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Explanation of RNActive vaccine technology.   

In molecular medicine, nucleic acids are being extensively investigated for use in gene therapy and in genetic vaccinations in which foreign nucleic acid is translated into proteins by the host cells. Vaccines based on DNA and messenger RNA (mRNA) are able to stimulate all effectors of the adaptive immune response: B lymphocytes, cytotoxic T cells, and T helper cells. This makes them a useful tool in the creation of prophylactic vaccines for infectious diseases and for cancer immunotherapy.

Messenger RNAs are non-toxic molecules that address the shortcomings of recombinant virus or DNA-based vaccination therapies. The physiological role of mRNA is to transfer genetic information from the nucleus to the cytoplasm where this information is translated into the corresponding protein. The safety of mRNA-based treatments supports the use of mRNA-vaccination for therapeutic or prophylactic approaches. RNA vaccines don’t contain the virus-derived promoter elements that DNA vaccines do. Also, as the result of homologous recombination or a random event, DNA is able to integrate into the host genome. This can lead to inactivation or activation of genes, may affect regulatory elements, possibly induce oncogenesis, or induce pathogenic anti-DNA antibodies. Despite this, gene therapy approaches involving nucleic acids have focused mostly on DNA-based strategies due to the instability and rapid degradation of RNA in the human body; RNA is prone to hydrolysis by ubiquitous ribonucleases.1

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Nevertheless, it has been shown in studies that local administration of naked mRNA leads to significant protein expression, and mRNA vaccination leads to the expression of the corresponding tumor-derived antigens and the subsequent induction of antigen-specific antitumor responses in mice.2 Although the use of naked RNA for vaccination in a clinical setting is not feasible, the development of protamine-protected RNA—which is more stable than naked RNA and easier to handle—has helped overcome these hurdles.2 Protamine is a small arginine-rich nuclear protein known to stabilize DNA during spermatogenesis. Notably, naked mRNA molecules barely induced maturation of antigen-presenting cells when added to mouse dendritic cells in vitro, but mRNA stabilized by association to a cationic component (like protamine) can mature dendritic cells.3 The complexation of mRNA—also required for strong immune-stimulating activity—may inhibit its translatability. Using a two-component mRNA vaccine that contains free and protamine-complexed mRNA, however, induces balanced adaptive immune responses and provides humoral and T cell-mediated immunity. Importantly, this two-component mRNA-based tumor vaccine supports both antigen expression and immune stimulation, mediated by Toll-like receptor 7 (TLR7).4

CureVac’s mRNA-technology platform, RNActive, modifies and stabilizes mRNA without changing the physiological properties, thus generating mRNA suitable for medical purposes. The technology is currently in clinical trials for castration-resistant prostate cancer. CV9103, a prostate cancer vaccine, contains four antigens as self-adjuvanted full-length mRNAs: prostate-specific antigen (PSA), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), and six transmembrane epithelial antigene of the prostate 1 (STEAP1). Data from a Phase 2a study showed that antigen-specific T-cells were detected in 79% of patients independent of their HLA-background. Additionally, 58% of the immunological responders reacted against multiple antigens. The frequency of antigen-unspecific B-cells was increased in 74% patients.5

References
1. Pascolo S. Messenger RNA-based vaccines. Expert Opin Biol Ther. 2004.
2. Hoerr I, et al. In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. Eur J Immunol. 2000.
3. Scheel B, et al: Immunostimulating capacities of stabilized RNA. Molecules. Eur J Immunol. 2004.
4. Fotin-Mleczek M, et al: Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity. J Immunother. 2011.
5. Kübler H, et al: Final analysis of a phase I/IIa study with CV9103, an intradermally administered prostate cancer. ASCO 2011.

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