Patent Publication Number: US-2021170017-A1

Title: Novel rsv rna molecules and compositions for vaccination

Description:
INTRODUCTION 
     The present invention is directed to artificial RNA suitable for use in the treatment or prophylaxis of an infection with Respiratory syncytial virus (RSV) or of a disorder related to such an infection. In particular, the artificial RNA of the invention comprises at least one heterologous untranslated region (UTR), preferably a 3′-UTR and/or a 5′-UTR, and a coding region encoding at least one antigenic peptide or protein derived from RSV, in particular at least one antigenic peptide or protein derived from RSV fusion (F) protein. The artificial RNA is preferably characterized by increased expression efficacies of coding regions operably linked to said UTR elements. The present invention is also directed to compositions and vaccines comprising said artificial RNA in association with a polymeric carrier, a polycationic protein or peptide, or a lipid nanoparticle (LNP). Further, the invention concerns a kit, particularly a kit of parts comprising the artificial RNA or composition or vaccine. The invention is further directed to a method of treating or preventing a disorder or a disease, and first and second medical uses of the artificial RNA, composition, or vaccine. 
     Respiratory syncytial virus (RSV) is an enveloped non-segmented negative-strand RNA virus in the family Paramyxoviridae, genus  Pneumovirus . It is the most common cause of bronchiolitis and pneumonia among children in their first year of life. RSV also causes repeated infections including severe lower respiratory tract disease, which may occur at any age, especially among the elderly or those with compromised cardiac, pulmonary, or immune systems. Currently, passive immunization is used to prevent severe illness caused by RSV infection, especially in infants with prematurity, bronchopulmonary dysplasia, or congenital heart disease. 
     Recommended treatment of RSV bronchiolitis primarily consists of respiratory support and hydration. No specific anti-viral therapy is recommended. The neutralizing monoclonal antibody Palivizumab is used for prophylaxis of infants at highest risk for severe infection but is too expensive and impractical for universal use. Currently, there is no licensed/approved RSV vaccine, and developing a safe and effective RSV vaccine is a global public health priority. 
     In a vaccine trial in the 1960s, infants and young children were immunized with a formalin-inactivated whole virion RSV preparation (FIRSV) or an equivalent paramyxovirus preparation (FIPIV). Five percent of the subjects who were immunized with F-PIV and then naturally infected by RSV during the next RSV season were hospitalized; 80% of those who were immunized with FI-RSV and then infected by RSV were hospitalized, and two children died. This enhancement of an RSV infection due to vaccination is a specific problem for the development of vaccines against RSV infections. 
     Therefore, Respiratory syncytial virus (RSV) infections are the greatest remaining unmet infant vaccine need in developed countries and an important unmet infant vaccine need worldwide. More than 40 years of effort have not yet resulted in a licensed RSV vaccine for humans. 
     Despite the above mentioned humanized monoclonal antibody Palivizumab, live-attenuated vaccine viruses were developed which elicit a strong immune response, but which are not recommended for use in the specific target groups (infants, children, the elderly and immunocompromised patients). Also, DNA vectors expressing RSV F protein which bears B-cell epitopes were used to induce the production of neutralizing antibodies. In this context, WO2008/077527 and WO96/040945 disclose vectors comprising DNA sequences encoding RSV F protein for the use as vaccines. However, the use of DNA as a vaccine may be dangerous due to unwanted insertion into the genome, possibly leading to interruption of functional genes and cancer or the formation of anti-DNA antibodies. 
     WO2015/024668 discloses RNA sequences encoding RSV antigenic peptides and proteins selected from fusion protein F, the glycoprotein G, the short hydrophobic protein SH, the matrix protein M, the nucleoprotein N, the large polymerase L, the M2-1 protein, the M2-2 protein, the phosphoprotein P, the non-structural protein NS1 or the non-structural protein NS2, and an antigenic composition comprising protamine-complexed RNA suitable for intradermal administration. 
     WO2017/070622 discloses a vaccine comprising RNA encoding RSV antigenic peptides and proteins selected from glycoprotein F and glycoprotein G, wherein the RNA is formulated in lipid nanoparticles. 
     Apart from some approaches cited above, there remains an unmet medical need for an efficient vaccine for prophylaxis or treatment of RSV infections. 
     Accordingly, it is the object of the underlying invention to provide novel artificial RNA coding for antigenic peptides or proteins of RSV and compositions/vaccines comprising said RNA for the use as vaccine for prophylaxis or treatment of RSV infections, particularly in infants, newborns, pregnant women, elderly, and immunocompromised patients. 
     Further it would be desirable that an RNA-based composition or vaccine has some of the following advantageous features:
         Improved translation of RNA constructs at the site of injection (e.g. muscle)   Very efficient induction of RSV antigen-specific immune responses against the encoded antigenic peptide or protein at a very low dosages and dosing regimen.   Suitability for maternal immunization   Suitability for vaccination of infants and/or newborns   Suitability for intramuscular administration   Induction of an RSV-specific functional humoral immune response   Induction of RSV-specific B-cell memory   Faster onset of immune protection against RSV   Longevity of the induced immune responses against RSV   Induction of broad cellular T-cell responses against RSV   Induction of a (local and transient) pro-inflammatory environment   No induction of systemic cytokine or chemokine response after application of the vaccine   Well tolerability, no side-effects, non toxic,   No enhancement of an RSV infection due to vaccination   Advantageous stability characteristics of the vaccine   Speed, adaptability, simplicity and scalability of RSV vaccine production       

     The objects outlined above are solved by the claimed subject matter. 
     Definitions 
     For the sake of clarity and readability the following definitions are provided. Any technical feature mentioned for these definitions may be read on each and every embodiment of the invention. Additional definitions and explanations may be specifically provided in the context of these embodiments. 
     Percentages in the context of numbers should be understood as relative to the total number of the respective items. In other cases, and unless the context dictates otherwise, percentages should be understood as percentages by weight (wt.-%). 
     Adaptive immune response: The term “adaptive immune response” as used herein will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to an antigen-specific response of the immune system (the adaptive immune system). Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is usually maintained in the body by “memory cells” (B-cells). In the context of the invention, the antigen is provided by the artificial RNA coding sequence encoding at least one antigenic peptide or protein. 
     Antigen: The term “antigen” as used herein will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to a substance which may be recognized by the immune system, preferably by the adaptive immune system, and is capable of triggering an antigen-specific immune response, e.g. by formation of antibodies and/or antigen-specific T cells as part of an adaptive immune response. Typically, an antigen may be or may comprise a peptide or protein which may be presented by the MHC to T-cells. Also fragments, variants and derivatives of peptides or proteins derived from e.g. RSV F protein comprising at least one epitope are understood as antigens in the context of the invention. In the context of the present invention, an antigen may be the product of translation of a provided artificial RNA as specified herein. 
     Antigenic peptide or protein: The term “antigenic peptide or protein” will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to a peptide, protein (or polyprotein) derived from a (antigenic) protein/polyprotein which may stimulate the body&#39;s adaptive immune system to provide an adaptive immune response. Therefore an “antigenic peptide or protein” comprises at least one epitope (as defined herein) or antigen (as defined herein) of the protein it is derived from (e.g., in the context of the invention, RSV peptide or protein, preferably RSV F protein or variants thereof). 
     Artificial nucleic acid: The terms “artificial nucleic acid” as used herein will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to an artificial nucleic acid that does not occur naturally. An artificial nucleic acid may be a DNA molecule, an RNA molecule or a hybrid-molecule comprising DNA and RNA portions. Typically, artificial nucleic acids may be designed and/or generated by genetic engineering methods to correspond to a desired artificial sequence of nucleotides (heterologous sequence). In this context an artificial sequence is usually a sequence that may not occur naturally, i.e. it differs from the wild type sequence by at least one nucleotide. The term “wild type” as used herein will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to a sequence occurring in nature. Further, the term “artificial nucleic acid” is not restricted to mean “one single molecule” but is, typically, understood to comprise an ensemble of essentially identical molecules. 
     Artificial RNA: The term “artificial RNA” as used herein is intended to refer to an RNA that does not occur naturally. In other words, an artificial RNA may be understood as a non-natural nucleic acid molecule. Such RNA molecules may be non-natural due to its individual sequence (which does not occur naturally, e.g. G/C content modified coding sequence, UTRs) and/or due to other modifications, e.g. structural modifications of nucleotides which do not occur naturally. Typically, artificial RNA may be designed and/or generated by genetic engineering methods to correspond to a desired artificial sequence of nucleotides (heterologous sequence). In this context an artificial RNA sequence is usually a sequence that may not occur naturally, i.e. it differs from the wild type sequence by at least one nucleotide. The term “artificial RNA” is not restricted to mean “one single molecule” but is, typically, understood to comprise an ensemble of essentially identical molecules. Accordingly, it may relate to a plurality of essentially identical RNA molecules contained in an aliquot or a sample. In the context of the invention, the RNA of the invention is an artificial RNA as defined herein. 
     Cationic: Unless a different meaning is clear from the specific context, the term “cationic” means that the respective structure bears a positive charge, either permanently or not permanently but in response to certain conditions such as pH. Thus, the term “cationic” covers both “permanently cationic” and “cationisable”. 
     Cationisable: The term “cationisable” as used herein means that a compound, or group or atom, is positively charged at a lower pH and uncharged at a higher pH of its environment. Also in non-aqueous environments where no pH value can be determined, a cationisable compound, group or atom is positively charged at a high hydrogen ion concentration and uncharged at a low concentration or activity of hydrogen ions. It depends on the individual properties of the cationisable or polycationisable compound, in particular the pKa of the respective cationisable group or atom, at which pH or hydrogen ion concentration it is charged or uncharged. In diluted aqueous environments, the fraction of cationisable compounds, groups or atoms bearing a positive charge may be estimated using the so-called Henderson-Hasselbalch equation which is well-known to a person skilled in the art. For example, in some embodiments, if a compound or moiety is cationisable, it is preferred that it is positively charged at a pH value of about 1 to 9, preferably 4 to 9, 5 to 8 or even 6 to 8, more preferably of a pH value of or below 9, of or below 8, of or below 7, most preferably at physiological pH values, e.g. about 7.3 to 7.4, i.e. under physiological conditions, particularly under physiological salt conditions of the cell in vivo. In other embodiments, it is preferred that the cationisable compound or moiety is predominantly neutral at physiological pH values, e.g. about 7.0-7.4, but becomes positively charged at lower pH values. In some embodiments, the preferred range of pKa for the cationisable compound or moiety is about 5 to about 7. 
     Coding sequence/coding region: The terms “coding sequence” or “coding region” and the corresponding abbreviation “cds” as used herein will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to a sequence of several nucleotide triplets, which may be translated into a peptide or protein. A coding sequence in the context of the present invention is preferably an RNA sequence, consisting of a number of nucleotides that may be divided by three, which starts with a start codon and which preferably terminates with a stop codon. 
     Composition: In the context of the invention, a “composition” refers to any type of composition in which the specified ingredients (e.g. artificial RNA of the invention in association with LNP), may be incorporated, optionally along with any further constituents, usually with at least one pharmaceutically acceptable carrier or excipient. Thus, the composition may be a dry composition such as a powder or granules, or a solid unit such as a lyophilized form or a tablet. Alternatively, the composition may be in liquid form, and each constituent may be independently incorporated in dissolved or dispersed (e.g. suspended or emulsified) form. 
     Compound: As used herein, a “compound” means a chemical substance, which is a material consisting of molecules having essentially the same chemical structure and properties. For a small molecular compound, the molecules are typically identical with respect to their atomic composition and structural configuration. For a macromolecular or polymeric compound, the molecules of a compound are highly similar but not all of them are necessarily identical. For example, a segment of a polymer that is designated to consist of 50 monomeric units may also contain individual molecules with e.g. 48 or 53 monomeric units. 
     Derived from: The term “derived from” as used throughout the present specification in the context of a nucleic acid, i.e. for a nucleic acid “derived from” (another) nucleic acid, means that the nucleic acid, which is derived from (another) nucleic acid, shares at least 50%, preferably at least 55%, preferably at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, 81%, 82%, 83%, 84%, more preferably at least 85%, 86%, 87%, 88%, 89% even more preferably at least 90%, 91%, 92%, 93%, 94%, even more preferably at least 95%, 96%, 97%, and particularly preferably at least 98%, 99% sequence identity with the nucleic acid from which it is derived. The skilled person is aware that sequence identity is typically calculated for the same types of nucleic acids, i.e. for DNA sequences or for RNA sequences. Thus, it is understood, if a DNA is “derived from” an RNA or if an RNA is “derived from” a DNA, in a first step the RNA sequence is converted into the corresponding DNA sequence (in particular by replacing the uracils (U) by thymidines (T) throughout the sequence) or, vice versa, the DNA sequence is converted into the corresponding RNA sequence (in particular by replacing the thymidines (T) by uracils (U) throughout the sequence). Thereafter, the sequence identity of the DNA sequences or the sequence identity of the RNA sequences is determined. 
     Preferably, a nucleic acid “derived from” a nucleic acid also refers to nucleic acid, which is modified in comparison to the nucleic acid from which it is derived, e.g. in order to increase RNA stability even further and/or to prolong and/or increase protein production. It goes without saying that such modifications are preferred, which do not impair RNA stability, e.g. in comparison to the nucleic acid from which it is derived. In the context of amino acid sequences (e.g. antigenic peptides or proteins) the term “derived from” means that the amino acid sequence, which is derived from (another) amino acid sequence (e.g. RSV F protein), shares at least 50%, preferably at least 55%, preferably at least 60%, preferably at least 65%, preferably at least 70%, more preferably at least 75%, more preferably at least 80%, 81%, 82%, 83%, 84%, more preferably at least 85%, 86%, 87%, 88%, 89% even more preferably at least 90%, 91%, 92%, 93%, 94%, even more preferably at least 95%, 96%, 97%, and particularly preferably at least 98%, 99% sequence identity with the amino acid sequence from which it is derived. 
     Thus, it is understood, if a antigenic peptides or protein is “derived from” an RSV fusion (F) protein, the antigenic peptides or protein that is “derived from” said RSV F protein may represent a variant or fragment of the RSV F protein, e.g. F0 (full-length precursor), F-del, F0_DSCav1, F_DSCav1_mut1, F_DSCav1_mut2, F_DSCav1_mut3, F-del_DSCav1, F-del_DSCav1_mut1, F-del_DSCav1_mut2, F-del_DSCav1_mut3 (as specified herein). Moreover, the antigenic peptides or protein that is “derived from” said RSV F proteins (e.g., F0, F-del, F0_DSCav1, F_DSCav1_mut1, F_DSCav1_mut2, F_DSCav1_mut3, F-del_DSCav1, F-del_DSCav1_mut1, F-del_DSCav1_mut2, F-del_DSCav1_mut3) may differ in the amino acid sequence, sharing a certain percentage of identity as defined above. Suitable further examples of RSV F proteins from which an antigenic peptides or protein may be “derived from” are provided in Table 1. 
     Epitope: The term “epitope” (also called “antigen determinant” in the art) as used herein will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to T cell epitopes and B cell epitopes. T cell epitopes or parts of the antigenic peptides or proteins may comprise fragments preferably having a length of about 6 to about 20 or even more amino acids, e.g. fragments as processed and presented by MHC class I molecules, preferably having a length of about 8 to about 10 amino acids, e.g. 8, 9, or 10, (or even 11, or 12 amino acids), or fragments as processed and presented by MHC class II molecules, preferably having a length of about 13 to about 20 or even more amino acids, wherein these fragments may be selected from any part of the amino acid sequence. These fragments are typically recognized by T cells in form of a complex consisting of the peptide fragment and an MHC molecule, i.e. the fragments are typically not recognized in their native form. B cell epitopes are typically fragments located on the outer surface of (native) protein or peptide antigens, preferably having 5 to 15 amino acids, more preferably having 5 to 12 amino acids, even more preferably having 6 to 9 amino acids, which may be recognized by antibodies, i.e. in their native form. Such epitopes of proteins or peptides may furthermore be selected from any of the herein mentioned variants of such proteins or peptides. In this context antigenic determinants can be conformational or discontinuous epitopes which are composed of segments of the proteins or peptides as defined herein that are discontinuous in the amino acid sequence of the proteins or peptides as defined herein but are brought together in the three-dimensional structure or continuous or linear epitopes which are composed of a single polypeptide chain. In the context of the present invention, an epitope may be the product of translation of a provided artificial RNA as specified herein. 
     Fragment: The term “fragment” as used throughout the present specification in the context of a nucleic acid sequence or an amino acid sequence may typically be a shorter portion of a full-length sequence of e.g. a nucleic acid sequence or an amino acid sequence. Accordingly, a fragment, typically, consists of a sequence that is identical to the corresponding stretch within the full-length sequence. A preferred fragment of a sequence in the context of the present invention, consists of a continuous stretch of entities, such as nucleotides or amino acids corresponding to a continuous stretch of entities in the molecule the fragment is derived from, which represents at least 5%, 10%, 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, and most preferably at least 80% of the total (i.e. full-length) molecule from which the fragment is derived (e.g. RSV F protein). The term “fragment” as used throughout the present specification in the context of proteins or peptides may, typically, comprise a sequence of a protein or peptide as defined herein, which is, with regard to its amino acid sequence (or its encoded nucleic acid molecule), N-terminally and/or C-terminally truncated compared to the amino acid sequence of the original (native) protein (or its encoded nucleic acid molecule). Such truncation may thus occur either on the amino acid level or correspondingly on the nucleic acid level. A sequence identity with respect to such a fragment as defined herein may therefore preferably refer to the entire protein or peptide as defined herein or to the entire (coding) nucleic acid molecule of such a protein or peptide. In the context of antigens such fragment may have a length of about 6 to about 20 or even more amino acids, e.g. fragments as processed and presented by MHC class I molecules, preferably having a length of about 8 to about 10 amino acids, e.g. 8, 9, or 10, (or even 6, 7, 11, or 12 amino acids), or fragments as processed and presented by MHC class I molecules, preferably having a length of about 13 or more amino acids, e.g. 13, 14, 15, 16, 17, 18, 19, 20 or even more amino acids, wherein these fragments may be selected from any part of the amino acid sequence. These fragments are typically recognized by T-cells in form of a complex consisting of the peptide fragment and an MHC molecule, i.e. the fragments are typically not recognized in their native form. Fragments of proteins or peptides (e.g. in the context of antigens) may comprise at least one epitope of those proteins or peptides. Furthermore also domains of a protein, like the extracellular domain, the intracellular domain or the transmembrane domain and shortened or truncated versions of a protein may be understood to comprise a fragment of a protein. 
     Heterologous: The terms “heterologous” or “heterologous sequence” as used throughout the present specification in the context of a nucleic acid sequence or an amino acid sequence refers to a sequence (e.g. DNA, RNA, amino acid) will be recognized and understood by the person of ordinary skill in the art, and is intended to refer to a sequence that is derived from another gene, from another allele, from another species. Two sequences are typically understood to be “heterologous” if they are not derivable from the same gene or in the same allele. I.e., although heterologous sequences may be derivable from the same organism, they naturally (in nature) do not occur in the same nucleic acid molecule, such as e.g. in the same RNA, or the same protein. 
     Humoral immune response: The terms “humoral immunity” or “humoral immune response” will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to B-cell mediated antibody production and optionally to accessory processes accompanying antibody production. A humoral immune response may be typically characterized, e.g. by Th2 activation and cytokine production, germinal center formation and isotype switching, affinity maturation and memory cell generation. Humoral immunity also typically may refer to the effector functions of antibodies, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination. 
     Identity (of a sequence): The term “identity” as used throughout the present specification in the context of a nucleic acid sequence or an amino acid sequence will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to the percentage to which two sequences are identical. To determine the percentage to which two sequences are identical, e.g. nucleic acid sequences or amino acid sequences as defined herein, preferably the amino acid sequences encoded by the artificial nucleic acid sequence as defined herein or the amino acid sequences themselves, the sequences can be aligned in order to be subsequently compared to one another. Therefore, e.g. a position of a first sequence may be compared with the corresponding position of the second sequence. If a position in the first sequence is occupied by the same component (residue) as is the case at a position in the second sequence, the two sequences are identical at this position. If this is not the case, the sequences differ at this position. If insertions occur in the second sequence in comparison to the first sequence, gaps can be inserted into the first sequence to allow a further alignment. If deletions occur in the second sequence in comparison to the first sequence, gaps can be inserted into the second sequence to allow a further alignment. The percentage to which two sequences are identical is then a function of the number of identical positions divided by the total number of positions including those positions which are only occupied in one sequence. The percentage to which two sequences are identical can be determined using a mathematical algorithm. A preferred, but not limiting, example of a mathematical algorithm which can be used is the algorithm is integrated in the BLAST program. Sequences which are identical to the sequences of the present invention to a certain extent can be identified by this program. 
     Immunogen, immunogenic: The terms “immunogen” or “immunogenic” will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to a compound that is able to stimulate/induce an immune response. Preferably, an immunogen is a peptide, polypeptide, or protein. An immunogen in the sense of the present invention is the product of translation of a provided artificial nucleic acid, preferably RNA, comprising at least one coding sequence encoding at least one antigenic peptide, protein derived from RSV as defined herein. Typically, an immunogen elicits an adaptive immune response. 
     Immune response: The term “immune response” will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to a specific reaction of the adaptive immune system to a particular antigen (so called specific or adaptive immune response) or an unspecific reaction of the innate immune system (so called unspecific or innate immune response), or a combination thereof. 
     Immune system: The term “immune system” will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to a system of the organism that may protect the organisms from infection. If a pathogen succeeds in passing a physical barrier of an organism and enters this organism, the innate immune system provides an immediate, but non-specific response. If pathogens evade this innate response, vertebrates possess a second layer of protection, the adaptive immune system. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered. According to this, the immune system comprises the innate and the adaptive immune system. Each of these two parts typically contains so called humoral and cellular components. 
     Innate immune system: The term “innate immune system” (also known as non-specific or unspecific immune system) will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to a system typically comprising the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner. This means that the cells of the innate system may recognize and respond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host. The innate immune system may be, e.g. activated by ligands of Toll-like receptors (TLRs) or other auxiliary substances such as lipopolysaccharides, TNF-alpha, CD40 ligand, or cytokines, monokines, lymphokines, interleukins or chemokines, IL-1 to IL-33, IFN-alpha, IFN-beta, IFN-gamma, GM-CSF, G-CSF, M-CSF, LT-beta, TNF-alpha, growth factors, and hGH, a ligand of human Toll-like receptor (e.g., TLR1 to TLR10), a ligand of murine Toll-like receptor, (e.g., TLR1 to TLR13), a ligand of a NOD-like receptor, a ligand of a RIG-I like receptor, an immunostimulatory nucleic acid, an immunostimulatory RNA (isRNA), a CpG-DNA, an antibacterial agent, or an anti-viral agent. 
     Lipidoid compound: A lipidoid compound, also simply referred to as lipidoid, is a lipid-like compound, i.e. an amphiphilic compound with lipid-like physical properties. In the context of the present invention the term lipid is considered to encompass lipidoid compounds. 
     Monovalent vaccine, monovalent composition: The terms “monovalent vaccine”, “monovalent composition” “univalent vaccine” or “univalent composition” will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to a composition or a vaccine comprising only one antigen from a virus. Accordingly, said vaccine or composition comprises only one RNA species encoding a single antigen for a single organism. The term “monovalent vaccine” includes the immunization against a single valence. In the context of the invention, a monovalent RSV vaccine or composition would comprise an artificial RNA encoding one single antigenic peptide or protein derived from one specific RSV (e.g. RSV F). 
     Nucleic acid: The terms “nucleic acid” or “nucleic acid molecule” will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to a molecule comprising, preferably consisting of nucleic acid components. The term nucleic acid molecule preferably refers to DNA or RNA molecules. It is preferably used synonymous with the term polynucleotide. Preferably, a nucleic acid or a nucleic acid molecule is a polymer comprising or consisting of nucleotide monomers, which are covalently linked to each other by phosphodiester-bonds of a sugar/phosphate-backbone. The term “nucleic acid molecule” also encompasses modified nucleic acid molecules, such as base-modified, sugar-modified or backbone-modified DNA or RNA molecules as defined herein. 
     Nucleic acid sequence/RNA sequence/amino acid sequence: The terms “nucleic acid sequence”, “RNA sequence” or “amino acid sequence” will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to particular and individual order of the succession of its nucleotides or amino acids respectively. 
     Permanently cationic: The term “permanently cationic” as used herein will be recognized and understood by the person of ordinary skill in the art, and means, for example, that the respective compound, or group or atom, is positively charged at any pH value or hydrogen ion activity of its environment. Typically, the positive charge is results from the presence of a quaternary nitrogen atom. Where a compound carries a plurality of such positive charges, it may be referred to as permanently polycationic, which is a subcategory of permanently cationic. 
     Pharmaceutically effective amount: The terms “pharmaceutically effective amount” or “effective amount” will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to an amount of a compound (e.g. the artificial RNA of the invention) that is sufficient to induce a pharmaceutical effect, such as, in the context of the invention, an immune response (e.g. against an antigenic peptide, protein, polyprotein as defined herein). 
     Polyvalent/multivalent vaccine, polyvalent/multivalent composition: The terms “polyvalent vaccine”, “polyvalent composition” “multivalent vaccine” or “multivalent composition” will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to a composition or a vaccine comprising antigens from more than one strain of a virus, or comprising different antigens of the same virus, or any combination thereof. The terms describe that said vaccine or composition has more than one valence. In the context of the invention, a polyvalent RSV vaccine would comprise a vaccine comprising an artificial RNA encoding antigenic peptides or proteins derived from several different RSV strains or comprising artificial RNA encoding different antigens from the same RSV strain, or a combination thereof. In preferred embodiment, a polyvalent RSV vaccine or composition comprises more than one, preferably 2, 3, 4 or even more different artificial RNA species each encoding at least one different antigenic peptide or protein of RSV (e.g. RSV F and RSV M or RSV F and RSV N). Methods to produce polyvalent mRNA vaccines are disclosed in the PCT application PCT/EP2016/082487 or in published patent application WO2017/1090134A1. 
     Stabilized nucleic acid molecule” or “stabilized RNA: The term “stabilized nucleic acid molecule” or “stabilized RNA” refer to a nucleic acid molecule, preferably an RNA molecule that is modified such, that it is more stable to disintegration or degradation, e.g., by environmental factors or enzymatic digest, such as by an exo- or endonuclease degradation, than the nucleic acid molecule without the modification. Preferably, a stabilized nucleic acid molecule, e.g. stabilized RNA, in the context of the present invention is stabilized in a cell, such as a prokaryotic or eukaryotic cell, preferably in a mammalian cell, such as a human cell. The stabilization effect may also be exerted outside of cells, e.g. in a buffer solution etc., for example, in a manufacturing process for a pharmaceutical composition comprising the stabilized nucleic acid molecule. 
     T-cell responses: The terms “cellular immunity” or “cellular immune response” or “cellular T-cell responses” as used herein will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to the activation of macrophages, natural killer cells (NK), antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen. In more general terms, cellular immunity is not based on antibodies, but on the activation of cells of the immune system. Typically, a cellular immune response may be characterized e.g. by activating antigen-specific cytotoxic T-lymphocytes that are able to induce apoptosis in cells, e.g. specific immune cells like dendritic cells or other cells, displaying epitopes of foreign antigens on their surface. In the context of the invention, the antigen is provided by the artificial RNA encoding at least one antigenic peptide or protein derived from RSV, suitably inducing T-cell responses. The artificial RNA, the composition, the vaccine of the invention advantageously elicit cellular T-cell responses against RSV F antigens. 
     Variant (of a sequence): The term “variant” as used throughout the present specification in the context of a nucleic acid sequence will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to a variant of nucleic acid sequences which forms the basis of a nucleic acid sequence. For example, a variant nucleic acid sequence may exhibit one or more nucleotide deletions, insertions, additions and/or substitutions compared to the nucleic acid sequence from which the variant is derived. Preferably, a variant of a nucleic acid sequence is at least 40%, preferably at least 50%, more preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, even more preferably at least 90%, most preferably at least 95% identical to the nucleic acid sequence the variant is derived from. Preferably, the variant is a functional variant. A “variant” of a nucleic acid sequence may have at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% nucleotide identity over a stretch of 10, 20, 30, 50, 75 or 100 nucleotide of such nucleic acid sequence. 
     The term “variant” as used throughout the present specification in the context of proteins or peptides will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to a proteins or peptide variant having an amino acid sequence which differs from the original sequence in one or more mutation(s), such as one or more substituted, inserted and/or deleted amino acid(s). Preferably, these fragments and/or variants have the same biological function or specific activity compared to the full-length native protein, e.g. its specific antigenic property. “Variants” of proteins or peptides as defined in the context of the present invention may comprise conservative amino acid substitution(s) compared to their native, i.e. non-mutated physiological, sequence. Those amino acid sequences as well as their encoding nucleotide sequences in particular fall under the term variants as defined herein. Substitutions in which amino acids, which originate from the same class, are exchanged for one another are called conservative substitutions. In particular, these are amino acids having aliphatic side chains, positively or negatively charged side chains, aromatic groups in the side chains or amino acids, the side chains of which can enter into hydrogen bridges, e.g. side chains which have a hydroxyl function. This means that e.g. an amino acid having a polar side chain is replaced by another amino acid having a likewise polar side chain, or, for example, an amino acid characterized by a hydrophobic side chain is substituted by another amino acid having a likewise hydrophobic side chain (e.g. serine (threonine) by threonine (serine) or leucine (isoleucine) by isoleucine (leucine)). Insertions and substitutions are possible, in particular, at those sequence positions which cause no modification to the three-dimensional structure or do not affect the binding region. Modifications to a three-dimensional structure by insertion(s) or deletion(s) can easily be determined e.g. using CD spectra (circular dichroism spectra). A “variant” of a protein or peptide may have at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% amino acid identity over a stretch of 10, 20, 30, 50, 75 or 100 amino acids of such protein or peptide. Preferably, a variant of a protein comprises a functional variant of the protein, which means that the variant exerts the same effect or functionality as the protein it is derived from. 
     3′-untranslated region, 3′-UTR element, 3′-UTR: The term “3′-untranslated region” or “3′-UTR element” will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to a part of a nucleic acid molecule, which is located 3′ (i.e. “downstream”) of a coding sequence and which is typically not translated into protein. Usually, a 3′-UTR is the part of an mRNA which is located between the coding sequence (cds) and the poly(A) sequence of the mRNA. In the context of the invention, the term 3′-UTR may also comprise elements, which are not encoded in the DNA template, from which an artificial RNA is transcribed, but which are added after transcription during maturation, e.g. a poly(A) sequence. 
     5-untranslated region, 5′-UTR element, 5′-UTR: The term “5′-untranslated region (5′-UTR)” will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to a part of a nucleic acid molecule, which is located 5′ (i.e. “upstream”) of a coding sequence and which is not translated into protein. A 5′-UTR is typically understood to be a particular section of messenger RNA (mRNA), which is located 5′ of the coding sequence of the mRNA. Typically, the 5′-UTR starts with the transcriptional start site and ends one nucleotide before the start codon of the coding sequence. Preferably, the 5′-UTRs have a length of more than 20, 30, 40 or 50 nucleotides. The 5′-UTR may comprise elements for controlling gene expression, also called regulatory elements. Such regulatory elements may be, for example, ribosomal binding sites. The 5′-UTR may be post-transcriptionally modified, for example by addition of a 5′-cap. 
     5-terminal oligopyrimidine tract (TOP), TOP-UTR: The term “5′-terminal oligopyrimidine tract (TOP)” has to be understood as a stretch of pyrimidine nucleotides located in the 5-terminal region of a nucleic acid molecule, such as the 5-terminal region of certain mRNA molecules or the 5-terminal region of a functional entity, e.g. the transcribed region, of certain genes. The sequence starts with a cytidine, which usually corresponds to the transcriptional start site, and is followed by a stretch of usually about 3 to 30 pyrimidine nucleotides. For example, the TOP may comprise 3-30 or even more nucleotides. The pyrimidine stretch and thus the 5′-TOP ends one nucleotide 5′ to the first purine nucleotide located downstream of the TOP. Messenger RNA that contains a 5′-terminal oligopyrimidine tract is often referred to as TOP mRNA. Accordingly, genes that provide such messenger RNAs are referred to as TOP genes. The term “TOP motif” or “5′-TOP motif” has to be understood as a nucleic acid sequence which corresponds to a 5′-TOP as defined above. Thus, a TOP motif in the context of the present invention is preferably a stretch of pyrimidine nucleotides having a length of 3-30 nucleotides. Preferably, the TOP-motif consists of at least 3 pyrimidine nucleotides, preferably at least 4 pyrimidine nucleotides, preferably at least 5 pyrimidine nucleotides, more preferably at least 6 nucleotides, more preferably at least 7 nucleotides, most preferably at least 8 pyrimidine nucleotides, wherein the stretch of pyrimidine nucleotides preferably starts at its 5′-end with a cytosine nucleotide. In TOP genes and TOP mRNAs, the TOP-motif preferably starts at its 5′-end with the transcriptional start site and ends one nucleotide 5′ to the first purine residue in said gene or mRNA. A TOP motif in the sense of the present invention is preferably located at the 5′-end of a sequence which represents a 5′-UTR or at the 5′-end of a sequence which codes for a 5′-UTR. Thus, preferably, a stretch of 3 or more pyrimidine nucleotides is called “TOP motif” in the sense of the present invention if this stretch is located at the 5′-end of a respective sequence, such as the artificial nucleic acid, the 5′-UTR element of the artificial nucleic acid, or the nucleic acid sequence which is derived from the 5′-UTR of a TOP gene as described herein. In other words, a stretch of 3 or more pyrimidine nucleotides, which is not located at the 5′-end of a 5′-UTR or a 5′-UTR element but anywhere within a 5′-UTR or a 5′-UTR element, is preferably not referred to as “TOP motif”. In some embodiments, the nucleic acid sequence of the 5′-UTR element, which is derived from a 5′-UTR of a TOP gene, terminates at its 3′-end with a nucleotide located at position 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 upstream of the start codon (e.g. A(U/T)G) of the gene or RNA it is derived from. Thus, the 5′-UTR element does not comprise any part of the protein coding sequence. Thus, preferably, the only protein coding part of the at least one nucleic acid sequence, particularly of the RNA sequence, is provided by the coding sequence. 
     SHORT DESCRIPTION OF THE INVENTION 
     The present invention is based on the inventor&#39;s surprising finding that at least one peptide or protein derived from of a Respiratory syncytial virus (RSV) F protein encoded by the artificial RNA of the invention can efficiently be expressed in a mammalian cell. Even more unexpected, the inventors showed that the artificial RNA of the invention can induce specific functional and protective immune responses in e.g. cotton rats (see e.g. Example 2, 3). Through different optimizations in RSV F antigen design, the immune responses could be further improved. In addition, the expression of the RSV F antigen encoded by the artificial nucleic RNA could be increased by selecting suitable heterologous 5′ untranslated regions (UTRs) and suitable heterologous 3 untranslated regions (UTRs) (see e.g. Example 4). Advantageously, said artificial RNA of the invention comprising advantageous 3-UTR/5′-UTR combinations induce very efficient antigen-specific immune responses against the encoded RSV F. Further, artificial RNA of the invention comprised in lipid nanoparticles (LNPs) very efficiently induces antigen-specific immune responses against RSV F at a very low dosages and dosing regimen (see e.g. Example 3). Further, e.g. Example 8 and Example 12 provide compositions/vaccines comprising a further artificial RNA encoding a further antigen wherein said artificial RNA encoding a further antigen suitably elicits or enhances T-cell responses and results in a Th1-biased immune response, which is considered to be an important prerequisite for a potential RSV vaccine (Th2-biased responses have been associated with enhanced respiratory disease (ERD) in animal models). Furthermore the compositions are suitable to induce T-cell responses. Accordingly, the artificial RNA, and the composition/vaccine comprising said artificial RNA of the invention are suitable for eliciting an immune response against RSV F in a mammalian subject. The artificial RNA and the composition/vaccine comprising said artificial RNA is therefore suitable for use as a vaccine, e.g. as a human vaccine, e.g. as a vaccine for pregnant women or infants. 
     In a first aspect, the present invention provides an artificial nucleic acid, preferably an artificial RNA comprising at least one 5′ untranslated region (UTR) and/or at least one 3′ untranslated region (UTR), and at least one coding sequence operably linked to said 3′-UTR and/or 5′-UTR encoding at least one antigenic peptide or protein derived from RSV F protein or a fragment or variant thereof. 
     In preferred embodiments, the artificial RNA comprises at least one nucleic acid sequence derived from a 3′-UTR of a gene selected from an ALB7 gene, an alpha-globin gene, a PSMB3, CASP1, COX6B1, GNAS, NDUFA1 and RPS9, or from a homolog, a fragment or a variant of any one of these genes 
     In preferred embodiments, the artificial RNA comprises at least one nucleic acid sequence derived from a 5′-UTR of gene selected from a RPL32 gene, a HSD17B4, ASAH1, ATP5A1, MP68, NDUFA4, NOSIP, RPL31, SLC7A3, TUBB4 and UBQLN2, or from a homolog, a fragment or variant of any one of these genes. 
     Suitably, the artificial RNA of the invention comprises at least one coding sequence encoding at least one antigenic peptide or protein derived from a RSV F protein operably linked to a 3′-UTR and a 5′-UTR selected from a-1 (HSD17B4/PSMB3), a-2 (Ndufa4/PSMB3), a-3 (SLC7A3/PSMB3), a-4 (NOSIP/PSMB3), a-5 (MP68/PSMB3), b-1 (UBQLN2/RPS9), b-2 (ASAH1/RPS9), b-3 (HSD17B4/RPS9), b-4 (HSD17B4/CASP1), b-5 (NOSIP/COX6B1), c-1 (NDUFA4/RPS9), c-2 (NOSIP/NDUFA1), c-3 (NDUFA4/COX6B1), c-4 (NDUFA4/NDUFA1), c-5 (ATP5A1/PSMB3), d-1 (Rpl31/PSMB3), d-2 (ATP5A1/CASP1), d-3 (SLC7A3/GNAS), d-4 (HSD17B4/NDUFA1), d-5 (Slc7a3/Ndufa1), e-1 (TUBB4B/RPS9), e-2 (RPL31/RPS9), e-3 (MP68/RPS9), e-4 (NOSIP/RPS9), e-5 (ATP5A1/RPS9), e-6 (ATP5A1/COX6B1), f-1 (ATP5A1/GNAS), f-2 (ATP5A1/NDUFA1), f-3 (HSD17B4/COX6B1), f-4 (HSD17B4/GNAS), f-5 (MP68/COX6B1), g-1 (MP68/NDUFA1), g-2 (NDUFA4/CASP1), g-3 (NDUFA4/GNAS), g-4 (NOSIP/CASP1), g-5 (RPL31/CASP1), h-1 (RPL31/COX6B1), h-2 (RPL31/GNAS), h-3 (RPL31/NDUFA1), h-4 (Slc7a3/CASP1), h-5 (SLC7A3/COX6B1), i-1 (SLC7A3/RPS9), i-2 (RPL32/ALB7), or i-3 (a-globin gene), wherein a-1 (HSD17B4/PSMB3), a-4 (NDUFA4/PSMB3), c-1 (NDUFA4/RPS9), e-4 NOSIP/RPS9), g-2 (NDUFA4/CASP1), i-2 (RPL32/ALB7), or i-3 (alpha-globin) are particularly preferred. 
     The at least one antigenic peptide or protein derived from RSV F protein may be a full-length F protein (referred to as “F0”, aa 1-574) or an F protein with deleted C-terminus (referred to as “F-del”, aa 1-553), or a fragment or a variant thereof. 
     The at least one antigenic peptide or protein may additionally comprise a mutation that stabilizes the antigen in pre-conformation state/pre-fusion conformation, preferably a DSCav1 mutation (S155C, S290C, S190F, and V207L) or a fragment or a variant, or a functional variant thereof (referred to as “DSCav1”, e.g. “F0_DSCav1” or “F-del_DSCav1”). 
     The at least one antigenic peptide or protein may be a fusion protein comprising the two subunits, F1 and F2 of mature F into a single chain, connected via a linker (GS) to enhance stability of the protein (F(1-103)-GS-F(145-574); F(1-103)-GS-F(145-553)). 
     The protein comprising the two subunits of mature F into a single chain (referred to as “F2-linker-F1”), e.g. (F(1-103)-GS-F(145-574); F(1-103)-GS-F(145-553) may additionally comprise a DSCav1 mutation (herein referred to as “mut0”). 
     The protein comprising the two subunits of mature F into a single chain (referred to as “F2-linker-F1”) may additionally to the DSCav1 mutation comprise at least one further mutation that promotes inter-protomer disulphide bonds, wherein the mutations may be selected from (S46G, A149C, S215P, Y458C, K465Q; herein referred to as “mut1”), (S46G, E92D, A149C, S215P, Y458C, K465Q; herein referred to as “mut2”), or (S46G, N671, E92D, A149C, S215P, Y458C, K465Q; herein referred to as “mut3”), (A149C, Y458C; herein referred to as “mut4”), (N183GC, N428C; herein referred to as “mut5”), (Q98C, Q361C, S46G, E92D, L95M, S215P, I217P, I221M, R429K, K465Q; herein referred to as “mut6”), (Q98C, Q361C, L95M, I221M, R429K; herein referred to as “mut7”), or (N183GC, N428C, S46G, N671, E92D, S215P, K465Q; herein referred to as “mut8”) or a fragment or a variant, or a functional variant thereof. 
     The at least one antigenic peptide or protein derived from RSV F protein encoded by the artificial RNA of the invention may be selected from F0, F-del, F0_DSCav1, F_DSCav1_mut1, F_DSCav1_mut2, F_DSCav1_mut3, F_DSCav1_mut4, F_DSCav1_mut5, F_DSCav1_mut6, F_DSCav1_mut7, F_DSCav1_mut8, F_DSCav1_mut0, F-del_DSCav1, F-del_DSCav1_mut1, F-del_DSCav1_mut2, F-del_DSCav1_mut3, F-del_DSCav1_mut4, F-del_DSCav1_mut5, F-del_DSCav1_mut6, F-del_DSCav1_mut7, F-del_DSCav1_mut8, F-del_DSCav1_mut0 are preferred. 
     The at least one coding sequence may encode at least one of the amino acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 68, 483, 898, 1267, 1636, 2005, 2374, 2743, 3112, 3481, 3850, 4219, 4588, 4957, 5326, 5695, 6064, 6433, 6802, 7171, 7540, 7909, 8279-9683, 11726, 12095, 12464, 12833, 13940, 14309, 14678, 15047, 15416, 15785, 13202, 13571, 16154, 16523, 16892, 17261, 17630, 17999, 18368, 18737, 19106, 19475 or a fragment or variant of any of these sequences. 
     Preferably, the artificial RNA may comprise a coding sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 69-77, 484-492, 899-906, 1268-1275, 1637-1644, 2006-2013, 2375-2382, 2744-2751, 3113-3120, 3482-3489, 3851-3858, 4220-4227, 4589-4596, 4958-4965, 5327-5334, 5696-5703, 6065-6072, 6434-6441, 6803-6810, 7172-7179, 7541-7548, 7910-7917, 21363-21384, 11727-11734, 12096-12103, 12465-12472, 12834-12841, 13941-13948, 14310-14317, 14679-14686, 15048-15055, 15417-15424, 15786-15793, 13203-13210, 13572-13579, 16155-16162, 16524-16531, 16893-16900, 17262-17269, 17631-17638, 18000-18007, 18369-18376, 18738-18745, 19107-19114, 19476-19483. 21389-21410 or a fragment or variant of any of these sequences. 
     The artificial RNA may comprise a codon modified coding sequence selected from C maximized coding sequence, CAI maximized coding sequence, human codon usage adapted coding sequence, G/C content modified coding sequence, and G/C optimized coding sequence, or any combination thereof. 
     The artificial RNA may be an mRNA, a viral RNA, self-replicating RNA, a circular RNA, or a replicon RNA. In preferred embodiments, the artificial RNA is an mRNA. 
     The artificial RNA, preferably mRNA, may further comprise at least one selected from a cap structure, a poly(A)sequence, a poly(C)sequence, a histone-stem loop, and/or a 3′-terminal sequence element. 
     The artificial RNA of the invention preferably comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 78-482, 11735-12094, 21415-21417, 21561-21563, 21489, 21490, 21635, 21636 or a fragment or variant of any of these (encoding F0), SEQ ID NOs: 493-897, 12104-12463, 21418-21420, 21564-21566, 21491, 21492, 21637, 21638 or a fragment or variant of any of these (encoding F-del), SEQ ID NOs: 907-1266, 12473-12832, 21421-21423, 21567-21569, 21493-21495, 21639-21641 or a fragment or variant of any of these (encoding F0_DSCav1), SEQ ID NOs: 1276-1635, 8278, 12842-13201, 21424-21426, 21570-21572, 21496-21498, 21642-21644 or a fragment or variant of any of these (encoding F-del_DSCav1), SEQ ID NOs: 1645-2004, 13949-14308, 21433-21435, 21579-21581, 21505-21507, 21651-21653 or a fragment or variant of any of these (encoding F_DSCav1_mut1), SEQ ID NOs: 2014-2373, 14318-14677, 21436-21438, 21582-21584, 21508-21510, 21654-21656 or a fragment or variant of any of these (encoding F-del_DSCav1_mut1), SEQ ID NOs: 2383-2742, 14687-15046, 21439-21441, 21585-21587, 21511-21513, 21657-21659 or a fragment or variant of any of these (encoding F_DSCav1_mut2), SEQ ID NOs: 2752-3111, 15056-15415, 21442-21444, 21588-21590, 21514-21516, 21660-21662 or a fragment or variant of any of these (encoding F-del_DSCav1_mut2), SEQ ID NOs: 3121-3480, 15425-15784, 21445-21447, 21591-21593, 21517-21519, 21663-21665 or a fragment or variant of any of these (encoding F_DSCav1_mut3), SEQ ID NOs: 3490-3849, 15794-16153, 21448-21450, 21594-21596, 21520-21522, 21666-21668 or a fragment or variant of any of these (encoding F-del_DSCav1_mut3), SEQ ID NOs: 3859-4218, 13211-13570, 21427-21429, 21573-21575, 21499-21501, 21645-21647 or a fragment or variant of any of these (encoding F_DSCav1_mut0), SEQ ID NOs: 4228-4587, 13580-13939, 21430-21432, 21576-21578, 21502-21504, 21648-21650 or a fragment or variant of any of these (encoding F-del_DSCav1_mut0), SEQ ID NOs: 4597-4956, 16163-16522, 21451-21453, 21597-21599, 21523-21525, 21669-21671 or a fragment or variant of any of these (encoding F_DSCav1_mut4), SEQ ID NOs: 4966-5325, 16532-16891, 21454-21456, 21600-21602, 21526-21528, 21672-21674 or a fragment or variant of any of these (encoding F-del_DSCav1_mut4), SEQ ID NOs: 5335-5694, 16901-17260, 21457-21459, 21603-21605, 21529-21531, 21675-21677 or a fragment or variant of any of these (encoding F_DSCav1_mut5), SEQ ID NOs: 5704-6063, 17270-17629, 21460-21462, 21606-21608, 21532-21534, 21678-21680 or a fragment or variant of any of these (encoding F-del_DSCav1_mut5), SEQ ID NOs: 6073-6432, 17639-17998, 21463-21465, 21609-21611, 21535-21537, 21681-21683 or a fragment or variant of any of these (encoding F_DSCav1_mut6), SEQ ID NOs: 6442-6801, 18008-18367, 21466-21468, 21612-21614, 21538-21540, 21684-21686 or a fragment or variant of any of these (encoding F-del_DSCav1_mut6), SEQ ID NOs: 6811-7170, 18377-18736, 21469-21471, 21615-21617, 21541-21543, 21687-21689 or a fragment or variant of any of these (encoding F_DSCav1_mut7), SEQ ID NOs: 7180-7539, 18746-19105, 21472-21474, 21618-21620, 21544-21546, 21690-21692 or a fragment or variant of any of these (encoding F-del_DSCav1_mut7), SEQ ID NOs: 7549-7908, 19115-19474, 21475-21477, 21621-21623, 21547-21549, 21693-21695 or a fragment or variant of any of these (encoding F_DSCav1_mut8), or SEQ ID NOs: 7918-8277, 19484-19843, 21478-21480, 21624-21626, 21550-21552, 21696-21698 or a fragment or variant of any of these (encoding F-del_DSCav1_mut8). 
     In a second aspect, the present invention provides a composition comprising the artificial RNA of the first aspect. 
     In preferred embodiments, the composition comprising the artificial RNA of the first aspect comprises at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV selected from matrix protein M, nucleoprotein N, M2-1 protein, and/or phosphoprotein P or combinations thereof. 
     Matrix protein M, nucleoprotein N, M2-1 protein, M2-2 protein, and/or phosphoprotein P are suitable T-cell antigens and may promote efficient T-cell responses of the composition or vaccine when administered to a subject. 
     The further artificial RNA may comprise a coding sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 9685-9692, 10135-10142, 10638-10645, 11184-11191, 21385-21388, 19845-19852, 20214-20221, 20583-20590, 20952-20959, 21411-21414 or a fragment or variant of any of these sequences. 
     Suitably, said further artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 9693-10052, 10143-10502, 10646-11005, 11192-11551, 19853-20212, 20222-20581, 20591-20950, 20960-21319, 21481-21488, 21627-21634, 21553-21560, 21699-21706 or a fragment or variant of any of these sequences. 
     Suitably, the composition may comprise the artificial RNA of the invention complexed with, encapsulated in, or associated with one or more lipids, thereby forming lipid nanoparticles. 
     The composition may preferably comprise the artificial RNA of the invention complexed with one or more lipids thereby forming lipid nanoparticles (LNP), wherein the LNP essentially consists of 
     (i) at least one cationic lipid as defined herein, preferably a lipid of formula (III), more preferably lipid III-3; 
     (ii) a neutral lipid as defined herein, preferably 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); 
     (iii) a steroid or steroid analogue as defined herein, preferably cholesterol; and 
     (iv) a PEG-lipid as defined herein, e.g. PEG-DMG or PEG-cDMA, preferably a PEGylated lipid of formula (IVa); wherein (i) to (iv) are in a molar ratio of about 20-60% cationic lipid: 5-25% neutral lipid: 25-55% sterol; 0.5-15% PEG-lipid. 
     The present invention also concerns a RSV vaccine comprising said artificial RNA or said composition. 
     The present invention is also directed to the use of the artificial RNA, the composition and the vaccine in treatment or prophylaxis of an infection with RSV. 
     In particular, the present invention is directed to the use of the artificial RNA, the composition and the vaccine in treatment or prophylaxis of an infection with RSV or a disorder related to such an infection. 
     The invention further concerns a method of treating or preventing a disorder or a disease in a subject, first and second medical uses of the artificial RNA, compositions and vaccines. Further, the invention is directed to a kit, particularly to a kit of parts, comprising the artificial RNA, compositions and vaccines. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The present application is filed together with a sequence listing in electronic format, which is part of the description of the present application (WIPO standard ST.25). The information contained in the electronic format of the sequence listing filed together with this application is incorporated herein by reference in its entirety. Where reference is made herein to a “SEQ ID NO” the corresponding nucleic acid sequence or amino acid (aa) sequence in the sequence listing having the respective identifier is referred to. For many sequences, the sequence listing also provides additional detailed information, e.g. regarding certain structural features, sequence optimizations, GenBank identifiers, or additional detailed information regarding its coding capacity. In particular, such information is provided under numeric identifier &lt;223&gt; in the WIPO standard ST.25 sequence listing. Accordingly, information provided under said numeric identifier &lt;223&gt; is explicitly included herein in its entirety and has to be understood as integral part of the description of the underlying invention. 
     Artificial Nucleic Acid: 
     In a first aspect, the invention relates to an artificial nucleic acid comprising
     a) at least one heterologous 5′ untranslated region (5′-UTR) and/or at least one heterologous 3′ untranslated region (3′-UTR); and   b) at least one coding sequence operably linked to said 3′-UTR and/or 5′-UTR encoding at least one antigenic peptide or protein derived from a Respiratory syncytial virus (RSV) or a fragment or variant thereof.   

     In a preferred embodiment of the first aspect, the invention relates to an artificial RNA, preferably an RNA suitable for vaccination, comprising
     a) at least one heterologous 5′ untranslated region (5′-UTR) and/or at least one heterologous 3′ untranslated region (3′-UTR); and   b) at least one coding sequence operably linked to said 3′-UTR and/or 5′-UTR encoding at least one antigenic peptide or protein derived from a RSV fusion (F) protein or a fragment or variant thereof.   

