RNA vaccine

from Wikipedia, the free encyclopedia

An RNA vaccine (also: RNA vaccine ) is a vaccine whose mechanism of action is based on ribonucleic acid (RNA). The RNA (usually a messenger RNA , also messenger RNA or mRNA) contains the code for the protein that is produced in a cell by translation and presented to the immune system ; it acts as an antigen . The immune system learns to selectively fight cells that express such antigens, such as virus-infected host cells or tumor cells .

RNA vaccines can be developed against all protein-based antigens, since after vaccination with an RNA vaccine, a protein is formed from the RNA template during translation. The proteins can be derived from viruses, bacteria or tumors ( tumor antigen ) , for example . The use of RNA vaccines for immunization against viral infectious diseases means that no longer reproductive pathogens or their fragments are introduced into the organism, as is the case with dead vaccines , but only an mRNA of the antigens with an auxiliary substance that introduces the RNA into cells (transfection reagent ). When the mRNA-transfected cells temporarily present this component of the virus to be controlled , the learnsImmune defense of the vaccinated to break down the antigen and, in the event of an actual infection, to protect it from the natural pathogen. The result: the host (human or animal) becomes immune .

designation

RNA is the English abbreviation for "ribonucleic acid", which is known in German-speaking countries as RNS, an abbreviation for ribonucleic acid.

history

The production of RNA outside an organism ( in vitro ) with subsequent translation in an organism ( in vivo ) was first described in 1990. In 1994, RNA was first used for vaccination. RNA vaccines are being studied against both pathogens and for use as a cancer vaccine .

Manufacturing

The production is mostly done by in vitro transcription . In order to smuggle the RNA into the cell, it is injected with a transfection reagent , electroporated , administered by gene gun or the vaccination takes place ex vivo with subsequent adoptive cell transfer . As a transfection reagent are lipids (so that there are lipid - nanoparticles , LNP), cell-penetrating peptides , proteins or polymers used. Gold nanoparticles with a diameter of around 80 nm (AuNPs) are also used. These formulations are necessary because of the limited stability of mRNA in vivo and for better uptake of the RNA in cells. During transfection, the RNA is taken up into the cell by receptor-mediated endocytosis . At least with DNA (which uses the same methods as RNA and which is taken up by cells via the same mechanisms) there is only a weak correlation between uptake in cell culture and in vivo and no correlation between uptake in cell culture and the Vaccination effect. This means that the vaccination effect can only be estimated from the phase of the preclinical studies , since only then can the vaccination effect be measured.

Mode of action

By the production of the antigen in the cytosol of the cell takes place after decomposition by proteases , a presentation of the epitopes of the antigen on the major histocompatibility complex MHC I (producing a cellular immune response ) and MHC II (generates a humoral immune response ). If a membrane protein is used as the antigen, the membrane protein is also presented on the cell surface . The more stable an mRNA, the more frequently it can be translated, i.e. the more protein is produced on this mRNA template. The biological half-life of the mRNA can vary widely and is between minutes (for example in the case of regulatory proteins) and a few hours. A cap structure at the 5 'end of the mRNA and an untranslated region (UTR) at the 5' and 3 'ends increase the biological half-life of the mRNA before it is broken down by ribonucleases (RNases), which means that more antigen is formed . A limited extension of the biological half-life and thus an increase in antigen production is achieved by means of small mRNA fragments, so-called replicable mRNA ( small activating mRNA , samRNA ). The samRNA acts as a sensor and stimulator for its own gene expression , which plays an active role in the specific positive feedback regulation of gene expression. As a result, the amount of RNA used for vaccination can be reduced with the same vaccination effect, since 50 ng RNA has been described as sufficient for a vaccination effect. Since samRNA is significantly larger than mRNA, the mechanism of uptake into the cell can be different. Adjuvants can be used to enhance the immune response . Self- replicating RNA vaccines are more effective when they are formulated in a cationic nanoemulsion ( emulsions with a droplet diameter of less than 100 nanometers ) based on the adjuvant MF59 . The effectiveness of mRNA can be enhanced by bringing the molecules together with TriMix . TriMix is a proprietary mRNA mixture which codes for three proteins that activate the immune system ( CD40 L, CD70 and ca TLR-4 ).

