adjuvants or transfection vehicles.

Modification

The Tübingen research group continued to work on overcoming the limitations imposed by the instability of mRNA. They found that the biomolecule mRNA can be delivered directly into tissue as a vaccine and therapeutic agent if its biological properties were appropriately modulated. To do this, protamine, a small, naturally occurring DNA-binding protein, was used to condense the RNA and protect it from degradation.

Discovery of mRNA as a vaccine

In their experiments, the researchers wanted to find out whether mRNA could be optimized in such a way that the immune system could use the vaccination to trigger the fight against tumors. In 1998, as part of his doctoral thesis, Ingmar Hoerr injected mice with both RNA protected by a liposome coat and naked RNA without a protective coat.

The result was surprising: even the naked RNA, which had been administered intradermally into the auricle, triggered a strong immune response, activated T and B cells and formed antibodies. This experiment demonstrated that RNA can remain stable for a sufficiently long time to trigger an immune response – this was a result that pointed to great potential for future vaccine research.

A vaccine based on RNA

mRNA presented itself as an almost ideal therapeutic option: it had been shown to be stable over a sufficiently long period of time and to decay after protein synthesis. It could also be produced easily and in large quantities. In his doctoral thesis, Ingmar Hoerr laid an experimental foundation for the development of mRNA-based vaccines. He demonstrated that mRNA could be optimized for direct delivery into tissue and used as a vaccine or active ingredient. Hoerr thus 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 fundamentals of the principle of mRNA vaccination. In the same year, he presented the results of his doctoral thesis publicly for the first time on a poster at a congress in India and patented the use of RNA as a vaccine. In January 2000, the finding was published in the European Journal of Immunology under the title “In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies.” It concluded that specially stabilized and protected mRNA molecules can be a tool for vaccination and have the potential to be used as both therapeutic and prophylactic vaccines.

Vision of a broad medical application

The many uses of mRNA in medicine motivated the research group to further develop the potential of 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 being able to treat people with mRNA vaccines, it was necessary to confirm the research results and test the safety and efficacy in human clinical trials. The vision was there, but the conditions had to be created.

Prerequisites

After deciding 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®. As financial start-up support, Dr. Hoerr and Dr. von der Mülbe received a grant from the Baden-Württemberg Ministry of Science which included the use of laboratory space at the university and the employment of graduate students. The company soon moved into the neighboring chemistry building. An existing room was converted into a laboratory specifically for the production of pure RNA.

Extension

Six of CureVac’s first RNA people drove the development of mRNA forward in 2002, supported by a financing round from a venture capital company. In order to expand production according to Good Manufacturing Practice (GMP) guidelines, which are required for the manufacture of pharmaceutical products in terms of a consistently high-quality standard, additional laboratory space and a production facility were required. The team received an offer to move into the newly developing technology park in the north of Tübingen as a tenant. They were able to carry out further research into the use of RNA therapies in humans as well as contract work for research and industry there for several years. During this time, CureVac produced short-chain ribonucleic acid molecules (siRNAs – small interfering RNA), which regulate the expression of genes, among other things.

Construction of the first GMP plant

With another round of financing and the arrival of 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 for its own therapeutic mRNA vaccines. A year later, a new era began with the contact to SAP co-founder and investor Dietmar Hopp. Through the financial commitment from his investment company, dievini Hopp BioTech holding GmbH & Co. KG, he offered CureVac long-term planning security. Following approval by the Tübingen Regional Council in 2006, CureVac put into operation the world’s first GMP-compliant production facility for the manufacture 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 started initial studies for an mRNA-based vaccine against prostate cancer and lung cancer. Data from a 2013 phase 1 trial for a rabies vaccine also produced encouraging results. The mRNA technology had proven itself in a variety of ways and had now also come 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

In 2011, CureVac entered into its first major collaboration with a pharmaceutical company, Sanofi Pasteur SA, to develop vaccines against infectious diseases. This was followed in 2014 with CureVac’s agreement with Boehringer Ingelheim Pharma GmbH & Co. KG to further develop and commercialize a therapeutic vaccine for the treatment of lung cancer.

CureVac received further recognition in 2014 when the company was awarded the European Commission’s Vaccine Prize. The RNActive® vaccines were deemed worthy of the prize because they did not need to be refrigerated and could be transported and stored without much effort.

In the 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 cost-effectively produce and easily transport vaccines for developing countries.

2015–2019

In 2015, CureVac opened an office in Boston, Massachusetts, USA, and founded the subsidiary CureVac Inc. This gave the company a foothold in a vibrant biotechnology landscape where research and development horizons were expanding. Further rounds of financing followed.

Construction of a fourth manufacturing building to produce mRNA on an industrial scale began in 2017. In 2019, CureVac received a manufacturing permit for its GMP III production facility from the Tübingen Regional Council. Clinical trial material is produced there in accordance with Good Manufacturing Practice (GMP) requirements. As a result, CureVac now holds EU GMP certification for three manufacturing sites.

Progress in 2020 and 2021

As the COVID-19 pandemic emerged in early 2020, CureVac decided to develop a vaccine against the virus, which was a landmark decision for the company. During this time, mRNA technology rapidly moved into the public focus. CureVac renewed and intensified existing partnerships and new partners were added. This was accompanied by financial support and funding from investors, partners and the federal government. At the same time, the company also moved into a new laboratory and office building at Friedrich-Miescher-Strasse 15 in Tübingen.

In March 2020, the company’s co-founder, Dr. Ingmar Hoerr, succeeded Daniel Menichella as CEO. As Hoerr fell ill shortly afterwards, Dr. Franz-Werner Haas took over the business – first as acting Chairman of the Management Board and Chief Operating Officer (COO), then as Chairman of the Management Board (CEO) from August 2020. Under his aegis, he realigned CureVac from a biotech to an integrated biopharma company.

The successful IPO on the New York Nasdaq 20 years after the company was founded, the start of a global phase 2b/3 clinical trial for the COVID-19 vaccine candidate and the partnerships with Bayer, GlaxoSmithKline and the UK government represented important milestones on this path. In addition, CureVac expanded its European manufacturing network with several contract manufacturers.

The start of clinical trial phases for its COVID-19 vaccine candidate, CVnCoV, accelerated the growth and development of the company as a whole – the number of employees increased from around 450 at the beginning of 2020 to over 600 in February 2021. This rapid development marks CureVac’s transition from a research-based biotechnology company to an integrated biopharma company.