     In general, the RNA of the invention may be composed of a protein-coding region, and 5′- and/or 3-untranslated regions (UTRs). The 3′-UTR is variable in sequence and size; it spans between the stop codon and the poly(A) tail. Importantly, the 3′-UTR sequence harbors several regulatory motifs that determine RNA turnover, stability and localization, and thus governs many aspects of post-transcriptional regulation. In medical application of RNA (e.g. immunotherapy applications, vaccination) the regulation of RNA translation into protein is of paramount importance to therapeutic safety and efficacy. The present inventors surprisingly discovered that certain combinations of 3-UTRs and/or 5′-UTRs act in concert to synergistically enhance the expression of operably linked nucleic acid sequences encoding RSV antigenic peptides or proteins. Artificial RNA molecules harboring the inventive UTR combinations advantageously enable the rapid and transient expression of high amounts of RSV antigenic peptides or proteins derived from RSV F. Accordingly, the artificial RNA provided herein is particularly useful and suitable for various applications in vivo, including the vaccination against RSV. 
     Suitably, the artificial RNA may comprise at least one heterologous 5′-UTR and/or at least one heterologous 3′-UTR. In this context, an UTR of the invention comprises or consists of a nucleic acid sequence derived from a 5′-UTR or a 3′-UTR of any naturally occurring gene or a fragment, a homolog or a variant thereof. Preferably, a 5-UTR or a 3′-UTR of the invention is heterologous to the at least one coding sequence encoding the at least one antigenic peptide or protein derived from RSV F. Suitable heterologous 5′-UTRs or heterologous 3′-UTRs are derived from naturally occurring genes (that are not derived from RSV). In other embodiments, synthetically engineered 5′-UTRs or 3-UTRs may be used in the context of the present invention. 
     In preferred embodiments, the at least one artificial RNA comprises at least one heterologous 3′-UTR. 
     Preferably, the at least one heterologous 3′-UTR comprises or consists of a nucleic acid sequence derived from a 3′-UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of a 3′-UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene. 
     Preferably the artificial RNA of the present invention comprises a 3′-UTR, which may be derivable from a gene that relates to an RNA with an enhanced half-life (that provides a stable RNA), for example a 3′-UTR as defined and described below. 
     Preferably, the at least one heterologous 3′-UTR comprises a nucleic acid sequence derived from a 3′-UTR of a gene, which preferably encodes a stable mRNA, or from a homolog, a fragment or a variant of said gene. 
     In preferred embodiments of the first aspect, the artificial RNA of the invention comprises at least one heterologous 3′-UTR, wherein the at least one heterologous 3′-UTR comprises a nucleic acid sequence derived from a 3′-UTR of a gene selected from PSMB3, ALB7, alpha-globin (referred to as “muag”), CASP1, COX6B1, GNAS, NDUFA1 and RPS9, or from a homolog, a fragment or variant of any one of these genes. 
     ALB7-derived 3′-UTR: In preferred embodiments, the 3′-UTR comprises or consists of a nucleic acid sequence which is derived from the 3′-UTR of a vertebrate albumin gene or from a variant thereof, preferably from the 3′-UTR of a mammalian albumin gene or from a variant thereof, more preferably from the 3′-UTR of a human albumin gene or from a variant thereof, even more preferably from the 3′-UTR of the human albumin gene according to GenBank Accession number NM_000477.5, or from a homolog, fragment or variant thereof. Accordingly, the artificial RNA of the invention may comprise a 3′-UTR derived from a ALB7 gene, wherein said 3′-UTR derived from a ALB7 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 35 or 36 or a fragment or a variant thereof. 
     Alpha-globin gene-derived 3′-UTR: In preferred embodiments, the 3′-UTR comprises or consists of a nucleic acid sequence which is derived from the 3′-UTR of a vertebrate alpha-globin gene (referred to as “muag”) or from a variant thereof, preferably from the 3′-UTR of a mammalian alpha-globin or from a variant thereof, more preferably from the 3′-UTR of a human alpha-globin gene or from a variant thereof, even more preferably from the 3′-UTR of the human alpha-globin gene. Accordingly, the RNA of the invention may comprise a 3′-UTR derived from a alpha-globin gene, wherein said 3′-UTR derived from a alpha-globin gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 37 or 38 or a fragment or a variant thereof. 
     PSMB3-derived 3′-UTR: The artificial RNA of the invention may comprise a 3′-UTR which is derived from a 3′-UTR of a gene encoding a proteasome subunit beta type-3 (PSMB3) protein, or a homolog, variant, fragment or derivative thereof. Such 3′-UTRs preferably comprise or consist of a nucleic acid sequences derived from the 3′-UTR of a proteasome subunit beta type-3 (PSMB3) gene, preferably from a vertebrate, more preferably a mammalian, most preferably a human proteasome subunit beta type-3 (PSMB3) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode a proteasome subunit beta type-3 (PSMB3) protein corresponding to a human proteasome subunit beta type-3 (PSMB3) protein (UniProt Ref. No. P49720, entry version #183 of 30 Aug. 2017). Accordingly, the artificial RNA of the invention may comprise a 3′-UTR derived from a PSMB3 gene, wherein said 3′-UTR derived from a PSMB3 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 23 or 24 or a fragment or a variant thereof. 
     CASP1-derived 3′-UTR: The artificial RNA of the invention may comprise a 3′-UTR which is derived from a 3′-UTR of a gene encoding a Caspase-1 (CASP1) protein, or a homolog, variant, fragment or derivative thereof. Such 3′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 3′-UTR of a Caspase-1 (CASP1) gene, preferably from a vertebrate, more preferably a mammalian, most preferably a human Caspase-1 (CASP1) gene, or a homolog, variant, fragment or derivative thereof. Accordingly, the RNA of the invention may comprise a 3′-UTR derived from a CASP1 gene, wherein said 3′-UTR derived from a CASP1 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 25 or 26 or a fragment or a variant thereof. 
     COX6B1-derived 3′-UTR: The artificial RNA of the invention may comprise a 3′-UTR which is derived from a 3′-UTR of a COX6B1 gene encoding a cytochrome c oxidase subunit 6B1 (COX6B1) protein, or a homolog, variant, fragment or derivative thereof. Such 3′-UTRs preferably comprise or consist of a nucleic acid sequence which is derived from the 3′-UTR of a cytochrome c oxidase subunit 6B1 (COX6B1) gene, preferably from a vertebrate, more preferably a mammalian, most preferably a human cytochrome c oxidase subunit 6B1 (COX6B1) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode a cytochrome c oxidase subunit 681 (COX6B1) protein corresponding to a human cytochrome c oxidase subunit 6B1 (COX6B1) protein (UniProt Ref. No. P14854, entry version #166 of 30 Aug. 2017). Accordingly, the artificial RNA of the invention may comprise a 3′-UTR derived from a COX6B1 gene, wherein said 3′-UTR derived from a COX6B1 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 27 or 28 or a fragment or a variant thereof. 
     GNAS-derived 3′-UTR: The artificial RNA of the invention may comprise a 3′-UTR which is derived from a 3′-UTR of a GNAS gene encoding a Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (GNAS) protein, or a homolog, variant, fragment or derivative thereof. Such 3-UTRs preferably comprise or consist of a nucleic acid sequence which is derived from the 3′-UTR of a Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (GNAS) gene, preferably from a vertebrate, more preferably a mammalian Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (GNAS) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode a Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (GNAS) protein corresponding to a human Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (GNAS) protein (UniProt Ref. No. P63092, entry version #153 of 30 Aug. 2017). Accordingly, the artificial RNA of the invention may comprise a 3′-UTR derived from a GNAS gene, wherein said 3′-UTR derived from a GNAS gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 29 or 30 or a fragment or a variant thereof. 
     NDUFA1-derived 3′-UTR: The artificial RNA of the invention may comprise a 3′-UTR which is derived from a 3′-UTR of a gene encoding a NADH dehydrogenase [ubiquinone] 1 alpha sub complex subunit 1 (NDUFA1) protein, or a homolog, variant, fragment or derivative thereof. Such 3′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 3′-UTR of a NADH dehydrogenase [ubiquinone] 1 alpha sub complex subunit 1 (NDUFA1) gene, preferably from a vertebrate, more preferably a mammalian NADH dehydrogenase [ubiquinone]1 alpha sub complex subunit 1 (NDUFA1) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode a NADH dehydrogenase [ubiquinone] 1 alpha sub complex subunit 1 (NDUFA1) protein corresponding to a human NADH dehydrogenase [ubiquinone] 1 alpha sub complex subunit 1 (NDUFA1) protein (UniProt Ref. No. 015239, entry version #152 of 30 Aug. 2017). Accordingly, the artificial RNA of the invention may comprise a 3′-UTR derived from a NDUFA1 gene, wherein said 3′-UTR derived from a NDUFA1 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 31 or 32 or a fragment or a variant thereof. 
     RPS9-derived 3′-UTR: The artificial RNA of the invention may comprise a 3′-UTR which is derived from a 3′-UTR of a gene encoding a 40S ribosomal protein S9 (RPS9) protein, or a homolog, variant, fragment or derivative thereof. Such 3′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 3′-UTR of a 40S ribosomal protein S9 (RPS9) gene, preferably from a vertebrate, more preferably a mammalian, most preferably a human 40S ribosomal protein S9 (RPS9) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode a 40S ribosomal protein S9 (RPS9) protein corresponding to a human 40S ribosomal protein S9 (RPS9) protein (UniProt Ref. No. P46781, entry version #179 of 30 Aug. 2017). Accordingly, the artificial RNA of the invention may comprise a 3′-UTR derived from a RPS9 gene, wherein said 3′-UTR derived from a RPS9 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 33 or 34 or a fragment or a variant thereof. 
     Further 3′-UTRs: In embodiments, the artificial RNA as defined herein comprises a 3′-UTR as described in WO2016/107877. In this context, the disclosure of WO2016/107877 relating to 3′-UTR sequences is herewith incorporated by reference. Particularly suitable 3′-UTRs are SEQ ID NOs: 1 to 24 and SEQ ID NOs: 49 to 318 of patent application WO2016/107877, or fragments or variants of these sequences. Accordingly, the 3′-UTRs of the artificial RNA of the present invention may comprise or consists of a corresponding RNA sequence of the nucleic acid sequence according SEQ ID NOs: 1 to 24 and SEQ ID NOs: 49 to 318 of the patent application WO2016/107877. In other embodiments, the artificial RNA as defined herein comprises a 3′-UTR as described in WO2017/036580. In this context, the disclosure of WO2017/036580 relating to 3′-UTR sequences is herewith incorporated by reference. Particularly suitable 3-UTRs are SEQ ID NOs: 152 to 204 of the patent application WO2017/036580, or fragments or variants of these sequences. Accordingly, the 3′-UTR of the artificial RNA of the present invention may comprise or consist of a corresponding RNA sequence of the nucleic acid sequence according SEQ ID NOs: 152 to 204 of the patent application WO2017/036580. 
     According to preferred embodiments the artificial RNA comprises at least one heterologous 5′-UTR. 
     In preferred embodiments, the at least one artificial nucleic acid as defined herein, particularly the RNA as defined herein may comprise at least one heterologous 5′-UTR. 
     Preferably, the at least one 5′-UTR comprises or consists of a nucleic acid sequence derived from the 5′-UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 5′-UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene. 
     Preferably the artificial RNA of the present invention comprises a 5′-UTR, which may be derivable from a gene that relates to an RNA with an enhanced half-life (that provides a stable RNA), for example a 5′-UTR as defined and described below. 
     Preferably, the at least one heterologous 5′-UTR comprises a nucleic acid sequence derived from a 5′-UTR of a gene, which preferably encodes a stable mRNA, or from a homolog, a fragment or a variant of said gene. 
     In preferred embodiments of the first aspect, the artificial RNA of the invention comprises at least one heterologous 5′-UTR, wherein the at least one heterologous 5′-UTR comprises a nucleic acid sequence derived from a 5′-UTR of gene selected from HSD17B4, RPL32, ASAH1, ATP5A1, MP68, NDUFA4, NOSIP, RPL31, SLC7A3, TUBB4B, and UBQLN2, or from a homolog, a fragment or variant of any one of these genes. 
     RPL32-derived 5′-UTR: The artificial RNA of the invention may comprise a 5′-UTR derived from a 5′-UTR of a gene encoding a 60S ribosomal protein L32, or a homolog, variant, fragment or derivative thereof, wherein said 5′-UTR preferably lacks the 5′TOP motif. Such 5′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 5′-UTR of a 60S ribosomal protein L32 (RPL32) gene, preferably from a vertebrate, more preferably a mammalian, most preferably a human 60S ribosomal protein L32 (RPL32) gene, or a homolog, variant, fragment or derivative thereof, wherein the 5′-UTR preferably does not comprise the 5′TOP of said gene. Said gene may preferably encode a 60S ribosomal protein L32 (RPL32) corresponding to a human 60S ribosomal protein L32 (RPL32) (UniProt Ref. No. P62899, entry version #138 of 30 Aug. 2017). Accordingly, the artificial RNA of the invention may comprise a 5′-UTR derived from a RPL32 gene, wherein said 5′-UTR derived from a RPL32 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 21 or 22 or a fragment or a variant thereof. 
     HSD17B4-derived 5′-UTR: The artificial RNA of the invention may comprise a 5′-UTR derived from a 5′-UTR of a gene encoding a 17-beta-hydroxysteroid dehydrogenase 4, or a homolog, variant, fragment or derivative thereof, preferably lacking the 5′TOP motif. Such 5′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 5′-UTR of a 17-beta-hydroxysteroid dehydrogenase 4 (also referred to as peroxisomal multifunctional enzyme type 2) gene, preferably from a vertebrate, more preferably mammalian, most preferably human 17-beta-hydroxysteroid dehydrogenase 4 (HSD17B4) gene, or a homolog, variant, fragment or derivative thereof, wherein preferably the 5′-UTR does not comprise the 5′TOP of said gene. Said gene may preferably encode a 17-beta-hydroxysteroid dehydrogenase 4 protein corresponding to human 17-beta-hydroxysteroid dehydrogenase 4 (UniProt Ref. No. Q9BPX1, entry version #139 of Aug. 30, 2017), or a homolog, variant, fragment or derivative thereof. Accordingly, the artificial RNA of the invention may comprise a 5′-UTR derived from a HSD17B4 gene, wherein said 5′-UTR derived from a HSD17B4 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1 or 2 or a fragment or a variant thereof. 
     ASAH1-derived 5′-UTR: The artificial RNA of the invention may comprise a 5′-UTR derived from a 5′-UTR of a gene encoding acid ceramidase (ASAH1), or a homolog, variant, fragment or derivative thereof. Such 5′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 5′-UTR of an acid ceramidase (ASAH1) gene, preferably from a vertebrate, more preferably mammalian, most preferably human acid ceramidase (ASAH1) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode an acid ceramidase (ASAH1) protein corresponding to human acid ceramidase (ASAH1) (UniProt Ref. No. Q13510, entry version #177 of Jun. 7, 2017), or a homolog, variant, fragment or derivative thereof. Accordingly, the artificial RNA of the invention may comprise a 5′-UTR derived from a ASAH1 gene, wherein said 5′-UTR derived from a ASAH1 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3 or 4 or a fragment or a variant thereof. 
     ATP5A1-derived 5′-UTR: The artificial RNA of the invention may comprise a 5′-UTR which is derived from a 5′-UTR of a gene encoding mitochondrial ATP synthase subunit alpha (ATP5A1), or a homolog, variant, fragment or derivative thereof, wherein said 5′-UTR preferably lacks the 5′TOP motif. Such 5′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 5′-UTR of a mitochondrial ATP synthase subunit alpha (ATP5A1) gene, preferably from a vertebrate, more preferably a mammalian and most preferably a human mitochondrial ATP synthase subunit alpha (ATP5A1) gene, or a homolog, variant, fragment or derivative thereof, wherein the 5′-UTR preferably does not comprise the 5′TOP of said gene. Said gene may preferably encode a mitochondrial ATP synthase subunit alpha protein corresponding to human acid mitochondrial ATP synthase subunit alpha (UniProt Ref. No. P25705, entry version #208 of Aug. 30, 2017), or a homolog, variant, fragment or derivative thereof. Accordingly, the artificial RNA of the invention may comprise a 5′-UTR derived from a ATP5A1 gene, wherein said 5′-UTR derived from a ATP5A1 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5 or 6 or a fragment or a variant thereof. 
     MP68-derived 5′-UTR: The artificial RNA of the invention may comprise a 5′-UTR which is derived from a 5′-UTR of a gene encoding MP68, or a homolog, fragment or variant thereof. Such 5′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 5′-UTR of a 6.8 kDa mitochondrial proteolipid (MP68) gene, preferably from a vertebrate, more preferably a mammalian 6.8 kDa mitochondrial proteolipid (MP68) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode a 6.8 kDa mitochondrial proteolipid (MP68) protein corresponding to a human 6.8 kDa mitochondrial proteolipid (MP68) protein (UniProt Ref. No. P56378, entry version #127 of 15 Feb. 2017). Accordingly, the artificial RNA of the invention may comprise a 5′-UTR derived from a MP68 gene, wherein said 5′-UTR derived from a MP68 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7 or 8 or a fragment or a variant thereof. 
     NDUFA4-derived 5′-UTR: The artificial RNA of the invention may comprise a 5′-UTR which is derived from a 5′-UTR of a gene encoding a Cytochrome c oxidase subunit (NDUFA4), or a homolog, fragment or variant thereof. Such 5′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 5′-UTR of a Cytochrome c oxidase subunit (NDUFA4) gene, preferably from a vertebrate, more preferably a mammalian Cytochrome c oxidase subunit (NDUFA4) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode a Cytochrome c oxidase subunit (NDUFA4) protein corresponding to a human Cytochrome c oxidase subunit (NDUFA4) protein (UniProt Ref. No. 000483, entry version #149 of 30 Aug. 2017). Accordingly, the artificial RNA of the invention may comprise a 5′-UTR derived from a NDUFA4 gene, wherein said 5′-UTR derived from a NDUFA4 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9 or 10 or a fragment or a variant thereof. 
     NOSIP-derived 5′-UTR: The artificial RNA of the invention may comprise a 5′-UTR which is derived from a 5-UTR of a gene encoding a Nitric oxide synthase-interacting (NOSIP) protein, or a homolog, variant, fragment or derivative thereof. Such 5′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 5′-UTR of a Nitric oxide synthase-interacting protein (NOSIP) gene, preferably from a vertebrate, more preferably a mammalian, most preferably a human Nitric oxide synthase-interacting protein (NOSIP) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode a Nitric oxide synthase-interacting protein (NOSIP) protein corresponding to a human Nitric oxide synthase-interacting protein (NOSIP) protein (UniProt Ref. No. Q9Y314, entry version #130 of 7 Jun. 2017). Accordingly, the artificial RNA of the invention may comprise a 5′-UTR derived from a NOSIP gene, wherein said 5′-UTR derived from a NOSIP gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11 or 12 or a fragment or a variant thereof. 
     RPL31-derived 5′-UTR: The artificial RNA of the invention may comprise a 5′-UTR which is derived from a 5′-UTR of a gene encoding a 60S ribosomal protein L31, or a homolog, variant, fragment or derivative thereof, wherein said 5′-UTR preferably lacks the 5′TOP motif. Such 5′-UTR preferably comprise or consist of a nucleic acid sequence derived from the 5′-UTR of a 60S ribosomal protein L31 (RPL31) gene, preferably from a vertebrate, more preferably a mammalian60S ribosomal protein L31 (RPL31) gene, or a homolog, variant, fragment or derivative thereof, wherein the 5′-UTR preferably does not comprise the 5′TOP of said gene. Said gene may preferably encode a 60S ribosomal protein L31 (RPL31) corresponding to a human 60S ribosomal protein L31 (RPL31) (UniProt Ref. No. P62899, entry version #138 of 30 Aug. 2017). Accordingly, the artificial RNA of the invention may comprise a 5′-UTR derived from a RPL31 gene, wherein said 5′-UTR derived from a RPL31 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13 or 14 or a fragment or a variant thereof. 
     SLC7A3-derived 5′-UTR: The artificial RNA of the invention may comprise a 5′-UTR which is derived from a 5′-UTR of a gene encoding a cationic amino acid transporter 3 (solute carrier family 7 member 3, SLC7A3) protein, or a homolog, variant, fragment or derivative thereof. Such 5′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 5′-UTR of a cationic amino acid transporter 3 (SLC7A3) gene, preferably from a vertebrate, more preferably a mammalian cationic amino acid transporter 3 (SLC7A3) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode a cationic amino acid transporter 3 (SLC7A3) protein corresponding to a human cationic amino acid transporter 3 (SLC7A3) protein (UniProt Ref. No. Q8WY07, entry version #139 of 30 Aug. 2017). Accordingly, the artificial RNA of the invention may comprise a 5′-UTR derived from a SLC7A3 gene, wherein said 5′-UTR derived from a SLC7A3 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 15 or 16 or a fragment or a variant thereof. 
     TUBB4B-derived 5′-UTR: The artificial RNA of the invention may comprise a 5′-UTR which is derived from a 5′-UTR of a gene encoding a tubulin beta-4B chain (TUBB4B) protein, or a homolog, variant, fragment or derivative thereof. Such 5′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 5′-UTR of a tubulin beta-4B chain (TUBB4B) gene, preferably from a vertebrate, more preferably a mammalian and most preferably a human tubulin beta-48 chain (TUBB4B) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode a tubulin beta-4B chain (TUBB4B) protein corresponding to human tubulin beta-4B chain (TUBB4B) protein (UniProt Ref. No. Q8WY07, entry version #142 of 30 Aug. 2017). Accordingly, the artificial RNA of the invention may comprise a 5′-UTR derived from a TUBB4B gene, wherein said 5′-UTR derived from a TUBB4B gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 17 or 18 or a fragment or a variant thereof. 
     UBQLN2-derived 5′-UTR: The artificial RNA of the invention may comprise a 5′-UTR which is derived from a 5′-UTR of a gene encoding an ubiquilin-2 (UBQLN2) protein, or a homolog, variant, fragment or derivative thereof. Such 5′-UTRs preferably comprise or consist of a nucleic acid sequence derived from the 5′-UTR of an ubiquilin-2 (UBQLN2) gene, preferably from a vertebrate, more preferably a mammalian ubiquilin-2 (UBQLN2) gene, or a homolog, variant, fragment or derivative thereof. Said gene may preferably encode an ubiquilin-2 (UBQLN2) protein corresponding to UniProt Ref. No. Q9UHD9, entry version #151 of 30 Aug. 2017. Accordingly, the artificial RNA of the invention may comprise a 5′-UTR derived from a UBQLN2 gene, wherein said 5′-UTR derived from a UBQLN2 gene comprises or consists of a nucleic acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 19 or 20 or a fragment or a variant thereof. 
     Further 5′-UTRs: In embodiments, the artificial RNA as defined herein comprises a 5′-UTR as described in WO2013/143700. In this context, the disclosure of WO2013/143700 relating to 5′-UTR sequences is herewith incorporated by reference. Particularly preferred 5′-UTRs are nucleic acid sequences derived from SEQ ID NOs: 1-1363, SEQ ID NO: 1395, SEQ ID NO: 1421 and SEQ ID NO: 1422 of the patent application WO2013/143700, or fragments or variants of these sequences. In this context, it is preferred that the 5′-UTR of the artificial RNA according to the present invention comprises or consists of a corresponding RNA sequence of the nucleic acid sequence according SEQ ID NOs: 1-1363, SEQ ID NO: 1395, SEQ ID NO: 1421 and SEQ ID NO: 1422 of the patent application WO2013/143700. In other embodiments, the artificial RNA of the invention comprises a 5′-UTR as described in WO2016/107877. In this context, the disclosure of WO2016/107877 relating to 5′-UTR sequences is herewith incorporated by reference. Particularly preferred 5′-UTRs are nucleic acid sequences according to SEQ ID NOs: 25 to 30 and SEQ ID NOs: 319 to 382 of the patent application WO2016/107877, or fragments or variants of these sequences. In this context, it is particularly preferred that the 5′-UTR of the artificial RNA comprises or consists of a corresponding RNA sequence of the nucleic acid sequence according SEQ ID NOs: 25 to 30 and SEQ ID NOs: 319 to 382 of the patent application WO2016/107877. In other embodiments, the artificial RNA of the invention comprises a 5′-UTR as described in WO2017/036580. In this context, the disclosure of WO2017/036580 relating to 5′-UTR sequences is herewith incorporated by reference. Particularly preferred 5′-UTRs are nucleic acid sequences according to SEQ ID NOs: 1 to 151 of the patent application WO2017/036580, or fragments or variants of these sequences. In this context, it is particularly preferred that the 5′-UTR of the artificial RNA comprises or consists of a corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NOs: 1 to 151 of the patent application WO2017/036580. 
     The inventors observed that certain combinations of at least one heterologous 5′-UTR and/or at least one heterologous 3′-UTR are advantageously increasing the translation of the at least one coding sequence operably linked to said 3′-UTR and/or 5′-UTR encoding at least one antigenic peptide or protein derived from a RSV F protein in the target tissue (e.g., muscle, dermis). 
     Accordingly it is preferred that the at least one heterologous 5′-UTR as defined herein and the at least one heterologous 3′-UTR as defined herein act synergistically to increase production (that is translation) of antigenic peptide or protein from the artificial RNA of the invention. These advantageous combinations of 5′-UTR and 3-UTR are specified in the following. Each of the abbreviation introduced below, namely “a-1”, “a-2”, “a-3”, “a-4”, “a-5”, “b-1”, “b-2”, “b-3”, “b-4”, “b-5”, “c-1”, “c-2”, “c-3” “c-4”, “c-5”, “d-1”, “d-2”, “d-3”, “d-4”, “d-5”, “e-1” “e-2” “e-3”, “e-4”, “e-5”, “e-6”, “f-1”, “f-2”, “f-3”, “f-4”, “f-5, “g-1”, “g-2”, “g-3”, “g-4”, “g-5”, “h-1”, “h-2”, “h-3”, “h-4”, “h-5”, i-1”, “i-2”, “i-3”, are used throughout the specification of the present invention and represent one advantageous combination of 5′-UTR and/or 3′UTR of the invention. 
     Accordingly, in preferred embodiments of the first aspect, the artificial RNA of the invention comprises
     a-1. at least one 5′-UTR derived from a 5′-UTR of a HSD174 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a PSMB3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   a-2. at least one 5′-UTR derived from a 5′-UTR of a NDUFA4 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a PSMB3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   a-3. at least one 5′-UTR derived from a 5′-UTR of a SLC7A3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a PSMB3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   a-4. at least one 5′-UTR from a 5′-UTR of a NOSIP gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a PSMB3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   a-5. at least one 5′-UTR derived from a 5′-UTR of a MP68 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a PSMB3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   b-1. at least one 5′-UTR derived from a 5′-UTR of a UBQLN2 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3-UTR derived from a 3′-UTR of a RPS9 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   b-2. at least one 5′-UTR derived from a 5′-UTR of a ASAH1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a RPS9 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   b-3. at least one 5′-UTR derived from a 5′-UTR of a HSD17B4 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a RPS9 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   b-4. at least one 5′-UTR derived from a 5′-UTR of a HSD17B4 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a CASP1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   b-5. at least one 5′-UTR derived from a 5′-UTR of a NOSIP gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a COX6B1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   c-1. at least one 5′-UTR derived from a 5′-UTR of a NDUFA4 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a RPS9 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   c-2. at least one 5′-UTR derived from a 5′-UTR of a NOSIP gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a NDUFA1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   c-3. at least one 5′-UTR derived from a 5′-UTR of a NDUFA4 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a COX6B1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   c-4. at least one 5′-UTR derived from a 5′-UTR of a NDUFA4 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a NDUFA1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   c-5. at least one 5′-UTR derived from a 5′-UTR of a ATP5A1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a PSMB3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   d-1. at least one 5′-UTR derived from a 5′-UTR of a RPL31 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a PSMB3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   d-2. at least one 5′-UTR derived from a 5′-UTR of a ATP5A1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a CASP1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   d-3. at least one 5′-UTR derived from a 5′-UTR of a SLC7A3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a GNAS gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   d-4. at least one 5′-UTR derived from a 5′-UTR of a HSD17B4 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a NDUFA1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   d-5. at least one 5′-UTR derived from a 5′-UTR of a SLC7A3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a NDUFA1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   e-1. at least one 5′-UTR derived from a 5′-UTR of a TUBB4B gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a RPS9 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   e-2. at least one 5′-UTR derived from a 5′-UTR of a RPL31 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a RPS9 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   e-3. at least one 5′-UTR derived from a 5′-UTR of a MP68 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a RPS9 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   e-4. at least one 5′-UTR derived from a 5′-UTR of a NOSIP gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a RPS9 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   e-5. at least one 5′-UTR derived from a 5′-UTR of a ATP5A1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a RPS9 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   e-6. at least one 5′-UTR derived from a 5′-UTR of a ATP5A1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a COX6B1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   f-1. at least one 5′-UTR derived from a 5′-UTR of a ATP5A1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a GNAS gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   f-2. at least one 5′-UTR derived from a 5′-UTR of a ATP5A1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a NDUFA1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   f-3. at least one 5′-UTR derived from a 5′-UTR of a HSD17B4 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a COX6B1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   f-4 at least one 5′-UTR derived from a 5′-UTR of a HSD17B4 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3-UTR of a GNAS gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   f-5. at least one 5′-UTR derived from a 5′-UTR of a MP68 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a COX6B1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   g-1. at least one 5′-UTR derived from a 5′-UTR of a MP68 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a NDUFA1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   g-2. at least one 5′-UTR derived from a 5′-UTR of a NDUFA4 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a CASP1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   g-3. at least one 5′-UTR derived from a 5′-UTR of a NDUFA4 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a GNAS gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   g-4. at least one 5′-UTR derived from a 5′-UTR of a NOSIP gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a CASP1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   g-5. at least one 5′-UTR derived from a 5′-UTR of a RPL31 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a CASP1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   h-1. at least one 5′-UTR derived from a 5′-UTR of a RPL31 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a COX6B1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   h-2. at least one 5′-UTR derived from a 5′-UTR of a RPL31 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a GNAS gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   h-3. at least one 5′-UTR derived from a 5′-UTR of a RPL31 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a NDUFA1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   h-4. at least one 5′-UTR derived from a 5′-UTR of a SLC7A3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3-UTR derived from a 3′-UTR of a CASP1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   h-5. at least one 5′-UTR derived from a 5′-UTR of a SLC7A3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a COX6B1 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof; or   i-1. at least one 5′-UTR derived from a 5′-UTR of a SLC7A3 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a RPS9 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof.   i-2. at least one 5′-UTR derived from a 5′-UTR of a RPL32 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof and at least one 3′-UTR derived from a 3′-UTR of a ALB7 gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof.   i-3. at least one 3′-UTR derived from a 3′-UTR of a alpha-globin gene gene, or from a corresponding RNA sequence, homolog, fragment or variant thereof.   

     Suitably, the artificial RNA of the invention comprises at least one coding sequence encoding at least one antigenic peptide or protein derived from a RSV F protein as specified herein operably linked to a 3′-UTR and a 5′-UTR selected from a-1 (HSD17B4/PSMB3), a-2 (Ndufa4/PSMB3), a-3 (SLC7A3/PSMB3), a-4 (NOSIP/PSMB3), a-5 (MP68/PSMB3), b-1 (UBQLN2/RPS9), b-2 (ASAH1/RPS9), b-3 (HSD17B4/RPS9), b-4 (HSD17B4/CASP1), b-5 (NOSIP/COX6B1), c-1 (NDUFA4/RPS9), c-2 (NOSIP/NDUFA1), c-3 (NDUFA4/COX6B1), c-4 (NDUFA4/NDUFA1), c-5 (ATP5A1/PSMB3), d-1 (Rpl31/PSMB3), d-2 (ATP5A1/CASP1), d-3 (SLC7A3/GNAS), d-4 (HSD17B4/NDUFA1), d-5 (Sc7a3/Ndufa1), e-1 (TUBB4B/RPS9), e-2 (RPL31/RPS9), e-3 (MP68/RPS9), e-4 (NOSIP/RPS9), e-5 (ATP5A1/RPS9), e-6 (ATP5A1/COX6B1), f-1 (ATP5A1/GNAS), f-2 (ATP5A1/NDUFA1), f-3 (HSD17B4/COX6B1), f-4 (HSD17B4/GNAS), f-5 (MP68/COX6B1), g-1 (MP68/NDUFA1), g-2 (NDUFA4/CASP1), g-3 (NDUFA4/GNAS), g-4 (NOSIP/CASP1), g-5 (RPL31/CASP1), h-1 (RPL31/COX6B1), h-2 (RPL31/GNAS), h-3 (RPL31/NDUFA1), h-4 (Slc7a3/CASP1), h-5 (SLC7A3/COX6B1), i-1 (SLC7A3/RPS9), i-2 (RPL32/ALB7), or i-3 (a-globin gene). 
     In particularly preferred embodiments of the first aspect, the artificial RNA of the invention comprise UTR elements according to a-1 (HSD17B4/PSMB3), a-4 (NDUFA4/PSMB3), c-1 (NDUFA4/RPS9), e-4 (NOSIP/RPS9), g-2 (NDUFA4/CASP1), i-2 (RPL32/ALB7), or i-3 (alpha-globin (muag)). 
     In a particularly preferred embodiment of the first aspect, the artificial RNA of the invention comprises UTR elements according to a-1 (HSD17B4/PSMB3). 
     The invention relates to an artificial RNA, preferably an RNA suitable for vaccination, comprising at least one heterologous 5′-UTR as defined above and/or at least one heterologous 3′-UTR as defined above and at least one coding sequence operably linked to said 3′-UTR and/or 5′-UTR, wherein said coding sequence encodes at least one antigenic peptide or protein derived from a Respiratory syncytial virus (“RSV”), or a fragment or variant thereof. 
     As used herein, the term “Respiratory syncytial virus” or the corresponding abbreviation “RSV” is not limited to a particular virus strain, variant, serotype, or isolate, etc. comprising any Respiratory syncytial virus of any origin. 
     According to various embodiments, the artificial RNA, preferably the coding sequence of the artificial RNA comprises or consists of a nucleic acid sequence that is derived from viruses, with NCBI Taxonomy ID (“NCBI-ID”) provided in List 1 below. 
     List 1: RSV Virus Strains: 
     Human orthopneumovirus, HRSV (NCBI-ID 11250); Human respiratory syncytial virus A, HRSV-A, Respiratory syncytial virus group A (NCBI-ID 208893); Human respiratory syncytial virus A strain Long, Human respiratory syncytial virus (subgroup A/strain Long) (NCBI-ID 11260); Human respiratory syncytial virus A2, Human respiratory syncytial virus (strain A2), HRSVA (NCBI-ID 11259); Human respiratory syncytial virus (strain RSB1734), (NCBI-ID 11253); Human respiratory syncytial virus (strain RSB5857) (NCBI-ID 11254); Human respiratory syncytial virus (strain RSB6190), (NCBI-ID 11255); Human respiratory syncytial virus (strain RSB6256), (NCBI-ID 11256); Human respiratory syncytial virus (strain RSB642), (NCBI-ID 11252); Human respiratory syncytial virus (strain RSB6614), (NCBI-ID 11257); Human respiratory syncytial virus B, HRSV-B, Respiratory syncytial virus group B, (NCBI-ID 208895); Human Respiratory syncytial virus 9320 (NCBI-ID 253182); Human respiratory syncytial virus B1 (NCBI-ID 79692); Human respiratory syncytial virus (subgroup B/strain 18537), (NCBI-ID 11251); Human respiratory syncytial virus (subgroup B/strain 8/60), (NCBI-ID 11258); Human respiratory syncytial virus S2, (NCBI-ID 410078); Human respiratory syncytial virus strain RSS-2, (NCBI-ID 11261); unclassified Human respiratory syncytial virus, (NCBI-ID 410233); Human respiratory syncytial virus (strain RSP112/Sweden/02-03), (NCBI-ID 410237); Human respiratory syncytial virus (strain RSP120/Sweden/02-03), (NCBI-ID 410238); Human respiratory syncytial virus (strain RSP121/Sweden/02-03), (NCBI-ID 410239); Human respiratory syncytial virus (strain RSP122/Sweden/02-03), (NCBI-ID 410247); Human respiratory syncytial virus (strain RSP13/Sweden/02-03), (NCBI-ID 410241); Human respiratory syncytial virus (strain RSP140/Sweden/02-03), (NCBI-ID 410248); Human respiratory syncytial virus (strain RSP16/Sweden/02-03), (NCBI-ID 410242); Human respiratory syncytial virus (strain RSP171/Sweden/02-03), (NCBI-ID 410246); Human respiratory syncytial virus (strain RSP183/Sweden/02-03), (NCBI-ID 410249); Human respiratory syncytial virus (strain RSP191/Sweden/02-03), (NCBI-ID 410240); Human respiratory syncytial virus (strain RSP199/Sweden/02-03), (NCBI-ID 410250); Human respiratory syncytial virus (strain RSP212/Sweden/02-03), (NCBI-ID 410251); Human respiratory syncytial virus (strain RSP41/Sweden/02-03), (NCBI-ID 410234); Human respiratory syncytial virus (strain RSP45/Sweden/02-03), (NCBI-ID 410235); Human respiratory syncytial virus (strain RSP56/Sweden/02-03), (NCBI-ID 410243); Human respiratory syncytial virus (strain RSP58/Sweden/02-03), (NCBI-ID 410236); Human respiratory syncytial virus (strain RSP67/Sweden/02-03), (NCBI-ID 410244); Human respiratory syncytial virus (strain RSP94/Sweden/02-03) (NCBI-ID 410245); Respiratory syncytial virus isolate RSV Memphis-37, (strain Memphis-37) (NCBI-ID 12814). 
     In preferred embodiments of the invention, the at least one antigenic peptide or protein is derived from a Respiratory syncytial virus isolate RSV Memphis-37 (strain Memphis-37) (NCBI-ID: 12814). Throughout the present invention, including the information contained in the ST25 sequence listing, the abbreviation “HRSV(Memphis-37)” is used for said particularly preferred RSV virus. 
     In preferred embodiments of the invention, the at least one antigenic peptide or protein is derived from a Human respiratory syncytial virus A2, Human respiratory syncytial virus (strain A2) (NCBI-ID: 11259). Throughout the present invention, including the information contained in the ST25 sequence listing, the abbreviation “HRSV(A2)” is used for said particularly preferred RSV virus. 
     It has to be understood that the skilled person may also use amino acid sequences and nucleic acid sequences derived from any RSV strains provided in List 1 to adapt the teaching of the present invention and to obtain RNA constructs, compositions, and vaccines according to the invention. 
     In various embodiments, the at least one antigenic peptide or protein may be selected from fusion protein (F), glycoprotein G, short hydrophobic protein SH, matrix protein M, nucleoprotein N, large polymerase L, M2-1 protein, M2-2 protein, phosphoprotein P, non-structural protein NS1, or non-structural protein NS2 of Respiratory syncytial virus (RSV) or a fragment, variant or derivative thereof. 
     In particularly preferred embodiments of the first aspect, the at least one antigenic peptide or protein is derived from an RSV fusion (F) protein. In this context, the amino acid sequence of the at least one antigenic peptide or protein may be selected from any peptide or protein derived from RSV fusion protein F or from a fragment, variant or derivative thereof. 
     RSV F protein is initially expressed (after infection of a host cell) as a single polypeptide precursor, designated full-length fusion protein F (herein referred to as “F0”). F0 forms a trimer in the endoplasmic reticulum and is processed by a cellular/host furin-like protease at two conserved sites, generating, F1, F2, and Pep27 polypeptides. The Pep27 polypeptide is excised and does not form part of the mature F protein. The F2 polypeptide originates from the N-terminal portion of the F0 precursor and links to the F1 polypeptide via two disulfide bonds. The F1 polypeptide originates from the C-terminal portion of the F0 precursor and anchors the mature F protein in the membrane via a transmembrane domain, which is linked to a cytoplasmic tail. Three F2-F1 heterodimer units (“protomers”) assemble to form a mature F protein. Initially, the mature F protein is in a metastable form (herein referred to as “pre-fusion conformation”). Upon triggering, it undergoes a dramatic and irreversible conformational change (herein referred to as “postfusion conformation”) that fuses the viral and target-cell membranes. 
     Accordingly, the artificial RNA of the first aspect, preferably the artificial RNA suitable for vaccination, encodes at least one antigenic peptide or protein derived from a RSV F protein or a fragment or variant thereof. 
     In preferred embodiments, at least one antigenic peptide or protein derived from a RSV F protein may be derived from any one of the following amino acid sequences (NCBI Protein Accession numbers) provided in List 2 below. 
     List 2: NCBI Protein Accession Numbers of RSV Fusion (F) Proteins: 
     Accession No. Protein, AJF44801.1, AJF44759.1, AJF44661.1, AJF44602.1, 2207424A, AAB38520.1, AAB38517.1, AAB38519.1, AAB38518.1, AVQ93587.1, AVQ93599.1, AVQ93571.1, AVQ93568.1, AVQ93589.1, AVQ93597.1, AVQ93563.1, AVQ93594.1, AVQ93606.1, AVQ93601.1, AVQ93562.1, AVQ93561.1, AVQ93607.1, AVQ93588.1, AVQ93575.1, AVQ93468.1, AVQ93467.1, AVQ93590.1, AVQ93552.1, AVQ93556.1, AVQ93471.1, AVQ93458.1, AVQ93494.1, AVQ93470.1, AVQ93489.1, AVQ93542.1, AVQ93472.1, AVQ93514.1, AVQ93485.1, AVQ93533.1, AVQ93481.1, AVQ93546.1, AVQ93512.1, AVQ93554.1, AVQ93551.1, AVQ93547.1, AVQ93558.1, AVQ93461.1, AVQ93500.1, AVQ93426.1, AVQ93398.1, AVQ93401.1, AVQ93361.1, AVQ93408.1, AVQ93443.1, AVQ93429.1, AVQ93359.1, AVQ93365.1, AVQ93366.1, AVQ93402.1, AVQ93377.1, AVQ93412.1, AVQ93391.1, AVQ93457.1, AVQ93372.1, AVQ93455.1, AVQ93364.1, AVQ93378.1, AVQ93393.1, AVQ93362.1, AVQ93585.1, ART28504.1, AVQ93404.1, AOS49123.1, AOS48496.1, AMT78271.1, AHX57174.1, AHW81390.1, AHV81506.1, AFX60128.1, AFX60129.1, AEQ63389.1, ARB66328.1, ANZ80034.1, AMN91253.1, P03420.1, A1008046.1, NP_056863.1, AFX60234.1, AFX60231.1, AFX60232.1, AFX60222.1, AFX60219.1, AFX60215.1, AFX60214.1, AFX60212.1, AFX60208.1, AFX60202.1, AFX60220.1, AFX60213.1, AFX60190.1, AFX60187.1, AFX60201.1, AFX60173.1, AFX60169.1, AFX60162.1, AFX60156.1, AFX60151.1, AFX60150.1, AFX60148.1, AFX60141.1, AFX60127.1, AFX60137.1, AFX60135.1, AFV46420.1, AFX60200.1, AFV46419.1, AFV46417.1, AFV46413.1, AFV46414.1, AFV46410.1, AFV46403.1, AFV46409.1, AFP99061.1, AFM95400.1, AFV46401.1, AFP99064.1, AFM95376.1, AFX60138.1, AFP99060.1, AFM95365.1, AFM55563.1, AFM55530.1, AFM55442.1, AFM55420.1, AFM55552.1, AFM55365.1, AFP99059.1, AFM95385.1, AFM55354.1, AFM55343.1, AFM55387.1, AFM55299.1, AFM55288.1, AFM55266.1, AFM55277.1, AFM55255.1, AFM55222.1, AFM55211.1, AFI25262.1, AFD34266.1, AFM55332.1, AFD34264.1, AFD34262.1, AFD34265.1, AFD34261.1, AFD34260.1, AFD34259.1, AEQ63641.1, AEQ63487.1, AEQ63520.1, AEQ63378.1, AEQ63367.1, 4CCF_A, AEQ63334.1, AEO45949.1, AEO45939.1, AEQ63312.1, AEQ63586.1, AEO45919.1, AEO45909.1, AEO45889.1, AEO45879.1, AEO45869.1, AEO45929.1, AEO45850.1, AEO45859.1, AEQ63444.1, AEO23054.1, AEO23052.1, AEO23051.1, AEC32087.1, ADZ95785.1, AEC32085.1, ADZ95784.1, ADZ95783.1, ADZ95782.1, ADZ95781.1, ADZ95779.1, ADZ95780.1, ADZ95777.1, ADZ95778.1, ADZ95776.1, ADZ95775.1, ACY68435.1, ACO83302.1, AB35685.1, AFI25251.1, AAX23994.1, AAQ97026.1, AAR14266.1, AAQ97027.1, AAQ97030.1, AAQ97028.1, AAC57027.1, AAQ97029.1, AAQ97031.1, AAM68160.1, AAM44851.1, P11209.2, P13843.1, AAO72325.1, AAM68157.1, CAA26143.1, 1512372A, AAB86664.1, AAO72324.1, AAB82446.1, AAO72323.1, AAM68154.1, AAA47410.1, P12568.1, ARB07894.1, AGG39517.1, BBC54612.1, BBC54636.1, BBC54627.1, BBC54621.1, BBC54570.1, BBC54579.1, BBC54595.1, BBC54555.1, BBC54552.1, BBC54564.1, BBC54581.1, BBC54571.1, BBC54553.1, BBC54565.1, BBC54245.1, BBC54243.1, BBC54238.1, BBC54242.1, BBC54239.1, BBC54235.1, BBC54234.1, BBC54236.1, BBC54244.1, BBC54186.1, BBC54178.1, BBC54202.1, BBC54151.1, BBC54142.1, BBC54134.1, BBC54170.1, BBC54210.1, BBC54169.1, BBC54213.1, BBC54203.1, BBC54160.1, BBC54163.1, BBC54215.1, BBC54156.1, BBC54179.1, BBC54150.1, BBC54207.1, BBC54194.1, BBC54149.1, BBC54138.1, BBC54199.1, BBC54220.1, BBC54181.1, BBC54132.1, BBC54146.1, BBC54122.1, BBC54124.1, BBB35202.1, BBB35201.1, BBB35192.1, BBB35193.1, BBB35199.1, BBB35184.1, BBB35126.1, BBB35133.1, BBB35130.1, BBB35160.1, BBB35162.1, BBB35181.1, BBB35165.1, BBB35121.1, BBB35138.1, BBB35176.1, BBB35142.1, BBB35136.1, BBB35153.1, BBB35115.1, BBB35150.1, BBB35097.1, BBB35109.1, BBB35094.1, BBB35183.1, BBB35104.1, BBB35099.1, BBB35188.1, AKA45871.1, ASV65838.1, AGG39373.1, AII22107.1, AGG39400.1, AGG39457.1, ARR29240.1, ARR29251.1, ARR29189.1, ARR29207.1, AUH15164.1, ATV81343.1, AUC68654.1, AUC68577.1, AUC68566.1, AUC68555.1, AUC68478.1, AUC68445.1, AUC68500.1, AUC68522.1, AUC68291.1, AUC68149.1, AUC68094.1, AMA67097.1, AMA66866.1, AMA66580.1, AIZ95750.1, AIZ95541.1, AIZ95519.1, AHY21419.1, AHY21331.1, AHY21165.1, AHY21143.1, AHY21132.1, AGG39478.1, ATV93506.1, ATV93509.1, AIZ95717.1, ATV81354.1, ART28317.1, BBA57890.1, BBA57901.1, ASZ70099.1, ART28361.1, AQX36844.1, ASK05520.1, ART28427.1, ART28339.1, ART28297.1, ART28328.1, ARQ15966.1, ARN61507.1, ARA15413.1, AGG39394.1, APW78845.1, APW78867.1, APW78900.1, APW78878.1, APW78779.1, APW78702.1, APW78713.1, APW78680.1, APW78658.1, APW78647.1, APW78636.1, AOS48870.1, APW78614.1, AMT78905.1, AMT77402.1, AOZ15479.1, AGN28484.1, AHX57240.1, AHX57031.1, AOS48980.1, AOS48848.1, AOS48815.1, AOS48738.1, AOS49068.1, AOS48727.1, AOS48716.1, AOS48683.1, AOS48551.1, AOS48485.1, AOS48518.1, AOS48441.1, AOS48397.1, AOS48375.1, AOS48353.1, AOS48287.1, AOS48320.1, AOS48265.1, AOS48254.1, AOS48221.1, ANZ79638.1, ALC74025.1, AHV81286.1, AOD40888.1, AOD40516.1, AOD40214.1, AOD40125.1, AOD40104.1, AOD40082.1, AOD39908.1, AJF44826.1, AJF44506.1, AJF44535.1, ANZ80463.1, ANZ80408.1, ANZ80397.1, ANZ80386.1, ANZ80331.1, ANZ80320.1, ANZ80364.1, ANZ80276.1, ANZ80221.1, ANZ80188.1, ANZ80144.1, ANZ80133.1, ANZ80111.1, ANZ80122.1, ANZ80056.1, ANZ80012.1, ANZ80067.1, ANZ79979.1, ANZ79935.1, ANZ79990.1, ANZ79902.1, ANZ79759.1, ANZ79715.1, ANZ79671.1, AMT79718.1, AMT79586.1, AMT79553.1, AMT79542.1, AMT79476.1, AMT79388.1, AMT79201.1, AMT79190.1, AMT79157.1, AMT79124.1, AMT79091.1, AMT79047.1, AMT79014.1, AMT79003.1, AMT78872.1, AMT78832.1, AMT78689.1, AMT78645.1, AMT78513.1, AMT78480.1, AMT78447.1, AMT78392.1, AMT78194.1, AMT78084.1, AMT78051.1, AMT77963.1, AMT77908.1, AMT77776.1, AMT77710.1, AMT77424.1, AMN91385.1, AMN91264.1, AMN91242.1, AHX57504.1, CUS01881.1, CUS01880.1, CUS01877.1, CUS01874.1, CUS01870.1, CUS01875.1, AMA67350.1, AMA67251.1, AMA67262.1, AMA67229.1, AMA67196.1, AMA67130.1, AMA67185.1, AMA67163.1, AMA67086.1, AMA67075.1, AMA66998.1, AMA66987.1, AMA66976.1, AMA66965.1, AMA66921.1, AMA66844.1, AMA66833.1, AMA66624.1, AMA66613.1, AMA66591.1, AMA66569.1, AMA66547.1, AMA66503.1, AMA66492.1, AMA66481.1, AMA66448.1, AMA66415.1, AMA66393.1, AMA66360.1, AGG39553.1, AGG39469.1, AJZ70144.1, AJZ70166.1, AJZ70155.1, AJZ70133.1, AJZ70067.1, AJZ70001.1, AJZ69990.1, AJZ69968.1, AJZ69946.1, AJZ69913.1, AJZ69880.1, AJZ69847.1, AJZ69869.1, AJZ69770.1, AJZ69748.1, AJZ69726.1, AJZ69682.1, AJZ69671.1, AJZ69704.1, AJZ69660.1, AJZ69715.1, AJZ69627.1, AJZ69616.1, AJZ69638.1, AJO16077.1, AJO16055.1, AKE31881.1, AKE31882.1, AKE31878.1, AJF44835.1, AJF44790.1, AJF44737.1, AJF44716.1, AJF44725.1, AJF44643.1, AJF44628.1, AJF44624.1, AJF44613.1, AJF44566.1, AJF44555.1, AJF44526.1, AJF44517.1, AKA45882.1, AKA45849.1, AHA83913.1, AGN28715.1, AHA83902.1, AHA83837.1, AHA83826.1, AHA83705.1, AHA83630.1, AGG39505.1, AIY70242.1, AIY70198.1, AII30203.1, AHY21463.1, AHY21397.1, AHY21320.1, AHY21298.1, AHY21287.1, AHY21276.1, AHY21254.1, AHY21199.1, AHY21176.1, AHX57537.1, AHX57471.1, AHX57427.1, AHX57042.1, AIZ95981.1, AIZ95893.1, AIZ95871.1, AIZ95816.1, AIZ95772.1, AIZ95629.1, AIZ95673.1, AIZ95596.1, AIZ95585.1, AIZ95552.1, AEQ63553.2, AEQ63542.2, AEQ63575.1, AEQ63531.1, AEQ63498.1, AEQ63422.1, AEQ63411.1, AHX57570.1, AHX57152.1, AHX57064.1, AHX57009.1, AHX56987.1, AHV82100.1, AHV82001.1, AHV81891.1, AHV81880.1, AHV81836.1, AHV81682.1, AHV81649.1, AHV81484.1, AHV81462.1, AHV81385.1, AHV81363.1, AHV81330.1, AHV81253.1, AHV81154.1, AHV81122.1, AHV81089.1, AHV81012.1, AHV80957.1, AHV80880.1, AHV80869.1, AHV80836.1, AHV80803.1, AGG39559.1, AGG39562.1, AGG39556.1, AGG39550.1, AGG39547.1, AGG39544.1, AGG39541.1, AGG39529.1, AGG39526.1, AGG39523.1, AGG39514.1, AGG39502.1, AGG39499.1, AGG39496.1, AGG39493.1, AGG39484.1, AGG39490.1, AGG39487.1, AGG39475.1, AGG39472.1, AGG39466.1, AGG39463.1, AGG39454.1, AGG39442.1, AGG39439.1, AGG39436.1, AGG39415.1, AGG39403.1, AGG39397.1, AGG39391.1, AGG39379.1, AHL84194.1, AHA84012.1, AHJ60043.1, BAO49770.1, BAO49766.1, BAO49767.1, AHA84034.1, AHA84023.1, AHA83990.1, AHA83957.1, AHA83924.1, AHA83891.1, AHA83880.1, AHA83782.1, AHA83760.1, AHA83694.1, AGT75357.1, AGN92848.1, AGN28792.1, AGN28781.1, AGN28759.1, AGN28748.1, AGN28693.1, AGN28638.1, AGN28627.1, AGN28539.1, AGN28528.1, AGN28462.1, AGN28440.1, AGL96787.1, AGL96786.1, AGL96784.1, AAS93662.1, AAS93657.1, AAS93656.1, AAS93659.1, AAS93660.1, AAS93663.1, AAS93664.1, AAS93655.1, CUS01869.1, AHG54517.1, ASF87348.1, ASF87341.1, ASF87344.1, ASF87351.1, ASF87338.1, ASF87342.1, ASF87352.1, ASF87337.1, ASF87336.1, AEQ98756.1, AEQ98757.1, AEQ98755.1, AEQ98752.1, AEQ98753.1, AEQ98747.1, ASF87325.1, ASF87326.1, 5W23_A, 5EA3_F, 5UDD_A, 5EA8_F, AHG54458.1, AEN74947.1, AHG54485.1, AHG54477.1, AHG54451.1, AHG54463.1, AHG54445.1, AEO12131.1, AEN74945.1, AEN74944.1, ASF87335.1, AHG54515.1, AHA61605.1, AHV81660.1, AHG54441.1 or AIY60640.1. 
     In the context of the present invention, “RSV F protein”, “RSV fusion protein (F)”, “RSV F”, or “F” may be understood in its broadest sense and refers to F0 (F polypeptide precursor), F1, F2 and Pep27 polypeptides, F2-F1 heterodimer, or the mature F protein (comprising three F2-F1 heterodimers), or fragments and variants of any of these. Accordingly, the term “peptide or protein derived from a RSV fusion (F) protein” refers to a peptide, protein, fragment or variant derived from e.g. F0 (F protein polypeptide precursor), F1, F2 and Pep27 polypeptides, F2-F1 heterodimer, or the mature F protein. Additionally, the term “peptide or protein derived from a RSV fusion (F) protein” refers to peptide, protein, fragment or variant derived from “RSV F protein” or “RSV fusion protein (F)” as defined above which may be genetically engineered to e.g. to lack certain protein elements (e.g. the cytoplasmic tail, the furin cleavage site, Pep27) or e.g. comprise additional elements (e.g., linker elements, heterologous signal peptides etc.). For example, the term “peptide or protein derived from a RSV fusion (F) protein” refers to peptide, protein, fragment or variant derived from F0, F-del, F0_DSCav1, F_DSCav1_mut1, F_DSCav1_mut2, F_DSCav1_mut3, F_DSCav1_mut4, F_DSCav1_mut5, F_DSCav1_mut6, F_DSCav1_mut7, F_DSCav1_mut8, F_DSCav1_mut0, F-del_DSCav1, F-del_DSCav1_mut1, F-del_DSCav1_mut2, F-del_DSCav1_mut3, F-del_DSCav1_mut4, F-del_DSCav1_mut5, F-del_DSCav1_mut6, F-del_DSCav1_mut7, F-del_DSCav1_mut8, F-del_DSCav1_mut0 (for explanation of the constructs see Table 1). Particularly suitable F protein variants that may be encoded by the RNA of the first aspect are specified in the following and are provided in Table 1. 
     It has to be noted that where reference is made to amino acid (aa) residues and their position in an RSV F protein, any numbering used herein—unless stated otherwise—relates to the position of the respective aa residue in a corresponding F0 precursor protein of HRSV(A2) (SEQ ID NO: 68) or a corresponding F0 precursor protein of HRSV(Memphis-37) (SEQ ID NO: 8937 or 11726) wherein position “1” corresponds to the first aa residue, i.e. the aa residue at the N-terminus of a HRSV(A2) F0 precursor protein or a HRSV(Memphis-37) F0 precursor protein. 
     In preferred embodiments, the at least one coding sequence of the RNA of the first aspect encodes at least one antigenic peptide or protein from RSV F protein, wherein RSV F protein is a full-length F protein (F0) or an F protein with deleted C-terminus (F-del), or a fragment or a variant thereof. 
     In this context, any RSV F full-length protein (precursor protein, referred to as “F0”) may be used as suitable antigen and may preferably be derived from any NCBI Protein Accession numbers provided in List 2 or may be chosen from any one of SEQ ID NOs: 68, 8279-8967 or 11726. In preferred embodiments of the invention, the full-length F protein (F0) of HRSV(A2) (SEQ ID NO: 68) is suitably used, see overview Table 1. In other preferred embodiments of the invention, the full-length F protein (F0) of HRSV(Memphis-37) (SEQ ID NO: 8937 or 11726) is suitably used, see overview Table 1. 
     In this context, any RSV F with deleted C-terminus (F-del) may be used as suitable antigen and may preferably be derived from any NCBI Protein Accession numbers provided in List 2 or may be chosen from any one of SEQ ID NOs: 483, 8968-9683, or 12095. An example of such a deletion mutant is the RSV-Fdel554-574 protein according to (Oomens et al. 2006. J. Virol. 80(21):10465-77) where aa residue 554-574 of the full-length F0 protein are removed. Deletion of the main part of the cytoplasmic tail (aa 554-574) of F0 leads to improved intracellular trafficking/cell surface transport in vitro and increases cell surface expression of RSV F significantly. Increased cell surface presentation results in improved B cell recognition (in line with published data; see WO2015024668). In preferred embodiments of the invention, F protein with deleted C-terminus, herein referred to as “F-del” (SEQ ID NO: 483, 9653 or 12095) is suitably used, see overview Table 1. In the light of high level of structural conservation of the RSV F protein among different RSV strains (see e.g. Hause et al., 2017, PLOS ONE 12(6): e0180623), the deletion of aa 554-574 is applicable to different RSV F protein sequences of different RSV isolates. 
     In particularly preferred embodiments, the artificial RNA of the first aspect encodes least one antigenic peptide or protein derived from RSV F protein, wherein said RSV F protein is designed to stabilize the antigen in pre-fusion conformation. A pre-fusion conformation is particularly advantageous in the context of an efficient RSV vaccine, as several potential epitopes for neutralizing antibodies are merely accessible in said protein conformation. 
     In several embodiments, the RSV F protein includes one or more amino acid substitutions that stabilize the F protein in the pre-fusion conformation, for example, substitutions that stabilize the membrane distal portion of the F protein (including the N-terminal region of the F1 polypeptide) in the pre-fusion conformation. For example, the amino acid substitution can introduce a non-natural disulfide bond or can be a cavity-filling amino acid substitution. 
     Accordingly, in several embodiments, a preferred RSV F protein includes S155C and S290C substitutions that form a non-natural disulfide bond that stabilizes the protein in a pre-fusion conformation; that is, in a conformation that specifically binds to one or more pre-fusion specification antibodies, and/or presents a suitable antigenic site that is present on the pre-fusion conformation but not in the postfusion conformation of RSV F protein. In further embodiments, the recombinant RSV F protein can additionally include F, L, W, Y, H, or M substitution at position 190, position 207, or positions 190 and 207. 
     An example of an RSV F protein designed to stabilize the antigen in pre-fusion conformation is RSV F protein comprising a DSCav1 mutation (S155C, S290C, S190F, and V207L), or a fragment or a variant thereof. Such RSV F DSCav1 proteins have been described in the art (W2014160463). 
     Accordingly, in particularly preferred embodiments, the artificial RNA of the first aspect encodes least one antigenic peptide or protein derived from RSV F protein, wherein the RSV F protein comprises a DSCav1 mutation (S155C, S290C, S190F, and V207L), or a fragment or a variant thereof. 
     It has to be understood in the context of the invention that any RSV F may be mutated at positions S155C, S290C, S190F, and V207L to stabilize the protein in the pre-fusion conformation and may be suitably used in the context of the invention. Accordingly, any NCBI Protein Accession numbers provided above, or any protein selected from SEQ ID NOs: 68, 8279-8967, 483, 8968-9683, 12095, or 11726 or fragments or variants thereof can be chosen by the skilled person to introduce such amino acid changes according to S155C, S290C, S190F, and V207L to generate various RSV F DSCav1 proteins. 
     In preferred embodiments, RSV F full-length protein (precursor protein, “F0”) of HRSV(A2) (SEQ ID NO: 68) is used to introduce S155C, S290C, S190F, and V207L amino acid changes, leading to an amino acid sequence according to SEQ ID NO: 898. Such a RSV F protein is herein referred to as “F0_DSCav1” throughout the present invention (see overview Table 1 (preferred RSV F protein antigen designs)). 
     In other preferred embodiments, RSV F_del protein (deleted cytoplasmic tail (aa 554-574)) of HRSV(A2) (SEQ ID NO: 483) is used to introduce S155C, S290C, S190F, and V207L amino acid changes, leading to an amino acid sequence according to SEQ ID NO: 1267. Such a RSV F protein is herein referred to as “F-del_DSCav1” throughout the present invention (see overview Table 1 (preferred RSV F protein antigen designs)). 
     In preferred embodiments, RSV F full-length protein (precursor protein, “F0”) of HRSV(Memphis-37) (SEQ ID NO: 8937 or 11726) is used to introduce S155C, S290C, S190F, and V207L amino acid changes, leading to an amino acid sequence according to SEQ ID NO: 12464. Such a RSV F protein is herein referred to as “FO_DSCav1” throughout the present invention (see overview Table 1 (preferred RSV F protein antigen designs)). 
     In other preferred embodiments, RSV F_del protein (deleted cytoplasmic tail (aa 554-574)) of HRSV(Memphis-37) (SEQ ID NO: 9653 or 12095) is used to introduce S155C, S290C, S190F, and V207L amino acid changes, leading to an amino acid sequence according to SEQ ID NO: 12833. Such a RSV F protein is herein referred to as “F-del_DSCav1” throughout the present invention (see overview Table 1 (preferred RSV F protein antigen designs). 
     In preferred embodiments, the at least one antigenic peptide or protein may be an engineered protein comprising the two subunits, F1 and F2 of mature F as a single polypeptide chain, wherein F2 and F1 are preferably connected via a linker (GS). Examples of said engineered F2-linker-F1 fusion proteins (e.g., F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553)) have been described in the art (Joyce, M. Gordon, et al. “Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV.” Nature structural &amp; molecular biology 23.9 (2016): 811; WO2017172890). Said F2-linker-F1 RSV F proteins lack aa104-144 (comprising the furine cleavage site and Pep27) and comprise a linker element between F2 polypeptide and F1 polypeptide (e.g. GSlinker). Said F2-linker-F1 proteins may show superior properties in terms of stability and/or antigenicity. 
     Accordingly, in preferred embodiments, the RSV F protein comprises the two subunits F2 and F1 fused into a single polypeptide chain, wherein F2 and F1 are connected via a linker element, preferably a GS linker as specified herein, preferably generating a stable F2-linker-F1 proteins. 
     Preferably, said F2-linker-F1 fusion proteins, e.g. F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553) additionally comprise a DScav1 mutation as outlined above (herein referred to as “mut0”; e.g., SEQ ID NOs: 3850, 4219 or 13940, 14309). 
     In particularly preferred embodiments, the RSV F protein may additionally comprise at least one further mutation selected from (S46G, A149C, S215P, Y458C, K465Q), (S46G, E92D, A149C, S215P, Y458C, K465Q), (S46G, N671, E92D, A149C, S215P, Y458C, K465Q), (A149C, Y458C), (N183GC, N428C), (Q98C, Q361C, S46G, E92D, L95M, S215P, I217P, I221M, R429K, K465Q), (Q98C, Q361C, L95M, I221M, R429K), or (N183GC, N428C, S46G, N671, E92D, S215P, K465Q) or a fragment or a variant thereof. 
     In particularly preferred embodiments, said F2-linker-F1 proteins (F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553)) may additionally comprise, preferably in addition to the DSCav1 mutation, at least one mutation selected from S46G, A149C, S215P, Y458C, K465Q, herein referred to as “mut1”, e.g., SEQ ID NOs: 1636, 2005, or 14678, 15047; or S46G, E92D, A149C, S215P, Y458C, K465Q, herein referred to as “mut2”, e.g., SEQ ID NOs: 2374, 2743 or 15416, 15785; or S46G, N671, E92D, A149C, S215P, Y458C, K465Q, herein referred to as “mut3”, e.g., SEQ ID NOs: 3112, 3481 or 13202, 13571, or a fragment or a variant of any of these (see overview Table 1 (preferred RSV F protein antigen designs)). 
     In other embodiments, said F2-linker-F1 proteins (F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553)) may additionally comprise, preferably in addition to the DSCav1 mutation, at least one mutation selected from A149C, Y458C, herein referred to as “mut4”, e.g., SEQ ID NOs: 4588, 4957 or 16154, 16523; or N183GC, N428C, herein referred to as “mut5”, e.g., SEQ ID NOs: 5326, 5695 or 16892, 17261; or Q98C, Q361C, S46G, E92D, L95M, S215P, I217P, I221M, R429K, K465Q, herein referred to as “mut6”, e.g., SEQ ID NOs: 6064, 6433 or 17630, 17999; or Q98C, Q361C, L95M, I221M, R429K, herein referred to as “mut7”, e.g., SEQ ID NOs: 6802, 7171 or 18368, 18737; or N183GC, N428C, S46G, N671, E92D, S215P, K465Q, herein referred to as “mut8”, e.g., SEQ ID NOs: 7540, 7909 or 19106, 19475, or a fragment or a variant thereof. 
     It has to be understood in the context of the invention that any RSV F may be adapted in a way that the two subunits, F1 and F2 are comprised in a single polypeptide chain, wherein F2 and F1 may be connected via a linker, e.g. a (GS) linker to enhance stability of the protein as explained for mutations “mut1”, “mut2” and “mut3”, e.g. by deleting aa104-144 of the F0 polypeptide chain (as explained above), by introducing a linker element between F2 and F1 as explained above, and by introducing suitable amino acid substitutions as explained above. Accordingly, any NCBI Protein Accession numbers provided above (see List 2), or any protein selected from SEQ ID NOs: 68, 8279-8967, 483, 8968-9683, 11726, 12095 or fragments or variants thereof can be adapted by the skilled person to generate F2-linker-F1 fusion proteins as outlined herein, and may additionally be adapted by introducing (S46G, A149C, S215P, Y458C, K465Q), (S46G, E92D, A149C, S215P, Y458C, K465Q), (S46G, N671, E92D, A149C, S215P, Y458C, K465Q), (A149C, Y458C), (N183GC, N428C), (Q98C, Q361C, S46G, E92D, L95M, S215P, I217P, I221M, R429K, K465Q), (Q98C, Q361C, L95M, I221M, R429K), or (N183GC, N428C, S46G, N671, E92D, S215P, K465Q) aa substitutions and/or a DSCav1 mutation. Moreover, apart from using a GS linker as outlined above, the skilled person may of course choose between various known linker elements to arrive at similar likewise suitable RSV F protein variants (e.g. selected from SEQ ID NOs: 117-162 of the patent application WO2017/172890 or fragments or variants of these sequences, or selected from SEQ ID NOs: 1509-1565 of the patent application WO2017/081082, or fragments or variants of these sequences). 
     In preferred embodiments, F2-linker-F1 proteins (F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553) comprise a DSCav-1 mutation as outlined above, herein referred to as F_DSCav1_mut0 or F-del_DSCav1_mut0. In preferred embodiments, F2-linker-F1 proteins (F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553) comprise a DSCav-1 mutation as outlined above, and additionally an amino acid substitution mut1 as defined above, herein referred to as F_DSCav1_mut1 or F-del_DSCav1_mut1. In preferred embodiments, F2-linker-F1 proteins (F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553) comprise a DSCav-1 mutation as outlined above, and additionally an amino acid substitution mut2 as defined above, herein referred to as F_DSCav1_mut2 or F-del_DSCav1_mut2. In preferred embodiments, F2-linker-F1 proteins (F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553) comprise a DSCav-1 mutation as outlined above, and additionally an amino acid substitution mut3 as defined above, herein referred to as F_DSCav1_mut3 or F-del_DSCav1_mut3. In preferred embodiments, F2-linker-F1 proteins (F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553) comprise a DSCav-1 mutation as outlined above, and additionally an amino acid substitution mut4 as defined above, herein referred to as F_DSCav1_mut4 or F-del_DSCav1_mut4. In preferred embodiments, F2-linker-F1 proteins (F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553) comprise a DSCav-1 mutation as outlined above, and additionally an amino acid substitution mut5 as defined above, herein referred to as F_DSCav1_mut5 or F-del_DSCav1_mut5. In preferred embodiments, F2-linker-F1 proteins (F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553) comprise a DSCav-1 mutation as outlined above, and additionally an amino acid substitution mut6 as defined above, herein referred to as F_DSCav1_mut6 or F-del_DSCav1_mut6 . In preferred embodiments, F2-linker-F1 proteins (F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553) comprise a DSCav-1 mutation as outlined above, and additionally an amino acid substitution mut7 as defined above, herein referred to as F_DSCav1_mut7 or F-del_DSCav1_mut7. In preferred embodiments, F2-linker-F1 proteins (F(1-103)-GS-F(145-574) or F(1-103)-GS-F(145-553) comprise a DSCav-1 mutation as outlined above, and additionally an amino acid substitution mut8 as defined above, herein referred to as F_DSCav1 mut8 or F-del_DSCav1 mut8. 
     A detailed description of particularly preferred RSV F proteins is provided in Table 1. 
     In Table 1 all references made to amino acid (aa) residues and their position in an RSV F protein relates to the position of the respective aa residue in a corresponding F0 precursor protein of HRSV(A2) (SEQ ID NO: 68) or HRSV(Memphis-37) (SEQ ID NO: 8937 or 11726). Moreover, the abbreviations for suitable RSV F protein antigen designs in Table 1 are used throughout the description of the invention (e.g., “F0”, “F-del”, “F0_DSCav1”, “F-del_DSCav1”, “F_DSCav1_mut1”, “F-del_DSCav1_mut1”, “F_DSCav1_mut2”, “F-del_DSCav1_mut2”, “F_DSCav1_mut3”, “F-del_DSCav1_mut3”, “F_DSCav1_mut4”, “F-del_DSCav1_mut4”, “F_DSCav1_mut5”, “F-del_DSCav1_mut5”, “F_DSCav1_mut6”, “F-del_DSCav1_mut6”, “F_DSCav1_mut7”, “F-del_DSCav1_mut7 ”, “F_DSCav1_mut8”, “F-del_DSCav1_mut8”, “F_DSCav1_mut0”, “F-del_DSCav1_mut0”). Column A of Table 1 provides protein SEQ ID NOs of respective RSV F protein antigen designs derived from HRSV(A2); Column B of Table 1 provides protein SEQ ID NOs of respective RSV F protein antigen designs derived from HRSV(Memphis-37). Notably, the description of the invention explicitly includes the information provided under &lt;223&gt; identifier of the ST25 sequence listing of the present application. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Preferred RSV F protein antigen designs 
               