Problematic immune response

One problem with the development of RNA vaccines is that the RNA can trigger an excessive immune response by activating the innate immune response . The activation of the innate immune response is accomplished by binding the RNA to Toll-like receptors (TLR including 7), RIG-I and protein kinase R . In order to minimize an excessive immune response against the RNA, the mRNA vaccine sequences are designed to mimic those produced by mammalian cells. In addition, an immune reaction against the RNA can be reduced by modified nucleosides ( pseudouridine , 5-methylcytidine , 2'-O-methylated nucleosides) or by codon optimization and the use of certain untranslated regions (an edge area of ​​the mRNA that does not code for the actual protein) which also slows down the degradation of the RNA. Furthermore, aborted transcripts and RNA interference , which leads to the premature degradation of double-stranded RNA, can reduce the duration of action. Therefore a multi-stage RNA purification is necessary. Undesired double-stranded RNA can be removed comparatively inexpensively by adsorption on cellulose . Certain purification techniques, such as Fast Protein Liquid Chromatography (FPLC), increase translation.

Extracellular RNA is known as a procoagulant and permeability-increasing factor. An increased permeability of endothelial cells can lead to edema , and stimulation of blood coagulation carries the risk of thrombus formation . The clinical pictures triggered by the latter include infarction , ischemic stroke , thrombosis or, as a consequence, pulmonary embolism .

Comparison with other types of vaccines

In contrast to DNA vaccines , RNA vaccines are not transported into the cell nucleus and are not dependent on import into the cell nucleus and on transcription . In contrast to DNA vaccines, there is also no risk of insertion into genomic DNA or, due to the comparatively short biological half-life of RNA, that it remains permanently in the cell. In contrast to attenuated vaccines ( consisting of pathogens with a weakened effect), no reversion (reverse mutation) to a pathogen can occur because only individual components of a pathogen are used. Furthermore, RNA vaccines can be produced in large quantities comparatively quickly and production is considered to be relatively inexpensive.

Clinical studies

COVID-19

Various RNA vaccines are vaccine candidates in the development of a coronavirus vaccine , especially a SARS-CoV-2 vaccine since the end of 2019 .

BNT162

On April 22, 2020, the Paul Ehrlich Institute approved a clinical study for such a vaccine for the first time in Germany ; it is the candidate BNT162 from BioNTech . The mRNA formats are uridine-containing mRNA (uRNA), nucleoside-modified mRNA (modRNA) and self-amplifying mRNA (saRNA) with high immunogenicity. Lipid nanoparticles (LNPs) are used as the mRNA transfection reagent. These LNPs are stable after injection and can enter cells together with the mRNA. They generate a strong antibody response and a strong T cell response ( CD8 , CD4 ).

The Phase I study at BioNTech began on April 29, 2020. The first results are expected in July 2020. The four most promising candidates were then selected from 20 vaccine variants. They have the sub-names a1, b1, b2, c2. These will be tested again on a total of 7,600 study participants - then also on high-risk patients. The groups include 18 to 55 years, 65 to 85 years and 18 to 85 years. The study consists of 3 phases. Phase 1: Identification of preferred vaccine candidates, dose level (s), number of doses and administration schedule (with the first 15 participants at each dose level of each vaccine candidate comprising a sentinel cohort); Phase 2: an extended cohort level; and phase 3; a final candidate / large dose stage. The company expects this second test phase to end in 2021. Further applications for approval are in preparation for studies in the USA (in cooperation with Pfizer ) and in China (with Fosun Pharma).

