The pressure is on to develop novel vaccines based on messenger RNA and aimed at combating cancer and protecting against pandemics. Although mRNA vaccination as a cancer monotherapy has suffered a setback this year, the industry is nevertheless confident that it will succeed because of existing proof that mRNA vaccines stimulate the body's immune defence.
The principle sounds simple: the transcribed genetic blueprint – the mRNA – of a protein exclusively found in disease pathogens or tumour-associated proteins is injected into the body, and the body is then left to produce the proteins itself. In the ideal case scenario, the body's immune system recognises these antigens as foreign and reacts in the same way as it does to a real infection.
It was only in 2016 that researchers from the Tübingen-based biotech company CureVac AG were able to show that mRNA molecules are taken up by different cell types at the site of injection. The cells then release inflammatory mediators that attract further immune cells and start producing antigens. Antibody production reaches its maximum after 24 hours and then slowly decreases. The cells present the foreign antigens to specific patrolling immune cells in the nearby lymph nodes, which then become active.
Unlike conventional vaccines containing attenuated or inactivated pathogens or isolated antigens, producing mRNA vaccines does not require huge numbers of chicken eggs or cells. All that is required is the desired gene, the enzyme that transcribes the gene and the four mRNA components. "The production process is always the same and does not need to be adapted for each vaccine," says Dr. Mariola Fotin-Mleczek, Chief Scientific Officer at CureVac, also pointing out that it takes around six weeks to produce an mRNA vaccine. Conventional vaccines take several months to produce. It is therefore possible to react quickly to rapidly mutating viruses such as the influenza virus. She also pointed out it is not difficult to prepare several vaccines in parallel.
In 2003, CureVac injected the first mRNA vaccine directly under the skin of patients suffering from skin cancer. This was done in cooperation with colleagues from the University of Tübingen. CureVac, which was founded in 2000 and has subsidiaries in Frankfurt and Boston, has acquired around 355 million euros for developing its patented mRNA vaccines. Eight clinical studies on various cancers and infectious diseases are in progress. Meanwhile, a handful of other pharmaceutical and biotech companies from Europe and the USA are working on the development of the first commercial mRNA vaccine for humans. The researchers from Tübingen have come the furthest so far.
Although a French physician by the name of Dr. Frédéric Martinon already demonstrated back in 1993 that mRNA vaccination in mice produced a specific immune response, the professional world remained sceptical. mRNA was considered too unstable to be used for medical treatment as it is rapidly degraded by ubiquitous ribonuclease enzymes. By chance, Dr. Ingmar Hoerr, one of the founders of CureVac AG, discovered as part of his doctoral thesis that mRNA is a very stable molecule and triggers a specific immune response if the ribonucleases are kept away. This discovery was what led to the creation of the company.
mRNA degradation can be further delayed and the translation into proteins stimulated when the vaccine experts replace non-coding mRNA regions with more stable ones and exchange individual nucleotides without altering the genetic information. The optimised mRNA vaccines even tolerate temperatures of up to 60 degrees Celsius and are therefore also suitable for developing countries where vaccine cooling is difficult. In 2014, the Tübingen-based company won an inducement prize from the European Commission to boost the development of heat-stable vaccines that could be used to help the developing world.
However, in early 2017, CureVac announced that its mRNA-based prostate cancer vaccine candidate CV9104 failed a Phase IIb clinical trial aimed at determining whether the administered vaccine was effective in increasing the chance of survival. However, progression-free survival of patients who received injections of mRNA molecules that encoded six tumour-associated antigens was similar to treatment with placebos. For CureVac’s Dr. Fotin-Mleczek, who has co-authored several of CureVac’s vaccine technology patents, this does not mean that mRNA-based cancer immunotherapy has failed: "We have learned that we need to combine different approaches for effective cancer treatment."
There is a further problem with cancer vaccines: many tumour antigens are also formed in smaller quantities by healthy cells. "The immune system tolerates them to a certain extent, and it is this tolerance that we need to break," says the biologist. A promising approach for producing a stronger immune response would be combining the mRNA vaccines with new immune therapeutics from the so-called checkpoint inhibitors class. This approach will be tested in clinical trials involving patients with non-small-cell lung carcinoma in cooperation with the pharmaceutical company Boehringer Ingelheim and the Ludwig Institute for Cancer Research.
Dr. Fotin-Mleczek is very confident about the interim results obtained in a Phase I clinical trial with an mRNA-based rabies vaccine in healthy volunteers designed to test the safety and immunogenicity of this human vaccine. The vaccine, CV7201, contains the mRNA that encodes for the G protein of the rabies virus. The vaccine appears to be well tolerated and no safety concerns were identified. In a cohort of 21 volunteers vaccinated at the lowest dose of 80 microgrammes, 17 volunteers had virus neutralising antibodies that exceeded the threshold considered preventive by the World Health Organisation. CureVac is also working with several partners to investigate vaccines against infectious pathogens including the respiratory syncytial virus and HIV, which vaccine experts usually consider a huge challenge.
However, the medical potential of mRNA molecules still remains largely untapped. In addition to its RNActive® vaccines, CureVac develops RNA-based vaccines and RNA-based efficacy enhancers for protein or mRNA vaccines. These RNAdjuvant® products are non-coding, long-chain RNA molecules combined with positively charged peptides. As this treatment makes them look very much like RNA viruses, they are detected by danger sensors in the human cells known as Toll-like receptors, which bring additional immune cells to the injection site. In principle, any conceivable therapeutic protein can be produced in the body using mRNA technology - antibodies for passive immunisation as well as protein replacements for defective proteins. For example, the Tübingen researchers are investigating mRNA encoding antibodies against the HI virus (RNAntibody®).
"Our approach, which involves using chemically unmodified nucleotides for mRNA optimisation together with improved mRNA packaging is the best basis for mRNA products of any kind," says Dr. Fotin-Mleczek. The company is currently constructing a new production plant in Tübingen where it will be able to produce up to 30 million vaccine doses per year.