            
           
           
               
               
               
               
            
               
                 Antigen Name 
                 Protein design description 
                 A 
                 B 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 F0 
                 aa1-574, 
                 68 
                 8937, 
               
               
                   
                 full-length RSV F0 precursor 
                   
                 11726 
               
               
                 F-del 
                 aa1-553, 
                 483 
                 9653, 
               
               
                   
                 deletion of aa 554-574 of the C-terminus 
                   
                 12095 
               
               
                 F0_DSCav1 
                 aa1-574, 
                 898 
                 12464 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L 
               
               
                 F-del_DSCav1 
                 aa1-553, 
                 1267 
                 12833 
               
               
                   
                 deletion of aa 554-574 of the C-terminus, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L 
               
               
                 F_DSCav1_mut0 
                 aa1-103 - GS(linker) - aa145-574 
                 3850 
                 13940 
               
               
                   
                 F2-linker-F1 construct 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L 
               
               
                 F-del_DSCav1_mut0 
                 aa1-103 - GS(linker) - aa145-553 
                 4219 
                 14309 
               
               
                   
                 deletion of aa 554-574 of the C-terminus, 
               
               
                   
                 F2-linker-F1 construct 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L 
               
               
                 F_DSCav1_mut1 
                 aa1-103 - GS(linker) - aa145-574, 
                 1636 
                 14678 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 S46G, A149C, S215P, Y458C, K465Q 
               
               
                 F-del_DSCav1_mut1 
                 aa1-103 - GS(linker) - aa145-553 
                 2005 
                 15047 
               
               
                   
                 deletion of aa 554-574 of the C-terminus, 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 S46G, A149C, S215P, Y458C, K465Q 
               
               
                 F_DSCav1_mut2 
                 aa1-103 - GS(linker) - aa145-574 
                 2374 
                 15416 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 S46G, E92D, A149C, S215P, Y458C, K465Q 
               
               
                 F-del_DSCav1_mut2 
                 aa1-103 - GS(linker) - aa145-553 
                 2743 
                 15785 
               
               
                   
                 deletion of aa 554-574 of the C-terminus, 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 S46G, E92D, A149C, S215P, Y458C, K465Q 
               
               
                 F_DSCav1_mut3 
                 aa1-103 - GS(linker) - aa145-574 
                 3112 
                 13202 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 S46G, N67I, E92D, A149C, S215P, Y458C, K465Q 
               
               
                 F-del_DSCav1_mut3 
                 aa1-103 - GS(linker) - aa145-553 
                 3481 
                 13571 
               
               
                   
                 deletion of aa 554-574 of the C-terminus, 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 S46G, N67I, E92D, A149C, S215P, Y458C, K465Q 
               
               
                 F_DSCav1_mut4 
                 aa1-103 - GS(linker) - aa145-574 
                 4588 
                 16154 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 A149C, Y458C 
               
               
                 F-del_DSCav1_mut4 
                 aa1-103 - GS(linker) - aa145-553 
                 4957 
                 16523 
               
               
                   
                 deletion of aa 554-574 of the C-terminus, 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 A149C, Y458C 
               
               
                 F_DSCav1_mut5 
                 aa1-103 - GS(linker) - aa145-574 
                 5326 
                 16892 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 N183GC, N428C 
               
               
                 F-del_DSCav1_mut5 
                 aa1-103 - GS(linker) - aa145-553 
                 5695 
                 17261 
               
               
                   
                 deletion of aa 554-574 of the C-terminus, 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 N183GC, N428C 
               
               
                 F_DSCav1_mut6 
                 aa1-103 - GS(linker) - aa145-574 
                 6064 
                 17630 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 Q98C, Q361C, S46G, E92D, L95M, S215P, I217P, I221M, 
               
               
                   
                 R429K, K465Q 
               
               
                 F-del_DSCav1_mut6 
                 aa1-103 - GS(linker) - aa145-553 
                 6433 
                 17999 
               
               
                   
                 deletion of aa 554-574 of the C-terminus, 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 Q98C, Q361C, S46G, E92D, L95M, S215P, I217P, I221M, 
               
               
                   
                 R429K, K465Q 
               
               
                 F_DSCav1_mut7 
                 aa1-103 - GS(linker) - aa145-574 
                 6802 
                 18368 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 Q98C, Q361C, L95M, I221M, R429K 
               
               
                 F-del_DSCav1_mut7 
                 aa1-103 - GS(linker) - aa145-553 
                 7171 
                 18737 
               
               
                   
                 deletion of aa 554-574 of the C-terminus, 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 Q98C, Q361C, L95M, I221M, R429K 
               
               
                 F_DSCav1_mut8 
                 aa1-103 - GS(linker) - aa145-574 
                 7540 
                 19106 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 N183GC, N428C, S46G, N67I, E92D, S215P, K465Q 
               
               
                 F-del_DSCav1_mut8 
                 aa1-103 - GS(linker) - aa145-553 
                 7909 
                 19475 
               
               
                   
                 deletion of aa 554-574 of the C-terminus, 
               
               
                   
                 F2-linker-F1 construct, 
               
               
                   
                 aa substitutions: S155C, S290C, S190F, and V207L; 
               
               
                   
                 N183GC, N428C, S46G, N67I, E92D, S215P, K465Q 
               
               
                   
               
            
           
         
       
     
     In particularly preferred embodiments, the artificial RNA according to the first aspect encodes at least one antigenic peptide or protein derived from a RSV fusion (F) protein, wherein the RSV F protein is selected from F0, F-del, F0_DSCav1, F_DSCav1_mut0, F_DSCav1_mut1, F_DSCav1_mut2, F_DSCav1_mut3, F_DSCav1_mut4, F_DSCav1_mut5, F_DSCav1_mut6, F_DSCav1_mut7, F_DSCav1_mut8, F-del_DSCav1, F-del_DSCav1_mut0, F-del_DSCav1_mut1, F-del_DSCav1_mut2, F-del_DSCav1_mut3, F-del_DSCav1_mut4, F-del_DSCav1_mut5, F-del_DSCav1_mut6, F-del_DSCav1_mut7, F-del_DSCav1_mut8, or a fragment or a variant thereof (see e.g. Table 1). 
     Particularly preferred and advantageous in the context of the invention are RSV F proteins selected from F-del_DSCav1, F-del_DSCav1_mut0, F-del_DSCav1_mut1, F-del_DSCav1_mut2, F-del_DSCav1_mut3, F-del_DSCav1_mut4, F-del_DSCav1_mut5, F-del_DSCav1_mut6, F-del_DSCav1_mut7, F-del_DSCav1_mut8 or a fragment or a variant thereof (see e.g. Table 1). 
     In preferred embodiments, the artificial RNA of the first aspect comprises at least one coding sequence encoding at least one antigenic peptide or protein comprising or consisting of at least one amino acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 19475 (see e.g. Table 1), or 8279-9683 or a fragment or variant of any of these sequences. Additional information regarding each of these suitable amino acid sequences encoding RSV proteins may also be derived from the or 99% identical to any one of SEQ ID NO: 68, 483, 898, 1267, 1636, 2005, 2374, 2743, 3112, 3481, 3850, 4219, 4588, 4957, 5326, 5695, 6064, 6433, 6802, 7171, 7540, 7909, 11726, 12095, 12464, 12833, 13940, 14309, 14678, 15047, 15416, 15785, 13202, 13571, 16154, 16523, 16892, 17261, 17630, 17999, 18368, 18737, 19106, sequence listing, in particular from the details provided therein under identifier &lt;223&gt; as explained in the following. 
     In preferred embodiments, the artificial RNA of the first aspect comprises at least one coding sequence encoding at least one antigenic peptide or protein comprising or consisting of at least one amino acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 68, 483, 898, 1267, 1636, 2005, 2374, 2743, 3112, 3481, 3850, 4219, 4588, 4957, 5326, 5695, 6064, 6433, 6802, 7171, 7540, 7909, 11726, 12095, 12464, 12833, 13940, 14309, 14678, 15047, 15416, 15785, 13202, 13571, 16154, 16523, 16892, 17261, 17630, 17999, 18368, 18737, 19106, 19475 (see e.g. Table 1) or a fragment or variant of any of these sequences. Additional information regarding each of these suitable amino acid sequences encoding RSV proteins may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt; as explained in the following. 
     In particularly preferred embodiments, the artificial RNA of the first aspect comprises at least one coding sequence encoding at least one antigenic peptide or protein comprising or consisting of at least one amino acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 1267, 2005, 2743, 3481, 4219, 4957, 5695, 6433, 7171, 7909, 12833, 14309, 15047, 15785, 13571, 16523, 17261, 17999, 18737, 19475 (see e.g. Table 1) or a fragment or variant of any of these sequences. Additional information regarding each of these suitable amino acid sequences encoding RSV proteins may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt; as explained in the following. 
     In other embodiments, the artificial RNA according to the first aspect comprises at least one coding sequence encoding at least one of the amino acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 8279-9683 a fragment or variant of any of these sequences. Additional information regarding each of these suitable amino acid sequences encoding RSV proteins may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt; as explained in the following. 
     In other embodiments, the artificial RNA as defined herein comprises at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV comprising or consisting of at least one amino acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-1428 of patent application WO2014/160463 or a fragment or variant of any of these sequences. In this context, SEQ ID NOs: 1-1428 of patent application WO2014/160463 and the disclosure related thereto are herewith incorporated by reference. 
     In other embodiments, the artificial RNA as defined herein comprises at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV comprising or consisting of at least one amino acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-11 of patent application WO2015/024668 or a fragment or variant of any of these sequences. In this context, SEQ ID NOs: 1-11 of patent application WO2015/024668 and the disclosure related thereto are herewith incorporated by reference. 
     In other embodiments, the artificial RNA as defined herein comprises at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV comprising or consisting of at least one amino acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 243, or 245 of patent application WO2017/070622 or a fragment or variant of any of these sequences. In this context SEQ ID NO: 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 243, or 245, of patent application WO2017/070622 and the disclosure related thereto are herewith incorporated by reference. 
     In other embodiments, the artificial RNA as defined herein comprises at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV comprising or consisting of at least one amino acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-65, 81-95, 110-116 of patent application WO2017/172890 or a fragment or variant of any of these sequences. In this context SEQ ID NOs: 1-65, 81-95, 110-116, of patent application WO2017/172890 and the disclosure related thereto are herewith incorporated by reference. 
     According to another preferred embodiment, the artificial RNA of the invention encodes at least one antigenic peptide or protein as defined above and may additionally encode at least one further heterologous peptide or protein element. 
     Suitably, the at least one further peptide or protein element may promote secretion of the encoded antigenic peptide or protein of the invention (e.g. via secretory signal sequences), promote anchoring of the encoded antigenic peptide or protein of the invention in the plasma membrane (e.g. via transmembrane elements), promote formation of antigen complexes (e.g. via multimerization domains), promote virus-like particle formation (VLP forming sequence). In addition, the artificial nucleic acid sequence according to the present invention may additionally encode peptide linker elements, self-cleaving peptides, immunologic adjuvant sequences or dendritic cell targeting sequences. Suitable multimerization domains may be selected from the list of amino acid sequences according to SEQ ID NOs: 1116-1167 of the patent application WO2017/081082, or fragments or variants of these sequences. Trimerization and tetramerization elements may be selected from e.g. engineered leucine zippers (engineered α-helical coiled coil peptide that adopt a parallel trimeric state), fibritin foldon domain from enterobacteria phage T4, GCN4pII, GCN4-pLI, and p53. In that context, fibritin foldon domain from enterobacteria phage T4, GCN4pII, GCN4-pLI, and p53 are preferred. Suitable transmembrane elements may be selected from the list of amino acid sequences according to SEQ ID NOs: 1228-1343 of the patent application WO2017/081082, or fragments or variants of these sequences. Suitable VLP forming sequences may be selected from the list of amino acid sequences according to SEQ ID NOs: 1168-1227 of the patent application WO2017/081082, or fragments or variants of these sequences. Suitable peptide linkers may be selected from the list of amino acid sequences according to SEQ ID NOs: 1509-1565 of the patent application WO2017/081082, or fragments or variants of these sequences. Suitable self-cleaving peptides may be selected from the list of amino acid sequences according to SEQ ID NOs: 1434-1508 of the patent application WO2017/081082, or fragments or variants of these sequences. Suitable immunologic adjuvant sequences may be selected from the list of amino acid sequences according to SEQ ID NOs: 1360-1421 of the patent application WO2017/081082, or fragments or variants of these sequences. Suitable dendritic cell (DCs) targeting sequences may be selected from the list of amino acid sequences according to SEQ ID NOs: 1344-1359 of the patent application WO2017/081082, or fragments or variants of these sequences. Suitable secretory signal peptides may be selected from the list of amino acid sequences according to SEQ ID NOs: 1-1115 and SEQ ID NO: 1728 of the patent application WO2017/081082, or fragments or variants of these sequences. On nucleic acid level, any nucleic acid sequence (e.g. RNA sequence) may be selected which encodes such amino acid sequences. In this context, the disclosure of WO2017/081082 is herewith incorporated by reference. The heterologous secretory signal sequence may increase the secretion of the encoded antigenic peptide or protein. 
     According to embodiments, the secretory signal sequence comprises an amino acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 21329-21362 or a fragment or variant of any of these sequences. Additional information regarding each of these suitable amino acid sequences encoding secretory signal sequences may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt;. 
     According to preferred embodiments, the artificial nucleic acid, particularly the artificial RNA comprises at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV as defined herein, preferably derived from RSV F protein, or fragments and variants thereof. In that context, any coding sequence encoding at least one antigenic peptide or protein derived from RSV, preferably derived from RSV F protein, or fragments and variants thereof may be understood as suitable coding sequence and may therefore be comprised in the artificial RNA of the first aspect. 
     In preferred embodiments, the artificial RNA of the first aspect may comprise or consist of at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV F protein as defined herein, preferably encoding any one of SEQ ID NO: 68, 483, 898, 1267, 1636, 2005, 2374, 2743, 3112, 3481, 3850, 4219, 4588, 4957, 5326, 5695, 6064, 6433, 6802, 7171, 7540, 7909, 11726, 12095, 12464, 12833, 13940, 14309, 14678, 15047, 15416, 15785, 13202, 13571, 16154, 16523, 16892, 17261, 17630, 17999, 18368, 18737, 19106, 19475 or fragments of variants thereof. It has to be understood that, on nucleic acid level, any nucleic acid sequence, in particular, any RNA sequence which encodes an amino acid sequences being identical to SEQ ID NO: 68, 483, 898, 1267, 1636, 2005, 2374, 2743, 3112, 3481, 3850, 4219, 4588, 4957, 5326, 5695, 6064, 6433, 6802, 7171, 7540, 7909, 11726, 12095, 12464, 12833, 13940, 14309, 14678, 15047, 15416, 15785, 13202, 13571, 16154, 16523, 16892, 17261, 17630, 17999, 18368, 18737, 19106, 19475 or fragments or variants thereof, or any nucleic acid sequence (e.g. DNA sequence, RNA sequence) which encodes amino acid sequences being at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 68, 483, 898, 1267, 1636, 2005, 2374, 2743, 3112, 3481, 3850, 4219, 4588, 4957, 5326, 5695, 6064, 6433, 6802, 7171, 7540, 7909, 11726, 12095, 12464, 12833, 13940, 14309, 14678, 15047, 15416, 15785, 13202, 13571, 16154, 16523, 16892, 17261, 17630, 17999, 18368, 18737, 19106, 19475 or fragments or variants thereof, may be selected and may accordingly be understood as suitable coding sequence and may therefore be comprised in the artificial RNA of the first aspect of the invention. 
     In other embodiments, the artificial RNA of the first aspect may comprise or consist of at least one coding sequence encoding any one of SEQ ID NOs: 8279-9683 or fragments of variants thereof. It has to be understood that, on nucleic acid level, any nucleic acid sequence, in particular, any RNA sequence which encodes an amino acid sequences being identical to SEQ ID NOs: 8279-9683 or fragments or variants thereof, or any nucleic acid sequence (e.g. DNA sequence, RNA sequence) which encodes amino acid sequences being at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 8279-9683 or fragments or variants thereof, may be selected and may accordingly be understood as suitable coding sequence and may therefore be comprised in the artificial RNA of the first aspect of the invention. 
     In other embodiments, the artificial RNA of the first aspect may comprise or consist of at least one coding sequence encoding any one of SEQ ID NOs: 1-1428 of patent application WO2014/160463 or fragments of variants thereof. It has to be understood that, on nucleic acid level, any nucleic acid sequence, in particular, any RNA sequence which encodes an amino acid sequences being identical to SEQ ID NOs: 1-1428 of patent application WO2014/160463 or fragments or variants thereof, or any nucleic acid sequence (e.g. DNA sequence, RNA sequence) which encodes amino acid sequences being at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-1428 of patent application WO2014/160463 or fragments or variants thereof, may be selected and may accordingly be understood as suitable coding sequence and may therefore be comprised in the artificial RNA of the first aspect of the invention. 
     In other embodiments, the artificial RNA of the first aspect may comprise or consist of at least one coding sequence encoding any one of SEQ ID NOs: 1-11 of patent application WO2015/024668 or fragments of variants thereof. It has to be understood that, on nucleic acid level, any nucleic acid sequence, in particular, any RNA sequence which encodes an amino acid sequences being identical to SEQ ID NOs: 1-11 of patent application WO2015/024668 or fragments or variants thereof, or any nucleic acid sequence (e.g. DNA sequence, RNA sequence) which encodes amino acid sequences being at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-11 of patent application WO2015/024668 or fragments or variants thereof, may be selected and may accordingly be understood as suitable coding sequence and may therefore be comprised in the artificial RNA of the first aspect of the invention. 
     In other embodiments, the artificial RNA of the first aspect may comprise or consist of at least one coding sequence encoding any one of SEQ ID NO: 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 243, or 245 of patent application WO2017/070622 or fragments of variants thereof. It has to be understood that, on nucleic acid level, any nucleic acid sequence, in particular, any RNA sequence which encodes an amino acid sequences being identical to SEQ ID NO: 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 243, or 245 of patent application WO2017/070622 or fragments or variants thereof, or any nucleic acid sequence (e.g. DNA sequence, RNA sequence) which encodes amino acid sequences being at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 243, or 245 of patent application WO2017/070622 or fragments or variants thereof, may be selected and may accordingly be understood as suitable coding sequence and may therefore be comprised in the artificial RNA of the first aspect of the invention. 
     In other embodiments, the artificial RNA of the first aspect may comprise or consist of at least one coding sequence encoding any one of SEQ ID NOs: 1-65, 81-95, 110-116 of patent application WO2017/172890 or fragments of variants thereof. It has to be understood that, on nucleic acid level, any nucleic acid sequence, in particular, any RNA sequence which encodes an amino acid sequences being identical to SEQ ID NOs: 1-65, 81-95, 110-116 of patent application WO2017/172890 or fragments or variants thereof, or any nucleic acid sequence (e.g. DNA sequence, RNA sequence) which encodes amino acid sequences being at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-65, 81-95, 110-116 of patent application WO2017/172890 or fragments or variants thereof, may be selected and may accordingly be understood as suitable coding sequence and may therefore be comprised in the artificial RNA of the first aspect of the invention. 
     Suitably, in particularly preferred embodiments, the artificial RNA of the first aspect comprises a coding sequence located between said 5′-UTR and said 3′-UTR, preferably downstream of said 5′-UTR and upstream of said 3′-UTR. 
     In preferred embodiments, the artificial RNA of the first aspect comprises a coding sequence that comprises at least one of the nucleic acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 69-482, 484-897, 899-1266, 1268-1635, 1637-2004, 2006-2373, 2375-2742, 2744-3111, 3113-3480, 3482-3849, 3851-4218, 4220-4587, 4589-4956, 4958-5325, 5327-5694, 5696-6063, 6065-6432, 6434-6801, 6803-7170, 7172-7539, 7541-7908, 7910-8277, 8278, 11727-12094, 12096-12463, 12465-12832, 12834-13201, 13941-14308, 14310-14677, 14679-15046, 15048-15415, 15417-15784, 15786-16153, 13203-13570, 13572-13939, 16155-16522, 16524-16891, 16893-17260, 17262-17629, 17631-17998, 18000-17998, 18369-18736, 18738-19105, 19107-19474, 19476-19843, 21363-21706 or a fragment or a fragment or variant of any of these sequences (see also Table 3-6). Additional information regarding each of these suitable nucleic acid sequences encoding may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt;. 
     In particularly preferred embodiments, the artificial RNA of the first aspect comprises a coding sequence that comprises at least one of the nucleic acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 69-77, 484-492, 899-906, 1268-1275, 1637-1644, 2006-2013, 2375-2382, 2744-2751, 3113-3120, 3482-3489, 3851-3858, 4220-4227, 4589-4596, 4958-4965, 5327-5334, 5696-5703, 6065-6072, 6434-6441, 6803-6810, 7172-7179, 7541-7548, 7910-7917, 21363-21384, 11727-11734, 12096-12103, 12465-12472, 12834-12841, 13941-13948, 14310-14317, 14679-14686, 15048-15055, 15417-15424, 15786-15793, 13203-13210, 13572-13579, 16155-16162, 16524-16531, 16893-16900, 17262-17269, 17631-17638, 18000-18007, 18369-18376, 18738-18745, 19107-19114, 19476-19483, 21389-21410 or a fragment or a fragment or variant of any of these sequences (see also Table 3 and 4). Additional information regarding each of these suitable nucleic acid sequences encoding may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt;. 
     In other embodiments, the artificial RNA of the first aspect comprises a coding sequence that comprises at least one of the nucleic acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 383-388 of patent application WO2014/160463 or a fragment or a fragment or variant of any of these sequences. 
     In other embodiments, the artificial RNA of the first aspect comprises a coding sequence that comprises at least one of the nucleic acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 12-22 of patent application WO2015/024668 or a fragment or a fragment or variant of any of these sequences. 
     In other embodiments, the artificial RNA of the first aspect comprises a coding sequence that comprises at least one of the nucleic acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 1, 2, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 242, 244, 246, 257, 258-280 of patent application WO2017/070622 or a fragment or a fragment or variant of any of these sequences. 
     In other embodiments, the artificial RNA of the first aspect comprises a coding sequence that comprises at least one of the nucleic acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 96-99 of patent application WO2017/172890 or a fragment or a fragment or variant of any of these sequences. 
     According to preferred embodiments, the artificial RNA is a modified and/or stabilized artificial RNA. 
     According to preferred embodiments, the artificial RNA of the present invention may thus be provided as a “stabilized artificial RNA” that is to say an RNA showing improved resistance to in vivo degradation and/or an artificial RNA showing improved stability in vivo, and/or an artificial RNA showing improved translatability in vivo. In the following, specific suitable modifications in this context are described which are suitably to “stabilize” the artificial RNA. 
     Such stabilization may be effected by providing a “dried RNA” and/or a “purified RNA” as specified herein. Alternatively or in addition to that, such stabilization can be effected, for example, by a modified phosphate backbone of the artificial RNA of the present invention. A backbone modification in connection with the present invention is a modification in which phosphates of the backbone of the nucleotides contained in the RNA are chemically modified. Nucleotides that may be preferably used in this connection contain e.g. a phosphorothioate-modified phosphate backbone, preferably at least one of the phosphate oxygens contained in the phosphate backbone being replaced by a sulfur atom. Stabilized RNAs may further include, for example: non-ionic phosphate analogues, such as, for example, alkyl and aryl phosphonates, in which the charged phosphonate oxygen is replaced by an alkyl or aryl group, or phosphodiesters and alkylphosphotriesters, in which the charged oxygen residue is present in alkylated form. Such backbone modifications typically include, without implying any limitation, modifications from the group consisting of methylphosphonates, phosphoramidates and phosphorothioates (e.g. cytidine-5-O-(1-thiophosphate)). 
     In the following, suitable modifications are described that are capable of “stabilizing” the artificial RNA of the invention. 
     According to embodiments, the artificial RNA according to the invention is a modified artificial RNA, wherein the modification refers to chemical modifications comprising backbone modifications as well as sugar modifications or base modifications. 
     In this context, a modified artificial RNA as defined herein may contain nucleotide analogues/modifications, e.g. backbone modifications, sugar modifications or base modifications. A backbone modification in connection with the present invention is a modification, in which phosphates of the backbone of the nucleotides contained in a nucleic acid, e.g. an artificial RNA, are chemically modified. A sugar modification in connection with the present invention is a chemical modification of the sugar of the nucleotides of the RNA as defined herein. Furthermore, a base modification in connection with the present invention is a chemical modification of the base moiety of the nucleotides of the RNA. In this context, nucleotide analogues or modifications are preferably selected from nucleotide analogues which are applicable for transcription and/or translation. 
     In particularly preferred embodiments of the present invention, the nucleotide analogues/modifications which may be incorporated into a modified nucleic acid or particularly into a modified RNA as described herein are preferably selected from 2-amino-6-chloropurineriboside-5′-triphosphate, 2-Aminopurine-riboside-5′-triphosphate; 2-aminoadenosine-5′-triphosphate, 2′-Amino-2′-deoxycytidine-triphosphate, 2-thiocytidine-5′-triphosphate, 2-thiouridine-5′-triphosphate, 2′-Fluorothymidine-5′-triphosphate, 2′-O-Methyl-inosine-5′-triphosphate 4-thiouridine-5′-triphosphate, 5-aminoallylcytidine-5′-triphosphate, 5-aminoallyluridine-5′-triphosphate, 5-bromocytidine-5′-triphosphate, 5-bromouridine-5′-triphosphate, 5-Bromo-2′-deoxycytidine-5′-triphosphate, 5-Bromo-2′-deoxyuridine-5′-triphosphate, 5-iodocytidine-5′-triphosphate, 5-Iodo-2′-deoxycytidine-5′-triphosphate, 5-iodouridine-5′-triphosphate, 5-Iodo-2′-deoxyuridine-5′-triphosphate, 5-methylcytidine-5′-triphosphate, 5-methyluridine-5′-triphosphate, 5-Propynyl-2′-deoxycytidine-5′-triphosphate, 5-Propynyl-2′-deoxyuridine-5′-triphosphate, 6-azacytidine-5′-triphosphate, 6-azauridine-5′-triphosphate, 6-chloropurineriboside-5′-triphosphate, 7-deazaadenosine-5′-triphosphate, 7-deazaguanosine-5′-triphosphate, 8-azaadenosine-5′-triphosphate, 8-azidoadenosine-5′-triphosphate, benzimidazole-riboside-5′-triphosphate, N1-methyladenosine-5′-triphosphate, N1-methylguanosine-5′-triphosphate, N6-methyladenosine-5′-triphosphate, 06-methylguanosine-5′-triphosphate, pseudouridine-5′-triphosphate, or puromycin-5′-triphosphate, xanthosine-5′-triphosphate. Particular preference is given to nucleotides for base modifications selected from the group of base-modified nucleotides consisting of 5-methylcytidine-5′-triphosphate, 7-deazaguanosine-5′-triphosphate, 5-bromocytidine-5′-triphosphate, and pseudouridine-5′-triphosphate, pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thiouridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxyuridine, 3-methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl-pseudouridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyluridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1-taurinomethyl-4-thio-uridine, 5-methyl-uridine, 1-methyl-pseudouridine, 4-thio-1-methyl-pseudouridine, 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, and 4-methoxy-2-thio-pseudouridine, 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza-pseudoisocytidine, 1-methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, and 4-methoxy-1-methyl-pseudoisocytidine, 2-aminopurine, 2, 6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aminopurine, 7-deaza-8-aza-2-aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine, N6-glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2-methylthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, and 2-methoxy-adenine, inosine, 1-methyl-inosine, wyosine, wybutosine, 7-deaza-guanosine, 7-deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1-methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, and N2,N2-dimethyl-6-thio-guanosine, 5′-O-(1-thiophosphate)-adenosine, 5′-O-(1-thiophosphate)-cytidine, 5′-O-(1-thiophosphate)-guanosine, 5′-O-(1-thiophosphate)-uridine, 5′-O-(1-thiophosphate)-pseudouridine, 6-aza-cytidine, 2-thio-cytidine, alpha-thio-cytidine, Pseudo-iso-cytidine, 5-aminoallyl-uridine, 5-iodo-uridine, N1-methyl-pseudouridine, 5,6-dihydrouridine, alpha-thio-uridine, 4-thio-uridine, 6-aza-uridine, 5-hydroxy-uridine, deoxy-thymidine, 5-methyl-uridine, Pyrrolo-cytidine, inosine, alpha-thio-guanosine, 6-methyl-guanosine, 5-methyl-cytdine, 8-oxo-guanosine, 7-deaza-guanosine, N1-methyl-adenosine, 2-amino-6-Chloro-purine, N6-methyl-2-amino-purine, Pseudo-iso-cytidine, 6-Chloro-purine, N6-methyl-adenosine, alpha-thio-adenosine, 8-azido-adenosine, 7-deaza-adenosine. Particularly preferred and suitable in the context of the invention are pseudouridine (ψ), N1-methylpseudouridine (m1ψ), 5-methylcytosine, and 5-methoxyuridine. Accordingly, the artificial RNA as defined herein may comprise at least one modified nucleotide selected from pseudouridine (ψ), N1-methylpseudouridine (m1ψ), 5-methylcytosine, and 5-methoxyuridine. 
     In preferred embodiments, the artificial RNA of the invention comprises at least one coding sequence, wherein the at least one coding sequence is a pseudouridine (ψ) modified coding sequence. 
     Accordingly, in preferred embodiments, the artificial RNA of the invention, or the at least one coding sequence, comprises a nucleic acid sequence wherein at least one or more than one, preferably wherein all uracil nucleotides are replaced by pseudouridine (ψ) nucleotides 
     In further preferred embodiments, the artificial RNA of the invention comprises at least one coding sequence, wherein the at least one coding sequence is a N1-methylpseudouridine (m1ψ) modified coding sequence. 
     Accordingly, in preferred embodiments, the artificial RNA of the invention, or the at least one coding sequence, comprises a nucleic acid sequence wherein at least one or more than one, preferably wherein all uracil nucleotides are replaced by N1-methylpseudouridine (m1ψ) nucleotides 
     In preferred embodiments, the artificial RNA of the invention comprises at least one coding sequence, wherein the at least one coding sequence is a codon modified coding sequence. 
     In preferred embodiments, the at least one coding sequence of the invention is a codon modified coding sequence, wherein the amino acid sequence encoded by the at least one codon modified coding sequence is preferably not being modified compared to the amino acid sequence encoded by the corresponding wild type coding sequence. 
     The term “codon modified coding sequence” relates to coding sequences that differ in at least one codon (triplets of nucleotides coding for one amino acid) compared to the corresponding wild type coding sequence. Suitably, a codon modified coding sequence in the context of the invention may show improved resistance to in vivo degradation and/or improved stability in vivo, and/or improved translatability in vivo. Codon modifications in the broadest sense make use of the degeneracy of the genetic code wherein multiple codons may encode the same amino acid and may be used interchangeably (cf. Table 2) to optimize/modify the coding sequence for in vivo applications as outlined above. 
     In particularly preferred embodiments of the first aspect, the at least one sequence is a codon modified coding sequence, wherein the codon modified coding sequence is selected from C maximized coding sequence, CAI maximized coding sequence, human codon usage adapted coding sequence, G/C content modified coding sequence, and G/C optimized coding sequence, or any combination thereof, or any combination thereof. 
     According to preferred embodiments, the artificial RNA of the invention may be modified, wherein the C content of the at least one coding sequence may be increased, preferably maximized, compared to the C content of the corresponding wild type coding sequence (herein referred to as “C maximized coding sequence”). The amino acid sequence encoded by the C maximized coding sequence of the RNA is preferably not modified as compared to the amino acid sequence encoded by the respective wild type nucleic acid coding sequence. The generation of a C maximized nucleic acid sequences may suitably be carried out using a modification method according to WO2015/062738. In this context, the disclosure of WO2015/062738 is included herewith by reference. Throughout the disclosure of the invention, including the &lt;223&gt; identifier of the sequence listing, C maximized coding sequences of suitable RSV nucleic acid sequences are indicated by the abbreviation “opt2”. 
     According to embodiments, the artificial RNA of the present invention may be modified, wherein the G/C content of the at least one coding sequence of the invention may be modified compared to the G/C content of the corresponding wild type coding sequence (herein referred to as “G/C content modified coding sequence”). In this context, the terms “G/C optimization” or “G/C content modification” relate to a nucleic acid, preferably an artificial nucleic acid of the invention that comprises a modified, preferably an increased number of guanosine and/or cytosine nucleotides as compared to the corresponding wild type nucleic acid sequence. Such an increased number may be generated by substitution of codons containing adenosine or thymidine nucleotides by codons containing guanosine or cytosine nucleotides. If the enriched G/C content occurs in a coding sequence of DNA or RNA, it makes use of the degeneracy of the genetic code. In particular, in case of RNA, sequences having an increased G (guanosine)/C (cytosine) content are more stable than sequences having an increased A (adenosine)/U (uracil) content. The amino acid sequence encoded by the G/C content modified coding sequence of the nucleic acid sequence is preferably not modified as compared to the amino acid sequence encoded by the respective wild type nucleic acid coding sequence. Preferably, the G/C content of the coding sequence of the artificial nucleic acid sequence, e.g. the RNA sequence of the present invention is increased by at least 10%, preferably by at least 20%, more preferably by at least 30%, most preferably by at least 40% compared to the G/C content of the coding sequence of the corresponding wild type nucleic acid sequence (e.g. RNA sequence), which codes for a RSV antigen as defined herein or a fragment or variant thereof. 
     According to preferred embodiments, the artificial RNA of the present invention may be modified, wherein the G/C content of the at least one coding sequence of the invention may be optimized compared to the G/C content of the corresponding wild type coding sequence (herein referred to as “G/C content optimized coding sequence”). “Optimized” in that context refers to a coding sequence wherein the G/C content is preferably increased to the essentially highest possible G/C content. The amino acid sequence encoded by the G/C content optimized coding sequence of the nucleic acid sequence is preferably not modified as compared to the amino acid sequence encoded by the respective wild type nucleic acid coding sequence. The generation of a G/C content optimized nucleic RNA sequence may suitably be carried out using a G/C content optimization method according to WO2002/098443. In this context, the disclosure of WO2002/098443 is included in its full scope in the present invention. Throughout the disclosure of the invention, including the &lt;223&gt; identifier of the sequence listing, G/C optimized coding sequences of suitable RSV nucleic acid sequences are indicated by the abbreviation “opt1, opt5, opt6, opt11”. 
     According to embodiments, the artificial RNA of the invention may be modified, wherein the codons in the at least one coding sequence of the invention may be adapted to human codon usage (herein referred to as “human codon usage adapted coding sequence”). Codons encoding the same amino acid occur at different frequencies in a subject, e.g. a human. Accordingly, the coding sequence of the artificial RNA is preferably modified such that the frequency of the codons encoding the same amino acid corresponds to the naturally occurring frequency of that codon according to the human codon usage e.g. as shown in Table 2. For example, in the case of the amino acid Ala, the wild type coding sequence is preferably adapted in a way that the codon “GCC” is used with a frequency of 0.40, the codon “GCT” is used with a frequency of 0.28, the codon “GCA” is used with a frequency of 0.22 and the codon “GCG” is used with a frequency of 0.10 etc. (see Table 2). Accordingly, such a procedure (as exemplified for Ala) is applied for each amino acid encoded by the coding sequence of the artificial nucleic acid of the invention to obtain sequences adapted to human codon usage. Throughout the disclosure of the invention, including the &lt;223&gt; identifier of the sequence listing, human codon usage adapted coding sequences of suitable RSV nucleic acid sequences are indicated by the abbreviation “opt3”. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Human codon usage table with frequencies 
               
               
                 indicated for each amino acid 
               
            
           
           
               
               
               
            
               
                 Amino acid 
                 codon 
                 frequency 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Ala 
                 GCG 
                 0.10 
               
               
                   
               
               
                 Ala 
                 GCA 
                 0.22 
               
               
                   
               
               
                 Ala 
                 GCT 
                 0.28 
               
               
                   
               
               
                 Ala 
                 GCC* 
                 0.40 
               
               
                   
               
               
                 Cys 
                 TGT 
                 0.42 
               
               
                   
               
               
                 Cys 
                 TGC* 
                 0.58 
               
               
                   
               
               
                 Asp 
                 GAT 
                 0.44 
               
               
                   
               
               
                 Asp 
                 GAC* 
                 0.56 
               
               
                   
               
               
                 Glu 
                 GAG* 
                 0.59 
               
               
                   
               
               
                 Glu 
                 GAA 
                 0.41 
               
               
                   
               
               
                 Phe 
                 TTT 
                 0.43 
               
               
                   
               
               
                 Phe 
                 TTC* 
                 0.57 
               
               
                   
               
               
                 Gly 
                 GGG 
                 0.23 
               
               
                   
               
               
                 Gly 
                 GGA 
                 0.26 
               
               
                   
               
               
                 Gly 
                 GGT 
                 0.18 
               
               
                   
               
               
                 Gly 
                 GGC* 
                 0.33 
               
               
                   
               
               
                 His 
                 CAT 
                 0.41 
               
               
                   
               
               
                 His 
                 CAC* 
                 0.59 
               
               
                   
               
               
                 Ile 
                 ATA 
                 0.14 
               
               
                   
               
               
                 Ile 
                 ATT 
                 0.35 
               
               
                   
               
               
                 Ile 
                 ATC* 
                 0.52 
               
               
                   
               
               
                 Lys 
                 AAG* 
                 0.60 
               
               
                   
               
               
                 Lys 
                 AAA 
                 0.40 
               
               
                   
               
               
                 Leu 
                 TTG 
                 0.12 
               
               
                   
               
               
                 Leu 
                 TTA 
                 0.06 
               
               
                   
               
               
                 Leu 
                 CTG* 
                 0.43 
               
               
                   
               
               
                 Leu 
                 CTA 
                 0.07 
               
               
                   
               
               
                 Leu 
                 CTT 
                 0.12 
               
               
                   
               
               
                 Leu 
                 CTC 
                 0.20 
               
               
                   
               
               
                 Met 
                 ATG* 
                 1 
               
               
                   
               
               
                 Asn 
                 AAT 
                 0.44 
               
               
                   
               
               
                 Asn 
                 AAC* 
                 0.56 
               
               
                   
               
               
                 Pro 
                 CCG 
                 0.11 
               
               
                   
               
               
                 Pro 
                 CCA 
                 0.27 
               
               
                   
               
               
                 Pro 
                 CCT 
                 0.29 
               
               
                   
               
               
                 Pro 
                 CCC* 
                 0.33 
               
               
                   
               
               
                 Gln 
                 CAG* 
                 0.73 
               
               
                   
               
               
                 Gln 
                 CAA 
                 0.27 
               
               
                   
               
               
                 Arg 
                 AGG 
                 0.22 
               
               
                   
               
               
                 Arg 
                 AGA* 
                 0.21 
               
               
                   
               
               
                 Arg 
                 CGG 
                 0.19 
               
               
                   
               
               
                 Arg 
                 CGA 
                 0.10 
               
               
                   
               
               
                 Arg 
                 CGT 
                 0.09 
               
               
                   
               
               
                 Arg 
                 CGC 
                 0.19 
               
               
                   
               
               
                 Ser 
                 AGT 
                 0.14 
               
               
                   
               
               
                 Ser 
                 AGC* 
                 0.25 
               
               
                   
               
               
                 Ser 
                 TCG 
                 0.06 
               
               
                   
               
               
                 Ser 
                 TCA 
                 0.15 
               
               
                   
               
               
                 Ser 
                 TCT 
                 0.18 
               
               
                   
               
               
                 Ser 
                 TCC 
                 0.23 
               
               
                   
               
               
                 Thr 
                 ACG 
                 0.12 
               
               
                   
               
               
                 Thr 
                 ACA 
                 0.27 
               
               
                   
               
               
                 Thr 
                 ACT 
                 0.23 
               
               
                   
               
               
                 Thr 
                 ACC* 
                 0.38 
               
               
                   
               
               
                 Val 
                 GTG* 
                 0.48 
               
               
                   
               
               
                 Val 
                 GTA 
                 0.10 
               
               
                   
               
               
                 Val 
                 GTT 
                 0.17 
               
               
                   
               
               
                 Val 
                 GTC 
                 0.25 
               
               
                   
               
               
                 Trp 
                 TGG* 
                 1 
               
               
                   
               
               
                 Tyr 
                 TAT 
                 0.42 
               
               
                   
               
               
                 Tyr 
                 TAC* 
                 0.58 
               
               
                   
               
               
                 Stop 
                 TGA* 
                 0.61 
               
               
                   
               
               
                 Stop 
                 TAG 
                 0.17 
               
               
                   
               
               
                 Stop 
                 TAA 
                 0.22 
               
               
                   
               
               
                 *most frequent human codon 
               
            
           
         
       
     
     According to embodiments, the artificial RNA of the present invention may be modified, wherein the codon adaptation index (CAI) may be increased or preferably maximised in the at least one coding sequence of the invention (herein referred to as “CAI maximized coding sequence”). Accordingly, it is preferred that all codons of the wild type nucleic acid sequence that are relatively rare in e.g. a human cell are exchanged fora respective codon that is frequent in the e.g. a human cell, wherein the frequent codon encodes the same amino acid as the relatively rare codon. Suitably, the most frequent codons are used for each encoded amino acid (see Table 2, most frequent human codons are marked with asterisks). Suitably, the artificial RNA of the invention comprises at least one coding sequence, wherein the codon adaptation index (CAI) of the at least one coding sequence is at least 0.5, at least 0.8, at least 0.9 or at least 0.95. Most preferably, the codon adaptation index (CAI) of the at least one coding sequence is 1. For example, in the case of the amino acid Ala, the wild type coding sequence is adapted in a way that the most frequent human codon “GCC” is always used for said amino acid. Accordingly, such a procedure (as exemplified for Ala) is applied for each amino acid encoded by the coding sequence of the artificial RNA of the invention to obtain CAI maximized coding sequences. Throughout the disclosure of the invention including the &lt;223&gt; identifier of the sequence listing, CAI maximized coding sequences of suitable RSV nucleic acid sequences are indicated by the abbreviation “opt4”. 
     Accordingly, in a particularly preferred embodiment, the artificial RNA of the first aspect comprises at least one coding sequence comprising a codon modified nucleic acid sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a codon modified nucleic acid sequence selected from the group consisting of SEQ ID NOs: 70-77, 485-492, 899-906, 1268-1275, 1637-1644, 2006-2013, 2375-2382, 2744-2751, 3113-3120, 3482-3489, 3851-3858, 4220-4227, 4589-4596, 4958-4965, 5327-5334, 5696-5703, 6065-6072, 6434-6441, 6803-6810, 7172-7179, 7541-7548, 7910-7917, 11728-11734, 12097-12103, 12465-12472, 12834-12841, 13941-13948, 14310-14317, 14679-14686, 15048-15055, 15417-15424, 15786-15793, 13203-13210, 13572-13579, 16155-16162, 16524-16531, 16893-16900, 17262-17269, 17631-17638, 18000-18007, 18369-18376, 18738-18745, 19107-19114, 19476-19483, 21363-21384, 21389-21410 or a fragment or variant of any of these sequences (see also Table 3 and 4). Additional information regarding each of these suitable nucleic acid sequences encoding may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt;. 
     In particularly preferred embodiment, the artificial RNA of the first aspect comprises at least one coding sequence comprising a codon modified nucleic acid sequence which is identical or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of the G/C optimized or G/C content modified nucleic acid sequence according to the SEQ ID NOs: 70-71, 75-77, 485-486, 490-492, 899-900, 904-906, 1268-1269, 1273-1275, 1637-1638, 1642-1644, 2006-2007, 2011-2013, 2375-2376, 2380-2382, 2744-2745, 2749-2751, 3113-3114, 3118-3120, 3482-3483, 3487-3489, 3852, 4221, 4590, 4959, 5328, 5697, 6066, 6435, 6804, 7173, 7542, 7911, 3856-3858, 4225-4227, 4594-4596, 4963-4965, 5332-5334, 5701-5703, 6070-6072, 6439-6441, 6808-6810, 7177-7179, 7546-7548, 7915-7917, 11728, 11732-11734, 12097, 12101-12103, 12465, 12466, 12470-12472, 12834, 12835, 12839-12841, 13941, 13942, 13946-13948, 14310, 14311, 14315-14317, 14679, 14680, 14684-14686, 15048, 15049, 15053-15055, 15417, 15418, 15422-15424, 15786, 15787, 15791-15793, 13203, 13204, 13208-13210, 13572, 13573, 13577-13579, 16155, 16156, 16160-16162, 16524, 16525, 16529-16531, 16893, 16894, 16898-16900, 17262, 17263, 17267-17269, 17631, 17632, 17636-17638, 18000, 18001, 18005-18007, 18369, 18370, 18374-18376, 18738, 18739, 18743-18745, 19107, 19108, 19112-19114, 19476, 19477, 19481-19483, 21363-21384, 21389-21410 or a fragment or variant of any of these sequences (see also Table 3 and 4; opt1, 5, 6, 11). Additional information regarding each of these suitable nucleic acid sequences encoding may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt;. 
     In preferred embodiment, the artificial RNA of the invention comprises at least one coding sequence comprising a codon modified nucleic acid sequence which is identical or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of the human codon usage adapted nucleic acid sequence according to the SEQ ID NOs: 73, 488, 902, 1271, 1640, 2009, 2378, 2747, 3116, 3485, 3854, 4223, 4592, 4961, 5330, 5699, 6068, 6437, 6806, 7175, 7544, 7913, 11730, 12099, 12468, 12837, 13944, 14313, 14682, 15051, 15420, 15789, 13206, 13575, 16158, 16527, 16896, 17265, 17634, 18003, 18372, 18741, 19110, 19479 or a fragment or variant of any of these sequences (see also Table 3 and 4; opt3). Additional information regarding each of these suitable nucleic acid sequences encoding may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt;. 
     In particularly preferred embodiment, the artificial RNA of the first aspect comprises at least one coding sequence comprising a codon modified nucleic acid sequence which is identical or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of the C maximized nucleic acid sequence according to the SEQ ID NOs: 72, 487, 901, 1270, 1639, 2008, 2377, 2746, 3115, 3484, 3853, 4222, 4591, 4960, 5329, 5698, 6067, 6436, 6805, 7174, 7543, 7912, 11729, 12098, 12467, 12836, 13943, 14312, 14681, 15050, 15419, 15788, 13205, 13574, 16157, 16526, 16895, 17264, 17633, 18002, 18371, 18740, 19109, 19478 or a fragment or variant of any of these sequences (see also Table 3 and 4; opt2). 
     Additional information regarding each of these suitable nucleic acid sequences encoding may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt;. 
     In preferred embodiment, the artificial RNA of the invention comprises at least one coding sequence comprising a codon modified nucleic acid sequence which is identical or at least 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of the CAI maximized nucleic acid sequence according to the SEQ ID NOs 74, 489, 903, 1272, 1641, 2010, 2379, 2748, 3117, 3486, 3855, 4224, 4593, 4962, 5331, 5700, 6069, 6438, 6807, 7176, 7545, 7914, 11731, 12100, 12469, 12838, 13945, 14314, 14683, 15052, 15421, 15790, 13207, 13576, 16159, 16528, 16897, 17266, 17635, 18004, 18373, 18742, 19111, 19480 or a fragment or variant of any of these sequences (see also Table 3 and 4; opt4). Additional information regarding each of these suitable nucleic acid sequences encoding may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt;. 
     In embodiments, the A/U content in the environment of the ribosome binding site of the artificial nucleic acid, particularly the artificial RNA of the invention may be increased compared to the A/U content in the environment of the ribosome binding site of its respective wild type nucleic acid. This modification (an increased A/U content around the ribosome binding site) increases the efficiency of ribosome binding to the nucleic acid, preferably the RNA. An effective binding of the ribosomes to the ribosome binding site in turn has the effect of an efficient translation of the RNA. Accordingly, in a particularly preferred embodiment, the artificial nucleic acid of the invention comprises a ribosome binding site, also referred to as “Kozak sequence” identical to or at least 80%, 85%, 90%, 95% identical to any one of the sequences SEQ ID NOs: 41, 42, or fragments or variants thereof. 
     Preferred RSV polypeptide and nucleic acid coding sequences (“cds”) are provided in Table 3A and 3B and Table 4A and 4B. 
     In Table 3A and 3B, Columns A to J represent specific suitable constructs of the invention derived from RSV Fusion (F) protein, wherein Column A provides suitable sequences for F0, Column B provides suitable sequences for F-del, Column C provides suitable sequences for F0_DSCav1, Column D provides suitable sequences for F-del_DSCav1, Column E provides suitable sequences for F_DSCav1_mut1, Column F provides suitable sequences for F-del_DSCav1_mut1, Column G provides suitable sequences for F_DSCav1_mut2, Column H provides suitable sequences for F-del_DSCav1_mut2, Column I provides suitable sequences for F_DSCav1_mut3, Column J provides suitable sequences for F-del_DSCav1_mut3. The specific protein SEQ ID NOs as provided in the sequence listing are in row 2 (“PRT”). The SEQ ID NOs of corresponding wild type/non-modified coding sequences are provided in row 3 (“wt”). The SEQ ID NOs of corresponding codon modified coding sequences for each protein construct are provided in row 4 to row 10 (“opt1”, “opt2”, “opt3”, “opt4”, “opt5”, “opt6”, “opt11”). In Table 3A, coding sequences derived from HRSV(A2) are provided, in Table 3B coding sequences derived from HRSV(Memphis-37) are provided. Further information is provided in the &lt;223&gt; identifier for each of the respective SEQ ID NO in the sequence listing. 
     