According to a release from BioNTech dated July 1, 2020, at least four experimental candidates will be evaluated, each of which represents a unique combination of the mRNA format and the target antigen. A manuscript describes the preliminary clinical data for the candidate for the nucleoside-modified messenger RNA (modRNA), designated BNT162b1, which encodes an optimized SARS-CoV-2 receptor binding domain (RBD) antigen , and is available on an online Preprint server available. Overall, the data showed that the tested BNT162b1 doses were well tolerated and produced dose-dependent immunogenicity, as measured by the RBD-binding IgG concentrations and the SARS-CoV-2-neutralizing antibody titers.

On July 14, 2020, the FDA promised an expedited approval process for the vaccine candidates BNT162b1 and BNT162b2 .

mRNA-1273

The American company Moderna had already started a clinical study for its vaccine candidate mRNA-1273 on March 16, 2020 , in collaboration with the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID), a section of the National Institute of Health (NIH). The vaccine mRNA-1273 contains the messenger RNA (mRNA) of the S-protein with which the coronaviruses dock on the epithelial cells. The mRNA is incorporated into lipid nanoparticles ( cholesterol , distearoylphosphatidylcholine (DSPC) and DMG-PEG 2000), which is absorbed by body cells after intramuscular injection. The cells then produce the S protein (spike protein). It is recognized as foreign by the immune system, which stimulates the formation of protective antibodies . The usual animal studies were skipped. The US Food and Drug Administration (FDA) appears to be relying on preclinical testing of vaccines made on the same platform against the first SARS coronavirus and against the MERS coronavirus , without any safety issues. However, they should be made up for in parallel to the clinical studies. Initial statements on immunity are available. After the vaccine has generated sufficient antibody titers , a phase 2 study will be carried out on a larger number of subjects. A phase 3 study with dosages between 25 µg and 100 µg has been carried out since July 27, 2020.

The Curevac AG received on 17 June 2020, the approval for the Phase 1 clinical trial of its vaccine program for the prevention of SARS-CoV-2 infection by the Paul Ehrlich Institute (PEI) and the Belgian Federal Agency for Medicines and Health Products (FAMHP). The vaccine candidate shows a balanced immune response and leads to the formation of spike protein-specific T-cell reactions. The dose-escalating clinical phase 1 comprised 168 healthy volunteers aged 18 to 60 years and covered a dose range from 2 µg to 8 µg. A phase 2 study has been running since the end of May with the aim of providing the first indications that a vaccine can be used in patients suffering from the disease. Without waiting for the results of the phase 2 study, Curevac started the phase 3 study with 30,000 test subjects in the USA at the end of July 2020, which met with fierce criticism.

COVAC1

The Imperial College London began in June 2020 of the study to a lipid nanoparticle formulation ( lipid nanoparticle , LNP) self- amplifying the RNA (Sarna) (LNP nCoVsaRNA) that runs under the name COVAC1. The study is supported by the Medical Research Council and the National Institute for Health Research , and the vaccine is manufactured by the Austrian Polymun Scientific Immunobiological Research GmbH.

More vaccines

RNA vaccines are also being investigated in clinical trials for use as a cancer vaccine, as well as an influenza vaccine and a rabies vaccine (CV7201).

Influenza vaccine

Influenza vaccines made from mRNA are supported in the European Union by, for example, CORDIS , a research and development information service of the European Community , and the UniVax project, with eleven institutions from seven EU countries. On the one hand, RNA vaccines are intended to ensure that the influenza virus no longer produces any reproductive offspring in the body of the vaccinated person. On the other hand, the immune system should be better prepared for future variants of the influenza virus.

Rabies vaccine

One of the new concepts for rabies vaccination is the use of mRNA to encode the major rabies virus antigen, envelope glycoprotein (RABV-G). Preclinical studies with RABV-G mRNA encapsulated in lipid nanoparticles show improved response in both mice and non-human primates. The results are currently being followed up in human clinical trials.

Cancer vaccine

The development of stabilized RNA-based vaccines for clinical use in cancer is currently in the early stages of clinical testing. Starting from a production plasmid, the mRNA is transcribed using recombinant RNA polymerases and then separated from the DNA template, from faulty, too short and too long transcripts and nucleotides in a multi-stage purification process. Proof of the potential of these novel active ingredients for combating currently untreatable cancers in humans has yet to be provided.