       
         
           
               
             
               
                 TABLE 3A 
               
             
            
               
                   
               
               
                 Preferred coding sequences encoding RSV F (columns A-J), derived from HRSV(A2) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 A 
                 B 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 J 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 PRT 
                 68 
                 483 
                 898 
                 1267 
                 1636 
                 2005 
                 2374 
                 2743 
                 3112 
                 3481 
               
               
                 wt 
                 69 
                 484 
               
               
                 opt1 
                 70, 71, 
                 485, 
                 899, 
                 1268, 
                 1637, 
                 2006, 
                 2375, 
                 2744, 
                 3113, 
                 3482, 
               
               
                   
                 21363 
                 486, 
                 900, 
                 1269, 
                 1638, 
                 2007, 
                 2376, 
                 2745, 
                 3114, 
                 3483, 
               
               
                   
                   
                 21364 
                 21365 
                 21366 
                 21369 
                 21370 
                 21371 
                 21372 
                 21373 
                 21374 
               
               
                 opt2 
                 72 
                 487 
                 901 
                 1270 
                 1639 
                 2008 
                 2377 
                 2746 
                 3115 
                 3484 
               
               
                 opt3 
                 73 
                 488 
                 902 
                 1271 
                 1640 
                 2009 
                 2378 
                 2747 
                 3116 
                 3485 
               
               
                 opt4 
                 74 
                 489 
                 903 
                 1272 
                 1641 
                 2010 
                 2379 
                 2748 
                 3117 
                 3486 
               
               
                 opt5 
                 75 
                 490 
                 904 
                 1273 
                 1642 
                 2011 
                 2380 
                 2749 
                 3118 
                 3487 
               
               
                 opt6 
                 76 
                 491 
                 905 
                 1274 
                 1643 
                 2012 
                 2381 
                 2750 
                 3119 
                 3488 
               
               
                 opt11 
                 77 
                 492 
                 906 
                 1275 
                 1644 
                 2013 
                 2382 
                 2751 
                 3120 
                 3489 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3B 
               
             
            
               
                   
               
               
                 Preferred coding sequences encoding RSV F (columns A-J), derived from HRSV(Memphis-37) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 A 
                 B 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 J 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 PRT 
                 11726 
                 12095 
                 12464 
                 12833 
                 13940 
                 14309 
                 14678 
                 15047 
                 15416 
                 15785 
               
               
                 wt 
                 11727 
                 12096 
               
               
                 opt1 
                 11728, 
                 12097, 
                 12465, 
                 12834, 
                 13941, 
                 14310, 
                 14679, 
                 15048, 
                 15417, 
                 15786, 
               
               
                   
                 21389 
                 21390 
                 12466, 
                 12835, 
                 13942, 
                 14311, 
                 14680, 
                 15049, 
                 15418, 
                 15787, 
               
               
                   
                   
                   
                 21391 
                 21392 
                 21395 
                 21396 
                 21397 
                 21398 
                 21399 
                 21400 
               
               
                 opt2 
                 11729 
                 12098 
                 12467 
                 12836 
                 13943 
                 14312 
                 14681 
                 15050 
                 15419 
                 15788 
               
               
                 opt3 
                 11730 
                 12099 
                 12468 
                 12837 
                 13944 
                 14313 
                 14682 
                 15051 
                 15420 
                 15789 
               
               
                 opt4 
                 11731 
                 12100 
                 12469 
                 12838 
                 13945 
                 14314 
                 14683 
                 15052 
                 15421 
                 15790 
               
               
                 opt5 
                 11732 
                 12101 
                 12470 
                 12839 
                 13946 
                 14315 
                 14684 
                 15053 
                 15422 
                 15791 
               
               
                 opt6 
                 11733 
                 12102 
                 12471 
                 12840 
                 13947 
                 14316 
                 14685 
                 15054 
                 15423 
                 15792 
               
               
                 opt11 
                 11734 
                 12103 
                 12472 
                 12841 
                 13948 
                 14317 
                 14686 
                 15055 
                 15424 
                 15793 
               
               
                   
               
            
           
         
       
     
     In Table 4A and 4B, Columns K to V represent specific suitable constructs of the invention derived from RSV Fusion (F) protein, wherein Column K provides suitable sequences for F_DSCav1_mut0, Column L provides suitable sequences for F-del_DSCav1_mut0, Column M provides suitable sequences for F_DSCav1_mut4, Column N provides suitable sequences for F-del_DSCav1_mut4, Column O provides suitable sequences for F_DSCav1_mut5, Column P provides suitable sequences for F-del_DSCav1_mut5, Column Q provides suitable sequences for F_DSCav1_mut6, Column R provides suitable sequences for F-del_DSCav1_mut6, Column S provides suitable sequences for F_DSCav1_mut7, Column T provides suitable sequences for F-del_DSCav1_mut7, Column U provides suitable sequences for F_DSCav1_mut8, Column V provides suitable sequences for F-del_DSCav1_mut8. The specific protein SEQ ID NOs as provided in the sequence listing are in row 2 (“PRT”). The SEQ ID NOs of corresponding codon modified coding sequences for each protein construct are provided in row 3 to row 9 (“opt1”, “opt2”, “opt3”, “opt4”, “opt5”, “opt6”, “opt11”). In Table 4A, coding sequences derived from HRSV(A2) are provided, in Table 4B coding sequences derived from HRSV(Memphis-37) are provided. Further information is provided in the &lt;223&gt; identifier for each of the respective SEQ ID NO in the sequence listing. 
     
       
         
           
               
             
               
                 TABLE 4A 
               
             
            
               
                   
               
               
                 Preferred coding sequences encoding RSV F (columns K-V), derived from HRSV(A2) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 K 
                 L 
                 M 
                 N 
                 O 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 U 
                 V 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 PRT 
                 3850 
                 4219 
                 4588 
                 4957 
                 5326 
                 5695 
                 6064 
                 6433 
                 6802 
                 7171 
                 7540 
                 7909 
               
               
                 opt1 
                 3851, 
                 4220, 
                 4589, 
                 4958, 
                 5327, 
                 5696, 
                 6065, 
                 6434, 
                 6803, 
                 7172, 
                 7541, 
                 7910, 
               
               
                   
                 3852, 
                 4221, 
                 4590, 
                 4959, 
                 5328, 
                 5697, 
                 6066, 
                 6435, 
                 6804, 
                 7173, 
                 7542, 
                 7911, 
               
               
                   
                 21367  
                 21368  
                 21375  
                 21376  
                 21377  
                 21378  
                 21379  
                 21380  
                 21381  
                 21382  
                 21383  
                 21384  
               
               
                 opt2 
                 3853 
                 4222 
                 4591 
                 4960 
                 5329 
                 5698 
                 6067 
                 6436 
                 6805 
                 7174 
                 7543 
                 7912 
               
               
                 opt3 
                 3854 
                 4223 
                 4592 
                 4961 
                 5330 
                 5699 
                 6068 
                 6437 
                 6806 
                 7175 
                 7544 
                 7913 
               
               
                 opt4 
                 3855 
                 4224 
                 4593 
                 4962 
                 5331 
                 5700 
                 6069 
                 6438 
                 6807 
                 7176 
                 7545 
                 7914 
               
               
                 opt5 
                 3856 
                 4225 
                 4594 
                 4963 
                 5332 
                 5701 
                 6070 
                 6439 
                 6808 
                 7177 
                 7546 
                 7915 
               
               
                 opt6 
                 3857 
                 4226 
                 4595 
                 4964 
                 5333 
                 5702 
                 6071 
                 6440 
                 6809 
                 7178 
                 7547 
                 7916 
               
               
                 opt11 
                 3858 
                 4227 
                 4596 
                 4965 
                 5334 
                 5703 
                 6072 
                 6441 
                 6810 
                 7179 
                 7548 
                 7917 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4B 
               
             
            
               
                   
               
               
                 Preferred coding sequences encoding RSV F (columns K-V) derived from HRSV(Memphis-37) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 K 
                 L 
                 M 
                 N 
                 O 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 U 
                 V 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 PRT 
                 13202 
                 13571 
                 16154 
                 16523 
                 16892 
                 17261 
                 17630 
                 17999 
                 18368 
                 18737 
                 19106 
                 19475 
               
               
                 opt1 
                 13203, 
                 13572, 
                 16155, 
                 16524, 
                 16893, 
                 17262, 
                 17631, 
                 18000, 
                 18369, 
                 18738, 
                 19107, 
                 19476, 
               
               
                   
                 13204, 
                 13573, 
                 16156, 
                 16525, 
                 16894, 
                 17263, 
                 17632, 
                 18001, 
                 18370, 
                 18739, 
                 19108, 
                 19477, 
               
               
                   
                 21393 
                 21394 
                 21401 
                 21402 
                 21403 
                 21404 
                 21405 
                 21406 
                 21407 
                 21408 
                 21409 
                 21410 
               
               
                 opt2 
                 13205 
                 13574 
                 16157 
                 16526 
                 16895 
                 17264 
                 17633 
                 18002 
                 18371 
                 18740 
                 19109 
                 19478 
               
               
                 opt3 
                 13206 
                 13575 
                 16158 
                 16527 
                 16896 
                 17265 
                 17634 
                 18003 
                 18372 
                 18741 
                 19110 
                 19479 
               
               
                 opt4 
                 13207 
                 13576 
                 16159 
                 16528 
                 16897 
                 17266 
                 17635 
                 18004 
                 18373 
                 18742 
                 19111 
                 19480 
               
               
                 opt5 
                 13208 
                 13577 
                 16160 
                 16529 
                 16898 
                 17267 
                 17636 
                 18005 
                 18374 
                 18743 
                 19112 
                 19481 
               
               
                 opt6 
                 13209 
                 13578 
                 16161 
                 16530 
                 16899 
                 17268 
                 17637 
                 18006 
                 18375 
                 18744 
                 19113 
                 19482 
               
               
                 opt11 
                 13210 
                 13579 
                 16162 
                 16531 
                 16900 
                 17269 
                 17638 
                 18007 
                 18376 
                 18745 
                 19114 
                 19483 
               
               
                   
               
            
           
         
       
     
     In embodiments, the artificial RNA of the first aspect is monocistronic, bicistronic, or multicistronic. 
     In preferred embodiments, the artificial RNA of the invention is monocistronic. 
     The term “monocistronic nucleic acid” or “monocistronic nucleic acid” will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to an artificial RNA that comprises only one coding sequences as defined herein. The terms “bicistronic nucleic acid, multicistronic nucleic acid” or “monocistronic RNA” as used herein will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to an artificial RNA that may have two (bicistronic) or even more (multicistronic) coding sequences. 
     In embodiments, the artificial RNA of the invention is monocistronic and the coding sequence of said monocistronic artificial RNA encodes at least two different antigenic peptides or proteins derived from RSV F as defined herein, or a fragment or variant thereof. Accordingly, the at least one coding sequence of the monocistronic artificial RNA may encode at least two, three, four, five, six, seven, eight and more antigenic peptides or proteins derived from a RSV, preferably a RSV F as defined herein linked with or without an amino acid linker sequence, wherein said linker sequence can comprise rigid linkers, flexible linkers, cleavable linkers (e.g. self-cleaving peptides) as defined above, or a combination thereof (herein referred to as “multi-antigen-constructs/nucleic acid”). 
     In embodiments, the artificial RNA of the invention is bicistronic or multicistronic and comprises at least two coding sequences, wherein the at least two coding sequences encode two or more different antigenic peptides or proteins derived from RSV, preferably RSV F as defined herein, or a fragment or variant of any of these. Accordingly, the coding sequences in a bicistronic or multicistronic artificial RNA suitably encodes distinct antigenic proteins or peptides as defined herein or a fragment or variant thereof. Preferably, the coding sequences in said bicistronic or multicistronic artificial RNA may be separated by at least one IRES (internal ribosomal entry site) sequence. Thus, the term “encoding two or more antigenic peptides or proteins” may mean, without being limited thereto, that the bicistronic or multicistronic artificial RNA encodes e.g. at least two, three, four, five, six or more (preferably different) antigenic peptides or proteins of different RSV or their fragments or variants within the definitions provided herein. Alternatively, the bicistronic or multicistronic artificial RNA may encode e.g. at least two, three, four, five, six or more (preferably different) antigenic peptides or proteins derived from the same RSV or fragments or variants within the definitions provided herein. In that context, suitable IRES sequences may be selected from the list of nucleic acid sequences according to SEQ ID NOs: 1566-1662 of the patent application WO2017/081082, or fragments or variants of these sequences. In this context, the disclosure of WO2017/081082 relating to IRES sequences is herewith incorporated by reference. 
     It has to be understood that in the context of the invention, certain combinations of coding sequences may be generated by any combination of monocistronic, bicistronic and multicistronic artificial nucleic acids and/or multi-antigen-constructs/nucleic acid to obtain a nucleic acid composition encoding multiple antigenic peptides or proteins as defined herein. 
     Preferably, the artificial RNA comprising at least one coding sequence as defined herein typically comprises a length of about 50 to about 20000, or 500 to about 20000 nucleotides, or about 500 to about 20000 nucleotides, or about 500 to about 10000 nucleotides, or of about 1000 to about 10000 nucleotides, or preferably of about 1000 to about 5000 nucleotides, or even more preferably of about 1000 to about 2500 nucleotides. 
     According to preferred embodiments, the artificial RNA of the first aspect may be an mRNA, a self-replicating RNA, a circular RNA, or a replicon RNA. 
     In embodiments, the artificial RNA is a circular RNA. As used herein, “circular RNA” or “circRNAs” has to be understood as a circular polynucleotide that can encode at least one antigenic peptide or protein as defined herein. Accordingly, in preferred embodiments, said circular RNA comprises at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV or a fragment or variant thereof as defined herein. The production of circRNAs can be performed using various methods provided in the art. For example, U.S. Pat. No. 6,210,931 teaches a method of synthesizing circRNAs by inserting DNA fragments into a plasmid containing sequences having the capability of spontaneous cleavage and self-circularization. U.S. Pat. No. 5,773,244 teaches producing circRNAs by making a DNA construct encoding an RNA cyclase ribozyme, expressing the DNA construct as an RNA, and then allowing the RNA to self-splice, which produces a circRNA free from intron in vitro. WO1992/001813 teaches a process of making single strand circular nucleic acids by synthesizing a linear polynucleotide, combining the linear nucleotide with a complementary linking oligonucleotide under hybridization conditions, and ligating the linear polynucleotide. The person skilled in the art may also use methods provided in WO2015/034925 or WO2016/011222 to produce circular RNA. Accordingly, methods for producing circular RNA as provided in U.S. Pat. Nos. 6,210,931, 5,773,244, WO1992/001813, WO2015/034925 and WO2016/011222 are incorporated herewith by reference. 
     In embodiments, the artificial RNA is a replicon RNA. The term “replicon RNA” will be recognized and understood by the person of ordinary skill in the art, and are for example intended to be optimized self-replicating artificial RNA constructs. Such constructs include replication elements (replicase) derived from alphaviruses and the substitution of the structural virus proteins with the artificial nucleic acid of interest (in the context of the invention, an artificial nucleic acid comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV. Alternatively, the replicase may be provided on an independent construct comprising a replicase RNA sequence derived from e.g. Semliki forest virus (SFV), Sindbis virus (SIN), Venezuelan equine Encephalitis virus (VEE), Ross-River virus (RRV), or other viruses belonging to the alphavirus family. Downstream of the replicase lies a sub-genomic promoter that controls replication of the artificial nucleic acid of the invention, i.e. an artificial nucleic acid comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV. 
     In preferred embodiments the artificial RNA of the first aspect is an mRNA. 
     The terms “RNA” and “mRNA” will be recognized and understood by the person of ordinary skill in the art, and are for example intended to be a ribonucleic acid molecule, i.e. a polymer consisting of nucleotides. These nucleotides are usually adenosine-monophosphate, uridine-monophosphate, guanosine-monophosphate and cytidine-monophosphate monomers which are connected to each other along a so-called backbone. The backbone is formed by phosphodiester bonds between the sugar, i.e. ribose, of a first and a phosphate moiety of a second, adjacent monomer. The specific succession of the monomers is called the RNA-sequence. The mRNA (messenger RNA) usually provides the nucleotide sequence that may be translated into an amino-acid sequence of a particular peptide or protein. 
     The artificial RNA, preferably the mRNA of the invention may be prepared using any method known in the art, including chemical synthesis such as e.g. solid phase RNA synthesis, as well as in vitro methods, such as RNA in vitro transcription reactions. 
     In a preferred embodiment, the artificial RNA, preferably the mRNA is obtained by RNA in vitro transcription. 
     Accordingly, the RNA of the invention is preferably an in vitro transcribed RNA. 
     The terms “RNA in vitro transcription” or “in vitro transcription” relate to a process wherein RNA is synthesized in a cell-free system (in vitro). RNA may be obtained by DNA-dependent in vitro transcription of an appropriate DNA template, which according to the present invention is a linearized plasmid DNA template or a PCR-amplified DNA template. The promoter for controlling RNA in vitro transcription can be any promoter for any DNA-dependent RNA polymerase. Particular examples of DNA-dependent RNA polymerases are the T7, T3, SP6, or Syn5 RNA polymerases. In a preferred embodiment of the present invention the DNA template is linearized with a suitable restriction enzyme, before it is subjected to RNA in vitro transcription. 
     Reagents used in RNA in vitro transcription typically include: a DNA template (linearized plasmid DNA or PCR product) with a promoter sequence that has a high binding affinity for its respective RNA polymerase such as bacteriophage-encoded RNA polymerases (T7, T3, SP6, or Syn5); ribonucleotide triphosphates (NTPs) for the four bases (adenine, cytosine, guanine and uracil); optionally, a cap analogue as defined herein (e.g. m7G(5′)ppp(5′)G (m7G, m7G(5′)ppp(5′)(2′OMeG)pG or m7G(5′)ppp(5′)(2′OMeA)pG)); optionally, further modified nucleotides as defined herein; a DNA-dependent RNA polymerase capable of binding to the promoter sequence within the DNA template (e.g. T7, T3, SP6, or Syn5 RNA polymerase); optionally, a ribonuclease (RNase) inhibitor to inactivate any potentially contaminating RNase; optionally, a pyrophosphatase to degrade pyrophosphate, which may inhibit RNA in vitro transcription; MgCl2, which supplies Mg2+ ions as a co-factor for the polymerase; a buffer (TRIS or HEPES) to maintain a suitable pH value, which can also contain antioxidants (e.g. DTT), and/or polyamines such as spermidine at optimal concentrations, e.g. a buffer system comprising TRIS-Citrate as disclosed in WO2017/109161. 
     In embodiments, the nucleotide mixture used in RNA in vitro transcription may additionally contain modified nucleotides as defined herein. In that context, preferred modified nucleotides comprise pseudouridine (ψ), N1-methylpseudouridine (m1ψ), 5-methylcytosine, and/or 5-methoxyuridine. 
     In preferred embodiments, the nucleotide mixture (i.e. the fraction of each nucleotide in the mixture) used for RNA in vitro transcription reactions may be optimized for the given RNA sequence, preferably as described WO2015/188933. 
     In embodiment where more than one different artificial RNA as defined herein has to be produced, e.g. where 2, 3, 4, 5, 6, 7, 8, 9, 10 or even more different artificial RNAs have to be produced (e.g. encoding different RSV F antigens, or e.g. a combination of RSV F and RSV G; see second aspect), procedures as described in WO2017/109134 may be suitably used. 
     In the context of RNA vaccine production, it may be required to provide GMP-grade RNA. GMP-grade RNA may be produced using a manufacturing process approved by regulatory authorities. Accordingly, in a particularly preferred embodiment, RNA production is performed under current good manufacturing practice (GMP), implementing various quality control steps on DNA and RNA level, preferably according to WO2016/180430. In preferred embodiments, the RNA of the invention is a GMP-grade RNA, particularly a GMP-grade mRNA. 
     The obtained RNA products are preferably purified using PureMessenger® (CureVac, Tubingen, Germany; RP-HPLC according to WO2008/077592) and/or tangential flow filtration (as described in WO2016/193206). 
     In a further preferred embodiment, the RNA, particularly the purified RNA, is lyophilized according to WO2016/165831 or WO2011/069586 to yield a temperature stable dried artificial RNA (powder) as defined herein. The RNA of the invention, particularly the purified RNA may also be dried using spray-drying or spray-freeze drying according to WO2016/184575 or WO2016184576 to yield a temperature stable RNA (powder) as defined herein. Accordingly, in the context of manufacturing and purifying RNA, the disclosures of WO2017/109161, WO2015/188933, WO2016/180430, WO2008/077592, WO2016/193206, WO2016/165831, WO2011/069586, WO2016/184575, and WO2016/184576 are incorporated herewith by reference. 
     Accordingly, in preferred embodiments, the RNA is a dried RNA, particularly a dried mRNA. 
     The term “dried RNA” as used herein has to be understood as RNA that has been lyophilized, or spray-dried, or spray-freeze dried as defined above to obtain a temperature stable dried RNA (powder). 
     In preferred embodiments, the artificial RNA of the invention is a purified RNA, particularly purified mRNA. 
     The term “purified RNA” or “purified mRNA” as used herein has to be understood as RNA which has a higher purity after certain purification steps (e.g. HPLC, TFF, Oligo d(T) purification, precipitation steps) than the starting material (e.g. in vitro transcribed RNA). Typical impurities that are essentially not present in purified RNA comprise peptides or proteins (e.g. enzymes derived from DNA dependent RNA in vitro transcription, e.g. RNA polymerases, RNases, pyrophosphatase, restriction endonuclease, DNase), spermidine, BSA, abortive RNA sequences, RNA fragments (short double stranded RNA fragments, abortive sequences etc.), free nucleotides (modified nucleotides, conventional NTPs, cap analogue), template DNA fragments, buffer components (HEPES, TRIS, MgCl2) etc. Other potential impurities that may be derived from e.g. fermentation procedures comprise bacterial impurities (bioburden, bacterial DNA) or impurities derived from purification procedures (organic solvents etc.). Accordingly, it is desirable in this regard for the “degree of RNA purity” to be as close as possible to 100%. It is also desirable for the degree of RNA purity that the amount of full-length RNA transcripts is as close as possible to 100%. Accordingly “purified RNA” as used herein has a degree of purity of more than 75%, 80%, 85%, very particularly 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% and most favorably 99% or more. The degree of purity may for example be determined by an analytical HPLC, wherein the percentages provided above correspond to the ratio between the area of the peak for the target RNA and the total area of all peaks representing the by-products. Alternatively, the degree of purity may for example be determined by an analytical agarose gel electrophoresis or capillary gel electrophoresis. 
     It has to be understood that “dried RNA” as defined herein and “purified RNA” as defined herein or “GMP-grade mRNA” as defined herein may have superior stability characteristics (in vitro, in vivo) and improved efficiency (e.g. better translatability of the mRNA in vivo) and are therefore particularly suitable in the context of the invention. Moreover, “dried RNA” as defined herein and “purified RNA” as defined herein or “GMP-grade mRNA” may be particularly suitable for medical use as defined herein. 
     The artificial RNA may suitably be modified by the addition of a 5′-cap structure, which preferably stabilizes the nucleic acid as described herein. Accordingly, in preferred embodiments, the artificial RNA of the first aspect comprises a 5′-cap structure, preferably m7G, cap0 (e.g. m7G(5′)ppp(5′)G), cap1 (e.g. m7G(5′)ppp(5′)(2′OMeG) or m7G(5′)ppp(5′)(2′OMeA)), cap2, a modified cap0, or a modified cap1 structure (generated using a cap analogue as defined below). 
     The term “5′-cap structure” as used herein will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to a modified nucleotide (cap analogue), particularly a guanine nucleotide, added to the 5′-end of an RNA molecule, e.g. an mRNA molecule. Preferably, the 5′-cap is added using a 5-5-triphosphate linkage (also named m7GpppN). Further examples of 5′-cap structures include glyceryl, inverted deoxy abasic residue (moiety), 4′,5′ methylene nucleotide, 1-(beta-D-erythrofuranosyl) nucleotide, 4′-thio nucleotide, carbocyclic nucleotide, 1,5-anhydrohexitol nucleotide, L-nucleotides, alpha-nucleotide, modified base nucleotide, threo-pentofuranosyl nucleotide, acyclic 3′,4′-seco nucleotide, acyclic 3,4-dihydroxybutyl nucleotide, acyclic 3,5 dihydroxypentyl nucleotide, 3′-3-inverted nucleotide moiety, 3′-3′-inverted abasic moiety, 3′-2′-inverted nucleotide moiety, 3′-2′-inverted abasic moiety, 1,4-butanediol phosphate, 3′-phosphoramidate, hexylphosphate, aminohexyl phosphate, 3′-phosphate, 3′phosphorothioate, phosphorodithioate, or bridging or non-bridging methylphosphonate moiety. 
     Further 5′-cap structures which may be suitable in the context of the present invention are cap1 (additional methylation of the ribose of the adjacent nucleotide of m7GpppN), cap2 (additional methylation of the ribose of the 2nd nucleotide downstream of the m7GpppN), cap3 (additional methylation of the ribose of the 3rd nucleotide downstream of the m7GpppN), cap4 (additional methylation of the ribose of the 4th nucleotide downstream of the m7GpppN), ARCA (anti-reverse cap analogue), modified ARCA (e.g. phosphothioate modified ARCA), inosine, N1-methyl-guanosine, 2′-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine. 
     A 5′-cap (cap0 or cap1) structure may also be formed in chemical RNA synthesis or, preferably, RNA in vitro transcription (co-transcriptional capping) using cap analogues. 
     The term “cap analogue” as used herein will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to a non-polymerizable di-nucleotide that has cap functionality in that it facilitates translation or localization, and/or prevents degradation of a nucleic acid molecule, particularly of an RNA molecule, when incorporated at the 5′-end of the nucleic acid molecule. Non-polymerizable means that the cap analogue will be incorporated only at the 5′-terminus because it does not have a 5′ triphosphate and therefore cannot be extended in the 3′-direction by a template-dependent polymerase, particularly, by template-dependent RNA polymerase. Examples of cap analogues include, but are not limited to, a chemical structure selected from the group consisting of m7GpppG, m7GpppA, m7GpppC; unmethylated cap analogues (e.g. GpppG); dimethylated cap analogue (e.g. m2,7GpppG), trimethylated cap analogue (e.g. m2,2,7GpppG), dimethylated symmetrical cap analogues (e.g. m7Gpppm7G), or anti reverse cap analogues (e.g. ARCA; m7,2′OmeGpppG, m7,2′dGpppG, m7,3′OmeGpppG, m7,3′dGpppG and their tetraphosphate derivatives). Further cap analogues have been described previously (WO2008/016473, WO2008/157688, WO2009/149253, WO2011/015347, and WO2013/059475). Further suitable cap analogons in that context are described in WO2017/066793, WO2017/066781, WO2017/066791, WO2017/066789, WO2017/053297, WO2017/066782, WO2018075827 and WO2017/066797 wherein the disclosures referring to cap analogues are incorporated herewith by reference. 
     The 5′-cap structure may suitably be added co-transcriptionally using cap-analogues as defined herein in an RNA in vitro transcription reaction as defined herein. 
     In preferred embodiments, a modified cap1 structure is generated using a cap analogue as disclosed in WO2017/053297, WO2017/066793, WO2017/066781, WO2017/066791, WO2017/066789, WO2017/066782, WO2018075827 and WO2017/066797. In particular, any cap structures derivable from the structure disclosed in claim 1-5 of WO2017/053297 may be suitably used to co-transcriptionally generate a modified cap1 structure. Further, any cap structures derivable from the structure defined in claim 1 or claim 21 of WO2018075827 may be suitably used to co-transcriptionally generate a modified cap1 structure. 
     Preferred cap-analogues are the di-nucleotide cap analogues m7G(5′)ppp(5′)G (m7G) or 3 O-Me-m7G(5′)ppp(5′)G to co-transcriptionally generate cap0 structures. Particularly preferred cap-analogues are the tri-nucleotide cap analogues m7G(5′)ppp(5′)(2′OMeA)pG or m7G(5′)ppp(5′)(2′OMeG)pG to co-transcriptionally generate cap1 structures. 
     In that context, it is preferred that the RNA of the invention comprises a Cap1 structure as defined above, which preferably result in an increased protein expression through e.g. high capping efficiencies and increased translation efficiencies. Further suitably, the RNA of the invention comprising a Cap1 structure displays a decreased stimulation of the innate immune system as compared to Cap0 constructs of the same nucleic acid sequence. The person of ordinary skill knows how to determine translation efficiencies, capping degree, and immune stimulation. 
     In a particularly preferred embodiment, the artificial RNA of the first aspect of the invention comprises a cap1 structure, wherein said cap1 structure may be formed enzymatically or co-transcriptionally (e.g. using m7G(5′)ppp(5′)(2′OMeA)pG or m7G(5′)ppp(5′)(2′OMeG)pG analogues). 
     In preferred embodiments, the artificial RNA of the first aspect comprises an m7G(5′)ppp(5′)(2′OMeA)pG cap structure. In such embodiments, the coding RNA comprises a 5′ terminal m7G cap, and an additional methylation of the ribose of the adjacent nucleotide of m7GpppN, in that case, a 2′O methylated adenosine. 
     In other preferred embodiments, the artificial RNA of the first aspect comprises an m7G(5′)ppp(5′)(2′OMeG)pG cap structure. In such embodiments, the coding RNA comprises a 5′ terminal m7G cap, and an additional methylation of the ribose of the adjacent nucleotide, in that case, a 2′O methylated guanosine. 
     Accordingly, whenever reference is made to suitable RNA or mRNA sequences in the context of the invention, the first nucleotide of said RNA or mRNA sequence, that is the nucleotide downstream of the m7G(5′)ppp structure, may be a 2′O methylated guanosine or a 2′O methylated adenosine. 
     Accordingly, in other embodiments, the artificial RNA of the invention may comprise a 5′-cap sequence element according to SEQ ID NOs: 43 or 21321, or a fragment or variant thereof. 
     In other embodiments, the 5′-cap structure is added via enzymatic capping using capping enzymes (e.g. vaccinia virus capping enzymes, commercially available capping kits) to generate cap or cap1 or cap2 structures. In other embodiments, the 5′-cap structure (cap0, cap1) is added via enzymatic capping using immobilized capping enzymes, e.g. using a capping reactor (WO2016/193226). 
     In preferred embodiments, the artificial RNA of the invention comprises at least one poly(A) sequence, preferably comprising 30 to 150 adenosine nucleotides. 
     In preferred embodiments, the poly(A) sequence, suitable located at the 3′ terminus, comprises 10 to 500 adenosine nucleotides, 10 to 200 adenosine nucleotides, 40 to 200 adenosine nucleotides or 40 to 150 adenosine nucleotides. In a particularly preferred embodiment, the poly(A) sequence comprises about 64 adenosine nucleotides. In further particularly preferred embodiments, the poly(A) sequence comprises about 75 adenosine nucleotides. In further particularly preferred embodiments, the poly(A) sequence comprises about 100 adenosine nucleotides. 
     The terms “poly(A) sequence”, “poly(A) tail” or “3′-poly(A) tail” as used herein will be recognized and understood by the person of ordinary skill in the art, and are for example intended to be a sequence of adenosine nucleotides, typically located at the 3′-end of an RNA, of up to about 1000 adenosine nucleotides. Preferably, said poly(A) sequence is essentially homopolymeric, e.g. a poly(A) sequence of e.g. 100 adenosine nucleotides has essentially the length of 100 nucleotides. In other embodiments, the poly(A) sequence may be interrupted by at least one nucleotide different from an adenosine nucleotide, e.g. a poly(A) sequence of e.g. 100 adenosine nucleotides may have a length of more than 100 nucleotides (comprising 100 adenosine nucleotides and in addition said at least one nucleotide different from an adenosine nucleotide). 
     In the context of the present invention, a poly(A) sequence may be located within an mRNA or any other nucleic acid molecule, such as, e.g., in a DNA vector, for example, in a vector serving as template for the generation of an RNA, preferably an mRNA, e.g., by transcription said DNA vector. 
     Preferably, the poly(A) sequence of the artificial RNA is obtained from a DNA template during RNA in vitro transcription. In other embodiments, the poly(A) sequence is obtained in vitro by common methods of chemical synthesis without being necessarily transcribed from a DNA template. In other embodiments, poly(A) sequences are generated by enzymatic polyadenylation of the RNA (after RNA in vitro transcription) using commercially available polyadenylation kits and corresponding protocols known in the art, or alternatively, by using immobilized poly(A)polymerases e.g. using a polyadenylation reactor (as described in WO2016/174271). 
     In embodiments, the artificial RNA of the invention may contain a poly(A) sequence derived from a vector and may comprise at least one additional poly(A) sequence generated by enzymatic polyadenylation, e.g. as described in WO2016/091391. 
     In preferred embodiments, the artificial RNA of the invention comprises at least one poly(C) sequence, preferably comprising 10 to 40 cytosine nucleotides. 
     In preferred embodiments, the poly(C) sequence, suitable located at the 3′ terminus, comprises 10 to 200 cytosine nucleotides, 10 to 100 cytosine nucleotides, 20 to 70 cytosine nucleotides, 20 to 60 cytosine nucleotides, or 10 to 40 cytosine nucleotides. In a particularly preferred embodiment, the poly(C) sequence comprises about cytosine nucleotides. 
     The term “poly(C) sequence” as used herein will be recognized and understood by the person of ordinary skill in the art, and are for example intended to be a sequence of cytosine nucleotides, typically located at the 3′-end of an RNA, of up to about 200 cytosine nucleotides. In the context of the present invention, a poly(C) sequence may be located within an mRNA or any other nucleic acid molecule, such as, e.g., in a DNA vector, for example, in a vector serving as template for the generation of an RNA, preferably an mRNA, e.g., by transcription of the vector. 
     Preferably, the poly(C) sequence in the RNA sequence of the present invention is derived from a DNA template by RNA in vitro transcription. In other embodiments, the poly(C) sequence is obtained in vitro by common methods of chemical synthesis without being necessarily transcribed from a DNA template. 
     In other embodiments, the artificial RNA of the invention does not comprises a poly(C) sequence as defined herein. 
     In preferred embodiments, the artificial RNA of the first aspect comprises at least one histone stem-loop. 
     The term “histone stem-loop” as used herein will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to nucleic acid sequences that are predominantly found in histone mRNAs. Exemplary histone stem-loop sequences are described in Lopez et al. (Davila Lopez et al, (2008), RNA, 14(1)). The stem-loops in histone pre-mRNAs are typically followed by a purine-rich sequence known as the histone downstream element (HDE). These pre-mRNAs are processed in the nucleus by a single endonucleolytic cleavage approximately 5 nucleotides downstream of the stem-loop, catalysed by the U7 snRNP through base pairing of the U7 snRNA with the HDE. 
     Histone stem-loop sequences/structures may suitably be selected from histone stem-loop sequences as disclosed in WO2012/019780, the disclosure relating to histone stem-loop sequences/structures incorporated herewith by reference. A histone stem-loop sequence that may be used within the present invention may preferably be derived from formulae (I) or (II) of the patent application WO2012/019780. According to a further preferred embodiment the RNA as defined herein may comprise at least one histone stem-loop sequence derived from at least one of the specific formulae (Ia) or (IIa) of the patent application WO2012/019780. 
     In particularly preferred embodiment, the artificial RNA of the invention comprises at least one histone stem-loop, wherein said histone stem-loop comprises a nucleic acid sequence according to SEQ ID NO: 39 or 40 or a fragments or variant thereof. 
     In other embodiments, the artificial RNA of the first aspect does not comprises a histone stem-loop as defined herein. 
     In further embodiments, the artificial RNA of the invention comprises a 3′-terminal sequence element. Said 3′-terminal sequence element has to be understood as a sequence element comprising a poly(A)sequence and a histone-stem-loop sequence, wherein said sequence element is located at the 3′ terminus of the artificial RNA of the invention. 
     In other embodiments, the artificial RNA of the invention may comprise a 3′-terminal sequence element according to SEQ ID NOs: 44-63 or 21322-21328 or a fragment or variant thereof. 
     In preferred embodiments, the artificial RNA of the invention comprises at least one pseudouridine (ψ) modified coding sequence. 
     Accordingly, in preferred embodiments, the artificial RNA of the invention, or the at least one coding sequence, comprises a nucleic acid sequence wherein at least one or more than one, preferably wherein all uracil nucleotides are replaced by pseudouridine (ψ) nucleotides. 
     In further preferred embodiments, the artificial RNA of the invention comprises at least one N1-methylpseudouridine (m1ψ) modified coding sequence. 
     Accordingly, in preferred embodiments, the artificial RNA of the invention, or the at least one coding sequence, comprises a nucleic acid sequence wherein at least one or more than one, preferably wherein all uracil nucleotides are replaced by N1-methylpseudouridine (m1P) nucleotides 
     In preferred embodiments of the first aspect, the artificial RNA, preferably mRNA comprises preferably in 5′- to 3-direction the following elements a)-i):
     a) 5′-cap structure, preferably as specified herein;   b) optionally, 5′-UTR as specified herein, preferably at least one selected from SEQ ID NOs: 1-22;   c) a ribosome binding site, preferably as specified herein   d) at least one coding sequence as specified herein, preferably as specified in Table 3 and Table 4;   e) 3′-UTR as specified herein, preferably at least one selected from SEQ ID NOs: 23-38;   f) optionally, a poly(A) sequence, preferably as specified herein;   g) optionally, a poly(C) sequence, preferably as specified herein;   h) optionally, a histone stem-loop, preferably as specified herein;   i) optionally, a 3′-terminal sequence element as specified herein, preferably according to according to SEQ ID NOs: 44-63, or 21322-21328; and   wherein optionally at least one or more than one, preferably wherein all uracil nucleotides are replaced by pseudouridine (L) nucleotides or N1-methylpseudouridine (m1ψ) nucleotides.   

     In further preferred embodiments of the first aspect, the artificial RNA, preferably mRNA comprises the following elements preferably in 5′- to 3-direction:
     a) 5′-cap structure, preferably as specified herein, most preferably a Cap1 structure;   b) a 3′-UTR and a 5′-UTR element according to a-1, a-4, c-1, e-4, g-2, i-2, or i-3 as specified herein;   c) a ribosome binding site, preferably as specified herein;   d) at least one coding sequence as specified herein, wherein said coding sequence is located between said 5′-UTR and said 3′-UTR, preferably downstream of said 5′-UTR and upstream of said 3′-UTR, wherein the coding sequence is preferably selected from any one specified in Table 3 and Table 4;   e) optionally, a poly(A) sequence, preferably as specified herein;   f) optionally, poly(C) sequence, preferably as specified herein;   g) optionally, histone stem-loop, preferably as specified herein;   h) optionally, a 3′-terminal sequence element as specified herein, preferably according to according to SEQ ID NOs: 44-63, 21322-21328, and   wherein optionally at least one or more than one, preferably wherein all uracil nucleotides are replaced by pseudouridine (ψ) nucleotides or N1-methylpseudouridine (m1ψ) nucleotides.   

     In further preferred embodiments of the first aspect, the artificial RNA, preferably mRNA comprises the following elements preferably in 5′- to 3-direction:
     a) 5′-cap structure, preferably as specified herein, most preferably a Cap1 structure;   b) a 3′-UTR and a 5′-UTR element according to a-1 or i-3 as specified herein;   c) a ribosome binding site, preferably as specified herein   d) at least one coding sequence as specified herein, wherein said coding sequence is located between said 5′-UTR and said 3′-UTR, preferably downstream of said 5′-UTR and upstream of said 3′-UTR, wherein the coding sequence is preferably selected from any one specified in Table 3 and Table 4;   e) optionally, a histone stem-loop, preferably as specified herein;   f) a poly(A) sequence, preferably comprising about 100 adenosine nucleotides;   g) optionally, a 3′-terminal sequence element as specified herein, preferably according to according to SEQ ID NOs: 21322-21328, and   wherein optionally at least one or more than one, preferably wherein all uracil nucleotides are replaced by pseudouridine (ψ) nucleotides or N1-methylpseudouridine (m1γ) nucleotides.   

     In further preferred embodiments of the first aspect, the artificial RNA, preferably mRNA comprises the following elements in 5′- to 3′-direction:
     a) 5′-cap structure, preferably as specified herein, most preferably a Cap1 structure;   b) a 3′-UTR and a 5′-UTR element according to a-1, a-4, c-1, e-4, g-2, i-2, or i-3 as specified herein;   c) a ribosome binding site, preferably as specified herein;   d) at least one coding sequence as specified herein, wherein said coding region is located between said 5′-UTR and said 3′-UTR, preferably downstream of said 5′-UTR and upstream of said 3′-UTR, wherein the coding sequence is preferably selected from any one of SEQ ID NOs: 69-77, 484-492, 899-906, 1268-1275, 1637-1644, 2006-2013, 2375-2382, 2744-2751, 3113-3120, 3482-3489, 3851-3858, 4220-4227, 4589-4596, 4958-4965, 5327-5334, 5696-5703, 6065-6072, 6434-6441, 6803-6810, 7172-7179, 7541-7548, 7910-7917, 11727-11734, 12096-12103, 12465-12472, 12834-12841, 13941-13948, 14310-14317, 14679-14686, 15048-15055, 15417-15424, 15786-15793, 13203-13210, 13572-13579, 16155-16162, 16524-16531, 16893-16900, 17262-17269, 17631-17638, 18000-18007, 18369-18376, 18738-18745, 19107-19114, 19476-19483, 21363-21384, 21389-21410 (or fragments or variants thereof);   e) a poly(A) sequence comprising about 64 adenosine;   f) a poly(C) sequence comprising about 30 cysteines;   g) a histone stem-loop according to SEQ ID NO: 39 or 40, and   wherein optionally at least one or more than one, preferably wherein all uracil nucleotides are replaced by pseudouridine (ψ) nucleotides or N1-methylpseudouridine (m1ψ) nucleotides.   

     In further preferred embodiments of the first aspect, the artificial RNA, preferably mRNA comprises the following elements in 5′- to 3′-direction:
     a) 5′-cap structure, preferably as specified herein, most preferably a Cap1 structure;   b) a 3′-UTR and a 5′-UTR element according to a-1, a-4, c-1, e-4, g-2, i-2, or i-3 as specified herein;   c) a ribosome binding site, preferably as specified herein;   d) at least one coding sequence as specified herein, wherein said coding region is located between said 5′-UTR and said 3′-UTR, preferably downstream of said 5′-UTR and upstream of said 3′-UTR, wherein the coding sequence is preferably selected from any one of SEQ ID NOs: 69-77, 484-492, 899-906, 1268-1275, 1637-1644, 2006-2013, 2375-2382, 2744-2751, 3113-3120, 3482-3489, 3851-3858, 4220-4227, 4589-4596, 4958-4965, 5327-5334, 5696-5703, 6065-6072, 6434-6441, 6803-6810, 7172-7179, 7541-7548, 7910-7917, 11727-11734, 12096-12103, 12465-12472, 12834-12841, 13941-13948, 14310-14317, 14679-14686, 15048-15055, 15417-15424, 15786-15793, 13203-13210, 13572-13579, 16155-16162, 16524-16531, 16893-16900, 17262-17269, 17631-17638, 18000-18007, 18369-18376, 18738-18745, 19107-19114, 19476-19483, 21363-21384, 21389-21410 (or fragments or variants thereof);   e) a poly(A) sequence comprising about 64 adenosine;   f) a histone stem-loop according to SEQ ID NO: 39 or 40, and   wherein optionally at least one or more than one, preferably wherein all uracil nucleotides are replaced by pseudouridine (ψ) nucleotides or N1-methylpseudouridine (m1ψ) nucleotides.   

     Preferred RSV polypeptide, nucleic acid, and mRNA sequences are provided in Table 5A, 5B and Table 6A, 6B. 
     In Table 5A and 5B, the protein designs are indicated in row 1. Therein, Columns A to J represent specific suitable constructs of the invention derived from RSV Fusion (F) protein, wherein Column A provides suitable sequences for F0, Column B provides suitable sequences for F-del, Column C provides suitable sequences for F0_DSCav1, Column D provides suitable sequences for F-del_DSCav1, Column E provides suitable sequences for F_DSCav1_mut1, Column F provides suitable sequences for F-del_DSCav1_mut1, Column G provides suitable sequences for F_DSCav1_mut2, Column H provides suitable sequences for F-del_DSCav1_mut2, Column I provides suitable sequences for F_DSCav1_mut3, Column J provides suitable sequences for F-del_DSCav1_mut3. 
     The protein designs are indicated in row 1 (Columns A to J), the specific protein SEQ ID NOs as provided in the sequence listing are in row 2 (“protein”). The SEQ ID NOs of corresponding coding sequences for each protein construct are provided in row 3 (“cds”, compare with Table 3 for different cds optimizations). Further information e.g. regarding the type of codon modified coding sequence (opt1, opt2, opt3, opt4, opt5, opt6, opt11 etc.) is provided in the &lt;223&gt; identifier of the respective SEQ ID NO in the sequence listing and in Table 3. The SEQ ID NOs of corresponding mRNA constructs comprising said coding sequences and suitable 3′-UTRs and 5′-UTRs according to the invention are provided in rows 4 to 47 (mRNA designs a-1 to i-3 as specified herein). In Table 5A, mRNA sequences derived from HRSV(A2) are provided, in Table 5B mRNA sequences derived from HRSV(Memphis-37) are provided. Further information e.g. regarding the type of coding sequence (wt, opt1, opt2, opt3, opt4, opt5, opt6, opt11 etc.) comprised in the mRNA constructs is provided in the &lt;223&gt; identifier of the respective SEQ ID NO in the sequence listing. 
     
       
         
           
               
             
               
                 TABLE 5A 
               
             
            
               
                   
               
               
                 Preferred mRNA constructs encoding RSV F (columns A-J), derived from HRSV(A2) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 1 
                   
                 A 
                 B 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 J 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 2 
                 Protein 
                 68 
                 483 
                 898 
                 1267 
                 1636 
                 2005 
                 2374 
                 2743 
                 3112 
                 3481 
               
               
                 3 
                 cds 
                 69-77, 
                 484- 
                 899- 
                 1268- 
                 1637- 
                 2006- 
                 2375- 
                 2744- 
                 3113- 
                 3482- 
               
               
                   
                   
                 21363 
                 492, 
                 906, 
                 1275, 
                 1644, 
                 2013, 
                 2382, 
                 2751, 
                 3120, 
                 3489, 
               
               
                   
                   
                   
                 21364 
                 21365 
                 21366 
                 21369 
                 21370 
                 21371 
                 21372 
                 21373 
                 21374 
               
               
                 4 
                 mRNA 
                 78-86, 
                 493- 
                 907- 
                 1276- 
                 1645- 
                 2014- 
                 2383- 
                 2752- 
                 3121- 
                 3490- 
               
               
                   
                 Design a-1 
                 21415- 
                 501, 
                 914, 
                 1283, 
                 1652, 
                 2021, 
                 2390, 
                 2759, 
                 3128, 
                 3497, 
               
               
                   
                   
                 21417, 
                 21418- 
                 21421- 
                 21424- 
                 21433- 
                 21436- 
                 21439- 
                 21442- 
                 21445- 
                 21448- 
               
               
                   
                   
                 21561- 
                 21420, 
                 21423, 
                 21426, 
                 21435, 
                 21438, 
                 21441, 
                 21444, 
                 21447, 
                 21450, 
               
               
                   
                   
                 21563 
                 21564- 
                 21567- 
                 21570- 
                 21579- 
                 21582- 
                 21585- 
                 21588- 
                 21591- 
                 21594- 
               
               
                   
                   
                   
                 21566 
                 21569 
                 21572 
                 21581 
                 21584 
                 21587 
                 21590 
                 21593 
                 21596 
               
               
                 5 
                 mRNA 
                 87-95 
                 502- 
                 915- 
                 1284- 
                 1653- 
                 2022- 
                 2391- 
                 2760- 
                 3129- 
                 3498- 
               
               
                   
                 Design a-2 
                   
                 510 
                 922 
                 1291 
                 1660 
                 2029 
                 2398 
                 2767 
                 3136 
                 3505 
               
               
                 6 
                 mRNA 
                  96-104 
                 511- 
                 923- 
                 1292- 
                 1661- 
                 2030- 
                 2399- 
                 2768- 
                 3137- 
                 3506- 
               
               
                   
                 Design a-3 
                   
                 519 
                 930 
                 1299 
                 1668 
                 2037 
                 2406 
                 2775 
                 3144 
                 3513 
               
               
                 7 
                 mRNA 
                 105-113 
                 520- 
                 931- 
                 1300- 
                 1669- 
                 2038- 
                 2407- 
                 2776- 
                 3145- 
                 3514- 
               
               
                   
                 Design a-4 
                   
                 528 
                 938 
                 1307 
                 1676 
                 2045 
                 2414 
                 2783 
                 3152 
                 3521 
               
               
                 8 
                 mRNA 
                 114-122 
                 529- 
                 939- 
                 1308- 
                 1677- 
                 2046- 
                 2415- 
                 2784- 
                 3153- 
                 3522- 
               
               
                   
                 Design a-5 
                   
                 537 
                 946 
                 1315 
                 1684 
                 2053 
                 2422 
                 2791 
                 3160 
                 3529 
               
               
                 9 
                 mRNA 
                 123-131 
                 538- 
                 947- 
                 1316- 
                 1685- 
                 2054- 
                 2423- 
                 2792- 
                 3161- 
                 3530- 
               
               
                   
                 Design b-1 
                   
                 546 
                 954 
                 1323 
                 1692 
                 2061 
                 2430 
                 2799 
                 3168 
                 3537 
               
               
                 10 
                 mRNA 
                 132-140 
                 547- 
                 955- 
                 1324- 
                 1693- 
                 2062- 
                 2431- 
                 2800- 
                 3169- 
                 3538- 
               
               
                   
                 Design b-2 
                   
                 555 
                 962 
                 1331 
                 1700 
                 2069 
                 2438 
                 2807 
                 3176 
                 3545 
               
               
                 11 
                 mRNA 
                 141-149 
                 556- 
                 963- 
                 1332- 
                 1701- 
                 2070- 
                 2439- 
                 2808- 
                 3177- 
                 3546- 
               
               
                   
                 Design b-3 
                   
                 564 
                 970 
                 1339 
                 1708 
                 2077 
                 2446 
                 2815 
                 3184 
                 3553 
               
               
                 12 
                 mRNA 
                 150-158 
                 565- 
                 971- 
                 1340- 
                 1709- 
                 2078- 
                 2447- 
                 2816- 
                 3185- 
                 3554- 
               
               
                   
                 Design b-4 
                   
                 573 
                 978 
                 1347 
                 1716 
                 2085 
                 2454 
                 2823 
                 3192 
                 3561 
               
               
                 13 
                 mRNA 
                 159-167 
                 574- 
                 979- 
                 1348- 
                 1717- 
                 2086- 
                 2455- 
                 2824- 
                 3193- 
                 3562- 
               
               
                   
                 Design b-5 
                   
                 582 
                 986 
                 1355 
                 1724 
                 2093 
                 2462 
                 2831 
                 3200 
                 3569 
               
               
                 14 
                 mRNA 
                 168-176 
                 583- 
                 987- 
                 1356- 
                 1725- 
                 2094- 
                 2463- 
                 2832- 
                 3201- 
                 3570- 
               
               
                   
                 Design c-1 
                   
                 591 
                 994 
                 1363 
                 1732 
                 2101 
                 2470 
                 2839 
                 3208 
                 3577 
               
               
                 15 
                 mRNA 
                 177-185 
                 592- 
                 995- 
                 1364- 
                 1733- 
                 2102- 
                 2471- 
                 2840- 
                 3209- 
                 3578- 
               
               
                   
                 Design c-2 
                   
                 600 
                 1002 
                 1371 
                 1740 
                 2109 
                 2478 
                 2847 
                 3216 
                 3585 
               
               
                 16 
                 mRNA 
                 186-194 
                 601- 
                 1003- 
                 1372- 
                 1741- 
                 2110- 
                 2479- 
                 2848- 
                 3217- 
                 3586- 
               
               
                   
                 Design c-3 
                   
                 609 
                 1010 
                 1379 
                 1748 
                 2117 
                 2486 
                 2855 
                 3224 
                 3593 
               
               
                 17 
                 mRNA 
                 195-203 
                 610- 
                 1011- 
                 1380- 
                 1749- 
                 2118- 
                 2487- 
                 2856- 
                 3225- 
                 3594- 
               
               
                   
                 Design c-4 
                   
                 618 
                 1018 
                 1387 
                 1756 
                 2125 
                 2494 
                 2863 
                 3232 
                 3601 
               
               
                 18 
                 mRNA 
                 204-212 
                 619- 
                 1019- 
                 1388- 
                 1757- 
                 2126- 
                 2495- 
                 2864- 
                 3233- 
                 3602- 
               
               
                   
                 Design c-5 
                   
                 627 
                 1026 
                 1395 
                 1764 
                 2133 
                 2502 
                 2871 
                 3240 
                 3609 
               
               
                 19 
                 mRNA 
                 213-221 
                 628- 
                 1027- 
                 1396- 
                 1765- 
                 2134- 
                 2503- 
                 2872- 
                 3241- 
                 3610- 
               
               
                   
                 Design d-1 
                   
                 636 
                 1034 
                 1403 
                 1772 
                 2141 
                 2510 
                 2879 
                 3248 
                 3617 
               
               
                 20 
                 mRNA 
                 222-230 
                 637- 
                 1035- 
                 1404- 
                 1773- 
                 2142- 
                 2511- 
                 2880- 
                 3249- 
                 3618- 
               
               
                   
                 Design d-2 
                   
                 645 
                 1042 
                 1411 
                 1780 
                 2149 
                 2518 
                 2887 
                 3256 
                 3625 
               
               
                 21 
                 mRNA 
                 231-239 
                 646- 
                 1043- 
                 1412- 
                 1781- 
                 2150- 
                 2519- 
                 2888- 
                 3257- 
                 3626- 
               
               
                   
                 Design d-3 
                   
                 654 
                 1050 
                 1419 
                 1788 
                 2157 
                 2526 
                 2895 
                 3264 
                 3633 
               
               
                 22 
                 mRNA 
                 240-248 
                 655- 
                 1051- 
                 1420- 
                 1789- 
                 2158- 
                 2527- 
                 2896- 
                 3265- 
                 3634- 
               
               
                   
                 Design d-4 
                   
                 663 
                 1058 
                 1427 
                 1796 
                 2165 
                 2534 
                 2903 
                 3272 
                 3641 
               
               
                 23 
                 mRNA 
                 249-257 
                 664- 
                 1059- 
                 1428- 
                 1797- 
                 2166- 
                 2535- 
                 2904- 
                 3273- 
                 3642- 
               
               
                   
                 Design d-5 
                   
                 672 
                 1066 
                 1435 
                 1804 
                 2173 
                 2542 
                 2911 
                 3280 
                 3649 
               
               
                 24 
                 mRNA 
                 258-266 
                 673- 
                 1067- 
                 1436- 
                 1805- 
                 2174- 
                 2543- 
                 2912- 
                 3281- 
                 3650- 
               
               
                   
                 Design e-1 
                   
                 681 
                 1074 
                 1443 
                 1812 
                 2181 
                 2550 
                 2919 
                 3288 
                 3657 
               
               
                 25 
                 mRNA 
                 267-275 
                 682- 
                 1075- 
                 1444- 
                 1813- 
                 2182- 
                 2551- 
                 2920- 
                 3289- 
                 3658- 
               
               
                   
                 Design e-2 
                   
                 690 
                 1082 
                 1451 
                 1820 
                 2189 
                 2558 
                 2927 
                 3296 
                 3665 
               
               
                 26 
                 mRNA 
                 276-284 
                 691- 
                 1083- 
                 1452- 
                 1821- 
                 2190- 
                 2559- 
                 2928- 
                 3297- 
                 3666- 
               
               
                   
                 Design e-3 
                   
                 699 
                 1090 
                 1459 
                 1828 
                 2197 
                 2566 
                 2935 
                 3304 
                 3673 
               
               
                 27 
                 mRNA 
                 285-293 
                 700- 
                 1091- 
                 1460- 
                 1829- 
                 2198- 
                 2567- 
                 2936- 
                 3305- 
                 3674- 
               
               
                   
                 Design e-4 
                   
                 708 
                 1098 
                 1467 
                 1836 
                 2205 
                 2574 
                 2943 
                 3312 
                 3681 
               
               
                 28 
                 mRNA 
                 294-302 
                 709- 
                 1099- 
                 1468- 
                 1837- 
                 2206- 
                 2575- 
                 2944- 
                 3313- 
                 3682- 
               
               
                   
                 Design e-5 
                   
                 717 
                 1106 
                 1475 
                 1844 
                 2213 
                 2582 
                 2951 
                 3320 
                 3689 
               
               
                 29 
                 mRNA 
                 303-311 
                 718- 
                 1107- 
                 1476- 
                 1845- 
                 2214- 
                 2583- 
                 2952- 
                 3321- 
                 3690- 
               
               
                   
                 Design e-6 
                   
                 726 
                 1114 
                 1483 
                 1852 
                 2221 
                 2590 
                 2959 
                 3328 
                 3697 
               
               
                 30 
                 mRNA 
                 312-320 
                 727- 
                 1115- 
                 1484- 
                 1853- 
                 2222- 
                 2591- 
                 2960- 
                 3329- 
                 3698- 
               
               
                   
                 Design f-1 
                   
                 735 
                 1122 
                 1491 
                 1860 
                 2229 
                 2598 
                 2967 
                 3336 
                 3705 
               
               
                 31 
                 mRNA 
                 321-329 
                 736- 
                 1123- 
                 1492- 
                 1861- 
                 2230- 
                 2599- 
                 2968- 
                 3337- 
                 3706- 
               
               
                   
                 Design f-2 
                   
                 744 
                 1130 
                 1499 
                 1868 
                 2237 
                 2606 
                 2975 
                 3344 
                 3713 
               
               
                 32 
                 mRNA 
                 330-338 
                 745- 
                 1131- 
                 1500- 
                 1869- 
                 2238- 
                 2607- 
                 2976- 
                 3345- 
                 3714- 
               
               
                   
                 Design f-3 
                   
                 753 
                 1138 
                 1507 
                 1876 
                 2245 
                 2614 
                 2983 
                 3352 
                 3721 
               
               
                 33 
                 mRNA 
                 339-347 
                 754- 
                 1139- 
                 1508- 
                 1877- 
                 2246- 
                 2615- 
                 2984- 
                 3353- 
                 3722- 
               
               
                   
                 Design f-4 
                   
                 762 
                 1146 
                 1515 
                 1884 
                 2253 
                 2622 
                 2991 
                 3360 
                 3729 
               
               
                 34 
                 mRNA 
                 348-356 
                 763- 
                 1147- 
                 1516- 
                 1885- 
                 2254- 
                 2623- 
                 2992- 
                 3361- 
                 3730- 
               
               
                   
                 Design f-5 
                   
                 771 
                 1154 
                 1523 
                 1892 
                 2261 
                 2630 
                 2999 
                 3368 
                 3737 
               
               
                 35 
                 mRNA 
                 357-365 
                 772- 
                 1155- 
                 1524- 
                 1893- 
                 2262- 
                 2631- 
                 3000- 
                 3369- 
                 3738- 
               
               
                   
                 Design g-1 
                   
                 780 
                 1162 
                 1531 
                 1900 
                 2269 
                 2638 
                 3007 
                 3376 
                 3745 
               
               
                 36 
                 mRNA 
                 366-374 
                 781- 
                 1163- 
                 1532- 
                 1901- 
                 2270- 
                 2639- 
                 3008- 
                 3377- 
                 3746- 
               
               
                   
                 Design g-2 
                   
                 789 
                 1170 
                 1539 
                 1908 
                 2277 
                 2646 
                 3015 
                 3384 
                 3753 
               
               
                 37 
                 mRNA 
                 375-383 
                 790- 
                 1171- 
                 1540- 
                 1909- 
                 2278- 
                 2647- 
                 3016- 
                 3385- 
                 3754- 
               
               
                   
                 Design g-3 
                   
                 798 
                 1178 
                 1547 
                 1916 
                 2285 
                 2654 
                 3023 
                 3392 
                 3761 
               
               
                 38 
                 mRNA 
                 384-392 
                 799- 
                 1179- 
                 1548- 
                 1917- 
                 2286- 
                 2655- 
                 3024- 
                 3393- 
                 3762- 
               
               
                   
                 Design g-4 
                   
                 807 
                 1186 
                 1555 
                 1924 
                 2293 
                 2662 
                 3031 
                 3400 
                 3769 
               
               
                 39 
                 mRNA 
                 393-401 
                 808- 
                 1187- 
                 1556- 
                 1925- 
                 2294- 
                 2663- 
                 3032- 
                 3401- 
                 3770- 
               
               
                   
                 Design g-5 
                   
                 816 
                 1194 
                 1563 
                 1932 
                 2301 
                 2670 
                 3039 
                 3408 
                 3777 
               
               
                 40 
                 mRNA 
                 402-410 
                 817- 
                 1195- 
                 1564- 
                 1933- 
                 2302- 
                 2671- 
                 3040- 
                 3409- 
                 3778- 
               
               
                   
                 Design h-1 
                   
                 825 
                 1202 
                 1571 
                 1940 
                 2309 
                 2678 
                 3047 
                 3416 
                 3785 
               
               
                 41 
                 mRNA 
                 411-419 
                 826- 
                 1203- 
                 1572- 
                 1941- 
                 2310- 
                 2679- 
                 3048- 
                 3417- 
                 3786- 
               
               
                   
                 Design h-2 
                   
                 834 
                 1210 
                 1579 
                 1948 
                 2317 
                 2686 
                 3055 
                 3424 
                 3793 
               
               
                 42 
                 mRNA 
                 420-428 
                 835- 
                 1211- 
                 1580- 
                 1949- 
                 2318- 
                 2687- 
                 3056- 
                 3425- 
                 3794- 
               
               
                   
                 Design h-3 
                   
                 843 
                 1218 
                 1587 
                 1956 
                 2325 
                 2694 
                 3063 
                 3432 
                 3801 
               
               
                 43 
                 mRNA 
                 429-437 
                 844- 
                 1219- 
                 1588- 
                 1957- 
                 2326- 
                 2695- 
                 3064- 
                 3433- 
                 3802- 
               
               
                   
                 Design h-4 
                   
                 852 
                 1226 
                 1595 
                 1964 
                 2333 
                 2702 
                 3071 
                 3440 
                 3809 
               
               
                 44 
                 mRNA 
                 438-446 
                 853- 
                 1227- 
                 1596- 
                 1965- 
                 2334- 
                 2703- 
                 3072- 
                 3441- 
                 3810- 
               
               
                   
                 Design h-5 
                   
                 861 
                 1234 
                 1603 
                 1972 
                 2341 
                 2710 
                 3079 
                 3448 
                 3817 
               
               
                 45 
                 mRNA 
                 447-455 
                 862- 
                 1235- 
                 1604- 
                 1973- 
                 2342- 
                 2711- 
                 3080- 
                 3449- 
                 3818- 
               
               
                   
                 Design i-1 
                   
                 870 
                 1242 
                 1611 
                 1980 
                 2349 
                 2718 
                 3087 
                 3456 
                 3825 
               
               
                 46 
                 mRNA 
                 456-473 
                 871- 
                 1243- 
                 1612- 
                 1981- 
                 2350- 
                 2719- 
                 3088- 
                 3457- 
                 3826- 
               
               
                   
                 Design i-2 
                   
                 888 
                 1258 
                 1627 
                 1996 
                 2365 
                 2734 
                 3103 
                 3472 
                 3841 
               
               
                 47 
                 mRNA 
                 474-482 
                 889- 
                 1259- 
                 1628- 
                 1997- 
                 2366- 
                 2735- 
                 3104- 
                 3473- 
                 3842- 
               
               
                   
                 Design i-3 
                   
                 897 
                 1266 
                 1635 
                 2004 
                 2373 
                 2742 
                 3111 
                 3480 
                 3849 
               
               
                 48 
                 mRNA 
                   
                   
                   
                 8278 
               
               
                   
                 Design i-4 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5B 
               
             
            
               
                   
               
               
                 Preferred mRNA constructs encoding RSV F (columns A-J), derived from HRSV(Memphis-37) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 1 
                   
                 A 
                 B 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 J 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 2 
                 Protein 
                 11726 
                 12095 
                 12464 
                 12833 
                 13940 
                 14309 
                 14678 
                 15047 
                 15416 
                 15785 
               
               
                 3 
                 cds 
                 11727- 
                 12096- 
                 12465- 
                 12834- 
                 13941- 
                 14310- 
                 14679- 
                 15048- 
                 15417- 
                 15786- 
               
               
                   
                   
                 11734, 
                 12103, 
                 12472, 
                 12841, 
                 13948, 
                 14317, 
                 14686, 
                 15055, 
                 15424, 
                 15793, 
               
               
                   
                   
                 21389 
                 21390 
                 21391 
                 21392 
                 21395 
                 21396 
                 21397 
                 21398 
                 21399 
                 21400 
               
               
                 4 
                 mRNA 
                 11735- 
                 12104- 
                 12473- 
                 12842- 
                 13949- 
                 14318- 
                 14687- 
                 15056- 
                 15425- 
                 15794- 
               
               
                   
                 Design a-1 
                 11742, 
                 12111, 
                 12480, 
                 12849, 
                 13956, 
                 14325, 
                 14694, 
                 15063, 
                 15432, 
                 15801, 
               
               
                   
                   
                 21489, 
                 21491, 
                 21493- 
                 21496- 
                 21505- 
                 21508- 
                 21511- 
                 21514- 
                 21517- 
                 21520- 
               
               
                   
                   
                 21490, 
                 21492, 
                 21495, 
                 21498, 
                 21507, 
                 21510, 
                 21513, 
                 21516, 
                 21519, 
                 21522, 
               
               
                   
                   
                 21635, 
                 21637, 
                 21639- 
                 21642- 
                 21651- 
                 21654- 
                 21657- 
                 21660- 
                 21663- 
                 21666- 
               
               
                   
                   
                 21636 
                 21638 
                 21641 
                 21644 
                 21653 
                 21656 
                 21659 
                 21662 
                 21665 
                 21668 
               
               
                 5 
                 mRNA 
                 11743- 
                 12112- 
                 12481- 
                 12850- 
                 13957- 
                 14326- 
                 14695- 
                 15064- 
                 15433- 
                 15802- 
               
               
                   
                 Design a-2 
                 11750 
                 12119 
                 12488 
                 12857 
                 13964 
                 14333 
                 14702 
                 15071 
                 15440 
                 15809 
               
               
                 6 
                 mRNA 
                 11751- 
                 12120- 
                 12489- 
                 12858- 
                 13965- 
                 14334- 
                 14703- 
                 15072- 
                 15441- 
                 15810- 
               
               
                   
                 Design a-3 
                 11758 
                 12127 
                 12496 
                 12865 
                 13972 
                 14341 
                 14710 
                 15079 
                 15448 
                 15817 
               
               
                 7 
                 mRNA 
                 11759- 
                 12128- 
                 12497- 
                 12866- 
                 13973- 
                 14342- 
                 14711- 
                 15080- 
                 15449- 
                 15818- 
               
               
                   
                 Design a-4 
                 11766 
                 12135 
                 12504 
                 12873 
                 13980 
                 14349 
                 14718 
                 15087 
                 15456 
                 15825 
               
               
                 8 
                 mRNA 
                 11767- 
                 12136- 
                 12505- 
                 12874- 
                 13981- 
                 14350- 
                 14719- 
                 15088- 
                 15457- 
                 15826- 
               
               
                   
                 Design a-5 
                 11774 
                 12143 
                 12512 
                 12881 
                 13988 
                 14357 
                 14726 
                 15095 
                 15464 
                 15833 
               
               
                 9 
                 mRNA 
                 11775- 
                 12144- 
                 12513- 
                 12882- 
                 13989- 
                 14358- 
                 14727- 
                 15096- 
                 15465- 
                 15834- 
               
               
                   
                 Design b-1 
                 11782 
                 12151 
                 12520 
                 12889 
                 13996 
                 14365 
                 14734 
                 15103 
                 15472 
                 15841 
               
               
                 10 
                 mRNA 
                 11783- 
                 12152- 
                 12521- 
                 12890- 
                 13997- 
                 14366- 
                 14735- 
                 15104- 
                 15473- 
                 15842- 
               
               
                   
                 Design b-2 
                 11790 
                 12159 
                 12528 
                 12897 
                 14004 
                 14373 
                 14742 
                 15111 
                 15480 
                 15849 
               
               
                 11 
                 mRNA 
                 11791- 
                 12160- 
                 12529- 
                 12898- 
                 14005- 
                 14374- 
                 14743- 
                 15112- 
                 15481- 
                 15850- 
               
               
                   
                 Design b-3 
                 11798 
                 12167 
                 12536 
                 12905 
                 14012 
                 14381 
                 14750 
                 15119 
                 15488 
                 15857 
               
               
                 12 
                 mRNA 
                 11799- 
                 12168- 
                 12537- 
                 12906- 
                 14013- 
                 14382- 
                 14751- 
                 15120- 
                 15489- 
                 15858- 
               
               
                   
                 Design b-4 
                 11806 
                 12175 
                 12544 
                 12913 
                 14020 
                 14389 
                 14758 
                 15127 
                 15496 
                 15865 
               
               
                 13 
                 mRNA 
                 11807- 
                 12176- 
                 12545- 
                 12914- 
                 14021- 
                 14390- 
                 14759- 
                 15128- 
                 15497- 
                 15866- 
               
               
                   
                 Design b-5 
                 11814 
                 12183 
                 12552 
                 12921 
                 14028 
                 14397 
                 14766 
                 15135 
                 15504 
                 15873 
               
               
                 14 
                 mRNA 
                 11815- 
                 12184- 
                 12553- 
                 12922- 
                 14029- 
                 14398- 
                 14767- 
                 15136- 
                 15505- 
                 15874- 
               
               
                   
                 Design c-1 
                 11822 
                 12191 
                 12560 
                 12929 
                 14036 
                 14405 
                 14774 
                 15143 
                 15512 
                 15881 
               
               
                 15 
                 mRNA 
                 11823- 
                 12192- 
                 12561- 
                 12930- 
                 14037- 
                 14406- 
                 14775- 
                 15144- 
                 15513- 
                 15882- 
               
               
                   
                 Design c-2 
                 11830 
                 12199 
                 12568 
                 12937 
                 14044 
                 14413 
                 14782 
                 15151 
                 15520 
                 15889 
               
               
                 16 
                 mRNA 
                 11831- 
                 12200- 
                 12569- 
                 12938- 
                 14045- 
                 14414- 
                 14783- 
                 15152- 
                 15521- 
                 15890- 
               
               
                   
                 Design c-3 
                 11838 
                 12207 
                 12576 
                 12945 
                 14052 
                 14421 
                 14790 
                 15159 
                 15528 
                 15897 
               
               
                 17 
                 mRNA 
                 11839- 
                 12208- 
                 12577- 
                 12946- 
                 14053- 
                 14422- 
                 14791- 
                 15160- 
                 15529- 
                 15898- 
               
               
                   
                 Design c-4 
                 11846 
                 12215 
                 12584 
                 12953 
                 14060 
                 14429 
                 14798 
                 15167 
                 15536 
                 15905 
               
               
                 18 
                 mRNA 
                 11847- 
                 12216- 
                 12585- 
                 12954- 
                 14061- 
                 14430- 
                 14799- 
                 15168- 
                 15537- 
                 15906- 
               
               
                   
                 Design c-5 
                 11854 
                 12223 
                 12592 
                 12961 
                 14068 
                 14437 
                 14806 
                 15175 
                 15544 
                 15913 
               
               
                 19 
                 mRNA 
                 11855- 
                 12224- 
                 12593- 
                 12962- 
                 14069- 
                 14438- 
                 14807- 
                 15176- 
                 15545- 
                 15914- 
               
               
                   
                 Design d-1 
                 11862 
                 12231 
                 12600 
                 12969 
                 14076 
                 14445 
                 14814 
                 15183 
                 15552 
                 15921 
               
               
                 20 
                 mRNA 
                 11863- 
                 12232- 
                 12601- 
                 12970- 
                 14077- 
                 14446- 
                 14815- 
                 15184- 
                 15553- 
                 15922- 
               
               
                   
                 Design d-2 
                 11870 
                 12239 
                 12608 
                 12977 
                 14084 
                 14453 
                 14822 
                 15191 
                 15560 
                 15929 
               
               
                 21 
                 mRNA 
                 11871- 
                 12240- 
                 12609- 
                 12978- 
                 14085- 
                 14454- 
                 14823- 
                 15192- 
                 15561- 
                 15930- 
               
               
                   
                 Design d-3 
                 11878 
                 12247 
                 12616 
                 12985 
                 14092 
                 14461 
                 14830 
                 15199 
                 15568 
                 15937 
               
               
                 22 
                 mRNA 
                 11879- 
                 12248- 
                 12617- 
                 12986- 
                 14093- 
                 14462- 
                 14831- 
                 15200- 
                 15569- 
                 15938- 
               
               
                   
                 Design d-4 
                 11886 
                 12255 
                 12624 
                 12993 
                 14100 
                 14469 
                 14838 
                 15207 
                 15576 
                 15945 
               
               
                 23 
                 mRNA 
                 11887- 
                 12256- 
                 12625- 
                 12994- 
                 14101- 
                 14470- 
                 14839- 
                 15208- 
                 15577- 
                 15946- 
               
               
                   
                 Design d-5 
                 11894 
                 12263 
                 12632 
                 13001 
                 14108 
                 14477 
                 14846 
                 15215 
                 15584 
                 15953 
               
               
                 24 
                 mRNA 
                 11895- 
                 12264- 
                 12633- 
                 13002- 
                 14109- 
                 14478- 
                 14847- 
                 15216- 
                 15585- 
                 15954- 
               
               
                   
                 Design e-1 
                 11902 
                 12271 
                 12640 
                 13009 
                 14116 
                 14485 
                 14854 
                 15223 
                 15592 
                 15961 
               
               
                 25 
                 mRNA 
                 11903- 
                 12272- 
                 12641- 
                 13010- 
                 14117- 
                 14486- 
                 14855- 
                 15224- 
                 15593- 
                 15962- 
               
               
                   
                 Design e-2 
                 11910 
                 12279 
                 12648 
                 13017 
                 14124 
                 14493 
                 14862 
                 15231 
                 15600 
                 15969 
               
               
                 26 
                 mRNA 
                 11911- 
                 12280- 
                 12649- 
                 13018- 
                 14125- 
                 14494- 
                 14863- 
                 15232- 
                 15601- 
                 15970- 
               
               
                   
                 Design e-3 
                 11918 
                 12287 
                 12656 
                 13025 
                 14132 
                 14501 
                 14870 
                 15239 
                 15608 
                 15977 
               
               
                 27 
                 mRNA 
                 11919- 
                 12288- 
                 12657- 
                 13026- 
                 14133- 
                 14502- 
                 14871- 
                 15240- 
                 15609- 
                 15978- 
               
               
                   
                 Design e-4 
                 11926 
                 12295 
                 12664 
                 13033 
                 14140 
                 14509 
                 14878 
                 15247 
                 15616 
                 15985 
               
               
                 28 
                 mRNA 
                 11927- 
                 12296- 
                 12665- 
                 13034- 
                 14141- 
                 14510- 
                 14879- 
                 15248- 
                 15617- 
                 15986- 
               
               
                   
                 Design e-5 
                 11934 
                 12303 
                 12672 
                 13041 
                 14148 
                 14517 
                 14886 
                 15255 
                 15624 
                 15993 
               
               
                 29 
                 mRNA 
                 11935- 
                 12304- 
                 12673- 
                 13042- 
                 14149- 
                 14518- 
                 14887- 
                 15256- 
                 15625- 
                 15994- 
               
               
                   
                 Design e-6 
                 11942 
                 12311 
                 12680 
                 13049 
                 14156 
                 14525 
                 14894 
                 15263 
                 15632 
                 16001 
               
               
                 30 
                 mRNA 
                 11943- 
                 12312- 
                 12681- 
                 13050- 
                 14157- 
                 14526- 
                 14895- 
                 15264- 
                 15633- 
                 16002- 
               
               
                   
                 Design f-1 
                 11950 
                 12319 
                 12688 
                 13057 
                 14164 
                 14533 
                 14902 
                 15271 
                 15640 
                 16009 
               
               
                 31 
                 mRNA 
                 11951- 
                 12320- 
                 12689- 
                 13058- 
                 14165- 
                 14534- 
                 14903- 
                 15272- 
                 15641- 
                 16010- 
               
               
                   
                 Design f-2 
                 11958 
                 12327 
                 12696 
                 13065 
                 14172 
                 14541 
                 14910 
                 15279 
                 15648 
                 16017 
               
               
                 32 
                 mRNA 
                 11959- 
                 12328- 
                 12697- 
                 13066- 
                 14173- 
                 14542- 
                 14911- 
                 15280- 
                 15649- 
                 16018- 
               
               
                   
                 Design f-3 
                 11966 
                 12335 
                 12704 
                 13073 
                 14180 
                 14549 
                 14918 
                 15287 
                 15656 
                 16025 
               
               
                 33 
                 mRNA 
                 11967- 
                 12336- 
                 12705- 
                 13074- 
                 14181- 
                 14550- 
                 14919- 
                 15288- 
                 15657- 
                 16026- 
               
               
                   
                 Design f-4 
                 11974 
                 12343 
                 12712 
                 13081 
                 14188 
                 14557 
                 14926 
                 15295 
                 15664 
                 16033 
               
               
                 34 
                 mRNA 
                 11975- 
                 12344- 
                 12713- 
                 13082- 
                 14189- 
                 14558- 
                 14927- 
                 15296- 
                 15665- 
                 16034- 
               
               
                   
                 Design f-5 
                 11982 
                 12351 
                 12720 
                 13089 
                 14196 
                 14565 
                 14934 
                 15303 
                 15672 
                 16041 
               
               
                 35 
                 mRNA 
                 11983- 
                 12352- 
                 12721- 
                 13090- 
                 14197- 
                 14566- 
                 14935- 
                 15304- 
                 15673- 
                 16042- 
               
               
                   
                 Design g-1 
                 11990 
                 12359 
                 12728 
                 13097 
                 14204 
                 14573 
                 14942 
                 15311 
                 15680 
                 16049 
               
               
                 36 
                 mRNA 
                 11991- 
                 12360- 
                 12729- 
                 13098- 
                 14205- 
                 14574- 
                 14943- 
                 15312- 
                 15681- 
                 16050- 
               
               
                   
                 Design g-2 
                 11998 
                 12367 
                 12736 
                 13105 
                 14212 
                 14581 
                 14950 
                 15319 
                 15688 
                 16057 
               
               
                 37 
                 mRNA 
                 11999- 
                 12368- 
                 12737- 
                 13106- 
                 14213- 
                 14582- 
                 14951- 
                 15320- 
                 15689- 
                 16058- 
               
               
                   
                 Design g-3 
                 12006 
                 12375 
                 12744 
                 13113 
                 14220 
                 14589 
                 14958 
                 15327 
                 15696 
                 16065 
               
               
                 38 
                 mRNA 
                 12007- 
                 12376- 
                 12745- 
                 13114- 
                 14221- 
                 14590- 
                 14959- 
                 15328- 
                 15697- 
                 16066- 
               
               
                   
                 Design g-4 
                 12014 
                 12383 
                 12752 
                 13121 
                 14228 
                 14597 
                 14966 
                 15335 
                 15704 
                 16073 
               
               
                 39 
                 mRNA 
                 12015- 
                 12384- 
                 12753- 
                 13122- 
                 14229- 
                 14598- 
                 14967- 
                 15336- 
                 15705- 
                 16074- 
               
               
                   
                 Design g-5 
                 12022 
                 12391 
                 12760 
                 13129 
                 14236 
                 14605 
                 14974 
                 15343 
                 15712 
                 16081 
               
               
                 40 
                 mRNA 
                 12023- 
                 12392- 
                 12761- 
                 13130- 
                 14237- 
                 14606- 
                 14975- 
                 15344- 
                 15713- 
                 16082- 
               
               
                   
                 Design h-1 
                 12030 
                 12399 
                 12768 
                 13137 
                 14244 
                 14613 
                 14982 
                 15351 
                 15720 
                 16089 
               
               
                 41 
                 mRNA 
                 12031- 
                 12400- 
                 12769- 
                 13138- 
                 14245- 
                 14614- 
                 14983- 
                 15352- 
                 15721- 
                 16090- 
               
               
                   
                 Design h-2 
                 12038 
                 12407 
                 12776 
                 13145 
                 14252 
                 14621 
                 14990 
                 15359 
                 15728 
                 16097 
               
               
                 42 
                 mRNA 
                 12039- 
                 12408- 
                 12777- 
                 13146- 
                 14253- 
                 14622- 
                 14991- 
                 15360- 
                 15729- 
                 16098- 
               
               
                   
                 Design h-3 
                 12046 
                 12415 
                 12784 
                 13153 
                 14260 
                 14629 
                 14998 
                 15367 
                 15736 
                 16105 
               
               
                 43 
                 mRNA 
                 12047- 
                 12416- 
                 12785- 
                 13154- 
                 14261- 
                 14630- 
                 14999- 
                 15368- 
                 15737- 
                 16106- 
               
               
                   
                 Design h-4 
                 12054 
                 12423 
                 12792 
                 13161 
                 14268 
                 14637 
                 15006 
                 15375 
                 15744 
                 16113 
               
               
                 44 
                 mRNA 
                 12055- 
                 12424- 
                 12793- 
                 13162- 
                 14269- 
                 14638- 
                 15007- 
                 15376- 
                 15745- 
                 16114- 
               
               
                   
                 Design h-5 
                 12062 
                 12431 
                 12800 
                 13169 
                 14276 
                 14645 
                 15014 
                 15383 
                 15752 
                 16121 
               
               
                 45 
                 mRNA 
                 12063- 
                 12432- 
                 12801- 
                 13170- 
                 14277- 
                 14646- 
                 15015- 
                 15384- 
                 15753- 
                 16122- 
               
               
                   
                 Design i-1 
                 12070 
                 12439 
                 12808 
                 13177 
                 14284 
                 14653 
                 15022 
                 15391 
                 15760 
                 16129 
               
               
                 46 
                 mRNA 
                 12071- 
                 12440- 
                 12809- 
                 13178- 
                 14285- 
                 14654- 
                 15023- 
                 15392- 
                 15761- 
                 16130- 
               
               
                   
                 Design i-2 
                 12086 
                 12455 
                 12824 
                 13193 
                 14300 
                 14669 
                 15038 
                 15407 
                 15776 
                 16145 
               
               
                 47 
                 mRNA 
                 12087- 
                 12456- 
                 12825- 
                 13194- 
                 14301- 
                 14670- 
                 15039- 
                 15408- 
                 15777- 
                 16146- 
               
               
                   
                 Design i-3 
                 12094 
                 12463 
                 12832 
                 13201 
                 14308 
                 14677 
                 15046 
                 15415 
                 15784 
                 16153 
               
               
                   
               
            
           
         
       
     
     In Table 6A and 6B, the protein designs are indicated in row 1. Therein, Columns K to V represent specific suitable constructs of the invention derived from RSV Fusion (F) protein, wherein Column K provides suitable sequences for F_DSCav1_mut0, Column L provides suitable sequences for F-del_DSCav1_mut0, Column M provides suitable sequences for F_DSCav1_mut4, Column N provides suitable sequences for F-del_DSCav1_mut4, Column O provides suitable sequences for F_DSCav1_mut5, Column P provides suitable sequences for F-del_DSCav1_mut5, Column Q provides suitable sequences for F_DSCav1_mut6, Column R provides suitable sequences for F-del_DSCav1_mut6, Column S provides suitable sequences for F_DSCav1_mut7, Column T provides suitable sequences for F-del_DSCav1_mut7, Column U provides suitable sequences for F_DSCav1_mut8, Column V provides suitable sequences for F-del_DSCav1_mut8. 
     The protein designs are indicated in the first row (Columns K to V), the specific protein SEQ ID NOs as provided in the sequence listing are in row 2, “PRT”. The SEQ ID NOs of corresponding coding sequences for each protein construct are provided in row 3, “cds” (compare with Table 4 for different cds optimizations). Further information e.g. regarding the type of codon modified coding sequence (opt1, opt2, opt3, opt4, opt5, opt6, opt11 etc.) is provided in the &lt;223&gt; identifier of the respective SEQ ID NO in the sequence listing and in Table 4. The SEQ ID NOs of corresponding mRNA constructs comprising said coding sequences and suitable 3′-UTRs and 5′-UTRs according to the invention are provided in each following row (mRNA designs “a-1” to “i-3” as specified herein). 
     In Table 6A, mRNA sequences derived from HRSV(A2) are provided, in Table 6B mRNA sequences derived from HRSV(Memphis-37) are provided 
     Further information e.g. regarding the type of coding sequence (wt, opt1, opt2, opt3, opt4, opt5, opt6, opt11 etc.) comprised in the mRNA constructs is provided in the &lt;223&gt; identifier of the respective SEQ ID NO in the sequence listing. 
     
       
         
           
               
             
               
                 TABLE 6A 
               
             
            
               
                   
               
               
                 Preferred mRNA constructs encoding RSV F (column K-V), derived from HRSV(A2) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 K 
                 L 
                 M 
                 N 
                 O 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 U 
                 V 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 PRT 
                 3850 
                 4219 
                 4588 
                 4957 
                 5326 
                 5695 
                 6064 
                 6433 
                 6802 
                 7171 
                 7540 
                 7909 
               
               
                 cds 
                 3851- 
                 4220- 
                 4589- 
                 4958- 
                 5327- 
                 5696- 
                 6065- 
                 6434- 
                 6803- 
                 7172- 
                 7541- 
                 7910- 
               
               
                   
                 3858, 
                 4227, 
                 4596, 
                 4965, 
                 5334, 
                 5703, 
                 6072, 
                 6441, 
                 6810, 
                 7179, 
                 7548, 
                 7917, 
               
               
                   
                 21367 
                 21368 
                 21375 
                 21376 
                 21377 
                 21378 
                 21379 
                 21380 
                 21381 
                 21382 
                 21383 
                 21384 
               
               
                 a-1 
                 3859- 
                 4228- 
                 4597- 
                 4966- 
                 5335- 
                 5704- 
                 6073- 
                 6442- 
                 6811- 
                 7180- 
                 7549- 
                 7918- 
               
               
                   
                 3866, 
                 4235, 
                 4604, 
                 4973, 
                 5342, 
                 5711, 
                 6080, 
                 6449, 
                 6818, 
                 7187, 
                 7556, 
                 7925, 
               
               
                   
                 21427- 
                 21430- 
                 21451- 
                 21454- 
                 21457- 
                 21460- 
                 21463- 
                 21466- 
                 21469- 
                 21472- 
                 21475- 
                 21478- 
               
               
                   
                 21429, 
                 21432, 
                 21453, 
                 21456, 
                 21459, 
                 21462, 
                 21465, 
                 21468, 
                 21471, 
                 21474, 
                 21477, 
                 21480, 
               
               
                   
                 21573- 
                 21576- 
                 21597- 
                 21600- 
                 21603- 
                 21606- 
                 21609- 
                 21612- 
                 21615- 
                 21618- 
                 21621- 
                 21624- 
               
               
                   
                 21575 
                 21578 
                 21599 
                 21602 
                 21605 
                 21608 
                 21611 
                 21614 
                 21617 
                 21620 
                 21623 
                 21626 
               
               
                 a-2 
                 3867- 
                 4236- 
                 4605- 
                 4974- 
                 5343- 
                 5712- 
                 6081- 
                 6450- 
                 6819- 
                 7188- 
                 7557- 
                 7926- 
               
               
                   
                 3874 
                 4243 
                 4612 
                 4981 
                 5350 
                 5719 
                 6088 
                 6457 
                 6826 
                 7195 
                 7564 
                 7933 
               
               
                 a-3 
                 3875- 
                 4244- 
                 4613- 
                 4982- 
                 5351- 
                 5720- 
                 6089- 
                 6458- 
                 6827- 
                 7196- 
                 7565- 
                 7934- 
               
               
                   
                 3882 
                 4251 
                 4620 
                 4989 
                 5358 
                 5727 
                 6096 
                 6465 
                 6834 
                 7203 
                 7572 
                 7941 
               
               
                 a-4 
                 3883- 
                 4252- 
                 4621- 
                 4990- 
                 5359- 
                 5728- 
                 6097- 
                 6466- 
                 6835- 
                 7204- 
                 7573- 
                 7942- 
               
               
                   
                 3890 
                 4259 
                 4628 
                 4997 
                 5366 
                 5735 
                 6104 
                 6473 
                 6842 
                 7211 
                 7580 
                 7949 
               
               
                 a-5 
                 3891- 
                 4260- 
                 4629- 
                 4998- 
                 5367- 
                 5736- 
                 6105- 
                 6474- 
                 6843- 
                 7212- 
                 7581- 
                 7950- 
               
               
                   
                 3898 
                 4267 
                 4636 
                 5005 
                 5374 
                 5743 
                 6112 
                 6481 
                 6850 
                 7219 
                 7588 
                 7957 
               
               
                 b-1 
                 3899- 
                 4268- 
                 4637- 
                 5006- 
                 5375- 
                 5744- 
                 6113- 
                 6482- 
                 6851- 
                 7220- 
                 7589- 
                 7958- 
               
               
                   
                 3906 
                 4275 
                 4644 
                 5013 
                 5382 
                 5751 
                 6120 
                 6489 
                 6858 
                 7227 
                 7596 
                 7965 
               
               
                 b-2 
                 3907- 
                 4276- 
                 4645- 
                 5014- 
                 5383- 
                 5752- 
                 6121- 
                 6490- 
                 6859- 
                 7228- 
                 7597- 
                 7966- 
               
               
                   
                 3914 
                 4283 
                 4652 
                 5021 
                 5390 
                 5759 
                 6128 
                 6497 
                 6866 
                 7235 
                 7604 
                 7973 
               
               
                 b-3 
                 3915- 
                 4284- 
                 4653- 
                 5022- 
                 5391- 
                 5760- 
                 6129- 
                 6498- 
                 6867- 
                 7236- 
                 7605- 
                 7974- 
               
               
                   
                 3922 
                 4291 
                 4660 
                 5029 
                 5398 
                 5767 
                 6136 
                 6505 
                 6874 
                 7243 
                 7612 
                 7981 
               
               
                 b-4 
                 3923- 
                 4292- 
                 4661- 
                 5030- 
                 5399- 
                 5768- 
                 6137- 
                 6506- 
                 6875- 
                 7244- 
                 7613- 
                 7982- 
               
               
                   
                 3930 
                 4299 
                 4668 
                 5037 
                 5406 
                 5775 
                 6144 
                 6513 
                 6882 
                 7251 
                 7620 
                 7989 
               
               
                 b-5 
                 3931- 
                 4300- 
                 4669- 
                 5038- 
                 5407- 
                 5776- 
                 6145- 
                 6514- 
                 6883- 
                 7252- 
                 7621- 
                 7990- 
               
               
                   
                 3938 
                 4307 
                 4676 
                 5045 
                 5414 
                 5783 
                 6152 
                 6521 
                 6890 
                 7259 
                 7628 
                 7997 
               
               
                 c-1 
                 3939- 
                 4308- 
                 4677- 
                 5046- 
                 5415- 
                 5784- 
                 6153- 
                 6522- 
                 6891- 
                 7260- 
                 7629- 
                 7998- 
               
               
                   
                 3946 
                 4315 
                 4684 
                 5053 
                 5422 
                 5791 
                 6160 
                 6529 
                 6898 
                 7267 
                 7636 
                 8005 
               
               
                 c-2 
                 3947- 
                 4316- 
                 4685- 
                 5054- 
                 5423- 
                 5792- 
                 6161- 
                 6530- 
                 6899- 
                 7268- 
                 7637- 
                 8006- 
               
               
                   
                 3954 
                 4323 
                 4692 
                 5061 
                 5430 
                 5799 
                 6168 
                 6537 
                 6906 
                 7275 
                 7644 
                 8013 
               
               
                 c-3 
                 3955- 
                 4324- 
                 4693- 
                 5062- 
                 5431- 
                 5800- 
                 6169- 
                 6538- 
                 6907- 
                 7276- 
                 7645- 
                 8014- 
               
               
                   
                 3962 
                 4331 
                 4700 
                 5069 
                 5438 
                 5807 
                 6176 
                 6545 
                 6914 
                 7283 
                 7652 
                 8021 
               
               
                 c-4 
                 3963- 
                 4332- 
                 4701- 
                 5070- 
                 5439- 
                 5808- 
                 6177- 
                 6546- 
                 6915- 
                 7284- 
                 7653- 
                 8022- 
               
               
                   
                 3970 
                 4339 
                 4708 
                 5077 
                 5446 
                 5815 
                 6184 
                 6553 
                 6922 
                 7291 
                 7660 
                 8029 
               
               
                 c-5 
                 3971- 
                 4340- 
                 4709- 
                 5078- 
                 5447- 
                 5816- 
                 6185- 
                 6554- 
                 6923- 
                 7292- 
                 7661- 
                 8030- 
               
               
                   
                 3978 
                 4347 
                 4716 
                 5085 
                 5454 
                 5823 
                 6192 
                 6561 
                 6930 
                 7299 
                 7668 
                 8037 
               
               
                 d-1 
                 3979- 
                 4348- 
                 4717- 
                 5086- 
                 5455- 
                 5824- 
                 6193- 
                 6562- 
                 6931- 
                 7300- 
                 7669- 
                 8038- 
               
               
                   
                 3986 
                 4355 
                 4724 
                 5093 
                 5462 
                 5831 
                 6200 
                 6569 
                 6938 
                 7307 
                 7676 
                 8045 
               
               
                 d-2 
                 3987- 
                 4356- 
                 4725- 
                 5094- 
                 5463- 
                 5832- 
                 6201- 
                 6570- 
                 6939- 
                 7308- 
                 7677- 
                 8046- 
               
               
                   
                 3994 
                 4363 
                 4732 
                 5101 
                 5470 
                 5839 
                 6208 
                 6577 
                 6946 
                 7315 
                 7684 
                 8053 
               
               
                 d-3 
                 3995- 
                 4364- 
                 4733- 
                 5102- 
                 5471- 
                 5840- 
                 6209- 
                 6578- 
                 6947- 
                 7316- 
                 7685- 
                 8054- 
               
               
                   
                 4002 
                 4371 
                 4740 
                 5109 
                 5478 
                 5847 
                 6216 
                 6585 
                 6954 
                 7323 
                 7692 
                 8061 
               
               
                 d-4 
                 4003- 
                 4372- 
                 4741- 
                 5110- 
                 5479- 
                 5848- 
                 6217- 
                 6586- 
                 6955- 
                 7324- 
                 7693- 
                 8062- 
               
               
                   
                 4010 
                 4379 
                 4748 
                 5117 
                 5486 
                 5855 
                 6224 
                 6593 
                 6962 
                 7331 
                 7700 
                 8069 
               
               
                 d-5 
                 4011- 
                 4380- 
                 4749- 
                 5118- 
                 5487- 
                 5856- 
                 6225- 
                 6594- 
                 6963- 
                 7332- 
                 7701- 
                 8070- 
               
               
                   
                 4018 
                 4387 
                 4756 
                 5125 
                 5494 
                 5863 
                 6232 
                 6601 
                 6970 
                 7339 
                 7708 
                 8077 
               
               
                 e-1 
                 4019- 
                 4388- 
                 4757- 
                 5126- 
                 5495- 
                 5864- 
                 6233- 
                 6602- 
                 6971- 
                 7340- 
                 7709- 
                 8078- 
               
               
                   
                 4026 
                 4395 
                 4764 
                 5133 
                 5502 
                 5871 
                 6240 
                 6609 
                 6978 
                 7347 
                 7716 
                 8085 
               
               
                 e-2 
                 4027- 
                 4396- 
                 4765- 
                 5134- 
                 5503- 
                 5872- 
                 6241- 
                 6610- 
                 6979- 
                 7348- 
                 7717- 
                 8086- 
               
               
                   
                 4034 
                 4403 
                 4772 
                 5141 
                 5510 
                 5879 
                 6248 
                 6617 
                 6986 
                 7355 
                 7724 
                 8093 
               
               
                 e-3 
                 4035- 
                 4404- 
                 4773- 
                 5142- 
                 5511- 
                 5880- 
                 6249- 
                 6618- 
                 6987- 
                 7356- 
                 7725- 
                 8094- 
               
               
                   
                 4042 
                 4411 
                 4780 
                 5149 
                 5518 
                 5887 
                 6256 
                 6625 
                 6994 
                 7363 
                 7732 
                 8101 
               
               
                 e-4 
                 4043- 
                 4412- 
                 4781- 
                 5150- 
                 5519- 
                 5888- 
                 6257- 
                 6626- 
                 6995- 
                 7364- 
                 7733- 
                 8102- 
               
               
                   
                 4050 
                 4419 
                 4788 
                 5157 
                 5526 
                 5895 
                 6264 
                 6633 
                 7002 
                 7371 
                 7740 
                 8109 
               
               
                 e-5 
                 4051- 
                 4420- 
                 4789- 
                 5158- 
                 5527- 
                 5896- 
                 6265- 
                 6634- 
                 7003- 
                 7372- 
                 7741- 
                 8110- 
               
               
                   
                 4058 
                 4427 
                 4796 
                 5165 
                 5534 
                 5903 
                 6272 
                 6641 
                 7010 
                 7379 
                 7748 
                 8117 
               
               
                 e-6 
                 4059- 
                 4428- 
                 4797- 
                 5166- 
                 5535- 
                 5904- 
                 6273- 
                 6642- 
                 7011- 
                 7380- 
                 7749- 
                 8118- 
               
               
                   
                 4066 
                 4435 
                 4804 
                 5173 
                 5542 
                 5911 
                 6280 
                 6649 
                 7018 
                 7387 
                 7756 
                 8125 
               
               
                 f-1 
                 4067- 
                 4436- 
                 4805- 
                 5174- 
                 5543- 
                 5912- 
                 6281- 
                 6650- 
                 7019- 
                 7388- 
                 7757- 
                 8126- 
               
               
                   
                 4074 
                 4443 
                 4812 
                 5181 
                 5550 
                 5919 
                 6288 
                 6657 
                 7026 
                 7395 
                 7764 
                 8133 
               
               
                 f-2 
                 4075- 
                 4444- 
                 4813- 
                 5182- 
                 5551- 
                 5920- 
                 6289- 
                 6658- 
                 7027- 
                 7396- 
                 7765- 
                 8134- 
               
               
                   
                 4082 
                 4451 
                 4820 
                 5189 
                 5558 
                 5927 
                 6296 
                 6665 
                 7034 
                 7403 
                 7772 
                 8141 
               
               
                 f-3 
                 4083- 
                 4452- 
                 4821- 
                 5190- 
                 5559- 
                 5928- 
                 6297- 
                 6666- 
                 7035- 
                 7404- 
                 7773- 
                 8142- 
               
               
                   
                 4090 
                 4459 
                 4828 
                 5197 
                 5566 
                 5935 
                 6304 
                 6673 
                 7042 
                 7411 
                 7780 
                 8149 
               
               
                 f-4 
                 4091- 
                 4460- 
                 4829- 
                 5198- 
                 5567- 
                 5936- 
                 6305- 
                 6674- 
                 7043- 
                 7412- 
                 7781- 
                 8150- 
               
               
                   
                 4098 
                 4467 
                 4836 
                 5205 
                 5574 
                 5943 
                 6312 
                 6681 
                 7050 
                 7419 
                 7788 
                 8157 
               
               
                 f-5 
                 4099- 
                 4468- 
                 4837- 
                 5206- 
                 5575- 
                 5944- 
                 6313- 
                 6682- 
                 7051- 
                 7420- 
                 7789- 
                 8158- 
               
               
                   
                 4106 
                 4475 
                 4844 
                 5213 
                 5582 
                 5951 
                 6320 
                 6689 
                 7058 
                 7427 
                 7796 
                 8165 
               
               
                 g-1 
                 4107- 
                 4476- 
                 4845- 
                 5214- 
                 5583- 
                 5952- 
                 6321- 
                 6690- 
                 7059- 
                 7428- 
                 7797- 
                 8166- 
               
               
                   
                 4114 
                 4483 
                 4852 
                 5221 
                 5590 
                 5959 
                 6328 
                 6697 
                 7066 
                 7435 
                 7804 
                 8173 
               
               
                 g-2 
                 4115- 
                 4484- 
                 4853- 
                 5222- 
                 5591- 
                 5960- 
                 6329- 
                 6698- 
                 7067- 
                 7436- 
                 7805- 
                 8174- 
               
               
                   
                 4122 
                 4491 
                 4860 
                 5229 
                 5598 
                 5967 
                 6336 
                 6705 
                 7074 
                 7443 
                 7812 
                 8181 
               
               
                 g-3 
                 4123- 
                 4492- 
                 4861- 
                 5230- 
                 5599- 
                 5968- 
                 6337- 
                 6706- 
                 7075- 
                 7444- 
                 7813- 
                 8182- 
               
               
                   
                 4130 
                 4499 
                 4868 
                 5237 
                 5606 
                 5975 
                 6344 
                 6713 
                 7082 
                 7451 
                 7820 
                 8189 
               
               
                 g-4 
                 4131- 
                 4500- 
                 4869- 
                 5238- 
                 5607- 
                 5976- 
                 6345- 
                 6714- 
                 7083- 
                 7452- 
                 7821- 
                 8190- 
               
               
                   
                 4138 
                 4507 
                 4876 
                 5245 
                 5614 
                 5983 
                 6352 
                 6721 
                 7090 
                 7459 
                 7828 
                 8197 
               
               
                 g-5 
                 4139- 
                 4508- 
                 4877- 
                 5246- 
                 5615- 
                 5984- 
                 6353- 
                 6722- 
                 7091- 
                 7460- 
                 7829- 
                 8198- 
               
               
                   
                 4146 
                 4515 
                 4884 
                 5253 
                 5622 
                 5991 
                 6360 
                 6729 
                 7098 
                 7467 
                 7836 
                 8205 
               
               
                 h-1 
                 4147- 
                 4516- 
                 4885- 
                 5254- 
                 5623- 
                 5992- 
                 6361- 
                 6730- 
                 7099- 
                 7468- 
                 7837- 
                 8206- 
               
               
                   
                 4154 
                 4523 
                 4892 
                 5261 
                 5630 
                 5999 
                 6368 
                 6737 
                 7106 
                 7475 
                 7844 
                 8213 
               