Preclinical Studies

COVID-19

Arcturus Therapeutics (LUNAR-COV19), Inovio Pharmaceuticals (INO-4800) and the OpenCorona consortium are also working preclinically on RNA vaccines against COVID-19 .

Further

mRNA is also conceivable for therapeutic use. An animal study showed that administration of nano-encapsulated mRNA, which codes for parts of a broadly neutralizing anti-HIV antibody , protected humanized mice from exposure to HIV. The data suggest that the use of nucleoside-modified mRNA for passive immunotherapy against HIV , cytomegalovirus (CMV), human papilomavirus (HPV), etc. could be expanded.

Veterinary sector

mRNA vaccines can also be used in the veterinary field to prevent infectious diseases in animals. It could be shown that the immunization with in vitro transcribed mRNA in mice induced protection against the foot-and-mouth disease virus . A self-amplifying mRNA vaccine encoding rabies virus glycoprotein induced an immune response in mice and may be useful in preventing rabies in dogs. An encapsulated modified mRNA vaccine encoding the prM and E genes of the deer tick Powassan virus (POWV) induced a humoral immune response not only against POWV strains, but also against the related Langat virus .

Admission

No RNA vaccine has yet been approved in the EU, nor are there any approvals in the USA, Japan or other countries (as of May 2020).

mRNA vaccines are modern biomedical drugs that can only be approved by the European Commission in the EU and the European Economic Area together in a centralized process coordinated by the European Medicines Agency (EMA) . Two member states are given lead responsibility for such a procedure.