               
                 h-2 
                 4155- 
                 4524- 
                 4893- 
                 5262- 
                 5631- 
                 6000- 
                 6369- 
                 6738- 
                 7107- 
                 7476- 
                 7845- 
                 8214- 
               
               
                   
                 4162 
                 4531 
                 4900 
                 5269 
                 5638 
                 6007 
                 6376 
                 6745 
                 7114 
                 7483 
                 7852 
                 8221 
               
               
                 h-3 
                 4163- 
                 4532- 
                 4901- 
                 5270- 
                 5639- 
                 6008- 
                 6377- 
                 6746- 
                 7115- 
                 7484- 
                 7853- 
                 8222- 
               
               
                   
                 4170 
                 4539 
                 4908 
                 5277 
                 5646 
                 6015 
                 6384 
                 6753 
                 7122 
                 7491 
                 7860 
                 8229 
               
               
                 h-4 
                 4171- 
                 4540- 
                 4909- 
                 5278- 
                 5647- 
                 6016- 
                 6385- 
                 6754- 
                 7123- 
                 7492- 
                 7861- 
                 8230- 
               
               
                   
                 4178 
                 4547 
                 4916 
                 5285 
                 5654 
                 6023 
                 6392 
                 6761 
                 7130 
                 7499 
                 7868 
                 8237 
               
               
                 h-5 
                 4179- 
                 4548- 
                 4917- 
                 5286- 
                 5655- 
                 6024- 
                 6393- 
                 6762- 
                 7131- 
                 7500- 
                 7869- 
                 8238- 
               
               
                   
                 4186 
                 4555 
                 4924 
                 5293 
                 5662 
                 6031 
                 6400 
                 6769 
                 7138 
                 7507 
                 7876 
                 8245 
               
               
                 i-1 
                 4187- 
                 4556- 
                 4925- 
                 5294- 
                 5663- 
                 6032- 
                 6401- 
                 6770- 
                 7139- 
                 7508- 
                 7877- 
                 8246- 
               
               
                   
                 4194 
                 4563 
                 4932 
                 5301 
                 5670 
                 6039 
                 6408 
                 6777 
                 7146 
                 7515 
                 7884 
                 8253 
               
               
                 i-2 
                 4195- 
                 4564- 
                 4933- 
                 5302- 
                 5671- 
                 6040- 
                 6409- 
                 6778- 
                 7147- 
                 7516- 
                 7885- 
                 8254- 
               
               
                   
                 4210 
                 4579 
                 4948 
                 5317 
                 5686 
                 6055 
                 6424 
                 6793 
                 7162 
                 7531 
                 7900 
                 8269 
               
               
                 i-3 
                 4211- 
                 4580- 
                 4949- 
                 5318- 
                 5687- 
                 6056- 
                 6425- 
                 6794- 
                 7163- 
                 7532- 
                 7901- 
                 8270- 
               
               
                   
                 4218 
                 4587 
                 4956 
                 5325 
                 5694 
                 6063 
                 6432 
                 6801 
                 7170 
                 7539 
                 7908 
                 8277 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6B 
               
             
            
               
                   
               
               
                 Preferred mRNA constructs encoding RSV F (column K-V), derived from HRSV(Memphis-37) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 K 
                 L 
                 M 
                 N 
                 O 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 U 
                 V 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 PRT 
                 13202 
                 13571 
                 16154 
                 16523 
                 16892 
                 17261 
                 17630 
                 17999 
                 18368 
                 18737 
                 19106 
                 19475 
               
               
                 cds 
                 13203- 
                 13572- 
                 16155- 
                 16524- 
                 16893- 
                 17262- 
                 17631- 
                 18000- 
                 18369- 
                 18738- 
                 19107- 
                 19476- 
               
               
                   
                 13210, 
                 13579, 
                 16162, 
                 16531, 
                 16900, 
                 17269, 
                 17638, 
                 18007, 
                 18376, 
                 18745, 
                 19114, 
                 19483, 
               
               
                   
                 21393 
                 21394 
                 21401 
                 21402 
                 21403 
                 21404 
                 21405 
                 21406 
                 21407 
                 21408 
                 21409 
                 21410 
               
               
                 a-1 
                 13211- 
                 13580- 
                 16163- 
                 16532- 
                 16901- 
                 17270- 
                 17639- 
                 18008- 
                 18377- 
                 18746- 
                 19115- 
                 19484- 
               
               
                   
                 13218, 
                 13587, 
                 16170, 
                 16539, 
                 16908, 
                 17277, 
                 17646, 
                 18015, 
                 18384, 
                 18753, 
                 19122, 
                 19491, 
               
               
                   
                 21499- 
                 21502- 
                 21523- 
                 21526- 
                 21529- 
                 21532- 
                 21535- 
                 21538- 
                 21541- 
                 21544- 
                 21547- 
                 21550- 
               
               
                   
                 21501, 
                 21504, 
                 21525, 
                 21528, 
                 21531, 
                 21534, 
                 21537, 
                 21540, 
                 21543, 
                 21546, 
                 21549, 
                 21552, 
               
               
                   
                 21645- 
                 21648- 
                 21669- 
                 21672- 
                 21675- 
                 21678- 
                 21681- 
                 21684- 
                 21687- 
                 21690- 
                 21693- 
                 21696- 
               
               
                   
                 21647 
                 21650 
                 21671 
                 21674 
                 21677 
                 21680 
                 21683 
                 21686 
                 21689 
                 21692 
                 21695 
                 21698 
               
               
                 a-2 
                 13219- 
                 13588- 
                 16171- 
                 16540- 
                 16909- 
                 17278- 
                 17647- 
                 18016- 
                 18385- 
                 18754- 
                 19123- 
                 19492- 
               
               
                   
                 13226 
                 13595 
                 16178 
                 16547 
                 16916 
                 17285 
                 17654 
                 18023 
                 18392 
                 18761 
                 19130 
                 19499 
               
               
                 a-3 
                 13227- 
                 13596- 
                 16179- 
                 16548- 
                 16917- 
                 17286- 
                 17655- 
                 18024- 
                 18393- 
                 18762- 
                 19131- 
                 19500- 
               
               
                   
                 13234 
                 13603 
                 16186 
                 16555 
                 16924 
                 17293 
                 17662 
                 18031 
                 18400 
                 18769 
                 19138 
                 19507 
               
               
                 a-4 
                 13235- 
                 13604- 
                 16187- 
                 16556- 
                 16925- 
                 17294- 
                 17663- 
                 18032- 
                 18401- 
                 18770- 
                 19139- 
                 19508- 
               
               
                   
                 13242 
                 13611 
                 16194 
                 16563 
                 16932 
                 17301 
                 17670 
                 18039 
                 18408 
                 18777 
                 19146 
                 19515 
               
               
                 a-5 
                 13243- 
                 13612- 
                 16195- 
                 16564- 
                 16933- 
                 17302- 
                 17671- 
                 18040- 
                 18409- 
                 18778- 
                 19147- 
                 19516- 
               
               
                   
                 13250 
                 13619 
                 16202 
                 16571 
                 16940 
                 17309 
                 17678 
                 18047 
                 18416 
                 18785 
                 19154 
                 19523 
               
               
                 b-1 
                 13251- 
                 13620- 
                 16203- 
                 16572- 
                 16941- 
                 17310- 
                 17679- 
                 18048- 
                 18417- 
                 18786- 
                 19155- 
                 19524- 
               
               
                   
                 13258 
                 13627 
                 16210 
                 16579 
                 16948 
                 17317 
                 17686 
                 18055 
                 18424 
                 18793 
                 19162 
                 19531 
               
               
                 b-2 
                 13259- 
                 13628- 
                 16211- 
                 16580- 
                 16949- 
                 17318- 
                 17687- 
                 18056- 
                 18425- 
                 18794- 
                 19163- 
                 19532- 
               
               
                   
                 13266 
                 13635 
                 16218 
                 16587 
                 16956 
                 17325 
                 17694 
                 18063 
                 18432 
                 18801 
                 19170 
                 19539 
               
               
                 b-3 
                 13267- 
                 13636- 
                 16219- 
                 16588- 
                 16957- 
                 17326- 
                 17695- 
                 18064- 
                 18433- 
                 18802- 
                 19171- 
                 19540- 
               
               
                   
                 13274 
                 13643 
                 16226 
                 16595 
                 16964 
                 17333 
                 17702 
                 18071 
                 18440 
                 18809 
                 19178 
                 19547 
               
               
                 b-4 
                 13275- 
                 13644- 
                 16227- 
                 16596- 
                 16965- 
                 17334- 
                 17703- 
                 18072- 
                 18441- 
                 18810- 
                 19179- 
                 19548- 
               
               
                   
                 13282 
                 13651 
                 16234 
                 16603 
                 16972 
                 17341 
                 17710 
                 18079 
                 18448 
                 18817 
                 19186 
                 19555 
               
               
                 b-5 
                 13283- 
                 13652- 
                 16235- 
                 16604- 
                 16973- 
                 17342- 
                 17711- 
                 18080- 
                 18449- 
                 18818- 
                 19187- 
                 19556- 
               
               
                   
                 13290 
                 13659 
                 16242 
                 16611 
                 16980 
                 17349 
                 17718 
                 18087 
                 18456 
                 18825 
                 19194 
                 19563 
               
               
                 c-1 
                 13291- 
                 13660- 
                 16243- 
                 16612- 
                 16981- 
                 17350- 
                 17719- 
                 18088- 
                 18457- 
                 18826- 
                 19195- 
                 19564- 
               
               
                   
                 13298 
                 13667 
                 16250 
                 16619 
                 16988 
                 17357 
                 17726 
                 18095 
                 18464 
                 18833 
                 19202 
                 19571 
               
               
                 c-2 
                 13299- 
                 13668- 
                 16251- 
                 16620- 
                 16989- 
                 17358- 
                 17727- 
                 18096- 
                 18465- 
                 18834- 
                 19203- 
                 19572- 
               
               
                   
                 13306 
                 13675 
                 16258 
                 16627 
                 16996 
                 17365 
                 17734 
                 18103 
                 18472 
                 18841 
                 19210 
                 19579 
               
               
                 c-3 
                 13307- 
                 13676- 
                 16259- 
                 16628- 
                 16997- 
                 17366- 
                 17735- 
                 18104- 
                 18473- 
                 18842- 
                 19211- 
                 19580- 
               
               
                   
                 13314 
                 13683 
                 16266 
                 16635 
                 17004 
                 17373 
                 17742 
                 18111 
                 18480 
                 18849 
                 19218 
                 19587 
               
               
                 c-4 
                 13315- 
                 13684- 
                 16267- 
                 16636- 
                 17005- 
                 17374- 
                 17743- 
                 18112- 
                 18481- 
                 18850- 
                 19219- 
                 19588- 
               
               
                   
                 13322 
                 13691 
                 16274 
                 16643 
                 17012 
                 17381 
                 17750 
                 18119 
                 18488 
                 18857 
                 19226 
                 19595 
               
               
                 c-5 
                 13323- 
                 13692- 
                 16275- 
                 16644- 
                 17013- 
                 17382- 
                 17751- 
                 18120- 
                 18489- 
                 18858- 
                 19227- 
                 19596- 
               
               
                   
                 13330 
                 13699 
                 16282 
                 16651 
                 17020 
                 17389 
                 17758 
                 18127 
                 18496 
                 18865 
                 19234 
                 19603 
               
               
                 d-1 
                 13331- 
                 13700- 
                 16283- 
                 16652- 
                 17021- 
                 17390- 
                 17759- 
                 18128- 
                 18497- 
                 18866- 
                 19235- 
                 19604- 
               
               
                   
                 13338 
                 13707 
                 16290 
                 16659 
                 17028 
                 17397 
                 17766 
                 18135 
                 18504 
                 18873 
                 19242 
                 19611 
               
               
                 d-2 
                 13339- 
                 13708- 
                 16291- 
                 16660- 
                 17029- 
                 17398- 
                 17767- 
                 18136- 
                 18505- 
                 18874- 
                 19243- 
                 19612- 
               
               
                   
                 13346 
                 13715 
                 16298 
                 16667 
                 17036 
                 17405 
                 17774 
                 18143 
                 18512 
                 18881 
                 19250 
                 19619 
               
               
                 d-3 
                 13347- 
                 13716- 
                 16299- 
                 16668- 
                 17037- 
                 17406- 
                 17775- 
                 18144- 
                 18513- 
                 18882- 
                 19251- 
                 19620- 
               
               
                   
                 13354 
                 13723 
                 16306 
                 16675 
                 17044 
                 17413 
                 17782 
                 18151 
                 18520 
                 18889 
                 19258 
                 19627 
               
               
                 d-4 
                 13355- 
                 13724- 
                 16307- 
                 16676- 
                 17045- 
                 17414- 
                 17783- 
                 18152- 
                 18521- 
                 18890- 
                 19259- 
                 19628- 
               
               
                   
                 13362 
                 13731 
                 16314 
                 16683 
                 17052 
                 17421 
                 17790 
                 18159 
                 18528 
                 18897 
                 19266 
                 19635 
               
               
                 d-5 
                 13363- 
                 13732- 
                 16315- 
                 16684- 
                 17053- 
                 17422- 
                 17791- 
                 18160- 
                 18529- 
                 18898- 
                 19267- 
                 19636- 
               
               
                   
                 13370 
                 13739 
                 16322 
                 16691 
                 17060 
                 17429 
                 17798 
                 18167 
                 18536 
                 18905 
                 19274 
                 19643 
               
               
                 e-1 
                 13371- 
                 13740- 
                 16323- 
                 16692- 
                 17061- 
                 17430- 
                 17799- 
                 18168- 
                 18537- 
                 18906- 
                 19275- 
                 19644- 
               
               
                   
                 13378 
                 13747 
                 16330 
                 16699 
                 17068 
                 17437 
                 17806 
                 18175 
                 18544 
                 18913 
                 19282 
                 19651 
               
               
                 e-2 
                 13379- 
                 13748- 
                 16331- 
                 16700- 
                 17069- 
                 17438- 
                 17807- 
                 18176- 
                 18545- 
                 18914- 
                 19283- 
                 19652- 
               
               
                   
                 13386 
                 13755 
                 16338 
                 16707 
                 17076 
                 17445 
                 17814 
                 18183 
                 18552 
                 18921 
                 19290 
                 19659 
               
               
                 e-3 
                 13387- 
                 13756- 
                 16339- 
                 16708- 
                 17077- 
                 17446- 
                 17815- 
                 18184- 
                 18553- 
                 18922- 
                 19291- 
                 19660- 
               
               
                   
                 13394 
                 13763 
                 16346 
                 16715 
                 17084 
                 17453 
                 17822 
                 18191 
                 18560 
                 18929 
                 19298 
                 19667 
               
               
                 e-4 
                 13395- 
                 13764- 
                 16347- 
                 16716- 
                 17085- 
                 17454- 
                 17823- 
                 18192- 
                 18561- 
                 18930- 
                 19299- 
                 19668- 
               
               
                   
                 13402 
                 13771 
                 16354 
                 16723 
                 17092 
                 17461 
                 17830 
                 18199 
                 18568 
                 18937 
                 19306 
                 19675 
               
               
                 e-5 
                 13403- 
                 13772- 
                 16355- 
                 16724- 
                 17093- 
                 17462- 
                 17831- 
                 18200- 
                 18569- 
                 18938- 
                 19307- 
                 19676- 
               
               
                   
                 13410 
                 13779 
                 16362 
                 16731 
                 17100 
                 17469 
                 17838 
                 18207 
                 18576 
                 18945 
                 19314 
                 19683 
               
               
                 e-6 
                 13411- 
                 13780- 
                 16363- 
                 16732- 
                 17101- 
                 17470- 
                 17839- 
                 18208- 
                 18577- 
                 18946- 
                 19315- 
                 19684- 
               
               
                   
                 13418 
                 13787 
                 16370 
                 16739 
                 17108 
                 17477 
                 17846 
                 18215 
                 18584 
                 18953 
                 19322 
                 19691 
               
               
                 f-1 
                 13419- 
                 13788- 
                 16371- 
                 16740- 
                 17109- 
                 17478- 
                 17847- 
                 18216- 
                 18585- 
                 18954- 
                 19323- 
                 19692- 
               
               
                   
                 13426 
                 13795 
                 16378 
                 16747 
                 17116 
                 17485 
                 17854 
                 18223 
                 18592 
                 18961 
                 19330 
                 19699 
               
               
                 f-2 
                 13427- 
                 13796- 
                 16379- 
                 16748- 
                 17117- 
                 17486- 
                 17855- 
                 18224- 
                 18593- 
                 18962- 
                 19331- 
                 19700- 
               
               
                   
                 13434 
                 13803 
                 16386 
                 16755 
                 17124 
                 17493 
                 17862 
                 18231 
                 18600 
                 18969 
                 19338 
                 19707 
               
               
                 f-3 
                 13435- 
                 13804- 
                 16387- 
                 16756- 
                 17125- 
                 17494- 
                 17863- 
                 18232- 
                 18601- 
                 18970- 
                 19339- 
                 19708- 
               
               
                   
                 13442 
                 13811 
                 16394 
                 16763 
                 17132 
                 17501 
                 17870 
                 18239 
                 18608 
                 18977 
                 19346 
                 19715 
               
               
                 f-4 
                 13443- 
                 13812- 
                 16395- 
                 16764- 
                 17133- 
                 17502- 
                 17871- 
                 18240- 
                 18609- 
                 18978- 
                 19347- 
                 19716- 
               
               
                   
                 13450 
                 13819 
                 16402 
                 16771 
                 17140 
                 17509 
                 17878 
                 18247 
                 18616 
                 18985 
                 19354 
                 19723 
               
               
                 f-5 
                 13451- 
                 13820- 
                 16403- 
                 16772- 
                 17141- 
                 17510- 
                 17879- 
                 18248- 
                 18617- 
                 18986- 
                 19355- 
                 19724- 
               
               
                   
                 13458 
                 13827 
                 16410 
                 16779 
                 17148 
                 17517 
                 17886 
                 18255 
                 18624 
                 18993 
                 19362 
                 19731 
               
               
                 g-1 
                 13459- 
                 13828- 
                 16411- 
                 16780- 
                 17149- 
                 17518- 
                 17887- 
                 18256- 
                 18625- 
                 18994- 
                 19363- 
                 19732- 
               
               
                   
                 13466 
                 13835 
                 16418 
                 16787 
                 17156 
                 17525 
                 17894 
                 18263 
                 18632 
                 19001 
                 19370 
                 19739 
               
               
                 g-2 
                 13467- 
                 13836- 
                 16419- 
                 16788- 
                 17157- 
                 17526- 
                 17895- 
                 18264- 
                 18633- 
                 19002- 
                 19371- 
                 19740- 
               
               
                   
                 13474 
                 13843 
                 16426 
                 16795 
                 17164 
                 17533 
                 17902 
                 18271 
                 18640 
                 19009 
                 19378 
                 19747 
               
               
                 g-3 
                 13475- 
                 13844- 
                 16427- 
                 16796- 
                 17165- 
                 17534- 
                 17903- 
                 18272- 
                 18641- 
                 19010- 
                 19379- 
                 19748- 
               
               
                   
                 13482 
                 13851 
                 16434 
                 16803 
                 17172 
                 17541 
                 17910 
                 18279 
                 18648 
                 19017 
                 19386 
                 19755 
               
               
                 g-4 
                 13483- 
                 13852- 
                 16435- 
                 16804- 
                 17173- 
                 17542- 
                 17911- 
                 18280- 
                 18649- 
                 19018- 
                 19387- 
                 19756- 
               
               
                   
                 13490 
                 13859 
                 16442 
                 16811 
                 17180 
                 17549 
                 17918 
                 18287 
                 18656 
                 19025 
                 19394 
                 19763 
               
               
                 g-5 
                 13491- 
                 13860- 
                 16443- 
                 16812- 
                 17181- 
                 17550- 
                 17919- 
                 18288- 
                 18657- 
                 19026- 
                 19395- 
                 19764- 
               
               
                   
                 13498 
                 13867 
                 16450 
                 16819 
                 17188 
                 17557 
                 17926 
                 18295 
                 18664 
                 19033 
                 19402 
                 19771 
               
               
                 h-1 
                 13499- 
                 13868- 
                 16451- 
                 16820- 
                 17189- 
                 17558- 
                 17927- 
                 18296- 
                 18665- 
                 19034- 
                 19403- 
                 19772- 
               
               
                   
                 13506 
                 13875 
                 16458 
                 16827 
                 17196 
                 17565 
                 17934 
                 18303 
                 18672 
                 19041 
                 19410 
                 19779 
               
               
                 h-2 
                 13507- 
                 13876- 
                 16459- 
                 16828- 
                 17197- 
                 17566- 
                 17935- 
                 18304- 
                 18673- 
                 19042- 
                 19411- 
                 19780- 
               
               
                   
                 13514 
                 13883 
                 16466 
                 16835 
                 17204 
                 17573 
                 17942 
                 18311 
                 18680 
                 19049 
                 19418 
                 19787 
               
               
                 h-3 
                 13515- 
                 13884- 
                 16467- 
                 16836- 
                 17205- 
                 17574- 
                 17943- 
                 18312- 
                 18681- 
                 19050- 
                 19419- 
                 19788- 
               
               
                   
                 13522 
                 13891 
                 16474 
                 16843 
                 17212 
                 17581 
                 17950 
                 18319 
                 18688 
                 19057 
                 19426 
                 19795 
               
               
                 h-4 
                 13523- 
                 13892- 
                 16475- 
                 16844- 
                 17213- 
                 17582- 
                 17951- 
                 18320- 
                 18689- 
                 19058- 
                 19427- 
                 19796- 
               
               
                   
                 13530 
                 13899 
                 16482 
                 16851 
                 17220 
                 17589 
                 17958 
                 18327 
                 18696 
                 19065 
                 19434 
                 19803 
               
               
                 h-5 
                 13531- 
                 13900- 
                 16483- 
                 16852- 
                 17221- 
                 17590- 
                 17959- 
                 18328- 
                 18697- 
                 19066- 
                 19435- 
                 19804- 
               
               
                   
                 13538 
                 13907 
                 16490 
                 16859 
                 17228 
                 17597 
                 17966 
                 18335 
                 18704 
                 19073 
                 19442 
                 19811 
               
               
                 i-1 
                 13539- 
                 13908- 
                 16491- 
                 16860- 
                 17229- 
                 17598- 
                 17967- 
                 18336- 
                 18705- 
                 19074- 
                 19443- 
                 19812- 
               
               
                   
                 13546 
                 13915 
                 16498 
                 16867 
                 17236 
                 17605 
                 17974 
                 18343 
                 18712 
                 19081 
                 19450 
                 19819 
               
               
                 i-2 
                 13547- 
                 13916- 
                 16499- 
                 16868- 
                 17237- 
                 17606- 
                 17975- 
                 18344- 
                 18713- 
                 19082- 
                 19451- 
                 19820- 
               
               
                   
                 13562 
                 13931 
                 16514 
                 16883 
                 17252 
                 17621 
                 17990 
                 18359 
                 18728 
                 19097 
                 19466 
                 19835 
               
               
                 i-3 
                 13563- 
                 13932- 
                 16515- 
                 16884- 
                 17253- 
                 17622- 
                 17991- 
                 18360- 
                 18729- 
                 19098- 
                 19467- 
                 19836- 
               
               
                   
                 13570 
                 13939 
                 16522 
                 16891 
                 17260 
                 17629 
                 17998 
                 18367 
                 18736 
                 19105 
                 19474 
                 19843 
               
               
                   
               
            
           
         
       
     
     In preferred embodiments, the artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of Seq ID NOs: 78-482, 493-897, 907-1266, 1276-1635, 1645-2004, 2014-2373, 2383-2742, 2752-3111, 3121-3480, 3490-3849, 3859-4218, 4228-4587, 4597-4956, 4966-5325, 5335-5694, 5704-6063, 6073-6432, 6442-6801, 6811-7170, 7180-7539, 7549-7908, 7918-8277, 8278, 21415-21480, 21561-21626, 11735-12094, 12104-12463, 12473-12832, 12842-13201, 13949-14308, 14318-14677, 14687-15046, 15056-15415, 15425-15784, 15794-16153, 13211-13570, 13580-13939, 16163-16522, 16532-16891, 16901-17260, 17270-17629, 17639-17998, 18008-18367, 18377-18736, 18746-19105, 19115-19474, 19484-19843, 21489-21552, 21635-21698 or a fragment or variant of any of these sequences, wherein, optionally, at least one or more than one, or wherein all uracil nucleotides are replaced by pseudouridine (ψ) nucleotides or N1-methylpseudouridine (m1ψ) nucleotides. 
     In preferred embodiments, the artificial RNA comprises (a) at least one heterologous 5′ untranslated region (5′-UTR) and/or at least one heterologous 3′ untranslated region (3′-UTR) and (b) at least one coding sequence operably linked to said 3′-UTR and/or 5′-UTR encoding at least one antigenic peptide or protein derived from a RSV F or a fragment or variant thereof, wherein
         said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 78-482, 11735-12094, 21415-21417, 21561-21563, 21489, 21490, 21635, 21636 (encoding F0) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 493-897, 12104-12463, 21418-21420, 21564-21566, 21491, 21492, 21637, 21638 (encoding F-del) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 907-1266, 12473-12832, 21421-21423, 21567-21569, 21493-21495, 21639-21641 (encoding F0_DSCav1) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1276-1635, 8278, 12842-13201, 21424-21426, 21570-21572, 21496-21498, 21642-21644 (encoding F-del_DSCav1) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1645-2004, 13949-14308, 21433-21435, 21579-21581, 21505-21507, 21651-21653 (encoding F_DSCav1_mut1) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 2014-2373, 14318-14677, 21436-21438, 21582-21584, 21508-21510, 21654-21656 (encoding F-del_DSCav1_mut1) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 2383-2742, 14687-15046, 21439-21441, 21585-21587, 21511-21513, 21657-21659 (encoding F_DSCav1_mut2) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 2752-3111, 15056-15415, 21442-21444, 21588-21590, 21514-21516, 21660-21662 (encoding F-del_DSCav1_mut2) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 3121-3480, 15425-15784, 21445-21447, 21591-21593, 21517-21519, 21663-21665 (encoding F_DSCav1_mut3) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 3490-3849, 15794-16153, 21448-21450, 21594-21596, 21520-21522, 21666-21668 (encoding F-del_DSCav1_mut3) or a fragment or variant of any of these sequences.   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 3859-4218, 13211-13570, 21427-21429, 21573-21575, 21499-21501, 21645-21647 (encoding F_DSCav1_mut0) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 4228-4587, 13580-13939, 21430-21432, 21576-21578, 21502-21504, 21648-21650 (encoding F-del_DSCav1_mut0) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 4597-4956, 16163-16522, 21451-21453, 21597-21599, 21523-21525, 21669-21671 (encoding F_DSCav1_mut4) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 4966-5325, 16532-16891, 21454-21456, 21600-21602, 21526-21528, 21672-21674 (encoding F-del_DSCav1_mut4) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 5335-5694, 16901-17260, 21457-21459, 21603-21605, 21529-21531, 21675-21677 (encoding F_DSCav1_mut5) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 5704-6063, 17270-17629, 21460-21462, 21606-21608, 21532-21534, 21678-21680 (encoding F-del_DSCav1_mut5) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 6073-6432, 17639-17998, 21463-21465, 21609-21611, 21535-21537, 21681-21683 (encoding F_DSCav1_mut6) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 6442-6801, 18008-18367, 21466-21468, 21612-21614, 21538-21540, 21684-21686 (encoding F-del_DSCav1_mut6) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 6811-7170, 18377-18736, 21469-21471, 21615-21617, 21541-21543, 21687-21689 (encoding F_DSCav1_mut7) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 7180-7539, 18746-19105, 21472-21474, 21618-21620, 21544-21546, 21690-21692 (encoding F-del_DSCav1_mut7) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 7549-7908, 19115-19474, 21475-21477, 21621-21623, 21547-21549, 21693-21695 (encoding F_DSCav1_mut8) or a fragment or variant of any of these sequences;   said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 7918-8277, 19484-19843, 21478-21480, 21624-21626, 21550-21552, 21696-21698 (encoding F-del_DSCav1_mut8) or a fragment or variant of any of these sequences, and
 
wherein, optionally, at least one or more than one, or wherein all uracil nucleotides are replaced by pseudouridine (ψ) nucleotides or N1-methylpseudouridine (m1ψ) nucleotides.
       

     In particularly preferred embodiments, the artificial RNA comprises (a) at least one heterologous 5′ untranslated region (5′-UTR) and/or at least one heterologous 3′ untranslated region (3′-UTR) and (b) at least one coding sequence operably linked to said 3′-UTR and/or 5′-UTR encoding at least one antigenic peptide or protein derived from a RSV F or a fragment or variant thereof, wherein said artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 5704-6063, 17270-17629, 21460-21462, 21606-21608, 21532-21534, 21678-21680 (encoding F-del_DSCav1_mut5) or a fragment or variant of any of these sequences. 
     As outlined throughout the specification, additional information regarding suitable amino acid sequences or nucleic acid sequences (coding sequences, mRNA sequences) may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt; as explained in the following. 
     For example, the numeric identifier &lt;223&gt; in the sequence listing of SEQ ID NO: 68 reads as follows: “derived and/or modified protein sequence (artificial) from HRSV(A2)_F0”. It has to be noted that throughout the sequence listing, information provided under numeric identifier &lt;223&gt; follows the same structure: “&lt;SEQUENCE_DESCRIPTOR&gt; from &lt;CONSTRUCT_IDENTIFIER&gt;”. The &lt;SEQUENCE_DESCRIPTOR&gt; relates to the type of sequence (e.g., “derived and/or modified protein sequence”, “derived and/or modified CDS” “mRNA product Design a-1 comprising derived and/or modified sequence”, or “mRNA product Design b-4 comprising derived and/or modified sequence”, or “mRNA product Design c-5 comprising derived and/or modified sequence”, or “mRNA product Design g-4 comprising derived and/or modified sequence” etc.) and whether the sequence comprises or consists of a wild type sequence (“wt”) or whether the sequence comprises or consists of a sequence-optimized sequence (e.g. “opt1”, “opt2”, “opt3”, “opt4”, “opt5”, “opt6”, “opt11”; sequence optimizations are described in further detail below). For example, the &lt;SEQUENCE_DESCRIPTOR&gt; provided under numeric identifier &lt;223&gt; of SEQ ID NO: 68 reads as follows: “derived and/or modified protein sequence (artificial)”. The &lt;CONSTRUCT_IDENTIFIER&gt; provided under numeric identifier &lt;223&gt; has the following structures: (“organism_construct name”, or “organism__accession number__construct name”) and is intended to help the person skilled in the art to explicitly derive suitable nucleic acid sequences (e.g., RNA, mRNA) encoding the same RSV protein according to the invention. For example, the &lt;CONSTRUCT_IDENTIFIER&gt; provided under numeric identifier &lt;223&gt; of SEQ ID NO: 68 reads as follows: “HRSV(A2)_F0”. In that example, the respective protein sequence is derived from “HRSV(A2)” (organism), wherein the protein comprises the structural elements “F0” (construct name, full-length F). If the skilled person uses the construct identifier of SEQ ID NO: 68, namely “HRSV(A2)_F0”, said person easily arrives at a list of suitable nucleic acid coding sequences, e.g. RNA coding sequences and mRNA sequences that can easily be retrieve from the sequence listing of the present invention. 
     Composition: 
     A second aspect relates to a composition comprising at least one artificial RNA of the first aspect. 
     In a preferred embodiment of the second aspect, the composition comprises at least one artificial RNA of the first aspect and, optionally, at least one pharmaceutically acceptable carrier. 
     The term “pharmaceutically acceptable carrier” as used herein preferably includes the liquid or non-liquid basis of the composition. If the composition is provided in liquid form, the carrier will preferably be water, typically pyrogen-free water; isotonic saline or buffered (aqueous) solutions, e.g. phosphate, citrate etc. buffered solutions. Water or preferably a buffer, more preferably an aqueous buffer, may be used, containing a sodium salt, preferably at least 50 mM of a sodium salt, a calcium salt, preferably at least 0.01 mM of a calcium salt, and optionally a potassium salt, preferably at least 3 mM of a potassium salt. According to a preferred embodiment, the sodium, calcium and, optionally, potassium salts may occur in the form of their halogenides, e.g. chlorides, iodides, or bromides, in the form of their hydroxides, carbonates, hydrogen carbonates, or sulfates, etc. Without being limited thereto, examples of sodium salts include e.g. NaCl, NaI, NaBr, Na 2 CO 3 , NaHC 3 , Na 2 SO 4 , examples of the optional potassium salts include e.g. KCl, KI, KBr, K 2 CO 3 , KHCO 3 , K 2 SO 4 , and examples of calcium salts include e.g. CaCl 2 , CaI 2 , CaBr 2 , CaCO 3 , CaSO 4 , Ca(OH) 2 . Furthermore, organic anions of the aforementioned cations may be contained in the buffer. 
     In embodiments, the composition as defined herein may comprise a plurality or at least more than one of the artificial RNAs as defined in the context of the first aspect or the second aspect of the invention. 
     In embodiments, the at least one RNA comprised in the composition is a bi- or multicistronic nucleic acid, particularly a bi- or multicistronic nucleic acid as defined herein, which encodes the at least two, three, four, five, six, seven, eight, nine, ten, eleven or twelve distinct antigenic peptides or protein derived from the same RSV and/or a different RSV. 
     In embodiment, the composition may comprise at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or even more different artificial RNAs as defined in the context of the first aspect of the invention each encoding at least one antigenic peptide or protein derived from genetically the same RSV or a fragment or variant thereof. The terms “same” or “same RSV” as used in the context of a virus, e.g. “same virus”, have to be understood as genetically the same. Particularly, said (genetically) same virus expresses the same proteins or peptides, wherein all proteins or peptides have the same amino acid sequence. Particularly, said (genetically) same RSV expresses essentially the same proteins, peptides or polyproteins, wherein these protein, peptide or polyproteins preferably do not differ in their amino acid sequence(s). A non-limiting list of exemplary RSV viruses is provided in List 1. 
     In embodiments, the composition comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or even more different RNAs as defined in the context of the first aspect of the invention each encoding at least one peptide or protein derived from a genetically different RSV or a fragment or variant thereof. The terms “different” or “different RSV” as used throughout the present specification in the context of a virus, e.g. “different” virus, has to be understood as the difference between at least two respective viruses, wherein the difference is manifested on the RNA genome of the respective different virus. Particularly, said (genetically) different RSV expresses at least one different protein, peptide or polyprotein, wherein the at least one different protein, peptide or polyprotein preferably differs in at least one amino acid. 
     In other embodiments, the composition comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or even more further RNA constructs encoding RSV antigens selected from glycoprotein G, short hydrophobic protein SH, matrix protein M, nucleoprotein N, large polymerase L, M2-1 protein, M2-2 protein, phosphoprotein P, non-structural protein NS1 or non-structural protein NS2, or any combination thereof. 
     For the production of a composition comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 further RNA constructs encoding RSV, methods as disclosed in the PCT application PCT/EP2016/082487 or in published patent application WO2017/1090134A1 are preferably used and adapted accordingly. 
     In preferred embodiments, the composition of the second aspect comprises at least one artificial RNA of the first aspect and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV selected from matrix protein M, nucleoprotein N, M2-1 protein, and/or phosphoprotein P or combinations thereof. The addition of a further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M, N, M2-1, and/or phosphoprotein P (or combinations thereof) is particularly advantageous to e.g. promote a T-cell immune response. 
     Notably, embodiments relating to the artificial RNA of the first aspect may likewise be read on and be understood as suitable embodiments of the at least one further artificial RNA of the second aspect (e.g., embodiments relating to UTR combinations, cds optimizations, histone stem loop, PolyA, PolyC, cap structure, mRNA structure, mRNA production and mRNA purification etc.). 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV matrix protein M. 
     Alternatively, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV N. 
     Alternatively, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M2-1. 
     Alternatively, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV P. 
     In preferred embodiments, the composition of the second aspect comprises two further artificial RNA species each comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV selected from matrix protein M, nucleoprotein N, M2-1, and phosphoprotein P. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M, and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV N. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV N, and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M2-1. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV P, and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M2-1. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV P, and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV N. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M, and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M2-1. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M, and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV P. 
     In preferred embodiments, the composition of the second aspect comprises three further artificial RNA species each comprising at comprising three further artificial RNA species each comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV selected from matrix protein M, nucleoprotein N, M2-1, and phosphoprotein P. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV N, and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV P. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M2-1, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV N, and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV P. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M2-1, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M, and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV P. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M2-1, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M, and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV N. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M2-1. 
     In preferred embodiments, the composition of the second aspect comprises four further artificial RNA species each comprising at comprising three further artificial RNA species each comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV selected from matrix protein M, nucleoprotein N, M2-1, and phosphoprotein P. 
     Accordingly, the composition of the second aspect may suitably comprise at least one artificial RNA of the first aspect encoding RSF F, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV N, at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV P, and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV M2-1. 
     In preferred embodiments of the second aspect, the coding sequence of the further artificial RNA encodes at least one of the amino acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 9684, 10053-10133, 10134, 10503-10636, 10637, 11006-11182, 11183, 11552-11725, 19844, 20213, 20582, 20951 or a fragment or variant of any of these sequences. Additional information regarding each of these suitable amino acid sequences encoding RSV proteins may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt; as explained in the following. 
     In further embodiments of the second aspect, the coding sequence of the further artificial RNA encodes at least one antigenic peptide or protein as defined herein and additionally a heterologous secretory signal sequence or heterologous secretory signal peptide. The heterologous secretory signal sequence may increase the secretion of the encoded antigenic peptide or protein. 
     Suitable secretory signal peptides may be selected from the list of amino acid sequences according to SEQ ID NOs: 1-1115 and SEQ ID NO: 1728 of the patent application WO2017/081082, or fragments or variants of these sequences. On nucleic acid level, any nucleic acid sequence (e.g. RNA sequence) may be selected which encodes such amino acid sequences. In this context, the disclosure of WO2017/081082 is herewith incorporated by reference. 
     According to embodiments, the secretory signal sequence comprises an amino acid sequence being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 21329-21362 or a fragment or variant of any of these sequences. Additional information regarding each of these suitable amino acid sequences encoding secretory signal sequences may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt;. 
     In preferred embodiments, the further artificial RNA of the composition comprises
     a) at least one heterologous 5′ untranslated region (5′-UTR) and/or at least one heterologous 3′ untranslated region (3′-UTR); and   b) at least one coding sequence operably linked to said 3′-UTR and/or 5′-UTR encoding at least one antigenic peptide or protein derived from a RSV M, N, M2-1, and/or phosphoprotein P or a fragment or variant thereof, preferably encoding an amino acid sequence selected from any one of SEQ ID NOs: 9684, 10053-10133, 10134, 10503-10636, 10637, 11006-11182, 11183, 11552-11725, 19844, 20213, 20582, 20951 or a fragment or variant of any of these sequences.   

     In preferred embodiments, the further artificial RNA of the composition comprises
     a) at least one heterologous 5′ untranslated region (5′-UTR) and/or at least one heterologous 3′ untranslated region (3′-UTR); and   b) at least one coding sequence operably linked to said 3′-UTR and/or 5′-UTR encoding at least one antigenic peptide or protein derived from a RSV M2-1 or a fragment or variant thereof, preferably encoding an amino acid sequence selected from any one of SEQ ID NOs: 11183, 20953, 21414 or a fragment or variant of any of these sequences.   

     Suitably, the further artificial RNA of the composition comprises a coding sequence is operably linked to a 3′-UTR and a 5′-UTR selected from a-1, a-2, a-3, a-4, a-5, b-1, b-2, b-3, b-4, b-5, c-1, c-2, c-3, c-4, c-5, d-1, d-2, d-3, d-4, d-5, e-1, e-2, e-3, e-4, e-5, e-6, f-1, f-2, f-3, f-4, f-5, g-1, g-2, g-3, g-4, g-5, h-1, h-2, h- 3, h-4, h-5, i-1, i-2, or i-3 (as defined in the context of the first aspect). 
     Suitably, the further artificial RNA of the composition comprises a coding sequence wherein at least one or more than one, or wherein preferably all uracil nucleotides are replaced by pseudouridine (L) nucleotides or N1-methylpseudouridine (m1L) nucleotides. 
     Accordingly, in other embodiments, the further artificial RNA of of the composition may comprise a 5′-cap sequence element according to SEQ ID NOs: 43 or 21321, or a fragment or variant thereof. 
     In preferred embodiments of the second aspect, the coding sequence of the further RNA comprises at least one of the nucleic acid sequences being identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 9685-9692, 10135-10142, 10638-10645, 11184-11119, 19845-19852, 20214-20221, 20583-20590, 20952-20959, 21385-21388, 21411-21414 or a fragment or a fragment or variant of any of these sequences (cds optimizations as defined in the context of the first aspect). Additional information regarding each of these suitable amino acid sequences encoding RSV proteins may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt; as explained in the following. 
     In preferred embodiments of the second aspect, the further artificial RNA, preferably the further mRNA of the composition comprises preferably in 5′- to 3-direction the following elements a)-i):
     a) 5′-cap structure, preferably as specified in the context of the first aspect, most preferably a Cap1 structure;   b) optionally, 5′-UTR as specified in the context of the first aspect, preferably at least one selected from SEQ ID NOs: 1-22;   c) a ribosome binding site, preferably as specified herein; d) at least one coding sequence selected from SEQ ID NOs: 9685-9692, 10135-10142, 10638-10645, 11184-11119, 19845-19852, 20214-20221, 20583-20590, 20952-20959, 21385-21388, 21411-21414;   e) 3′-UTR as as specified in the context of the first aspect, preferably at least one selected from SEQ ID NOs: 23-38;   f) optionally, a poly(A) sequence, preferably as specified in the context of the first aspect;   g) optionally, a poly(C) sequence, preferably as specified in the context of the first aspect;   h) optionally, a histone stem-loop, preferably as specified in the context of the first aspect;   i) optionally, a 3′-terminal sequence element as specified in the context of the first aspect, preferably
       according to according to SEQ ID NOs: 44-63, or 21322-21328, and wherein optionally at least one or more than one, preferably wherein all uracil nucleotides are replaced by pseudouridine (ψ) nucleotides or N1-methylpseudouridine (m1ψ) nucleotides.   
       

     In particularly preferred embodiments of the second aspect, the further artificial RNA, preferably the further mRNA of the composition comprises preferably in 5′- to 3′-direction the following elements a)-i):
     a) 5′-cap structure, preferably as specified in the context of the first aspect, most preferably a Cap1 structure;   b) optionally, 5′-UTR as specified in the context of the first aspect, preferably at least one selected from SEQ ID NOs: 1-22;   c) a ribosome binding site, preferably as specified herein;   d) at least one coding sequence selected from SEQ ID NOs: 11185-11191, 21388, 20952-20959, 21414;   e) 3′-UTR as as specified in the context of the first aspect, preferably at least one selected from SEQ ID NOs: 23-38;   f) optionally, a poly(A) sequence, preferably as specified in the context of the first aspect;   g) optionally, a poly(C) sequence, preferably as specified in the context of the first aspect;   h) optionally, a histone stem-loop, preferably as specified in the context of the first aspect;   i) optionally, a 3′-terminal sequence element as specified in the context of the first aspect, preferably according to according to SEQ ID NOs: 44-63, or 21322-21328, and
       wherein optionally at least one or more than one, preferably wherein all uracil nucleotides are replaced by pseudouridine (Ly) nucleotides or N1-methylpseudouridine (m1Ly) nucleotides.   
       

     In that context, preferred RSV polypeptide, nucleic acid, and mRNA sequences of the second aspect are provided in Table 7A. 
     In Table 7A, Columns A to D represent specific suitable constructs of the second aspect derived from RSV protein, wherein Column A provides suitable sequences for M, Column B provides suitable sequences for N, Column C provides suitable sequences for P, and Column D provides suitable sequences M2-1. 
     The protein names/designs are indicated in row 1 (Columns A to D), the protein SEQ ID NOs as provided in the sequence listing are in row 2 (“PRT”). Preferred protein SEQ ID NOs of HRSV(A2) are provided in row 3 (“HRSV(A2) PRT”). The SEQ ID NOs of corresponding coding sequences for each indicated HRSV(A2) protein are provided in rows 4-11 (“cds wt”, “cds opt1”, “cds opt2”, “cds opt3”, “cds opt4”, “cds opt5”, “cds opt6”, “cds opt11”, respectively). The SEQ ID NOs of corresponding mRNA constructs comprising said coding sequences and suitable 3′-UTRs and 5′-UTRs according to the invention are provided in rows 12 to 55 (“mRNA design a-1” to “mRNA design i-3” as specified herein). 
     Preferred protein SEQ ID NOs of HRSV(Memphis-37) are provided in row 56 (“Memphis-37 PRT”). The SEQ ID NOs of corresponding coding sequences for each indicated HRSV(Memphis-37) protein are provided in rows 57-64 (“cds wt”, “cds opt1”, “cds opt2”, “cds opt3”, “cds opt4”, “cds opt5”, “cds opt6”, “cds opt11”, respectively). 
     The SEQ ID NOs of corresponding mRNA constructs comprising said coding sequences and suitable 3′-UTRs and 5′-UTRs according to the invention are provided in rows 65 to 108 (“mRNA design a-” to “mRNA design i-3” as specified herein). 
     Further information e.g. regarding the type of coding sequence comprised in the indicated mRNA constructs is provided in the &lt;223&gt; identifier of the respective SEQ ID NO in the sequence listing. 
     
       
         
           
               
             
               
                 TABLE 7A 
               
             
            
               
                   
               
               
                 Preferred further coding sequences and mRNA constructs of the composition or vaccine 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 A 
                 B 
                 C 
                 D 
               
               
                 1 
                 Strain 
                 Description 
                 RSV M 
                 RSV N 
                 RSV P 
                 RSV M2-1 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 2 
                 divers 
                 PRT 
                 10053-10133 
                 10503-10636 
                 11006-11182 
                 11552-11725 
               
               
                 3 
                 HRSV(A2) 
                 PRT 
                 9684 
                 10134 
                 10637 
                 11183 
               
               
                 4 
                 HRSV(A2) 
                 cds wt 
                 9685 
                 10135 
                 10638 
                 11184 
               
               
                 5 
                 HRSV(A2) 
                 CDS opt1 
                 9686, 21385 
                 10136, 21386 
                 10639, 21387 
                 11185, 21388 
               
               
                 6 
                 HRSV(A2) 
                 cds opt2 
                 9687 
                 10137 
                 10640 
                 11186 
               
               
                 7 
                 HRSV(A2) 
                 cds opt3 
                 9688 
                 10138 
                 10641 
                 11187 
               
               
                 8 
                 HRSV(A2) 
                 cds opt4 
                 9689 
                 10139 
                 10642 
                 11188 
               
               
                 9 
                 HRSV(A2) 
                 cds opt5 
                 9690 
                 10140 
                 10643 
                 11189 
               
               
                 10 
                 HRSV(A2) 
                 cds opt6 
                 9691 
                 10141 
                 10644 
                 11190 
               
               
                 11 
                 HRSV(A2) 
                 cds opt11 
                 9692 
                 10142 
                 10645 
                 11191 
               
               
                 12 
                 HRSV(A2) 
                 mRNA Design a-1 
                 9693-9700, 
                 10143-10150, 
                 10646-10653, 
                 11192-11199, 
               
               
                   
                   
                   
                 21481, 21482, 
                 21483, 21484, 
                 21485, 21486, 
                 21487, 21488, 
               
               
                   
                   
                   
                 21627, 21628 
                 21629, 21630 
                 21631, 21632 
                 21633, 21634 
               
               
                 13 
                 HRSV(A2) 
                 mRNA Design a-2 
                 9701-9708 
                 10151-10158 
                 10654-10661 
                 11200-11207 
               
               
                 14 
                 HRSV(A2) 
                 mRNA Design a-3 
                 9709-9716 
                 10159-10166 
                 10662-10669 
                 11208-11215 
               
               
                 15 
                 HRSV(A2) 
                 mRNA Design a-4 
                 9717-9724 
                 10167-10174 
                 10670-10677 
                 11216-11223 
               
               
                 16 
                 HRSV(A2) 
                 mRNA Design a-5 
                 9725-9732 
                 10175-10182 
                 10678-10685 
                 11224-11231 
               
               
                 17 
                 HRSV(A2) 
                 mRNA Design b-1 
                 9733-9740 
                 10183-10190 
                 10686-10693 
                 11232-11239 
               
               
                 18 
                 HRSV(A2) 
                 mRNA Design b-2 
                 9741-9748 
                 10191-10198 
                 10694-10701 
                 11240-11247 
               
               
                 19 
                 HRSV(A2) 
                 mRNA Design b-3 
                 9749-9756 
                 10199-10206 
                 10702-10709 
                 11248-11255 
               
               
                 20 
                 HRSV(A2) 
                 mRNA Design b-4 
                 9757-9764 
                 10207-10214 
                 10710-10717 
                 11256-11263 
               
               
                 21 
                 HRSV(A2) 
                 mRNA Design b-5 
                 9765-9772 
                 10215-10222 
                 10718-10725 
                 11264-11271 
               
               
                 22 
                 HRSV(A2) 
                 mRNA Design c-1 
                 9773-9780 
                 10223-10230 
                 10726-10733 
                 11272-11279 
               
               
                 23 
                 HRSV(A2) 
                 mRNA Design c-2 
                 9781-9788 
                 10231-10238 
                 10734-10741 
                 11280-11287 
               
               
                 24 
                 HRSV(A2) 
                 mRNA Design c-3 
                 9789-9796 
                 10239-10246 
                 10742-10749 
                 11288-11295 
               
               
                 25 
                 HRSV(A2) 
                 mRNA Design c-4 
                 9797-9804 
                 10247-10254 
                 10750-10757 
                 11296-11303 
               
               
                 26 
                 HRSV(A2) 
                 mRNA Design c-5 
                 9805-9812 
                 10255-10262 
                 10758-10765 
                 11304-11311 
               
               
                 27 
                 HRSV(A2) 
                 mRNA Design d-1 
                 9813-9820 
                 10263-10270 
                 10766-10773 
                 11312-11319 
               
               
                 28 
                 HRSV(A2) 
                 mRNA Design d-2 
                 9821-9828 
                 10271-10278 
                 10774-10781 
                 11320-11327 
               
               
                 29 
                 HRSV(A2) 
                 mRNA Design d-3 
                 9829-9836 
                 10279-10286 
                 10782-10789 
                 11328-11335 
               
               
                 30 
                 HRSV(A2) 
                 mRNA Design d-4 
                 9837-9844 
                 10287-10294 
                 10790-10797 
                 11336-11343 
               
               
                 31 
                 HRSV(A2) 
                 mRNA Design d-5 
                 9845-9852 
                 10295-10302 
                 10798-10805 
                 11344-11351 
               
               
                 32 
                 HRSV(A2) 
                 mRNA Design e-1 
                 9853-9860 
                 10303-10310 
                 10806-10813 
                 11352-11359 
               
               
                 33 
                 HRSV(A2) 
                 mRNA Design e-2 
                 9861-9868 
                 10311-10318 
                 10814-10821 
                 11360-11367 
               
               
                 34 
                 HRSV(A2) 
                 mRNA Design e-3 
                 9869-9876 
                 10319-10326 
                 10822-10829 
                 11368-11375 
               
               
                 35 
                 HRSV(A2) 
                 mRNA Design e-4 
                 9877-9884 
                 10327-10334 
                 10830-10837 
                 11376-11383 
               
               
                 36 
                 HRSV(A2) 
                 mRNA Design e-5 
                 9885-9892 
                 10335-10342 
                 10838-10845 
                 11384-11391 
               
               
                 37 
                 HRSV(A2) 
                 mRNA Design e-6 
                 9893-9900 
                 10343-10350 
                 10846-10853 
                 11392-11399 
               
               
                 38 
                 HRSV(A2) 
                 mRNA Design f-1 
                 9901-9908 
                 10351-10358 
                 10854-10861 
                 11400-11407 
               
               
                 39 
                 HRSV(A2) 
                 mRNA Design f-2 
                 9909-9916 
                 10359-10366 
                 10862-10869 
                 11408-11415 
               
               
                 40 
                 HRSV(A2) 
                 mRNA Design f-3 
                 9917-9924 
                 10367-10374 
                 10870-10877 
                 11416-11423 
               
               
                 41 
                 HRSV(A2) 
                 mRNA Design f-4 
                 9925-9932 
                 10375-10382 
                 10878-10885 
                 11424-11431 
               
               
                 42 
                 HRSV(A2) 
                 mRNA Design f-5 
                 9933-9940 
                 10383-10390 
                 10886-10893 
                 11432-11439 
               
               
                 43 
                 HRSV(A2) 
                 mRNA Design g-1 
                 9941-9948 
                 10391-10398 
                 10894-10901 
                 11440-11447 
               
               
                 44 
                 HRSV(A2) 
                 mRNA Design g-2 
                 9949-9956 
                 10399-10406 
                 10902-10909 
                 11448-11455 
               
               
                 45 
                 HRSV(A2) 
                 mRNA Design g-3 
                 9957-9964 
                 10407-10414 
                 10910-10917 
                 11456-11463 
               
               
                 46 
                 HRSV(A2) 
                 mRNA Design g-4 
                 9965-9972 
                 10415-10422 
                 10918-10925 
                 11464-11471 
               
               
                 47 
                 HRSV(A2) 
                 mRNA Design g-5 
                 9973-9980 
                 10423-10430 
                 10926-10933 
                 11472-11479 
               
               
                 48 
                 HRSV(A2) 
                 mRNA Design h-1 
                 9981-9988 
                 10431-10438 
                 10934-10941 
                 11480-11487 
               
               
                 49 
                 HRSV(A2) 
                 mRNA Design h-2 
                 9989-9996 
                 10439-10446 
                 10942-10949 
                 11488-11495 
               
               
                 50 
                 HRSV(A2) 
                 mRNA Design h-3 
                  9997-10004 
                 10447-10454 
                 10950-10957 
                 11496-11503 
               
               
                 51 
                 HRSV(A2) 
                 mRNA Design h-4 
                 10005-10012 
                 10455-10462 
                 10958-10965 
                 11504-11511 
               
               
                 52 
                 HRSV(A2) 
                 mRNA Design h-5 
                 10013-10020 
                 10463-10470 
                 10966-10973 
                 11512-11519 
               
               
                 53 
                 HRSV(A2) 
                 mRNA Design i-1 
                 10021-10028 
                 10471-10478 
                 10974-10981 
                 11520-11527 
               
               
                 54 
                 HRSV(A2) 
                 mRNA Design i-2 
                 10029-10044 
                 10479-10494 
                 10982-10997 
                 11528-11543 
               
               
                 55 
                 HRSV(A2) 
                 mRNA Design i-3 
                 10045-10052 
                 10495-10502 
                 10998-11005 
                 11544-11551 
               
               
                 56 
                 Memphis-37 
                 PRT 
                 19844 
                 20213 
                 20582 
                 20951 
               
               
                 57 
                 Memphis-37 
                 CDS wt 
                 19845 
                 20214 
                 20583 
                 20952 
               
               
                 58 
                 Memphis-37 
                 CDS opt1 
                 19846, 21411 
                 20215, 21412 
                 20584, 21413 
                 20953, 21414 
               
               
                 59 
                 Memphis-37 
                 CDS opt2 
                 19847 
                 20216 
                 20585 
                 20954 
               
               
                 60 
                 Memphis-37 
                 CDS opt3 
                 19848 
                 20217 
                 20586 
                 20955 
               
               
                 61 
                 Memphis-37 
                 CDS opt4 
                 19849 
                 20218 
                 20587 
                 20956 
               