Web links

Individual evidence

  1. a b c Rein Verbeke, Ine Lentacker, Stefaan C. De Smedt, Heleen Dewitte: Three decades of messenger RNA vaccine development. In: Nano Today. 28, 2019, p. 100766, doi : 10.1016 / j.nantod.2019.100766 .
  2. ^ JA Wolff, RW Malone, P. Williams, W. Chong, G. Acsadi, A. Jani, PL Felgner: Direct gene transfer into mouse muscle in vivo. In: Science . Volume 247, number 4949 Pt 1, March 1990, pp. 1465-1468, doi : 10.1126 / science.1690918 , PMID 1690918 .
  3. X. Zhou, P. Berglund, G. Rhodes, SE Parker, M. Jondal, P. Liljeström: Self-replicating Semliki Forest virus RNA as recombinant vaccine. In: Vaccine . Volume 12, Number 16, December 1994, pp. 1510-1514, doi : 10.1016 / 0264-410x (94) 90074-4 , PMID 7879415 .
  4. ^ MA McNamara, SK Nair, EK Holl: RNA-Based Vaccines in Cancer Immunotherapy. In: Journal of immunology research. Volume 2015, 2015, p. 794528, doi : 10.1155 / 2015/794528 , PMID 26665011 , PMC 4668311 (free full text).
  5. a b c d e f g h i j C. Poveda, AB Biter, ME Bottazzi, U. Strych: Establishing Preferred Product Characterization for the Evaluation of RNA Vaccine Antigens. In: Vaccines. Volume 7, number 4, September 2019, p., Doi : 10.3390 / vaccines7040131 , PMID 31569760 , PMC 6963847 (free full text).
  6. KE Broderick, LM Humeau: Electroporation-enhanced delivery of nucleic acid vaccines. In: Expert review of vaccines. Volume 14, Number 2, February 2015, pp. 195-204, doi : 10.1586 / 14760584.2015.990890 , PMID 25487734 .
  7. ^ A b N. Pardi, MJ Hogan, FW Porter, D. Weissman: mRNA vaccines - a new era in vaccinology. In: Nature reviews. Drug discovery. Volume 17, number 4, 04 2018, pp. 261-279, doi : 10.1038 / nrd.2017.243 , PMID 29326426 , PMC 5906799 (free full text).
  8. D. Benteyn, C. Heirman, A. Bonehill, K. Thielemans, K. Breckpot: mRNA-based dendritic cell vaccines. In: Expert review of vaccines. Volume 14, number 2, February 2015, pp. 161-176, doi : 10.1586 / 14760584.2014.957684 , PMID 25196947 .
  9. ^ AM Reichmuth, MA Oberli, A. Jaklenec, R. Langer, D. Blankschtein: mRNA vaccine delivery using lipid nanoparticles. In: Therapeutic delivery. Volume 7, number 5, 2016, pp. 319–334, doi : 10.4155 / tde-2016-0006 , PMID 27075952 , PMC 5439223 (free full text).
  10. a b Gómez-Aguado, Rodríguez-Castejón, Vicente-Pascual, Rodríguez-Gascón, Ángeles Solinís, Pozo-Rodríguez: " Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives " Nanomaterials 2020, 20 Feb 2020; doi: 10.3390 / nano10020364
  11. Jump up VK Udhayakumar, A. De Beuckelaer, J. McCaffrey, CM McCrudden, JL Kirschman, D. Vanover, L. Van Hoecke, K. Roose, K. Deswarte, BG De Geest, S. Lienenklaus, PJ Santangelo, J. Grooten , HO McCarthy, S. De Koker: Arginine-Rich Peptide-Based mRNA Nanocomplexes Efficiently Instigate Cytotoxic T Cell Immunity Dependent on the Amphipathic Organization of the Peptide. In: Advanced healthcare materials. Volume 6, number 13, July 2017, p., Doi : 10.1002 / adhm.201601412 , PMID 28436620 .
  12. T. Démoulins, PC Englezou, P. Milona, ​​N. Ruggli, N. Tirelli, C. Pichon, C. Sapet, T. Ebensen, CA Guzmán, KC McCullough: Self-Replicating RNA Vaccine Delivery to Dendritic Cells. In: Methods in molecular biology. Volume 1499, 2017, pp. 37-75, doi : 10.1007 / 978-1-4939-6481-9_3 , PMID 27987142 .
  13. ^ Stanley A. Plotkin et al .: Plotkin's Vaccines . 7th edition. Elsevier, Philadelphia 2017, ISBN 978-0-323-35761-6 , pp. 1297 ( elsevier.com ).
  14. J. Probst, B. Weide, B. Scheel, BJ Pichler, I. Hoerr, HG Rädenee, S. Pascolo: Spontaneous cellular uptake of exogenous messenger RNA in vivo is nucleic acid-specific, saturable and ion dependent. In: Gene therapy. Volume 14, Number 15, August 2007, pp. 1175-1180, doi : 10.1038 / sj.gt.3302964 , PMID 17476302 .