               
                 62 
                 Memphis-37 
                 CDS opt5 
                 19850 
                 20219 
                 20588 
                 20957 
               
               
                 63 
                 Memphis-37 
                 CDS opt6 
                 19851 
                 20220 
                 20589 
                 20958 
               
               
                 64 
                 Memphis-37 
                 CDS opt11 
                 19852 
                 20221 
                 20590 
                 20959 
               
               
                 65 
                 Memphis-37 
                 mRNA Design a-1 
                 19853-19860, 
                 20222-20229, 
                 20591-20598, 
                 20960-20967, 
               
               
                   
                   
                   
                 21553, 21554, 
                 21555, 21556, 
                 21557, 21558, 
                 21559, 21560, 
               
               
                   
                   
                   
                 21699, 21700 
                 21701, 21702 
                 21703, 21704 
                 21705, 21706 
               
               
                 66 
                 Memphis-37 
                 mRNA Design a-2 
                 19861-19868 
                 20230-20237 
                 20599-20606 
                 20968-20975 
               
               
                 67 
                 Memphis-37 
                 mRNA Design a-3 
                 19869-19876 
                 20238-20245 
                 20607-20614 
                 20976-20983 
               
               
                 68 
                 Memphis-37 
                 mRNA Design a-4 
                 19877-19884 
                 20246-20253 
                 20615-20622 
                 20984-20991 
               
               
                 69 
                 Memphis-37 
                 mRNA Design a-5 
                 19885-19892 
                 20254-20261 
                 20623-20630 
                 20992-20999 
               
               
                 70 
                 Memphis-37 
                 mRNA Design b-1 
                 19893-19900 
                 20262-20269 
                 20631-20638 
                 21000-21007 
               
               
                 71 
                 Memphis-37 
                 mRNA Design b-2 
                 19901-19908 
                 20270-20277 
                 20639-20646 
                 21008-21015 
               
               
                 72 
                 Memphis-37 
                 mRNA Design b-3 
                 19909-19916 
                 20278-20285 
                 20647-20654 
                 21016-21023 
               
               
                 73 
                 Memphis-37 
                 mRNA Design b-4 
                 19917-19924 
                 20286-20293 
                 20655-20662 
                 21024-21031 
               
               
                 74 
                 Memphis-37 
                 mRNA Design b-5 
                 19925-19932 
                 20294-20301 
                 20663-20670 
                 21032-21039 
               
               
                 75 
                 Memphis-37 
                 mRNA Design c-1 
                 19933-19940 
                 20302-20309 
                 20671-20678 
                 21040-21047 
               
               
                 76 
                 Memphis-37 
                 mRNA Design c-2 
                 19941-19948 
                 20310-20317 
                 20679-20686 
                 21048-21055 
               
               
                 77 
                 Memphis-37 
                 mRNA Design c-3 
                 19949-19956 
                 20318-20325 
                 20687-20694 
                 21056-21063 
               
               
                 78 
                 Memphis-37 
                 mRNA Design c-4 
                 19957-19964 
                 20326-20333 
                 20695-20702 
                 21064-21071 
               
               
                 79 
                 Memphis-37 
                 mRNA Design c-5 
                 19965-19972 
                 20334-20341 
                 20703-20710 
                 21072-21079 
               
               
                 80 
                 Memphis-37 
                 mRNA Design d-1 
                 19973-19980 
                 20342-20349 
                 20711-20718 
                 21080-21087 
               
               
                 81 
                 Memphis-37 
                 mRNA Design d-2 
                 19981-19988 
                 20350-20357 
                 20719-20726 
                 21088-21095 
               
               
                 82 
                 Memphis-37 
                 mRNA Design d-3 
                 19989-19996 
                 20358-20365 
                 20727-20734 
                 21096-21103 
               
               
                 83 
                 Memphis-37 
                 mRNA Design d-4 
                 19997-20004 
                 20366-20373 
                 20735-20742 
                 21104-21111 
               
               
                 84 
                 Memphis-37 
                 mRNA Design d-5 
                 20005-20012 
                 20374-20381 
                 20743-20750 
                 21112-21119 
               
               
                 85 
                 Memphis-37 
                 mRNA Design e-1 
                 20013-20020 
                 20382-20389 
                 20751-20758 
                 21120-21127 
               
               
                 86 
                 Memphis-37 
                 mRNA Design e-2 
                 20021-20028 
                 20390-20397 
                 20759-20766 
                 21128-21135 
               
               
                 87 
                 Memphis-37 
                 mRNA Design e-3 
                 20029-20036 
                 20398-20405 
                 20767-20774 
                 21136-21143 
               
               
                 88 
                 Memphis-37 
                 mRNA Design e-4 
                 20037-20044 
                 20406-20413 
                 20775-20782 
                 21144-21151 
               
               
                 89 
                 Memphis-37 
                 mRNA Design e-5 
                 20045-20052 
                 20414-20421 
                 20783-20790 
                 21152-21159 
               
               
                 90 
                 Memphis-37 
                 mRNA Design e-6 
                 20053-20060 
                 20422-20429 
                 20791-20798 
                 21160-21167 
               
               
                 91 
                 Memphis-37 
                 mRNA Design f-1 
                 20061-20068 
                 20430-20437 
                 20799-20806 
                 21168-21175 
               
               
                 92 
                 Memphis-37 
                 mRNA Design f-2 
                 20069-20076 
                 20438-20445 
                 20807-20814 
                 21176-21183 
               
               
                 93 
                 Memphis-37 
                 mRNA Design f-3 
                 20077-20084 
                 20446-20453 
                 20815-20822 
                 21184-21191 
               
               
                 94 
                 Memphis-37 
                 mRNA Design f-4 
                 20085-20092 
                 20454-20461 
                 20823-20830 
                 21192-21199 
               
               
                 95 
                 Memphis-37 
                 mRNA Design f-5 
                 20093-20100 
                 20462-20469 
                 20831-20838 
                 21200-21207 
               
               
                 96 
                 Memphis-37 
                 mRNA Design g-1 
                 20101-20108 
                 20470-20477 
                 20839-20846 
                 21208-21215 
               
               
                 97 
                 Memphis-37 
                 mRNA Design g-2 
                 20109-20116 
                 20478-20485 
                 20847-20854 
                 21216-21223 
               
               
                 98 
                 Memphis-37 
                 mRNA Design g-3 
                 20117-20124 
                 20486-20493 
                 20855-20862 
                 21224-21231 
               
               
                 99 
                 Memphis-37 
                 mRNA Design g-4 
                 20125-20132 
                 20494-20501 
                 20863-20870 
                 21232-21239 
               
               
                 100 
                 Memphis-37 
                 mRNA Design g-5 
                 20133-20140 
                 20502-20509 
                 20871-20878 
                 21240-21247 
               
               
                 101 
                 Memphis-37 
                 mRNA Design h-1 
                 20141-20148 
                 20510-20517 
                 20879-20886 
                 21248-21255 
               
               
                 102 
                 Memphis-37 
                 mRNA Design h-2 
                 20149-20156 
                 20518-20525 
                 20887-20894 
                 21256-21263 
               
               
                 103 
                 Memphis-37 
                 mRNA Design h-3 
                 20157-20164 
                 20526-20533 
                 20895-20902 
                 21264-21271 
               
               
                 104 
                 Memphis-37 
                 mRNA Design h-4 
                 20165-20172 
                 20534-20541 
                 20903-20910 
                 21272-21279 
               
               
                 105 
                 Memphis-37 
                 mRNA Design h-5 
                 20173-20180 
                 20542-20549 
                 20911-20918 
                 21280-21287 
               
               
                 106 
                 Memphis-37 
                 mRNA Design i-1 
                 20181-20188 
                 20550-20557 
                 20919-20926 
                 21288-21295 
               
               
                 107 
                 Memphis-37 
                 mRNA Design i-2 
                 20189-20204 
                 20558-20573 
                 20927-20942 
                 21296-21311 
               
               
                 108 
                 Memphis-37 
                 mRNA Design i-3 
                 20205-20212 
                 20574-20581 
                 20943-20950 
                 21312-21319 
               
               
                   
               
            
           
         
       
     
     Accordingly, in preferred embodiments, the composition of the second aspect comprises at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV selected from matrix protein M, nucleoprotein N, M2-1 protein, phosphoprotein P, wherein the further artificial RNA comprises or consists of an RNA sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 9693-10052, 10143-10502, 10646-11005, 11192-11551, 19853-20212, 20222-20581, 20591-20950, 20960-21319, 21481-21488, 21627-21634, 21553-21560, 21699-21706 or a fragment or variant of any of these sequences, wherein, optionally, at least one or more than one, or wherein all uracil nucleotides are replaced by pseudouridine (ψ) nucleotides or N1-methylpseudouridine (m1 ψ) nucleotides. Additional information regarding each of these suitable amino acid sequences encoding RSV proteins may also be derived from the sequence listing, in particular from the details provided therein under identifier &lt;223&gt; as explained in the following. 
     In particularly preferred embodiments of the second aspect, the composition of the second aspect comprises
         at least one artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 78-482, 493-897, 907-1266, 1276-1635, 1645-2004, 2014-2373, 2383-2742, 2752-3111, 3121-3480, 3490-3849, 3859-4218, 4228-4587, 4597-4956, 4966-5325, 5335-5694, 5704-6063, 6073-6432, 6442-6801, 6811-7170, 7180-7539, 7549-7908, 7918-8277, 8278, 11735-12094, 12104-12463, 12473-12832, 12842-13201, 13949-14308, 14318-14677, 14687-15046, 15056-15415, 15425-15784, 15794-16153, 13211-13570, 13580-13939, 16163-16522, 16532-16891, 16901-17260, 17270-17629, 17639-17998, 18008-18367, 18377-18736, 18746-19105, 19115-19474, 19484-19843, 21415-21480, 21561-21626, 21489-21552, 21635-21698 (encoding RSV F as defined in the first aspect) and a further artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 9693-10052, 19853-20212, 21481, 21482, 21627, 21628, 21553, 21554, 21699, 21700 (encoding RSV M); or   at least one artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 78-482, 493-897, 907-1266, 1276-1635, 1645-2004, 2014-2373, 2383-2742, 2752-3111, 3121-3480, 3490-3849, 3859-4218, 4228-4587, 4597-4956, 4966-5325, 5335-5694, 5704-6063, 6073-6432, 6442-6801, 6811-7170, 7180-7539, 7549-7908, 7918-8277, 8278, 11735-12094, 12104-12463, 12473-12832, 12842-13201, 13949-14308, 14318-14677, 14687-15046, 15056-15415, 15425-15784, 15794-16153, 13211-13570, 13580-13939, 16163-16522, 16532-16891, 16901-17260, 17270-17629, 17639-17998, 18008-18367, 18377-18736, 18746-19105, 19115-19474, 19484-19843, 21415-21480, 21561-21626, 21489-21552, 21635-21698 (encoding RSV F as defined in the first aspect) and a further artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 10143-10502, 20222-20581, 21483, 21484, 21629, 21630, 21555, 21556, 21701, 21702 (encoding RSV N); or   at least one artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 78-482, 493-897, 907-1266, 1276-1635, 1645-2004, 2014-2373, 2383-2742, 2752-3111, 3121-3480, 3490-3849, 3859-4218, 4228-4587, 4597-4956, 4966-5325, 5335-5694, 5704-6063, 6073-6432, 6442-6801, 6811-7170, 7180-7539, 7549-7908, 7918-8277, 8278, 11735-12094, 12104-12463, 12473-12832, 12842-13201, 13949-14308, 14318-14677, 14687-15046, 15056-15415, 15425-15784, 15794-16153, 13211-13570, 13580-13939, 16163-16522, 16532-16891, 16901-17260, 17270-17629, 17639-17998, 18008-18367, 18377-18736, 18746-19105, 19115-19474, 19484-19843, 21415-21480, 21561-21626, 21489-21552, 21635-21698 (encoding RSV F as defined in the first aspect) and at least one further artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 10646-11005, 20591-20950, 21485, 21486, 21631, 21632, 21557, 21558, 21703, 21704 (encoding RSV P); or   at least one artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 78-482, 493-897, 907-1266, 1276-1635, 1645-2004, 2014-2373, 2383-2742, 2752-3111, 3121-3480, 3490-3849, 3859-4218, 4228-4587, 4597-4956, 4966-5325, 5335-5694, 5704-6063, 6073-6432, 6442-6801, 6811-7170, 7180-7539, 7549-7908, 7918-8277, 8278, 11735-12094, 12104-12463, 12473-12832, 12842-13201, 13949-14308, 14318-14677, 14687-15046, 15056-15415, 15425-15784, 15794-16153, 13211-13570, 13580-13939, 16163-16522, 16532-16891, 16901-17260, 17270-17629, 17639-17998, 18008-18367, 18377-18736, 18746-19105, 19115-19474, 19484-19843, 21415-21480, 21561-21626, 21489-21552, 21635-21698 (encoding RSV F as defined in the first aspect) and at least one further artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 11192-11551, 20960-21319, 21487, 21488, 21633, 21634, 21559, 21560, 21705, 21706 (encoding RSV M2-1); or   at least one artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 78-482, 493-897, 907-1266, 1276-1635, 1645-2004, 2014-2373, 2383-2742, 2752-3111, 3121-3480, 3490-3849, 3859-4218, 4228-4587, 4597-4956, 4966-5325, 5335-5694, 5704-6063, 6073-6432, 6442-6801, 6811-7170, 7180-7539, 7549-7908, 7918-8277, 8278, 11735-12094, 12104-12463, 12473-12832, 12842-13201, 13949-14308, 14318-14677, 14687-15046, 15056-15415, 15425-15784, 15794-16153, 13211-13570, 13580-13939, 16163-16522, 16532-16891, 16901-17260, 17270-17629, 17639-17998, 18008-18367, 18377-18736, 18746-19105, 19115-19474, 19484-19843, 21415-21480, 21561-21626, 21489-21552, 21635-21698 (encoding RSV F as defined in the first aspect) and at least one further artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 9693-10052, 19853-20212, 21481, 21482, 21627, 21628, 21553, 21554, 21699, 21700 (encoding RSV M) and a further artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 10646-11005, 20591-20950, 21485, 21486, 21631, 21632, 21557, 21558, 21703, 21704 (encoding RSV P);   at least one artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 78-482, 493-897, 907-1266, 1276-1635, 1645-2004, 2014-2373, 2383-2742, 2752-3111, 3121-3480, 3490-3849, 3859-4218, 4228-4587, 4597-4956, 4966-5325, 5335-5694, 5704-6063, 6073-6432, 6442-6801, 6811-7170, 7180-7539, 7549-7908, 7918-8277, 8278, 11735-12094, 12104-12463, 12473-12832, 12842-13201, 13949-14308, 14318-14677, 14687-15046, 15056-15415, 15425-15784, 15794-16153, 13211-13570, 13580-13939, 16163-16522, 16532-16891, 16901-17260, 17270-17629, 17639-17998, 18008-18367, 18377-18736, 18746-19105, 19115-19474, 19484-19843, 21415-21480, 21561-21626, 21489-21552, 21635-21698 (encoding RSV F as defined in the first aspect) and at least one further artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 9693-10052, 19853-20212, 21481, 21482, 21627, 21628, 21553, 21554, 21699, 21700 (encoding RSV M) and a further artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 10646-11005, 20591-20950, 21485, 21486, 21631, 21632, 21557, 21558, 21703, 21704 (encoding RSV P) and a further artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 10143-10502, 20222-20581, 21483, 21484, 21629, 21630, 21555, 21556, 21701, 21702 (encoding RSV N), or   at least one artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from SEQ ID NOs: 78-86, 21415-21417, 21561-21563, 474-482, 11735-11742, 21489, 21490, 21635, 21636, 12087-12094, 493-501, 21418-21420, 21564-21566, 889-897, 12104-12111, 21491, 21492, 21637, 21638, 12456-12463, 907-914, 21421-21423, 21567-21569, 1259-1266, 12473-12480, 21493-21495, 21639-21641, 12825-12832, 1276-1283, 21424-21426, 21570-21572, 1628-1635, 12842-12849, 21496-21498, 21642-21644, 13194-13201, 1645-1652, 21433-21435, 21579-21581, 1997-2004, 13949-13956, 21505-21507, 21651-21653, 14301-14308, 2014-2021, 21436-21438, 21582-21584, 2366-2373, 14318-14325, 21508-21510, 21654-21656, 14670-14677, 2383-2390, 21439-21441, 21585-21587, 2735-2742, 14687-14694, 21511-21513, 21657-21659, 15039-15046, 2752-2759, 21442-21444, 21588-21590, 3104-3111, 15056-15063, 21514-21516, 21660-21662, 15408-15415, 3121-3128, 21445-21447, 21591-21593, 3473-3480, 15425-15432, 21517-21519, 21663-21665, 15777-15784, 3490-3497, 21448-21450, 21594-21596, 3842-3849, 15794-15801, 21520-21522, 21666-21668, 16146-16153, 3859-3866, 21427-21429, 21573-21575, 4211-4218, 13211-13218, 21499-21501, 21645-21647, 13563-13570, 4228-4235, 21430-21432, 21576-21578, 4580-4587, 13580-13587, 21502-21504, 21648-21650, 13932-13939, 4597-4604, 21451-21453, 21597-21599, 4949-4956, 16163-16170, 21523-21525, 21669-21671, 16515-16522, 4966-4973, 21454-21456, 21600-21602, 5318-5325, 16532-16539, 21526-21528, 21672-21674, 16884-16891, 5335-5342, 21457-21459, 21603-21605, 5687-5694, 16901-16908, 21529-21531, 21675-21677, 17253-17260, 5704-5711, 21460-21462, 21606-21608, 6056-6063, 17270-17277, 21532-21534, 21678-21680, 17622-17629 (encoding RSV F as defined in the first aspect) and at least one further artificial RNA which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 11192-11551, 20960-21319, 21487, 21488, 21633, 21634, 21559, 21560, 21705, 21706 (encoding RSV M2-1),       

     wherein, optionally, at least one or more than one, or wherein all uracil nucleotides are replaced by pseudouridine (ψ) nucleotides or N1-methylpseudouridine (m1ψ) nucleotides. 
     In various embodiments, different combinations of RSV F (F0, F-del, F0_DSCav1, F-del_DSCav1, F_DSCav1_mut0, F-del_DSCav1_mut0, F_DSCav1_mut1, F-del_DSCav1_mut1, F_DSCav1_mut2, F-del_DSCav1_mut2, F_DSCav1_mut3, F-del_DSCav1_mut3, F_DSCav1_mut4, F-del_DSCav1_mut4, F_DSCav1_mut5, F-del_DSCav1_mut5, F_DSCav1_mut6, F-del_DSCav1_mut6, F_DSCav1_mut7, F-del_DSCav1_mut7, F_DSCav1_mut8, F-del_DSCav1_mut8) RNA constructs and RSV T-cell antigen RNA constructs (RSV M, N, M2-1, or P) are suitably comprised in the composition (as disclosed in Table 7B; combinations 1-64). The combinations 49-64 are preferred, combination 64 is particularly preferred. 
     
       
         
           
               
             
               
                 TABLE 7B 
               
             
            
               
                   
               
               
                 Suitable combinations of RNA constructs encoding 
               
               
                 RSV F and RNA constructs encoding T-cell antigens 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ ID NO: 
                 T-cell antigen 
                 SEQ ID NO: 
               
               
                 Combination 
                 RSV F construct 
                 Protein 
                 construct 
                 Protein 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1 
                 F0 
                 68 
                 M 
                 9684 
               
               
                 2 
                 F-del 
                 483 
                 M 
                 9684 
               
               
                 3 
                 F_DSCav1 
                 898 
                 M 
                 9684 
               
               
                 4 
                 F-del_DSCav1 
                 1267 
                 M 
                 9684 
               
               
                 5 
                 F_DSCav1_mut1 
                 1636 
                 M 
                 9684 
               
               
                 6 
                 F-del_DSCav1_mut1 
                 2005 
                 M 
                 9684 
               
               
                 7 
                 F_DSCav1_mut2 
                 2374 
                 M 
                 9684 
               
               
                 8 
                 F-del_DSCav1_mut2 
                 2743 
                 M 
                 9684 
               
               
                 9 
                 F_DSCav1_mut3 
                 3112 
                 M 
                 9684 
               
               
                 10 
                 F-del_DSCav1_mut3 
                 3481 
                 M 
                 9684 
               
               
                 11 
                 F_DSCav1_mut0 
                 3850 
                 M 
                 9684 
               
               
                 12 
                 F-del_DSCav1_mut0 
                 4219 
                 M 
                 9684 
               
               
                 13 
                 F_DSCav1_mut4 
                 4588 
                 M 
                 9684 
               
               
                 14 
                 F-del_DSCav1_mut4 
                 4957 
                 M 
                 9684 
               
               
                 15 
                 F_DSCav1_mut5 
                 5326 
                 M 
                 9684 
               
               
                 16 
                 F-del_DSCav1_mut5 
                 5695 
                 M 
                 9684 
               
               
                 17 
                 F0 
                 68 
                 N 
                 10134 
               
               
                 18 
                 F-del 
                 483 
                 N 
                 10134 
               
               
                 19 
                 F_DSCav1 
                 898 
                 N 
                 10134 
               
               
                 20 
                 F-del_DSCav1 
                 1267 
                 N 
                 10134 
               
               
                 21 
                 F_DSCav1_mut1 
                 1636 
                 N 
                 10134 
               
               
                 22 
                 F-del_DSCav1_mut1 
                 2005 
                 N 
                 10134 
               
               
                 23 
                 F_DSCav1_mut2 
                 2374 
                 N 
                 10134 
               
               
                 24 
                 F-del_DSCav1_mut2 
                 2743 
                 N 
                 10134 
               
               
                 25 
                 F_DSCav1_mut3 
                 3112 
                 N 
                 10134 
               
               
                 26 
                 F-del_DSCav1_mut3 
                 3481 
                 N 
                 10134 
               
               
                 27 
                 F_DSCav1_mut0 
                 3850 
                 N 
                 10134 
               
               
                 28 
                 F-del_DSCav1_mut0 
                 4219 
                 N 
                 10134 
               
               
                 29 
                 F_DSCav1_mut4 
                 4588 
                 N 
                 10134 
               
               
                 30 
                 F-del_DSCav1_mut4 
                 4957 
                 N 
                 10134 
               
               
                 31 
                 F_DSCav1_mut5 
                 5326 
                 N 
                 10134 
               
               
                 32 
                 F-del_DSCav1_mut5 
                 5695 
                 N 
                 10134 
               
               
                 33 
                 F0 
                 68 
                 P 
                 10637 
               
               
                 34 
                 F-del 
                 483 
                 P 
                 10637 
               
               
                 35 
                 F_DSCav1 
                 898 
                 P 
                 10637 
               
               
                 36 
                 F-del_DSCav1 
                 1267 
                 P 
                 10637 
               
               
                 37 
                 F_DSCav1_mut1 
                 1636 
                 P 
                 10637 
               
               
                 38 
                 F-del_DSCav1_mut1 
                 2005 
                 P 
                 10637 
               
               
                 39 
                 F_DSCav1_mut2 
                 2374 
                 P 
                 10637 
               
               
                 40 
                 F-del_DSCav1_mut2 
                 2743 
                 P 
                 10637 
               
               
                 41 
                 F_DSCav1_mut3 
                 3112 
                 P 
                 10637 
               
               
                 42 
                 F-del_DSCav1_mut3 
                 3481 
                 P 
                 10637 
               
               
                 43 
                 F_DSCav1_mut0 
                 3850 
                 P 
                 10637 
               
               
                 44 
                 F-del_DSCav1_mut0 
                 4219 
                 P 
                 10637 
               
               
                 45 
                 F_DSCav1_mut4 
                 4588 
                 P 
                 10637 
               
               
                 46 
                 F-del_DSCav1_mut4 
                 4957 
                 P 
                 10637 
               
               
                 47 
                 F_DSCav1_mut5 
                 5326 
                 P 
                 10637 
               
               
                 48 
                 F-del_DSCav1_mut5 
                 5695 
                 P 
                 10637 
               
               
                 49 
                 F0 
                 68 
                 M2-1 
                 11183 
               
               
                 50 
                 F-del 
                 483 
                 M2-1 
                 11183 
               
               
                 51 
                 F_DSCav1 
                 898 
                 M2-1 
                 11183 
               
               
                 52 
                 F-del_DSCav1 
                 1267 
                 M2-1 
                 11183 
               
               
                 53 
                 F_DSCav1_mut1 
                 1636 
                 M2-1 
                 11183 
               
               
                 54 
                 F-del_DSCav1_mut1 
                 2005 
                 M2-1 
                 11183 
               
               
                 55 
                 F_DSCav1_mut2 
                 2374 
                 M2-1 
                 11183 
               
               
                 56 
                 F-del_DSCav1_mut2 
                 2743 
                 M2-1 
                 11183 
               
               
                 57 
                 F_DSCav1_mut3 
                 3112 
                 M2-1 
                 11183 
               
               
                 58 
                 F-del_DSCav1_mut3 
                 3481 
                 M2-1 
                 11183 
               
               
                 59 
                 F_DSCav1_mut0 
                 3850 
                 M2-1 
                 11183 
               
               
                 60 
                 F-del_DSCav1_mut0 
                 4219 
                 M2-1 
                 11183 
               
               
                 61 
                 F_DSCav1_mut4 
                 4588 
                 M2-1 
                 11183 
               
               
                 62 
                 F-del_DSCav1_mut4 
                 4957 
                 M2-1 
                 11183 
               
               
                 63 
                 F_DSCav1_mut5 
                 5326 
                 M2-1 
                 11183 
               
               
                 64 
                 F-del_DSCav1_mut5 
                 5695 
                 M2-1 
                 11183 
               
               
                   
               
            
           
         
       
     
     Table 7B discloses compositions of the second aspect comprising at least one RNA encoding RSV F from the strain A2 as defined in the first aspect and at least one further artificial RNA comprising at least one coding sequence encoding at least one antigenic peptide or protein derived from RSV from the strain A2 selected from matrix protein M, nucleoprotein N, M2-1 protein, phosphoprotein P. In further embodiments of the invention all disclosed compositions in Table 7B are also applicable for antigenic peptides or proteins derived from a RSV isolate Memphis-37 (strain Memphis-37). 
     In a particularly preferred embodiment, the composition comprises one RSV F RNA construct (F0, F-del, F0_DSCav1, F-del_DSCav1, F_DSCav1_mut0, F-del_DSCav1_mut0, F_DSCav1_mut1, F-del_DSCav1_mut1, F_DSCav1_mut2, F-del_DSCav1_mut2, F_DSCav1_mut3, F-del_DSCav1_mut3, F_DSCav1_mut4, F-del_DSCav1_mut4, F_DSCav1_mut5, F-del_DSCav1_mut5, F_DSCav1_mut6, F-del_DSCav1_mut6, F_DSCav1_mut7, F-del_DSCav1_mut7, F_DSCav1_mut8, F-del_DSCav1_mut8) and, in addition, one RSV M2-1 RNA construct, preferably F-del_DSCav1_mut5 and M2-1. 
     In particularly preferred embodiments, one RNA construct encoding RSV F, selected from SEQ ID NOs: 5704-5711, 21460-21462, 21606-21608, 17270-17277, 21532-21534, 21678-21680 and one RNA construct encoding M2-1, selected from SEQ ID NOs: 11192-11199, 21487, 21488, 21633, 21634, 20960-20967, 21559, 21560, 21705, 21706 are comprised in the composition of the invention. 
     In various embodiments, the at least one artificial RNA of the first aspect and the at least one further artificial RNA as specified herein are derived from the same RSV virus (e.g. any virus selected from List 1). 
     In preferred embodiments, the at least one artificial RNA of the first aspect is derived from HRSV(A2) and the at least one further artificial RNA as specified herein is derived from HRSV(A2). 
     In preferred embodiments, the at least one artificial RNA of the first aspect is derived from HRSV(Memphis-37) and the at least one further artificial RNA as specified herein is derived from HRSV(Memphis-37). 
     It has to be understood that in the context of the invention, certain combinations of coding sequences may be generated by any combination of monocistronic, bicistronic and multicistronic artificial nucleic acids and/or multi-antigen-constructs/nucleic acid to obtain a nucleic acid composition encoding multiple antigenic peptides or proteins as defined herein. 
     Furthermore, one or more compatible solid or liquid fillers or diluents or encapsulating compounds may be used as well, which are suitable for administration to a person. The term “compatible” as used herein means that the constituents of the composition are capable of being mixed with the at least one RNA and, optionally, the further artificial RNA of the composition, in such a manner that no interaction occurs, which would substantially reduce the biological activity or the pharmaceutical effectiveness of the composition under typical use conditions. Pharmaceutically acceptable carriers, fillers and diluents must have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to a person to be treated. Compounds which may be used as pharmaceutically acceptable carriers, fillers or constituents thereof are sugars, such as, for example, lactose, glucose, trehalose and sucrose; starches, such as, for example, corn starch or potato starch; dextrose; cellulose and its derivatives, such as, for example, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; tallow; solid glidants, such as, for example, stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as, for example, groundnut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil from theobroma; polyols, such as, for example, polypropylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid. 
     Further additives, which may be included in the composition are emulsifiers, such as, for example, Tween; wetting agents, such as, for example, sodium lauryl sulfate; colouring agents; taste-imparting agents, pharmaceutical carriers; tablet-forming agents; stabilizers; antioxidants; preservatives. 
     Complexation: 
     In a preferred embodiment of the second aspect, the at least one artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed or associated with or at least partially complexed or partially associated with one or more cationic or polycationic compound, preferably cationic or polycationic polymer, cationic or polycationic polysaccharide, cationic or polycationic lipid, cationic or polycationic protein, cationic or polycationic peptide, or any combinations thereof. 
     The term “cationic or polycationic compound” as used herein will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to a charged molecule, which is positively charged at a pH value ranging from about 1 to 9, at a pH value ranging from about 3 to 8, at a pH value ranging from about 4 to 8, at a pH value ranging from about 5 to 8, more preferably at a pH value ranging from about 6 to 8, even more preferably at a pH value ranging from about 7 to 8, most preferably at a physiological pH, e.g. ranging from about 7.2 to about 7.5. Accordingly, a cationic component, e.g. a cationic peptide, cationic protein, cationic polymer, cationic polysaccharide, cationic lipid may be any positively charged compound or polymer which is positively charged under physiological conditions. A “cationic or polycationic peptide or protein” may contain at least one positively charged amino acid, or more than one positively charged amino acid, e.g. selected from Arg, His, Lys or Orn. Accordingly, “polycationic” components are also within the scope exhibiting more than one positive charge under the given conditions. 
     Cationic or polycationic compounds, being particularly preferred in this context may be selected from the following list of cationic or polycationic peptides or proteins of fragments thereof: protamine, nucleoline, spermine or spermidine, or other cationic peptides or proteins, such as poly-L-lysine (PLL), poly-arginine, basic polypeptides, cell penetrating peptides (CPPs), including HIV-binding peptides, HIV-1 Tat (HIV), Tat-derived peptides, Penetratin, VP22 derived or analog peptides, HSV VP22 (Herpes simplex), MAP, KALA or protein transduction domains (PTDs), PpT620, prolin-rich peptides, arginine-rich peptides, lysine-rich peptides, MPG-peptide(s), Pep-1, L-oligomers, Calcitonin peptide(s), Antennapedia-derived peptides, pAntp, ps, FGF, Lactoferrin, Transportan, Buforin-2, Bac715-24, SynB, SynB(1), pVEC, hCT-derived peptides, SAP, or histones. More preferably, the nucleic acid as defined herein, preferably the mRNA as defined herein, is complexed with one or more polycations, preferably with protamine or oligofectamine, most preferably with protamine. 
     In a preferred embodiment of the second aspect, the at least one artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed with protamine 
     Further preferred cationic or polycationic compounds, which can be used as transfection or complexation agent may include cationic polysaccharides, for example chitosan, polybrene etc.; cationic lipids, e.g. DOTMA, DMRIE, di-C14-amidine, DOTIM, SAINT, DC-Chol, BGTC, CTAP, DOPC, DODAP, DOPE: Dioleyl phosphatidylethanol-amine, DOSPA, DODAB, DOIC, DMEPC, DOGS, DIMRI, DOTAP, DC-6-14, CLIP1, CLIP6, CLIP9, oligofectamine; or cationic or polycationic polymers, e.g. modified polyaminoacids, such as beta-aminoacid-polymers or reversed polyamides, etc., modified polyethylenes, such as PVP etc., modified acrylates, such as pDMAEMA etc., modified amidoamines such as pAMAM etc., modified polybetaaminoester (PBAE), such as diamine end modified 1,4 butanediol diacrylate-co-5-amino-1-pentanol polymers, etc., dendrimers, such as polypropylamine dendrimers or pAMAM based dendrimers, etc., polyimine(s), such as PEI, poly(propyleneimine), etc., polyallylamine, sugar backbone based polymers, such as cyclodextrin based polymers, dextran based polymers, etc., silan backbone based polymers, such as PMOXA-PDMS copolymers, etc., blockpolymers consisting of a combination of one or more cationic blocks (e.g. selected from a cationic polymer as mentioned above) and of one or more hydrophilic or hydrophobic blocks (e.g. polyethyleneglycole); etc. 
     In this context it is particularly preferred that the at least one artificial RNA as defined herein and, optionally, the further artificial RNA of the second aspect, is complexed or at least partially complexed with a cationic or polycationic compound and/or a polymeric carrier, preferably cationic proteins or peptides. In this context, the disclosure of WO2010/037539 and WO2012/113513 is incorporated herewith by reference. Partially means that only a part of the artificial nucleic acid is complexed with a cationic compound and that the rest of the artificial nucleic acid is (comprised in the inventive (pharmaceutical) composition) in uncomplexed form (“free”). 
     In a preferred embodiment of the second aspect, the at least one artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed with one or more cationic or polycationic compounds, preferably protamine, and at least one free artificial RNA of the first aspect and, optionally the further RNA of the second aspect. 
     In this context it is particularly preferred that the at least one artificial RNA as defined herein, and, optionally, the further artificial RNA of the second aspect, is complexed, or at least partially complexed with protamine. 
     Preferably, the molar ratio of the nucleic acid, particularly the RNA of the protamine-complexed RNA to the free RNA may be selected from a molar ratio of about 0.001:1 to about 1:0.001, including a ratio of about 1:1. Suitably, the complexed RNA is complexed with protamine by addition of protamine-trehalose solution to the RNA sample at a RNA:protamine weight to weight ratio (w/w) of 2:1. 
     Further preferred cationic or polycationic proteins or peptides that may be used for complexation can be derived from formula (Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x of the patent application WO2009/030481 or WO2011/026641, the disclosure of WO2009/030481 or WO2011/026641 relating thereto incorporated herewith by reference. 
     In a preferred embodiment of the second aspect, the at least one artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed, or at least partially complexed with at least one cationic or polycationic proteins or peptides preferably selected from SEQ ID NOs: 64-67, 21320 or any combinations thereof. 
     According to embodiments, the composition of the present invention comprises the RNA as defined herein, and a polymeric carrier. 
     The term “polymeric carrier” as used herein will be recognized and understood by the person of ordinary skill in the art, and are for example intended to refer to a compound that facilitates transport and/or complexation of another compound (cargo). A polymeric carrier is typically a carrier that is formed of a polymer. A polymeric carrier may be associated to its cargo (nucleic acid, RNA) by covalent or non-covalent interaction. 
     A suitable polymeric carrier may be a polymeric carrier formed by disulfide-crosslinked cationic compounds. The disulfide-crosslinked cationic compounds may be the same or different from each other. The polymeric carrier can also contain further components. The polymeric carrier used according to the present invention may comprise mixtures of cationic peptides, proteins or polymers and optionally further components as defined herein, which are crosslinked by disulfide bonds (via —SH groups). 
     In this context, polymeric carriers according to formula {(Arg)I;(Lys)m;(His)n;(Orn)o;(Xaa′)x(Cys)y} and formula Cys,{(Arg);(Lys)m;(His)n;(Orn)o;(Xaa)x}Cys2 of the patent application WO2012/013326 are preferred, the disclosure of WO2012/013326 relating thereto incorporated herewith by reference. 
     In embodiments, the polymeric carrier used to complex the RNA as defined herein may be derived from a polymeric carrier molecule according formula (L-P 1 -S-[S-P 2 -S] n -S-P 1 -L) of the patent application WO2011/026641, the disclosure of WO2011/026641 relating thereto incorporated herewith by reference. 
     In embodiments, the polymeric carrier compound is formed by, or comprises or consists of the peptide elements CysArg12Cys (SEQ ID NO: 64) or CysArg12 (SEQ ID NO: 65) or TrpArg12Cys (SEQ ID NO: 66). In particularly preferred embodiments, the polymeric carrier compound consists of a (R 12 C)-(R 12 C) dimer, a (WR 12 C)-(WR 12 C) dimer, or a (CR 12 )-(CR 12 C)-(CR 12 ) trimer, wherein the individual peptide elements in the dimer (e.g. (WR 12 C)), or the trimer (e.g. (CR 12 )), are connected via —SH groups. 
     In a preferred embodiment of the second aspect, the at least one artificial RNA of the first aspect and optionally the further artificial RNA of the second aspect, is complexed or associated with a polyethylene glycol/peptide polymer comprising HO-PEG5000-S-(S-CHHHHHHRRRRHHHHHHC-S-)7-S-PEG5000-OH (SEQ ID NO: 67 as peptide monomer). 
     In a further preferred embodiment of the second aspect, the at least one artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed or associated with a polyethylene glycol/peptide polymer comprising HO-PEG5000-S-(S-CHHHHHHRRRRHHHHHHC-S-)4-S-PEG5000-OH (SEQ ID NO: 67 as peptide monomer). 
     In a further preferred embodiment of the second aspect, the at least one artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed or associated with a polyethylene glycol/peptide polymer comprising HO-PEG5000-S-(S-CGHHHHHRRRRHHHHHGC-S-)7-S-PEG5000-OH (SEQ ID NO: 21320 as peptide monomer). 
     In a further preferred embodiment of the second aspect, the at least one artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed or associated with a polyethylene glycol/peptide polymer comprising HO-PEG5000-S-(S-CGHHHHHRRRRHHHHHGC-S-)4-S-PEG5000-OH (SEQ ID NO: 21320 as peptide monomer). 
     In other embodiments, the composition comprises at least one artificial RNA as described herein, and, optionally, the further artificial RNA of the second aspect, wherein the at least one artificial RNA and, optionally, the further artificial RNA of the second aspect, is complexed or associated with polymeric carriers and, optionally, with at least one lipid component as described in the published PCT applications WO2017/212008A1, WO2017/212006A1, WO2017/212007A1, and WO2017/212009A1. In this context, the disclosures of WO2017/212008A1, WO2017/212006A1, WO2017/212007A1, and WO2017/212009A1 are herewith incorporated by reference. 
     In a particularly preferred embodiment, the polymeric carrier is a peptide polymer, preferably a polyethylene glycol/peptide polymer as defined above, and a lipid component, preferably a lipidoid component, more preferably lipidoid component. 
     In preferred embodiment of the second aspect, the at least one artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed or associated with a polymeric carrier, preferably with a polyethylene glycol/peptide polymer as defined above, and a lipidoid component, wherein the lipidoid component is a compound according to formula A 
     
       
         
         
             
             
         
       
     
     wherein
         R A  is independently selected for each occurrence an unsubstituted, cyclic or acyclic, branched or unbranched C 1-20  aliphatic group; a substituted or unsubstituted, cyclic or acyclic, branched or unbranched C 1-20  heteroaliphatic group; a substituted or unsubstituted aryl; a substituted or unsubstituted heteroaryl;       

     
       
         
         
             
             
         
       
     
     wherein at least one R A  is 
     
       
         
         
             
             
         
       
         
         
           
             R 5  is independently selected for each occurrence of from an unsubstituted, cyclic or acyclic, branched or unbranched C 8-16  aliphatic; a substituted or unsubstituted aryl; or a substituted or unsubstituted heteroaryl; 
             each occurrence of x is an integer from 1 to 10; 
             each occurrence of y is an integer from 1 to 10; 
           
         
       
    
     or a pharmaceutically acceptable salt thereof. 
     In a preferred embodiment, the lipidoid component is 3-C12-OH according to formula B 
     
       
         
         
             
             
         
       
     
     In preferred embodiments, the peptide polymer comprising lipidoid 3-C12-OH as specified above is used to complex the RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, to form complexes having an N/P ratio from about 0.1 to about 20, or from about 0.2 to about 15, or from about 2 to about 15, or from about 2 to about 12, wherein the N/P ratio is defined as the mole ratio of the nitrogen atoms of the basic groups of the cationic peptide or polymer to the phosphate groups of the artificial nucleic acid. In that context, the disclosure of WO2017/212009A1, in particular Claims 1 to 10 of WO2017/212009A1, and the specific disclosure relating thereto is herewith incorporated by reference. 
     Encapsulation/Complexation in LNPs: 
     In preferred embodiments of the second aspect, the artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed or associated with one or more lipids (e.g. cationic lipids and/or neutral lipids), thereby forming liposomes, lipid nanoparticles (LNPs), lipoplexes, and/or nanoliposomes. 
     For compositions comprising more than one artificial RNA construct as defined herein (e,g, F-del and M2-1), said constructs may be co-formulated in e.g. LNPs to form the respective composition. 
     Alternatively, said more than one artificial RNA constructs may be formulated separately, and may subsequently be combined, to form the respective composition. 
     In this context, the terms “complexed” or “associated” refer to the essentially stable combination of artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, with one or more lipids into larger complexes or assemblies without covalent binding. 
     The term “lipid nanoparticle”, also referred to as “LNP”, is not restricted to any particular morphology, and include any morphology generated when a cationic lipid and optionally one or more further lipids are combined, e.g. in an aqueous environment and/or in the presence of RNA. For example, a liposome, a lipid complex, a lipoplex and the like are within the scope of a lipid nanoparticle (LNP). 
     Accordingly, in preferred embodiments of the second aspect, the artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed with one or more lipids thereby forming lipid nanoparticles (LNP). 
     LNPs typically comprise a cationic lipid and one or more excipient selected from neutral lipids, charged lipids, steroids and polymer conjugated lipids (e.g. PEGylated lipid). The RNA may be encapsulated in the lipid portion of the LNP or an aqueous space enveloped by some or the entire lipid portion of the LNP. The RNA or a portion thereof may also be associated and complexed with the LNP. An LNP may comprise any lipid capable of forming a particle to which the nucleic acids are attached, or in which the one or more nucleic acids are encapsulated. 
     Preferably, the LNP comprising nucleic acids comprises one or more cationic lipids, and one or more stabilizing lipids. Stabilizing lipids include neutral lipids and PEGylated lipids. 
     The cationic lipid of an LNP may be cationisable, i.e. it becomes protonated as the pH is lowered below the pK of the ionizable group of the lipid, but is progressively more neutral at higher pH values. At pH values below the pK, the lipid is then able to associate with negatively charged nucleic acids. In certain embodiments, the cationic lipid comprises a zwitterionic lipid that assumes a positive charge on pH decrease. 
     The LNP may comprise any further cationic or cationisable lipid, i.e. any of a number of lipid species which carry a net positive charge at a selective pH, such as physiological pH. 
     Such lipids include, but are not limited to, N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), 1,2-dioleoyltrimethyl ammonium propane chloride (DOTAP) (also known as N-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride and 1,2-Dioleyloxy-3-trimethylaminopropane chloride salt), N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA), 1,2-DiLinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 1,2-di-y-linolenyloxy-N,N-dimethylaminopropane (γ-DLenDMA), 1,2-Dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1,2-Dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-Dilinoleyoxy-3-morpholinopropane (DLin-MA), 1,2-Dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-Dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-Linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-Dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.CI), 1,2-Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.CI), 1,2-Dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), or 3-(N,N-Dilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-Dioleylamino)-1,2-propanedio (DOAP), 1,2-Dilinoleyloxo-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DM A), 2,2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA) or analogs thereof, (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9,12-dienyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-5-amine, (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butanoate (MC3), 1,1′-(2-(4-(2-((2-(bis(2-hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amino)ethyl)piperazin-1-yl)ethylazanediyl)didodecan-2-ol(C12-200), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane(DLin-K-C2-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino) butanoate (DLin-M-C3-DMA), 3-((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)-N,N-dimethylpropan-1-amine (MC3 Ether), 4-((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)-N,N-dimethylbutan-1-amine (MC4 Ether), LIPOFECTIN® (commercially available cationic liposomes comprising DOTMA and 1,2-dioleoyl-sn-3phosphoethanolamine (DOPE), from GIBCO/BRL, Grand Island, N.Y.); LIPOFECTAMINE® (commercially available cationic liposomes comprising N-(1-(2,3dioleyloxy)propyl)-N-(2-(sperminecarboxamido)ethyl)-N,N-dimethylammonium trifluoroacetate (DOSPA) and (DOPE), from GIBCO/BRL); and TRANSFECTAM® (commercially available cationic lipids comprising dioctadecylamidoglycyl carboxyspermine (DOGS) in ethanol from Promega Corp., Madison, Wis.) or any combination of any of the foregoing. 
     In some embodiments, the lipid is selected from the group consisting of 98N12-5, C12-200, and ckk-E12. 
     In one embodiment, the further cationic lipid is an amino lipid. 
     Representative amino lipids include, but are not limited to, 1,2-dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-dilinoleyoxy-3morpholinopropane (DLin-MA), 1,2-dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-linoleoyl-2-linoleyloxy-3dimethylaminopropane (DLin-2-DMAP), 1,2-dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.CI), 1,2-dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.CI), 1,2-dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), 3-(N,Ndilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-dioleylamino)-1,2-propanediol (DOAP), 1,2-dilinoleyloxo-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), and 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA); dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA); MC3 (US20100324120). 
     In one embodiment, the artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, may be formulated in an aminoalcohol lipidoid. Aminoalcohol lipidoids which may be used in the present invention may be prepared by the methods described in U.S. Pat. No. 8,450,298, herein incorporated by reference in its entirety. Suitable (ionizable) lipids can also be the compounds as disclosed in Tables 1, 2 and 3 and as defined in claims 1-24 of WO2017/075531A1, hereby incorporated by reference. 
     In another embodiment, ionizable lipids can also be the compounds as disclosed in WO2015/074085A1 (i.e. ATX-001 to ATX-032 or the compounds as specified in claims 1-26), U.S. Appl. Nos. 61/905,724 and 15/614,499 or U.S. Pat. Nos. 9,593,077 and 9,567,296 hereby incorporated by reference in their entirety. 
     In that context, any lipid derived from generic formula (X1) 
     
       
         
         
             
             
         
       
     
     wherein, Ri and R2 are the same or different, each a linear or branched alkyl consisting of 1 to 9 carbons, an alkenyl or alkynyl consisting of 2 to 11 carbons, Li and L2 are the same or different, each a linear alkylene or alkenylene consisting of 5 to 18 carbons, or forming a heterocycle with N, Xi is a bond, or is —CO—O— whereby -L2-CO—O—R2 is formed, X2 is S or O, L3 is a bond or a linear or branched alkylene consisting of 1 to 6 carbons, or forming a heterocycle with N, R3 is a linear or branched alkylene consisting of 1 to 6 carbons, and R4 and R 5 are the same or different, each hydrogen or a linear or branched alkyl consisting of 1 to 6 carbons; or a pharmaceutically acceptable salt thereof may be suitably used. 
     In other embodiments, suitable cationic lipids can also be the compounds as disclosed in WO2017/117530A1 (i.e. lipids 13, 14, 15, 16, 17, 18, 19, 20, or the compounds as specified in the claims), hereby incorporated by reference in its entirety. 
     In that context, any lipid derived from generic formula (X2) 
     
       
         
         
             
             
         
       
     
     wherein 
     X is a linear or branched alkylene or alkenylene, monocyclic, bicyclic, or tricyclic arene or heteroarene; 
     Y is a bond, an ethene, or an unsubstituted or substituted aromatic or heteroaromatic ring; Z is S or O; 
     L is a linear or branched alkylene of 1 to 6 carbons; 
     R-3 and R4 are independently a linear or branched alkyl of 1 to 6 carbons; 
     Ri and R2 are independently a linear or branched alkyl or alkenyl of 1 to 20 carbons; r is 0 to 6; and 
     m, n, p, and q are independently 1 to 18; 
     wherein when n=q, m=p, and Ri=R2, then X and Y differ; 
     wherein when X=Y, n=q, m=p, then Ri and R2 differ; 
     wherein when X=Y, n=q, and Ri=R2, then m and p differ; and 
     wherein when X=Y, m=p, and Ri=R2, then n and q differ; 
     or a pharmaceutically acceptable salt thereof. 
     In preferred embodiments, a lipid may be used derived from formula (X2), wherein, X is a bond, linear or branched alkylene, alkenylene, or monocyclic, bicyclic, or tricyclic arene or heteroarene; Y is a monocyclic, bicyclic, or tricyclic arene or heteroarene; Z is S or O; L is a linear or branched alkylene of 1 to 6 carbons; R3 and R4 are independently a linear or branched alkyl of 1 to 6 carbons; Ri and R2 are independently a linear or branched alkyl or alkenyl of 1 to 20 carbons; r is 0 to 6; and m, n, p, and q are independently 1 to 18; or a pharmaceutically acceptable salt thereof may be suitably used. 
     In preferred embodiments, ionizable lipids may also be selected from the lipid compounds disclosed in PCT application PCT/EP2017/077517 (i.e. lipid compounds derived form formula I, II, and III of PCT/EP2017/077517, or lipid compounds as specified in Claims 1 to 12 of PCT/EP2017/077517), the disclosure of PCT/EP2017/077517 hereby incorporated by reference in its entirety. In that context, lipid compounds disclosed in Table 7 of PCT/EP2017/077517 (e.g. lipid compounds derived from formula I-1 to I-41) and lipid compounds disclosed in Table 8 of PCT/EP2017/077517 (e.g. lipid compounds derived from formula I-1 to II-36) may be suitably used in the context of the invention. Accordingly, formula I-1 to formula I-41 and formula II-1 to formula I-36 of PCT/EP2017/077517, and the specific disclosure relating thereto, are herewith incorporated by reference. 
     In particularly preferred embodiments of the second aspect, a suitable lipid may be a cationic lipid according to formula (III) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein, R1, R2, R3, L1, L2, G1, G2, and G3 are as below. 
     Formula (III) is further defined in that: 
     one of L 1  or L 2  is —O(C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O)—, —S—S—, —C(═O)S—, SC(═O)—, —NR a C(═O)—, —C(═O)NR a —, —NR a C(═O)NR a —, —OC(═O)NR a — or —NR a C(═O)O—, and the other of L1 or L 2  is —O(C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O)—, —S—S—, —C(═O)S—, SC(═O)—, —NR a C(═O)—, —C(═O)NR a —, —NR a C(═O)NR a —, —OC(═O)NR a — or —NR a C(═O)O— or a direct bond; 
     G 1  and G 2  are each independently unsubstituted C 1 -C 12  alkylene or C 1 -C 12  alkenylene; 
     G 3  is C 1 -C 24  alkylene, C 1 -C 24  alkenylene, C 3 -C 8  cycloalkylene, C 3 -C 8  cycloalkenylene; 
     R a  is H or C 1 -C 12  alkyl; 
     R 1  and R 2  are each independently C 6 -C 24  alkyl or C 6 -C 24  alkenyl; 
     R 3  is H, OR 5 , CN, —C(═O)OR 4 , —OC(═O)R 4  or —NR 5 C(═O)R 4 ; 
     R 4  is C 1 -C 12  alkyl; 
     R 5  is H or C 1 -C 12  alkyl; and 
     x is 0, 1 or 2. 
     In some of the foregoing embodiments of formula (III), the lipid has one of the following structures (IIIA) or (IIIB): 
     
       
         
         
             
             
         
       
     
     wherein: 
     A is a 3 to 8-membered cycloalkyl or cycloalkylene ring; R 6  is, at each occurrence, independently H, OH or C 1 -C 24  alkyl; n is an integer ranging from 1 to 15. 
     In some of the foregoing embodiments of formula (III), the lipid has structure (IIIA), and in other embodiments, the lipid has structure (IIIB). 
     In other embodiments of formula (III), the lipid has one of the following structures (IIC) or (IIID): 
     
       
         
         
             
             
         
       
     
     wherein y and z are each independently integers ranging from 1 to 12. 
     In any of the foregoing embodiments of formula (III), one of L 1  or L 2  is —O(C═O)—. For example, in some embodiments each of L 1  and L 2  are —O(C═O)—. In some different embodiments of any of the foregoing, L 1  and L 2  are each independently —(C═O)O— or —O(C═O)—. For example, in some embodiments each of L 1  and L 2  is —(C═O)O—. 
     In preferred embodiments of the second aspect, the cationic lipid of the LNP is a compound of formula I, wherein: 
     L 1  and L 2  are each independently —O(C═O)— or (C═O)—O—; 
     G 3  is C 1 -C 24  alkylene or C 1 -C 24  alkenylene; and 
     R 3  is H or OR 5 . 
     In some different embodiments of formula (III), the lipid has one of the following structures (IIIE) or (IIIF): 
     
       
         
         
             
             
         
       
     
     In some of the foregoing embodiments of formula (III), the lipid has one of the following structures (IIIG), (IIIH), 
     
       
         
         
             
             
         
       
     
     In some of the foregoing embodiments of formula (III), n is an integer ranging from 2 to 12, for example from 2 to 8 or from 2 to 4. In some embodiments, n is 3, 4, 5 or 6. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some other of the foregoing embodiments of formula (III), y and z are each independently an integer ranging from 2 to 10. For example, in some embodiments, y and z are each independently an integer ranging from 4 to 9 or from 4 to 6. In some of the foregoing embodiments of formula (II), R 6  is H. In other of the foregoing embodiments, R 6  is C 1 -C 24  alkyl. In other embodiments, R 6  is OH. In some embodiments of formula (III), G3 is unsubstituted. In other embodiments, G3 is substituted. In various different embodiments, G 3  is linear C 1 -C 24  alkylene or linear C 1 -C 24  alkenylene. In some other foregoing embodiments of formula (III), R 1  or R 2 , or both, is C 6 -C 24  alkenyl. For example, in some embodiments, R 1  and R 2  each, independently have the following structure: 
     
       
         
         
             
             
         
       
     
     wherein: 
     R 7a  and R 7b  are, at each occurrence, independently H or C 1 -C 12  alkyl; and a is an integer from 2 to 12, wherein 
     R 7a , R 7b  and a are each selected such that R 1  and R 2  each independently comprise from 6 to 20 carbon atoms. For example, in some embodiments a is an integer ranging from 5 to 9 or from 8 to 12. In some of the foregoing embodiments of formula (III), at least one occurrence of R 7a  is H. For example, in some embodiments, R 7a  is H at each occurrence. In other different embodiments of the foregoing, at least one occurrence of R 7b  is C 1 -C 8  alkyl. For example, in some embodiments, C 1 -C 8  alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl. 
     In different embodiments of formula (III), R 1  or R 2 , or both, has one of the following structures: 
     
       
         
         
             
             
         
       
     
     In preferred embodiments of the second aspect, the cationic lipid of the LNP is a compound of formula III, wherein: 
     L 1  and L 2  are each independently —O(C═O)— or (C═O)—O—; and 
     R 1  and R 2  each independently have one of the following structures: 
     
       
         
         
             
             
         
       
     