  15. C. Lorenz, M. Fotin-Mleczek, G. Roth, C. Becker, TC Dam, WP Verdurmen, R. Brock, J. Probst, T. Schlake: Protein expression from exogenous mRNA: uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway. In: RNA biology. Volume 8, Number 4, 2011 Jul-Aug, pp. 627-636, doi : 10.4161 / rna.8.4.15394 , PMID 21654214 .
  16. K. Paunovska, CD Sago, CM Monaco, WH Hudson, MG Castro, TG Rudoltz, S. Kalathoor, DA Vanover, PJ Santangelo, R. Ahmed, AV Bryksin, JE Dahlman: A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation. In: Nano letters. Volume 18, number 3, 03 2018, pp. 2148-2157, doi : 10.1021 / acs.nanolett.8b00432 , PMID 29489381 , PMC 6054134 (free full text).
  17. SE McNeil, A. Vangala, VW Bramwell, PJ Hanson, Y. Perrie: lipoplex formulation and optimization: in vitro transfection studies reveal no correlation with in vivo vaccination studies. In: Curr Drug Deliv . (2010), Volume 7, No. 2, pp. 175-187. PMID 20158478 .
  18. ^ T. Kramps, K. Elbers: Introduction to RNA Vaccines. In: Methods in molecular biology. Volume 1499, 2017, pp. 1-11, doi : 10.1007 / 978-1-4939-6481-9_1 , PMID 27987140 .
  19. Eukaryotic gene regulation: RNA stability in eukaryotes. In: ChemgaPedia. Wiley Information Services GmbH, accessed June 9, 2020 .
  20. A. Rodríguez-Gascón, A. del Pozo-Rodríguez, M. Solinís: Development of nucleic acid vaccines: use of self-amplifying RNA in lipid nanoparticles. In: International journal of nanomedicine. Volume 9, 2014, pp. 1833-1843, doi : 10.2147 / IJN.S39810 , PMID 24748793 , PMC 3986288 (free full text).
  21. KC McCullough, P. Milona, ​​L. Thomann-Harwood, T. Démoulins, P. Englezou, R. Suter, N. Ruggli: Self-Amplifying Replicon RNA Vaccine Delivery to Dendritic Cells by Synthetic Nanoparticles. In: Vaccines. Volume 2, number 4, October 2014, pp. 735-754, doi : 10.3390 / vaccines2040735 , PMID 26344889 , PMC 4494254 (free full text).
  22. ^ AB Vogel, L. Lambert, E. Kinnear, D. Busse, S. Erbar, KC Reuter, L. Wicke, M. Perkovic, T. Beissert, H. Haas, ST Reece, U. Sahin, JS Tregoning: Self -Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses. In: Molecular therapy: the journal of the American Society of Gene Therapy. Volume 26, number 2, 02 2018, pp. 446–455, doi : 10.1016 / j.ymthe.2017.11.017 , PMID 29275847 , PMC 5835025 (free full text).
  23. MA Marc, E. Domínguez-Álvarez, C. Gamazo: Nucleic acid vaccination strategies against infectious diseases. In: Expert opinion on drug delivery. Volume 12, number 12, 2015, pp. 1851-1865, doi : 10.1517 / 17425247.2015.1077559 , PMID 26365499 .
  24. The TriMix technology , Etherna immunotherapies NV, Belgium, accessed on May 25, 2020
  25. a b K. Karikó, H. Muramatsu, J. Ludwig, D. Weissman: Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. In: Nucleic acids research. Volume 39, number 21, November 2011, p. E142, doi : 10.1093 / nar / gkr695 , PMID 21890902 , PMC 3241667 (free full text).
  26. a b M. Fotin-Mleczek, KM Duchardt, C. Lorenz, R. Pfeiffer, S. Ojkić-Zrna, J. Probst, KJ Kallen: Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity. In: Journal of immunotherapy. Volume 34, Number 1, January 2011, pp. 1-15, doi : 10.1097 / CJI.0b013e3181f7dbe8 , PMID 21150709 .
  27. a b A. Thess, S. Grund, BL Mui, MJ Hope, P. Baumhof, M. Fotin-Mleczek, T. Schlake: Sequence-engineered mRNA Without Chemical Nucleoside Modifications Enables an Effective Protein Therapy in Large Animals. In: Molecular therapy: the journal of the American Society of Gene Therapy. Volume 23, number 9, September 2015, pp. 1456–1464, doi : 10.1038 / mt.2015.103 , PMID 26050989 , PMC 4817881 (free full text).
  28. ^ University of Cambridge, PHG Foundation: RNA vaccines: an introduction. Retrieved April 20, 2020 .
  29. a b L. Warren, PD Manos, T. Ahfeldt, YH Loh, H. Li, F. Lau, W. Ebina, PK Mandal, ZD Smith, A. Meissner, GQ Daley, AS Brack, JJ Collins, C. Cowan, TM Schlaeger, DJ Rossi: Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. In: Cell stem cell. Volume 7, number 5, November 2010, pp. 618-630, doi : 10.1016 / j.stem.2010.08.012 , PMID 20888316 , PMC 3656821 (free full text).
  30. K. Karikó, M. Buckstein, H. Ni, D. Weissman: Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. In: Immunity. Volume 23, Number 2, August 2005, pp. 165-175, doi : 10.1016 / j.immuni.2005.06.008 , PMID 16111635 .
  31. N. Pardi, D. Weissman: Nucleoside Modified mRNA Vaccines for Infectious Diseases. In: Methods in molecular biology. Volume 1499, 2017, pp. 109-121, doi : 10.1007 / 978-1-4939-6481-9_6 , PMID 27987145 .
  32. a b N. Pardi, MJ Hogan, D. Weissman: Recent advances in mRNA vaccine technology. In: Current opinion in immunology. [electronic publication before printing] March 2020, doi : 10.1016 / j.coi.2020.01.008 , PMID 32244193 .
  33. G. Hager: Nonclinical Safety Testing of RNA vaccines. In: Methods in molecular biology. Volume 1499, 2017, pp. 253-272, doi : 10.1007 / 978-1-4939-6481-9_16 , PMID 27987155 .
  34. M. Baiersdörfer, G. Boros, H. Muramatsu, A. Mahiny, I. Vlatkovic, U. Sahin, K. Karikó: A Facile Method for the Removal of dsRNA Contaminant from In Vitro-Transcribed mRNA. In: Molecular therapy. Nucleic acids. Volume 15, April 2019, pp. 26–35, doi : 10.1016 / j.omtn.2019.02.018 , PMID 30933724 , PMC 6444222 (free full text).
  35. Functional importance of the extracellular RNA / RNase system for vascular homeostasis , German Research Foundation. Retrieved May 25, 2020.
  36. Heart attack and stroke: when thrombi clog the blood vessels. In: Deutsche Apothekerzeitung . September 7, 1997, accessed May 28, 2020 .
  37. T. Schlake, A. Thess, M. Fotin-Mleczek, KJ Kallen: Developing mRNA vaccine technologies. In: RNA biology. Volume 9, number 11, November 2012, pp. 1319-1330, doi : 10.4161 / rna.22269 , PMID 23064118 , PMC 3597572 (free full text).
  38. Gene-based vaccines: hope also for protection against SARS-CoV-2 Ärzteblatt. Retrieved July 17, 2020
  39. ^ Vaccination with genes Pharmaceutical newspaper. Retrieved July 17, 2020
  40. First clinical trial of a COVID-19 vaccine approved in Germany. Paul Ehrlich Institute, April 22, 2020, accessed on April 22, 2020 .
  41. Background information on the development of SARS-CoV-2 vaccines on the occasion of the approval of the first clinical trial of a SARS-CoV-2 vaccine in Germany , Paul-Ehrlich-Institut, April 22, 2020. Retrieved on May 21, 2020.
  42. NCT04368728 Study to Describe the Safety, Tolerability, Immunogenicity, and Potential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults , ClinicalTrials.gov, as of June 5, 2020. Retrieved June 12, 2020.
  43. BNT162b1
  44. Pfizer and BioNTech Announce Early Positive Data from an Ongoing Phase 1/2 Study of mRNA-based Vaccine Candidate Against SARS-CoV-2 , BioNTech, July 1, 2020. Accessed July 22, 2020.
  45. FDA grants fast track status to Pfizer and BioNTech Covid-19 vaccines , Pharmaceutical technology, July 14, 2020. Accessed July 22, 2020.
  46. ^ Ulrich Martin: The Biologics News and Reports Portal. Retrieved April 23, 2020 (UK English).
  47. Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19) , US National Library of Medicine. As of May 4, 2020. Accessed May 27, 2020.
  48. SARS-CoV-2: First vaccine study has started in the USA , Ärzteblatt, March 17, 2020. Accessed on May 19, 2020.
  49. PM: Moderna Announces Positive Interim Phase 1 Data for its mRNA Vaccine (mRNA-1273) Against Novel Coronavirus , May 18, 2020. Accessed May 19, 2020.
  50. NCT04405076 Dose-Confirmation Study to Evaluate the Safety, Reactogenicity, and Immunogenicity of mRNA-1273 COVID-19 Vaccine in Adults Aged 18 Years and Older , ClinicalTrials.gov, as of May 28, 2020. Accessed June 12, 2020.
  51. Phase 3 clinical trial of investigational vaccine for COVID-19 begins. July 25, 2020, accessed on July 30, 2020 .
  52. Stephanie Soucheray | News reporter | CIDRAP News | Jul 27, 2020: Phase 3 trial for Moderna COVID-19 vaccine begins amid US summer surge. Accessed July 30, 2020 (English).
  53. CureVac receives the green light from German and Belgian regulatory authorities to start clinical phase 1 with its SARS-CoV-2 vaccine candidate , PM CureVac, June 17, 2020. Accessed June 17, 2020.
  54. Phase 3 Clinical Trial of Investigational Vaccine for COVID-19 Begins , Drugs.com, July 27, 2020. Accessed August 10, 2020.
  55. First volunteer receives Imperial COVID-19 vaccine. Ryan O'Hare, June 23, 2020. Accessed June 26, 2020 .
  56. ^ Liposomal Formulation of Drugs. Polymun, Reference projects. Retrieved June 26, 2020 .
  57. B. Weide, JP Carralot, A. Reese, B. Scheel, TK Eigenler, I. Hoerr, HG Rädenee, C. Garbe, S. Pascolo: Results of the first phase I / II clinical vaccination trial with direct injection of mRNA . In: Journal of immunotherapy. Volume 31, Number 2, 2008 Feb-Mar, pp. 180-188, doi : 10.1097 / CJI.0b013e31815ce501 , PMID 18481387 .
  58. B. Weide, S. Pascolo, B. Scheel, E. Derhovanessian, A. Pflugfelder, TK Eigenler, G. Pawelec, I. Hoerr, HG R Bäumenee, C. Garbe: Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients. In: Journal of immunotherapy. Volume 32, Number 5, June 2009, pp. 498-507, doi : 10.1097 / CJI.0b013e3181a00068 , PMID 19609242 .
  59. Megan A. McNamara et al .: RNA-Based Vaccines in Cancer Immunotherapy . In: Journal of Immunology Research . tape 2015 , 2015, doi : 10.1155 / 2015/794528 , PMID 26665011 , PMC 4668311 (free full text).
  60. ^ FB Scorza, N. Pardi: New Kids on the Block: RNA-Based Influenza Virus Vaccines. In: Vaccines. Volume 6, number 2, April 2018, p., Doi : 10.3390 / vaccines6020020 , PMID 29614788 , PMC 6027361 (free full text).
  61. N. Armbruster, E. Jasny, B. Petsch: Advances in RNA Vaccines for Preventive Indications: A Case Study of A Vaccine Against Rabies. In: Vaccines. Volume 7, number 4, September 2019, p., Doi : 10.3390 / vaccines7040132 , PMID 31569785 , PMC 6963972 (free full text).
  62. EU Commission: A “Universal” Influenza Vaccine through Synthetic, Dendritic Cell-Targeted, Self-Replicating RNA Vaccines , accessed on May 27, 2020
  63. UniVax project: self-description
  64. Francesco Berlanda Scorza1, Norbert Pardi: New Kids on the Block: RNA-Based Influenza Virus Vaccines . April 1, 2018, PMC 6027361 (free full text)
  65. . Armbruster,. Jasny,. Petsch: Advances in RNA Vaccines for Preventive Indications: A Case Study of A Vaccine Against Rabies. In: Vaccines. 7, 2019, p. 132, doi : 10.3390 / vaccines7040132 .
  66. Messenger RNA-based vaccines for the treatment of cancer , BIOspektrum. accessed on May 28, 2020.
  67. ^ A b C. Zhang et al .: Advances in mRNA Vaccines for Infectious Diseases . In: Frontiers in Immunology . tape 10 , March 27, 2019, doi : 10.3389 / fimmu.2019.00594 .
  68. FAQ on the press briefing of the Paul Ehrlich Institute , Paul Ehrlich Institute, April 22, 2020, p. 5 ( PDF ).