     In some of the foregoing embodiments of formula (III), R 3  is OH, CN, —C(═O)OR 4 , —OC(═O)R 4  or —NHC(═O)R 4 . In some embodiments, R 4  is methyl or ethyl. 
     In preferred embodiments of the second aspect, the cationic lipid of the LNP is a compound of formula II, wherein R 3  is OH. 
     In particularly preferred embodiment of the second aspect, the artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed with one or more lipids thereby forming lipid nanoparticles (LNP), wherein the LNP is selected from structures III-1 to III-36 (see Table 8). 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Representative lipid compounds derived from formula (III) 
               
            
           
           
               
               
            
               
                 No. 
                 Structure 
               
               
                   
               
               
                 III-1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 III-36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the LNPs comprise a lipid of formula (III), an artificial RNA of the first aspect, and, optionally, the further artificial RNA of the second aspect, and one or more excipient selected from neutral lipids, steroids and PEGylated lipids. In some embodiments the lipid of formula (III) is compound III-3. In some embodiments the lipid of formula (III) is compound III-7. 
     In preferred embodiments, the LNP comprises a cationic lipid selected from: 
     
       
         
         
             
             
         
       
     
     In particularly preferred embodiment of the second aspect, the artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed with one or more lipids thereby forming lipid nanoparticles (LNP), wherein the LNP comprises the following cationic lipid (lipid according to formula III-3 of Table 8): 
     
       
         
         
             
             
         
       
     
     In certain embodiments, the cationic lipid as defined herein, preferably as disclosed in Table 8, more preferably cationic lipid compound III-3, is present in the LNP in an amount from about 30 to about 95 mole percent, relative to the total lipid content of the LNP. If more than one cationic lipid is incorporated within the LNP, such percentages apply to the combined cationic lipids. 
     In one embodiment, the cationic lipid is present in the LNP in an amount from about 30 to about 70 mole percent. In one embodiment, the cationic lipid is present in the LNP in an amount from about 40 to about 60 mole percent, such as about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 mole percent, respectively. In embodiments, the cationic lipid is present in the LNP in an amount from about 47 to about 48 mole percent, such as about 47.0, 47.1, 47.2, 47.3, 47.4, 47.5, 47.6, 47.7, 47.8, 47.9, 50.0 mole percent, respectively, wherein 47.7 mole percent are particularly preferred. 
     In some embodiments, the cationic lipid is present in a ratio of from about 20 mol % to about 70 or 75 mol % or from about 45 to about 65 mol % or about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or about 70 mol % of the total lipid present in the LNP. In further embodiments, the LNPs comprise from about 25% to about 75% on a molar basis of cationic lipid, e.g., from about 20 to about 70%, from about 35 to about 65%, from about 45 to about 65%, about 60%, about 57.5%, about 57.1%, about 50% or about 40% on a molar basis (based upon 100% total moles of lipid in the lipid nanoparticle). In some embodiments, the ratio of cationic lipid to nucleic acid, preferably to the artificial RNA of the first aspect, and, optionally, the further artificial RNA of the second aspect, is from about 3 to about 15, such as from about 5 to about 13 or from about 7 to about 11. 
     In some embodiments of the invention the LNP comprises a combination or mixture of any the lipids described above. 
     Other suitable (cationic) lipids are disclosed in WO2009/086558, WO2009/127060, WO2010/048536, WO2010/054406, WO2010/088537, WO2010/129709, WO2011/153493, US2011/0256175, US2012/0128760, US2012/0027803, U.S. Pat. No. 8,158,601, WO2016/118724, WO2016/118725, WO2017/070613, WO2017/070620, WO2017/099823, and WO2017/112865. In that context, the disclosures of WO2009/086558, WO2009/127060, WO2010/048536, WO2010/054406, WO2010/088537, WO2010/129709, WO2011/153493, US2011/0256175, US2012/0128760, US2012/0027803, U.S. Pat. No. 8,158,601, WO2016/118724, WO2016/118725, WO2017/070613, WO2017/070620, WO2017/099823, and WO2017/112865 specifically relating to (cationic) lipids suitable for LNPs are incorporated herewith by reference. 
     In some embodiments, the lipid is selected from the group consisting of 98N12-5, C12-200, and ckk-E12. 
     In some embodiments, amino or cationic lipids as defined herein have at least one protonatable or deprotonatable group, such that the lipid is positively charged at a pH at or below physiological pH (e.g. pH 7.4), and neutral at a second pH, preferably at or above physiological pH. It will, of course, be understood that the addition or removal of protons as a function of pH is an equilibrium process, and that the reference to a charged or a neutral lipid refers to the nature of the predominant species and does not require that all of lipids have to be present in the charged or neutral form. Lipids having more than one protonatable or deprotonatable group, or which are zwitterionic, are not excluded and may likewise suitable in the context of the present invention. 
     In some embodiments, the protonatable lipids have a pKa of the protonatable group in the range of about 4 to about 11, e.g., a pKa of about 5 to about 7. 
     LNPs can comprise two or more (different) cationic lipids. The cationic lipids may be selected to contribute different advantageous properties. For example, cationic lipids that differ in properties such as amine pKa, chemical stability, half-life in circulation, half-life in tissue, net accumulation in tissue, or toxicity can be used in the LNP. In particular, the cationic lipids can be chosen so that the properties of the mixed-LNP are more desirable than the properties of a single-LNP of individual lipids. 
     The amount of the permanently cationic lipid or lipidoid may be selected taking the amount of the nucleic acid cargo into account. In one embodiment, these amounts are selected such as to result in an N/P ratio of the nanoparticle(s) or of the composition in the range from about 0.1 to about 20. In this context, the N/P ratio is defined as the mole ratio of the nitrogen atoms (“N”) of the basic nitrogen-containing groups of the lipid or lipidoid to the phosphate groups (“P”) of the RNA which is used as cargo. The N/P ratio may be calculated on the basis that, for example, 1 μg RNA typically contains about 3 nmol phosphate residues, provided that the RNA exhibits a statistical distribution of bases. The “N”-value of the lipid or lipidoid may be calculated on the basis of its molecular weight and the relative content of permanently cationic and—if present—cationisable groups. 
     LNP in vivo characteristics and behavior can be modified by addition of a hydrophilic polymer coating, e.g. polyethylene glycol (PEG), to the LNP surface to confer steric stabilization. Furthermore, LNPs can be used for specific targeting by attaching ligands (e.g. antibodies, peptides, and carbohydrates) to its surface or to the terminal end of the attached PEG chains (e.g. via PEGylated lipids). 
     In some embodiments, the LNPs comprise a polymer conjugated lipid. The term “polymer conjugated lipid” refers to a molecule comprising both a lipid portion and a polymer portion. An example of a polymer conjugated lipid is a PEGylated lipid. The term “PEGylated lipid” refers to a molecule comprising both a lipid portion and a polyethylene glycol portion. PEGylated lipids are known in the art and include 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-s-DMG) and the like. 
     In certain embodiments, the LNP comprises an additional, stabilizing-lipid which is a polyethylene glycol-lipid (PEGylated lipid). Suitable polyethylene glycol-lipids include PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramides (e.g. PEG-CerC14 or PEG-CerC20), PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols. Representative polyethylene glycol-lipids include PEG-c-DOMG, PEG-c-DMA, and PEG-s-DMG. In one embodiment, the polyethylene glycol-lipid is N-[(methoxy poly(ethylene glycol)2000)carbamyl]-1,2-dimyristyloxlpropyl-3-amine (PEG-c-DMA). In a preferred embodiment, the polyethylene glycol-lipid is PEG-2000-DMG. In one embodiment, the polyethylene glycol-lipid is PEG-c-DOMG). In other embodiments, the LNPs comprise a PEGylated diacylglycerol (PEG-DAG) such as 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG), a PEGylated phosphatidylethanoloamine (PEG-PE), a PEG succinate diacylglycerol (PEG-S-DAG) such as 4-O-(2′,3′-di(tetradecanoyloxy)propyl-1-O-(w-methoxy(polyethoxy)ethyl)butanedioate (PEG-S-DMG), a PEGylated ceramide (PEG-cer), or a PEG dialkoxypropylcarbamate such as w-methoxy(polyethoxy)ethyl-N-(2,3di(tetradecanoxy)propyl)carbamate or 2,3-di(tetradecanoxy)propyl-N-(w-methoxy(polyethoxy)ethyl)carbamate. 
     In preferred embodiments of the second aspect, the artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed with one or more lipids thereby forming lipid nanoparticles (LNP), wherein the LNP additionally comprises a PEGylated lipid with the formula (IV): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 8  and R 9  are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and w has mean value ranging from 30 to 60. 
     In some of the foregoing embodiments of the PEGylated lipid according to formula (IV), R 8  and R 9  are not both n-octadecyl when w is 42. In some other embodiments, R 8  and R 9  are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 18 carbon atoms. In some embodiments, R 8  and R 9  are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 12 to 16 carbon atoms. In some embodiments, R 8  and R 9  are each independently a straight or branched, saturated or unsaturated alkyl chain containing 12 carbon atoms. In some embodiments, R 8  and R 9  are each independently a straight or branched, saturated or unsaturated alkyl chain containing 14 carbon atoms. In other embodiments, R 8  and R 9  are each independently a straight or branched, saturated or unsaturated alkyl chain containing 16 carbon atoms. In still more embodiments, R 8  and R 9  are each independently a straight or branched, saturated or unsaturated alkyl chain containing 18 carbon atoms. In still other embodiments, R 8  is a straight or branched, saturated or unsaturated alkyl chain containing 12 carbon atoms and R 9  is a straight or branched, saturated or unsaturated alkyl chain containing 14 carbon atoms. 
     In various embodiments, w spans a range that is selected such that the PEG portion of the PEGylated lipid according to formula (IV) has an average molecular weight of about 400 to about 6000 g/mol. In some embodiments, the average w is about 50. 
     In preferred embodiments of the second aspect, R 8  and R 9  of the PEGylated lipid according to formula (IV) are saturated alkyl chains. 
     In a particularly preferred embodiment of the second aspect, the artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed with one or more lipids thereby forming lipid nanoparticles (LNP), wherein the LNP additionally comprises a PEGylated lipid, wherein the PEG lipid is of formula (IVa) 
     
       
         
         
             
             
         
       
     
     wherein n has a mean value ranging from 30 to 60, such as about 28 to about 32, about 30 to about 34, 32 to about 36, about 34 to about 38, 36 to about 40, about 38 to about 42, 40 to about 44, about 42 to about 46, 44 to about 48, about 46 to about 50, 48 to about 52, about 50 to about 54, 52 to about 56, about 54 to about 58, 56 to about 60, about 58 to about 62. In preferred embodiments, n is about 45, 46, 47, 48, 49, 50, 51, 52, 53, 54. In a most preferred embodiment n has a mean value of 49. 
     In other embodiments, the PEGylated lipid has one of the following structures: 
     
       
         
         
             
             
         
       
     
     wherein n is an integer selected such that the average molecular weight of the PEGylated lipid is about 2500 g/mol, most preferably n is about 49. 
     Further examples of PEG-lipids suitable in that context are provided in US2015/0376115A1 and WO2015/199952, each of which is incorporated by reference in its entirety. 
     In some embodiments, LNPs include less than about 3, 2, or 1 mole percent of PEG or PEG-modified lipid, based on the total moles of lipid in the LNP. In further embodiments, LNPs comprise from about 0.1% to about 20% of the PEG-modified lipid on a molar basis, e.g., about 0.5 to about 10%, about 0.5 to about 5%. about 10%. about 5%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, about 1%, about 0.5%, or about 0.3% on a molar basis (based on 100% total moles of lipids in the LNP). In preferred embodiments, LNPs comprise from about 1.0% to about 2.0% of the PEG-modified lipid on a molar basis, e.g., about 1.2 to about 1.9%, about 1.2 to about 1.8%, about 1.3 to about 1.8%, about 1.4 to about 1.8%, about 1.5 to about 1.8%, about 1.6 to about 1.8%, in particular about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, most preferably 1.7% (based on 100% total moles of lipids in the LNP). In various embodiments, the molar ratio of the cationic lipid to the PEGylated lipid ranges from about 100:1 to about 25:1. 
     In preferred embodiments, the LNP additionally comprises one or more additional lipids which stabilize the formation of particles during their formation (e.g. neutral lipid and/or one or more steroid or steroid analogue). 
     In preferred embodiments of the second aspect, the artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed with one or more lipids thereby forming lipid nanoparticles (LNP), wherein the LNP additionally comprises one or more neutral lipid and/or one or more steroid or steroid analogue. 
     Suitable stabilizing lipids include neutral lipids and anionic lipids. The term “neutral lipid” refers to any one of a number of lipid species that exist in either an uncharged or neutral zwitterionic form at physiological pH. Representative neutral lipids include diacylphosphatidylcholines, diacylphosphatidylethanolamines, ceramides, sphingomyelins, dihydro sphingomyelins, cephalins, and cerebrosides. 
     In embodiments of the second aspect, the LNP additionally comprises one or more neutral lipids, wherein the neutral lipid is selected from the group comprising distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE) and dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidylethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1-trans PE, 1-stearioyl-2-oleoylphosphatidyethanol amine (SOPE), and 1,2-dielaidoyl-sn-glycero-3-phophoethanolamine (transDOPE). 
     In some embodiments, the LNPs comprise a neutral lipid selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM. In various embodiments, the molar ratio of the cationic lipid to the neutral lipid ranges from about 2:1 to about 8:1. 
     In preferred embodiments of the second aspect, the neutral lipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). The molar ratio of the cationic lipid to DSPC may be in the range from about 2:1 to 8:1. 
     In preferred embodiments of the second aspect, the steroid is cholesterol. The molar ratio of the cationic lipid to cholesterol may be in the range from about 2:1 to 1:1. 
     The sterol can be about 10 mol % to about 60 mol % or about 25 mol % to about 40 mol % of the lipid particle. In one embodiment, the sterol is about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or about 60 mol % of the total lipid present in the lipid particle. In another embodiment, the LNPs include from about 5% to about 50% on a molar basis of the sterol, e.g., about 15% to about 45%, about 20% to about 40%, about 48%, about 40%, about 38.5%, about 35%, about 34.4%, about 31.5% or about 31% on a molar basis (based upon 100% total moles of lipid in the lipid nanoparticle). 
     Preferably, lipid nanoparticles (LNPs) comprise: (a) at least one artificial RNA of the first aspect, and, optionally, the further artificial RNA of the second aspect, (b) a cationic lipid, (c) an aggregation reducing agent (such as polyethylene glycol (PEG) lipid or PEG-modified lipid), (d) optionally a non-cationic lipid (such as a neutral lipid), and (e) optionally, a sterol. 
     In other preferred embodiments, lipid nanoparticles (LNPs) comprise: (a) at least one artificial RNA encoding F of the first aspect or a derivative or fragment thereof and at least one artificial RNA encoding N, M, P, or M2-1 of the second aspect or a derivative or fragment thereof, (b) a cationic lipid, (c) an aggregation reducing agent (such as polyethylene glycol (PEG) lipid or PEG-modified lipid), (d) optionally a non-cationic lipid (such as a neutral lipid), and (e) optionally, a sterol. 
     In some embodiments, the LNPs comprise a lipid of formula (III), an artificial RNA as defined herein, a neutral lipid, a steroid and a PEGylated lipid. In preferred embodiments, the lipid of formula (III) is lipid compound III-3, the neutral lipid is DSPC, the steroid is cholesterol, and the PEGylated lipid is the compound of formula (IVa). 
     In a preferred embodiment of the second aspect, the LNP consists essentially of (i) at least one cationic lipid; (ii) a neutral lipid; (iii) a sterol, e.g., cholesterol; and (iv) a PEG-lipid, e.g. PEG-DMG or PEG-cDMA, in a molar ratio of about 20-60% cationic lipid: 5-25% neutral lipid: 25-55% sterol; 0.5-15% PEG-lipid. 
     In particularly preferred embodiments of the second aspect, the artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, is complexed with one or more lipids thereby forming lipid nanoparticles (LNP), wherein the LNP essentially consists of 
     (i) at least one cationic lipid as defined herein, preferably a lipid of formula (III), more preferably lipid III-3;
 
(ii) a neutral lipid as defined herein, preferably 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC);
 
(iii) a steroid or steroid analogue as defined herein, preferably cholesterol; and
 
(iv) a PEG-lipid as defined herein, e.g. PEG-DMG or PEG-cDMA, preferably a PEGylated lipid of formula (IVa),
 
wherein (i) to (iv) are in a molar ratio of about 20-60% cationic lipid: 5-25% neutral lipid: 25-55% sterol; 0.5-15% PEG-lipid.
 
     In one preferred embodiment, the lipid nanoparticle comprises: a cationic lipid with formula (III) and/or PEG lipid with formula (IV), optionally a neutral lipid, preferably 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and optionally a steroid, preferably cholesterol, wherein the molar ratio of the cationic lipid to DSPC is optionally in the range from about 2:1 to 8:1, wherein the molar ratio of the cationic lipid to cholesterol is optionally in the range from about 2:1 to 1:1. 
     In a particular preferred embodiment, the composition of the second aspect comprising the artificial RNA of the first aspect and, optionally, the further artificial RNA of the second aspect, comprises lipid nanoparticles (LNPs), which have a molar ratio of approximately 50:10:38.5:1.5, preferably 47.5:10:40.8:1.7 or more preferably 47.4:10:40.9:1.7 (i.e. proportion (mol %) of cationic lipid (preferably lipid III-3), DSPC, cholesterol and PEG-lipid ((preferably PEG-lipid of formula (IVa) with n=49); solubilized in ethanol). 
     In a particular preferred embodiment, the composition of the second aspect comprises lipid nanoparticles (LNPs), which have a molar ratio of approximately 50:10:38.5:1.5, preferably 47.5:10:40.8:1.7 or more preferably 47.4:10:40.9:1.7 (i.e. proportion (mol %) of cationic lipid (preferably lipid III-3), DSPC, cholesterol and PEG-lipid ((preferably PEG-lipid of Formula (IVa) with n=49); solubilized in ethanol), wherein the lipid nanoparticles comprise at least one RNA encoding F (F0, F-del, F0_DSCav1, F-del_DSCav1, F_DSCav1_mut0, F-del_DSCav1_mut0, F_DSCav1_mut1, F-del_DSCav1_mut1, F_DSCav1_mut2, F-del_DSCav1_mut2, F_DSCav1_mut3, F-del_DSCav1_mut3, F_DSCav1_mut4, F-del_DSCav1_mut4, F_DSCav1_mut5, F-del_DSCav1_mut5, F_DSCav1_mut6, F-del_DSCav1_mut6, F_DSCav1_mut7, F-del_DSCav1_mut7, F_DSCav1_mut8, or F-del_DSCav1_mut8), and, additionally lipid nanoparticles (LNPs), which have a molar ratio of approximately 50:10:38.5:1.5, preferably 47.5:10:40.8:1.7 or more preferably 47.4:10:40.9:1.7 (i.e. proportion (mol %) of cationic lipid (preferably lipid III-3), DSPC, cholesterol and PEG-lipid ((preferably PEG-lipid of Formula (IVa) with n=49); solubilized in ethanol), wherein the lipid nanoparticles comprise at least one RNA encoding M, N, M2-1, or P. 
     In a particular preferred embodiment, the composition of the second aspect comprises lipid nanoparticles (LNPs), which have a molar ratio of approximately 50:10:38.5:1.5, preferably 47.5:10:40.8:1.7 or more preferably 47.4:10:40.9:1.7 (i.e. proportion (mol %) of cationic lipid (preferably lipid III-3), DSPC, cholesterol and PEG-lipid ((preferably PEG-lipid of Formula (IVa) with n=49); solubilized in ethanol), wherein the lipid nanoparticles comprise at least one RNA encoding F (F0, F-del, F0_DSCav1, F-del_DSCav1, F_DSCav1_mut0, F-del_DSCav1_mut0, F_DSCav1_mut1, F-del_DSCav1_mut1, F_DSCav1_mut2, F-del_DSCav1_mut2, F_DSCav1_mut3, F-del_DSCav1_mut3, F_DSCav1_mut4, F-del_DSCav1_mut4, F_DSCav1_mut5, F-del_DSCav1_mut5, F_DSCav1_mut6, F-del_DSCav1_mut6, F_DSCav1_mut7, F-del_DSCav1_mut7, F_DSCav1_mut8, or F-del_DSCav1_mut8), and at least one RNA encoding M, N, M2-1, or P. 
     The total amount of RNA in the lipid nanoparticles may vary and is defined depending on the e.g. RNA to total lipid w/w ratio. In one embodiment of the invention the artificial RNA to total lipid ratio is less than 0.06 w/w, preferably between 0.03 w/w and 0.04 w/w. 
     In various embodiments, the LNP as defined herein have a mean diameter of from about 50 nm to about 200 nm, from about 60 nm to about 200 nm, from about 70 nm to about 200 nm, from about 80 nm to about 200 nm, from about 90 nm to about 200 nm, from about 90 nm to about 190 nm, from about 90 nm to about 180 nm, from about 90 nm to about 170 nm, from about 90 nm to about 160 nm, from about 90 nm to about 150 nm, from about 90 nm to about 140 nm, from about 90 nm to about 130 nm, from about 90 nm to about 120 nm, from about 90 nm to about 100 nm, from about 70 nm to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, or 200 nm and are substantially non-toxic. As used herein, the mean diameter may be represented by the z-average as determined by dynamic light scattering as commonly known in the art. 
     In another preferred embodiment of the invention the lipid nanoparticles have a hydrodynamic diameter in the range from about 50 nm to about 300 nm, or from about 60 nm to about 250 nm, from about 60 nm to about 150 nm, or from about 60 nm to about 120 nm, respectively. 
     According to further embodiments, the composition of the second aspect may comprise at least one adjuvant. Suitably, the adjuvant is preferably added to enhance the immunostimulatory properties of the composition. 
     The term “adjuvant” as used herein will be recognized and understood by the person of ordinary skill in the art, and is for example intended to refer to a pharmacological and/or immunological agent that may modify, e.g. enhance, the effect of other agents (herein: the effect of the artificial nucleic acid of the invention) or that may be suitable to support administration and delivery of the composition. The term “adjuvant” refers to a broad spectrum of substances. Typically, these substances are able to increase the immunogenicity of antigens. For example, adjuvants may be recognized by the innate immune systems and, e.g., may elicit an innate immune response (that is, a non-specific immune response). “Adjuvants” typically do not elicit an adaptive immune response. In the context of the invention, adjuvants may enhance the effect of the antigenic peptide or protein provided by the artificial nucleic acid as defined herein or the polyprotein as defined herein. 
     In that context, the at least one adjuvant may be selected from any adjuvant known to a skilled person and suitable for the present case, i.e. supporting the induction of an immune response in a subject, e.g. in a human subject. 
     Accordingly, the composition of the second aspect may comprise at least one adjuvant, wherein the at least one adjuvant may be suitably selected from any adjuvant provided in of published PCT application WO2016/203025. 
     Adjuvants disclosed in any of the claims 2 to 17 of WO2016/203025, preferably adjuvants disclosed in claim 17 of WO2016/203025 are particularly suitable, the specific content relating thereto herewith incorporated by reference. 
     The composition of the second aspect may comprise, besides the components specified herein, at least one further component which may be selected from the group consisting of further antigens (e.g. in the form of a peptide or protein) or further antigen-encoding nucleic acids; a further immunotherapeutic agent; one or more auxiliary substances (cytokines, such as monokines, lymphokines, interleukins or chemokines); or any further compound, which is known to be immune stimulating due to its binding affinity (as ligands) to human Toll-like receptors; and/or an adjuvant nucleic acid, preferably an immunostimulatory RNA (isRNA), e.g. CpG-RNA etc. 
     Polypeptide and Composition Comprising the Polypeptide 
     In a third aspect, the present invention provides a polypeptide, preferably an antigenic polypeptide, wherein the polypeptide comprises an amino acid sequence or a fragment thereof encoded by the artificial RNA of the first aspect. 
     In embodiments, the polypeptide has an amino acid sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 68, 483, 898, 1267, 1636, 2005, 2374, 2743, 3112, 3481, 3850, 4219, 4588, 4957, 5326, 5695, 6064, 6433, 6802, 7171, 7540, 7909, 11726, 12095, 12464, 12833, 13940, 14309, 14678, 15047, 15416, 15785, 13202, 13571, 16154, 16523, 16892, 17261, 17630, 17999, 18368, 18737, 19106, 19475 or a variant of any of these polypeptides. 
     In preferred embodiments, the polypeptide has an amino acid sequence which is identical or at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 1267, 2005, 2743, 3481, 4219, 4957, 5695, 6433, 7171, 7909, 12833, 14309, 15047, 15785, 13571, 16523, 17261, 17999, 18737, 19475 or a variant of any of these polypeptides. 
     In a fourth aspect, the invention relates to an immunogenic composition, comprising the polypeptide of the third aspect. In preferred embodiments, the composition of the fourth aspect may additionally comprise at least one pharmaceutically acceptable carrier as defined herein. In preferred embodiments, the composition of the fourth aspect may additionally comprise at least one artificial RNA of the first aspect and, optionally, at least one further artificial RNA of the second aspect, or an RNA composition of the second aspect. 
     Notably, embodiments relating to the composition of the second aspect or the vaccine of the fifth aspect may likewise be read on and be understood as suitable embodiments of the composition of the fourth aspect. 
     Vaccine: 
     In a fifth aspect, the present invention provides a vaccine wherein the vaccine comprises the RNA of the first aspect, and, optionally, the composition of the second aspect, the polypeptide of the third aspect, or the composition of the fourth aspect. 
     Notably, embodiments relating to the composition of the second aspect or the composition of the fourth aspect may likewise be read on and be understood as suitable embodiments of the vaccine of the fifth aspect. Also, embodiments relating to the vaccine of the fifth aspect may likewise be read on and be understood as suitable embodiments of the composition of the second aspect (comprising the RNA of the first aspect and, optionally, the further artificial RNA of the second aspect) or the composition of the fourth aspect (comprising the polypeptide of the third aspect). 
     The term “vaccine” will be recognized and understood by the person of ordinary skill in the art, and is for example intended to be a prophylactic or therapeutic material providing at least one epitope or antigen, preferably an immunogen. In the context of the invention the antigen or antigenic function is provided by the inventive RNA of the first aspect (said RNA comprising a coding sequence encoding a antigenic peptide or protein derived from RSV F protein), the composition of the second aspect (comprising the RNA of the first aspect and, optionally, the further artificial RNA of the second aspect), the polypeptide of the third aspect, or the composition of the fourth aspect (comprising said polypeptide). 
     In preferred embodiments of the fifth aspect, the vaccine comprises the RNA of the first aspect, the composition of the second aspect (comprising the RNA of the first aspect and, optionally, the further artificial RNA of the second aspect), the polypeptide of the third aspect, or the composition of the fourth aspect wherein said RNA, said composition of the second aspect, said polypeptide, or said composition of the fourth aspect (comprising said polypeptide) elicits an adaptive immune response. 
     In particularly preferred embodiments, the vaccine comprises the RNA of the first aspect or the composition of the second aspect wherein said RNA or said composition elicits an adaptive immune response, preferably an adaptive immune response against RSV. 
     In particularly preferred embodiments, the vaccine comprises the RNA of the first aspect or the composition of the second aspect wherein said RNA or said composition induces a T cell immune response, According to a preferred embodiment of the fifth aspect, the vaccine as defined herein may further comprise a pharmaceutically acceptable carrier and optionally at least one adjuvant as specified in the context of the second aspect. 
     Suitable adjuvants in that context may be selected from adjuvants disclosed in claim 17 of WO2016/203025. 
     In a preferred embodiment, the vaccine is a monovalent vaccine. 
     In embodiments the vaccine is a polyvalent vaccine comprising a plurality or at least more than one of the artificial RNAs as defined in the context of the first aspect, and, optionally, at least more than one of the further artificial RNAs as defined in the context of the second aspect. Embodiments relating to a polyvalent composition as disclosed in the context of the second aspect may likewise be read on and be understood as suitable embodiments of the polyvalent vaccine of the fifth aspect. 
     The vaccine of the fifth aspect typically comprises a safe and effective amount of the RNA of the first aspect and, optionally, the further RNA of the second aspect. As used herein, “safe and effective amount” means an amount of the RNA that is sufficient to significantly induce a positive modification of a disease or disorder related to an infection with a RSV. At the same time, a “safe and effective amount” is small enough to avoid serious side-effects. In relation to the vaccine or composition of the present invention, the expression “safe and effective amount” preferably means an amount of the RNA that is suitable for stimulating the adaptive immune system in such a manner that no excessive or damaging immune reactions are achieved but, preferably, also no such immune reactions below a measurable level. 
     A “safe and effective amount” of the RNA of the composition or vaccine as defined above will furthermore vary in connection with the particular condition to be treated and also with the age and physical condition of the patient to be treated, the severity of the condition, the duration of the treatment, the nature of the accompanying therapy, of the particular pharmaceutically acceptable carrier used, and similar factors, within the knowledge and experience of the accompanying medical doctor. Moreover, the “safe and effective amount” of the RNA, the composition, the vaccine may depend from application route (intradermal, intramuscular), application device (jet injection, needle injection, microneedle patch) and/or complexation (protamine complexation or LNP encapsulation). Moreover, the “safe and effective amount” of the artificial RNA, the composition, the vaccine may depend from the condition of the treated subject (infant, pregnant women, immunocompromised human subject etc.). Accordingly, the suitable “safe and effective amount” has to be adapted accordingly and will be chosen and defined by the skilled person. 
     The vaccine can be used according to the invention for human medical purposes and also for veterinary medical purposes (mammals, vertebrates, avian species), as a pharmaceutical composition, or as a vaccine. 
     In a preferred embodiment, the RNA, the composition (comprising said RNA and, optionally, a further RNA), the polypeptide, the composition (comprising said polypeptide), or the vaccine is provided in lyophilized form (using e.g. lyophilisation methods as described in WO2016/165831, WO2011/069586, WO2016/184575 or WO2016/184576). Preferably, the lyophilized RNA, the lyophilized composition, the lyophilized polypeptide, the lyophilized composition comprising the polypeptide, or the lyophilized vaccine is reconstituted in a suitable buffer, advantageously based on an aqueous carrier, prior to administration, e.g. Ringer-Lactate solution or a phosphate buffer solution. 
     Accordingly, the pharmaceutically acceptable carrier as used herein preferably includes the liquid or non-liquid basis of the inventive vaccine. If the inventive vaccine is provided in liquid form, the carrier will be water, typically pyrogen-free water; isotonic saline or buffered (aqueous) solutions, e.g. phosphate, citrate etc. buffered solutions. Preferably, Ringer-Lactate solution is used as a liquid basis for the vaccine or the composition according to the invention as described in WO2006/122828, the disclosure relating to suitable buffered solutions incorporated herewith by reference. 
     The choice of a pharmaceutically acceptable carrier as defined herein is determined, in principle, by the manner, in which the pharmaceutical composition(s) or vaccine according to the invention is administered. The vaccine can be administered, for example, systemically or locally. Routes for systemic administration in general include, for example, transdermal, oral, parenteral routes, including subcutaneous, intravenous, intramuscular, intra-arterial, intradermal and intraperitoneal injections and/or intranasal administration routes. Routes for local administration in general include, for example, topical administration routes but also intradermal, transdermal, subcutaneous, or intramuscular injections or intralesional, intracranial, intrapulmonal, intracardial, intraarticular and sublingual injections. More preferably, composition or vaccines according to the present invention may be administered by an intradermal, subcutaneous, or intramuscular route, preferably by injection, which may be needle-free and/or needle injection. Compositions/vaccines are therefore preferably formulated in liquid or solid form. The suitable amount of the vaccine or composition according to the invention to be administered can be determined by routine experiments, e.g. by using animal models. Such models include, without implying any limitation, rabbit, sheep, mouse, rat, dog and non-human primate models. Preferred unit dose forms for injection include sterile solutions of water, physiological saline or mixtures thereof. The pH of such solutions should be adjusted to about 7.4. Suitable carriers for injection include hydrogels, devices for controlled or delayed release, polylactic acid and collagen matrices. Suitable pharmaceutically acceptable carriers for topical application include those which are suitable for use in lotions, creams, gels and the like. If the inventive compositionor vaccine is to be administered perorally, tablets, capsules and the like are the preferred unit dose form. The pharmaceutically acceptable carriers for the preparation of unit dose forms which can be used for oral administration are well known in the prior art. The choice thereof will depend on secondary considerations such as taste, costs and storability, which are not critical for the purposes of the present invention, and can be made without difficulty by a person skilled in the art. 
     The inventive vaccine or composition as defined herein can additionally contain one or more auxiliary substances as defined above in order to further increase the immunogenicity. A synergistic action of the nucleic acid contained in the inventive composition and of an auxiliary substance, which may be optionally be co-formulated (or separately formulated) with the inventive vaccine or composition as described above, is preferably achieved thereby. Such immunogenicity increasing agents or compounds may be provided separately (not co-formulated with the inventive vaccine or composition) and administered individually. 
     Further additives which may be included in the inventive vaccine or composition are emulsifiers, such as for example, Tween; wetting agents, such as, for example, sodium lauryl sulfate; colouring agents; taste-imparting agents, pharmaceutical carriers; tablet-forming agents; stabilizers; antioxidants; preservatives. 
     Kit or Kit of Parts, Application, Medical Uses, Method of Treatment: 
     In a sixth aspect, the present invention provides a kit or kit of parts, wherein the kit or kit of parts comprises the RNA of the first aspect, the composition of the second aspect (comprising said RNA), the polypeptide of the third aspect, the composition of the fourth aspect (comprising said polypeptide), and/or the vaccine of the fifth aspect, optionally comprising a liquid vehicle for solubilising, and optionally technical instructions providing information on administration and dosage of the components. 
     In a preferred embodiment, the kit of the sixth aspect comprises at least the following components
     a) at least one RNA of the first aspect, preferably encoding at least one antigenic peptide or protein derived from a RSV fusion (F) protein (RNA sequences preferably selected from Table 5 or 6), wherein said artificial RNA is preferably complexed with one or more lipids thereby forming lipid nanoparticles (LNP); and   b) at least one, two, or three further artificial RNA encoding an antigenic peptide or protein derived from RSV selected from M, N, M2-1, or P (RNA sequences preferably selected from Table 7A), wherein said further RNA is preferably complexed with one or more lipids thereby forming lipid nanoparticles (LNP), wherein components a) and b) are provided as separate entities or as a single entity.   

     In a preferred embodiment, the kit of the sixth aspect comprises at least the following components
     a) at least one RNA of the first aspect, preferably encoding at least one antigenic peptide or protein derived from a RSV fusion (F) protein (RNA sequences preferably selected from Table 5 or 6), wherein said artificial RNA is preferably complexed with one or more lipids thereby forming lipid nanoparticles (LNP); and   b) at least one further artificial RNA encoding an antigenic peptide or protein derived from RSV selected from M (RNA sequences preferably selected from Table 7A, Column A), wherein said further RNA is preferably complexed with one or more lipids thereby forming lipid nanoparticles (LNP); and   c) at least one further artificial RNA encoding an antigenic peptide or protein derived from RSV selected from P (RNA sequences preferably selected from Table 7A, Column C), wherein said further RNA is preferably complexed with one or more lipids thereby forming lipid nanoparticles (LNP),   

     wherein components a), b) and c) are provided as separate entities or as a single entity. 
     In a preferred embodiment, the kit of the sixth aspect comprises at least the following components
     a) at least one RNA of the first aspect, preferably encoding at least one antigenic peptide or protein derived from a RSV fusion (F) protein (RNA sequences preferably selected from Table 5 or 6), wherein said artificial RNA is preferably complexed with one or more lipids thereby forming lipid nanoparticles (LNP); and   b) at least one further artificial RNA encoding an antigenic peptide or protein derived from RSV selected from M (RNA sequences preferably selected from Table 7A, Column A), wherein said further RNA is preferably complexed with one or more lipids thereby forming lipid nanoparticles (LNP); and   c) at least one further artificial RNA encoding an antigenic peptide or protein derived from RSV selected from P (RNA sequences preferably selected from Table 7A, Column C), wherein said further RNA is preferably complexed with one or more lipids thereby forming lipid nanoparticles (LNP); and   d) at least one further artificial RNA encoding an antigenic peptide or protein derived from RSV selected from P (RNA sequences preferably selected from Table 7A, Column B), wherein said further RNA is preferably complexed with one or more lipids thereby forming lipid nanoparticles (LNP),   

     wherein components a), b), c) and d) are provided as separate entities or as a single entity. 
     The kit may further comprise additional components as described in the context of the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, and/or the vaccine of the fifth aspect. 
     The technical instructions of said kit may contain information about administration and dosage and patient groups. Such kits, preferably kits of parts, may be applied e.g. for any of the applications or uses mentioned herein, preferably for the use of the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, or the vaccine of the fifth aspect, for the treatment or prophylaxis of an infection or diseases caused by RSV or disorders related thereto. Preferably, the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, or the vaccine of the fifth aspect is provided in a separate part of the kit, wherein the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, or the vaccine of the fifth aspect is preferably lyophilised. The kit may further contain as a part a vehicle (e.g. buffer solution) for solubilising the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition fourth aspect, or the vaccine of the fifth aspect. 
     In preferred embodiments, the kit or kit of parts as defined herein comprises Ringer lactate solution. 
     Any of the above kits may be used in a treatment or prophylaxis as defined herein. More preferably, any of the above kits may be used as a vaccine, preferably a vaccine against infections caused by RSV as defined herein. 
     Medical Use: 
     In a further aspect, the present invention relates to the first medical use of the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect. 
     Accordingly, the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect is for use as a medicament. 
     The present invention furthermore provides several applications and uses of the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect. 
     In particular, said RNA, composition (comprising said RNA), polypeptide, composition (comprising said polypeptide), vaccine, or the kit or kit of parts may be used for human medical purposes and also for veterinary medical purposes, preferably for human medical purposes. 
     In particular, said RNA, composition (comprising said RNA), polypeptide, composition (comprising said polypeptide), vaccine, or the kit or kit of parts may is for use as a medicament for human medical purposes, wherein said RNA, composition (comprising said RNA), polypeptide, composition (comprising said polypeptide), vaccine, or the kit or kit of parts may be particularly suitable for young infants, newborns, immunocompromised recipients, as well as pregnant and breast-feeding women and elderly people. 
     In yet another aspect, the present invention relates to the second medical use of the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect. 
     Accordingly, the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect is for use in the treatment or prophylaxis of an infection with a pathogen (e.g. a virus), in particular with Respiratory syncytial virus (RSV), or a disorder related to such an infection. 
     In particular, the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect may be used in the treatment or prophylaxis of an infection with a virus, in particular with RSV, or a disorder related to such an infection for human and also for veterinary medical purposes, preferably for human medical purposes. 
     In particular, said RNA, composition (comprising said RNA), polypeptide, composition (comprising said polypeptide), vaccine, or the kit or kit of parts may be particularly suitable for young infants, newborns, immunocompromised recipients, as well as pregnant and breast-feeding women and elderly people for use in the treatment or prophylaxis of an infection with RSV. 
     As used herein, “a disorder related to a RSV infection” may preferably comprise a typical symptom or a complication of an RSV infection. 
     Particularly, the artificial RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect may be used in a method of prophylactic (pre-exposure prophylaxis or post-exposure prophylaxis) and/or therapeutic treatment of infections caused by RSV. 
     The composition or the vaccine as defined herein may preferably be administered locally. In particular, composition or vaccines may be administered by an intradermal, subcutaneous, intranasal, or intramuscular route. Inventive compositions or vaccines of the invention are therefore preferably formulated in liquid (or sometimes in solid) form. In embodiments, the inventive vaccine may be administered by conventional needle injection or needle-free jet injection. Preferred in that context is the RNA, the composition, the vaccine is administered by intramuscular needle injection. 
     The term “jet injection”, as used herein, refers to a needle-free injection method, wherein a fluid (vaccine, composition of the invention) containing e.g. at least one RNA of the first aspect is forced through an orifice, thus generating an ultra-fine liquid stream of high pressure that is capable of penetrating mammalian skin and, depending on the injection settings, subcutaneous tissue or muscle tissue. In principle, the liquid stream perforates the skin, through which the liquid stream is pushed into the target tissue. Preferably, jet injection is used for intradermal, subcutaneous or intramuscular injection of the RNA, the compositions, the vaccines disclosed herein. 
     In embodiments, the RNA as comprised in a composition or vaccine as defined herein is provided in an amount of about 100 ng to about 500 μg, in an amount of about 1 μg to about 200 μg, in an amount of about 1 μg to about 100 μg, in an amount of about 5 μg to about 100 μg, preferably in an amount of about 10 μg to about 50 μg, specifically, in an amount of about 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg or 100 μg. 
     Depending from application route (intradermal, intramuscular, intranasal), application device (jet injection, needle injection, microneedle patch) and/or complexation (preferably LNP encapsulation) the suitable amount has to be adapted accordingly and will be chosen and defined by the skilled person. 
     The immunization protocol for the treatment or prophylaxis of an infection as defined herein, i.e. the immunization of a subject against a RSV, typically comprises a series of single doses or dosages of the composition or the vaccine. A single dosage, as used herein, refers to the initial/first dose, a second dose or any further doses, respectively, which are preferably administered in order to “boost” the immune reaction. 
     In one embodiment, the immunization protocol for the treatment or prophylaxis of an infection as defined herein, i.e. the immunization of a subject against a RSV, comprises one single doses of the composition or the vaccine. 
     In preferred embodiments, the immunization protocol for the prophylaxis of an infection with RSV comprises at least one single dose of the composition or the vaccine as defined herein, wherein said at least one single dose is administered to a pregnant women for maternal immunization, thereby achieving immunization of the unborn child and/or wherein said at least one single dose is administered to a breast-feeding women for thereby achieving passive immunization of the breast-fed child. 
     The treatment or prophylaxis as defined above may comprise the administration of a further active pharmaceutical ingredient. In the case of the inventive vaccine or composition, which is based on the artificial RNA of the first aspect, a polypeptide, preferably of the third aspect may be co-administered as a further active pharmaceutical ingredient. 
     For example, at least one RSV protein or peptide as described herein, or a fragment or variant thereof, may be co-administered in order to induce or enhance an immune response. Further, two distinct artificial RNAs of the first aspect and, optionally further RNAs of the second aspect may be administered at different time points, preferably in a prime-boost scenario, e.g. using a composition comprising at least one RSV polypeptide as prime vaccination and a composition/vaccine comprising at least one artificial RNA of the first aspect as boost vaccination. 
     Suitably, the treatment or prophylaxis as defined above comprises the administration of a further active pharmaceutical ingredient, wherein the further active pharmaceutical ingredient may be an immunotherapeutic agent that can be selected from immunoglobulins, preferably IgGs, monoclonal or polyclonal antibodies, polyclonal serum or sera, etc., most preferably immunoglobulins directed against a RSV protein or peptide as defined herein. Preferably, such a further immunotherapeutic agent may be provided as a peptide/protein or may be encoded by a nucleic acid, preferably by a DNA or an RNA, more preferably an mRNA. Such an immunotherapeutic agent allows providing passive vaccination additional to active vaccination triggered by the inventive artificial RNA or by the inventive polypeptide. 
     Method of Treatment and Use, Diagnostic Method and Use: 
     In another aspect, the present invention relates to a method of treating or preventing a disorder. 
     In preferred embodiments, the present invention relates to a method of treating or preventing a disorder, wherein the method comprises applying or administering to a subject in need thereof the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect. 
     In preferred embodiments, the disorder is an infection with Respiratory syncytial virus (RSV), or a disorder related to such an infection. 
     In preferred embodiments, the present invention relates to a method of treating or preventing a disorder, wherein the method comprises applying or administering to a subject in need thereof the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect, wherein the subject in need is preferably a mammalian subject. In particularly preferred embodiments, the mammalian subject is a human subject, particularly an infant, a newborn, a pregnant women, a breast-feeding woman, an elderly, or an immunocompromised human subject. 
     In particular, such a method may preferably comprise the steps of:
     a) providing the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect;   b) applying or administering said RNA of the first aspect, composition of the second aspect, polypeptide of the third aspect, composition of the fourth aspect, vaccine of the fifth aspect, or kit or kit of parts of the sixth aspect to a tissue or an organism;   c) optionally, administering immunoglobulin (IgGs) against a RSV;   d) optionally, administering a further substance (adjuvant, auxiliary substance, further antigen).   

     According to a further aspect, the present invention also provides a method for expression of at least one polypeptide comprising at least one peptide or protein derived from a RSV, or a fragment or variant thereof, wherein the method preferably comprises the following steps:
     a) providing the RNA of the first aspect or the composition of the second aspect; and   b) applying or administering said RNA or composition to an expression system (cells), a tissue, an organism.   

     The method may be applied for laboratory, for research, for diagnostic, for commercial production of peptides or proteins and/or for therapeutic purposes. The method may furthermore be carried out in the context of the treatment of a specific disease, particularly in the treatment of infectious diseases, particularly RSV infections. 
     Likewise, according to another aspect, the present invention also provides the use of the artificial RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect preferably for diagnostic or therapeutic purposes, e.g. for expression of an encoded RSV antigenic peptide or protein, e.g. by applying or administering said RNA, composition comprising said RNA, vaccine comprising said RNA, e.g. to a cell-free expression system, a cell (e.g. an expression host cell or a somatic cell), a tissue or an organism. In specific embodiments, applying or administering said RNA, composition comprising said RNA, vaccine comprising said RNA to a tissue or an organism is followed by e.g. a step of obtaining induced RSV F antibodies e.g. RSV F specific (monoclonal) antibodies. 
     The use may be applied for a (diagnostic) laboratory, for research, for diagnostics, for commercial production of peptides, proteins, or RSV antibodies and/or for therapeutic purposes. The use may be carried out in vitro, in vivo or ex vivo. The use may furthermore be carried out in the context of the treatment of a specific disease, particularly in the treatment of an RSV infection or a related disorder. 
     In a particularly preferred embodiment, the invention provides the RNA of the first aspect, the composition of the second aspect, the polypeptide of the third aspect, the composition of the fourth aspect, the vaccine of the fifth aspect, or the kit or kit of parts of the sixth aspect for use as a medicament, for use in treatment or prophylaxis, preferably treatment or prophylaxis of an RSV infection or a related disorder, or for use as a vaccine. 
     BRIEF DESCRIPTION OF LISTS AND TABLES 
     List 1: Suitable RSV virus strains 
     List 2: NCBI Protein Accession numbers of suitable RSV fusion (F) proteins 
     Table 1: Preferred RSV F protein antigen designs 
     Table 2: Human codon usage table with frequencies indicated for each amino acid 
     Table 3A: Preferred coding sequences encoding RSV F (columns A-J), derived from HRSV(A2) 
     Table 3B: Preferred coding sequences encoding RSV F (columns A-J), derived from HRSV(Memphis-37) 
     Table 4A: Preferred coding sequences encoding RSV F (columns K-V), derived from HRSV(A2) 
     Table 4B: Preferred coding sequences encoding RSV F (columns K-V), derived from HRSV(Memphis-37) 
     Table 5A: Preferred mRNA constructs encoding RSV F (columns A-J), derived from HRSV(A2) 
     Table 5B: Preferred mRNA constructs encoding RSV F (columns A-J), derived from HRSV(Memphis-37) 
     Table 6A: Preferred mRNA constructs encoding RSV F (column K-V), derived from HRSV(A2) 
     Table 6B: Preferred mRNA constructs encoding RSV F (column K-V), derived from HRSV(Memphis-37) 
     Table 7A: Preferred further coding sequences and mRNA constructs of the composition or vaccine 
     Table 7B: Suitable combinations of RNA constructs 
     Table 8: Representative lipid compounds derived from formula (III) 
     Table 9: mRNA constructs used in the present examples (see Examples section) 
     Table 10: Animal groups and vaccination schedule of Example 2 (see Examples section) 
     Table 11: Animal groups and vaccination schedule of Example 3 (see Examples section) 
     Table 12: mRNA constructs with different UTR combinations of Example 4 (see Examples section) 
     Table 13: Animal groups and vaccination schedule of Example 5 (see Examples section) 
     Table 14: Animal groups and vaccination schedule of Example 6 (see Examples section) 
     Table 15: Animal groups and vaccination schedule of Example 7 (see Examples section) 
     Table 15: Animal groups and vaccination schedule of Example 7 (see Examples section) 
     Table 16: Overview of mRNA constructs used in Example 8 (see Examples section) 
     Table 17: Animal groups and vaccination schedule of Example 9 (see Examples section) 
     Table 18: Animal groups and vaccination schedule of Example 10 (see Examples section) 
     Table 19: Overview of mRNA constructs used in Example 11 (see Examples section) 
     Table 20: Animal groups and vaccination schedule of Example 12 (see Examples section) 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  shows that LNP-formulated mRNA encoding RSV F-protein (F-del_DSCav1) induces high virus neutralization titers (VNTs) in serum of cotton rats after i.m. and i.d. vaccinations. Vaccination with protamine-formulated mRNA induces only weak responses. Vaccination schedule see Table 10. Further details are provided in Example 2. 
         FIG. 2  shows that LNP-formulated mRNA encoding RSV F-protein (F-del_DSCav1) reduces RSV infection of the lung in cotton rats after i.m. and i.d. vaccination. Vaccination schedule see Table 10. Further details are provided in Example 2. 
         FIG. 3  shows the results of a lung histopathology analysis from the RSV cotton rat challenge study described in Example 2. Animals vaccinated with LNP-formulated mRNA do not show increased lung histopathology/enhanced inflammation after viral challenge in contrast to the vaccination with formalin-inactivated RSV virus vaccine. Vaccination schedule see Table 10. Further details are provided in Example 2. 
         FIG. 4  shows that LNP-formulated mRNA encoding RSV F-protein (F0, F-del, and F-del_DSCav1) induces high (virus neutralization titers) VNTs in the serum of cotton rats after two i.m. vaccinations. VNTs determined performed on day 48. Vaccination schedule see Table 11. Further details are provided in Example 3. 
         FIG. 5  shows that LNP-formulated mRNA encoding RSV F-protein (F0, F-del, and F-del_DSCav1) induces specific humoral immune responses in cotton rats against the RSV-F protein. The experiment was performed as described in Example 3 and antibody total IgG titers were determined by ELISA. RSV-F (formulated in LNP) and RSV-F-del (formulated in LNP) vaccines induce higher titers of RSV-F specific IgGs already after prime vaccination (day 28) than live virus.  FIG. 5 a   : Antibody titers determined on day 49;  FIGS. 5 b  and 5 c   : time-dependent IgG titers in serum with 10 μg mRNA ( FIG. 5 b   ) or 100 μg mRNA ( FIG. 5 c   ) encoding RSV F-protein (F, F-del, and F-del_DSCav1). Vaccination schedule see Table 11. Further details are provided in Example 3. 
         FIG. 6  shows that LNP-formulated mRNA encoding RSV F-protein (F0, F-del, and F-del_DSCav1) reduces RSV infection of the lung in cotton rats after i.m. vaccination. The experiment was performed as described in Example 3. All animal groups vaccinated with mRNA vaccines showed virus titers below the level of detection demonstrating protection of vaccinated cotton rats in terms of viral lung titers. In comparison to the mRNA vaccines the vaccine based on formalin-inactivated virus was not able to prevent virus titers in the lung. Vaccination schedule see Table 11. Further details are provided in Example 3. 
         FIG. 7  shows that LNP-formulated mRNA encoding RSV F-protein (F0, F-del, and F-del_DSCav1) reduces RSV titers in the nose of cotton rats after i.m. vaccination. The experiment was performed as described in Example 3. All animal groups vaccinated with mRNA vaccines show strongly reduced viral titers in the nasal tissue in viral challenge infection experiments. In comparison to the mRNA vaccines the vaccine based on formalin-inactivated virus was not able to reduce nasal virus titers. Vaccination schedule see Table 11. Further details are provided in Example 3. 
         FIG. 8  shows the results of a lung histopathology analysis from the RSV cotton rat challenge study described in Example 3. Animals vaccinated with LNP-formulated mRNA do not show increased lung histopathology/enhanced inflammation after viral challenge in contrast to the vaccination with formalin-inactivated RSV virus vaccine. Vaccination schedule see Table 11. Further details are provided in Example 3. 
         FIG. 9  shows that UTR combinations according to the invention increase the expression of RSV F-Protein in vitro. HEK 293T cells were transfected with different Lipofectamine-formulated mRNA constructs, which all contain the same coding sequence encoding pre-fusion stabilized truncated RSV-F (F-del_DSCav1) but use different combinations of 5′ and 3′-UTRs (see Table 12). RSV-F expression was analyzed by flow cytometry. Values show % of the detected RSV-F signal. Values normalized to 100% according to the expression of the reference mRNA construct (UTR combination RPL32/ALB7). Water for injection (WFI) serves as a control. N=2. Further details are provided in Example 4. 
         FIG. 10  shows that the used mRNA constructs encoding RSV F-protein ( FIG. 10 a   : F0, F-del, F0_DSCav1, F-del_DSCav1, F_DSCav1_mut1, F-del_DSCav1_mut1, F_DSCav1_mut2, F-del_DSCav1_mut2, F_DSCav1_mut3, F-del_DSCav1_mut3,  FIG. 10 b   : F0, F-del, F0_DSCav1, F-del_DSCav1, F_DSCav1_mut0, F-del_DSCav1_mut0, F_DSCav1_mut4, F-del_DSCav1_mut4, F_DSCav1_mut5, F-del_DSCav1_mut5) led to a detectable intracellular RSV F protein expression as well as to a detectable protein expression at the cell surface. Further details are provided in Table 16 and Example 8. 
         FIG. 11  shows that all tested LNP-formulated mRNA constructs encoding different RSV F proteins (F0, F0_DSCav1, F_DSCav1_mut3, F_DSCav1_mut1, F_DSCav1_mut2, F-del, F-del_DSCav1, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) induce humoral immune responses in cotton rats against the RSV-F protein. Antibody total IgG titers were determined by ELISA. Vaccination schedule see Table 17. Further details are provided in Example 9. 
         FIG. 12  shows that all LNP-formulated RSV-F (F0, F0_DSCav1, F_DSCav1_mut3, F_DSCav1_mut1, F_DSCav1_mut2, F-del, F-del_DSCav1, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) mRNA vaccines induced the formation of RSV specific functional antibodies in cotton rats as shown by high virus neutralizing antibody titers. Vaccination schedule see Table 17. Further details are provided in Example 9. 
         FIG. 13  shows the lung histopathology analysis from the RSV cotton rat challenge study. None of the mRNA vaccinated groups displayed enhanced lung pathology as it is the case for the group that was vaccinated using the formalin-inactivated RSV vaccine Vaccination schedule see Table 17. Further details are provided in Example 9. 
         FIG. 14  shows the results of the analysis of lung viral titers ( FIG. 14 a   ) and of nose viral titers ( FIG. 14 b   ) in cotton rats challenged with RSV virus. Vaccination schedule see Table 17. Further details are provided in Example 9. 
         FIG. 15  shows that all tested LNP-formulated mRNA constructs encoding different RSV F proteins (F-del, F-del_DSCav1_mut2, F-del_DSCav1_mut0, F-del_DSCav1_mut5, F-del_DSCav1_mut4) induce humoral immune responses in cotton rats against the RSV-F protein. Antibody total IgG titers were determined by ELISA. Vaccination schedule see Table 18. Further details are provided in Example 10. 
         FIG. 16  shows that all LNP-formulated RSV-F (F-del, F-del_DSCav1_mut2, F-del_DSCav1_mut0, F-del_DSCav1_mut5, F-del_DSCav1_mut4) mRNA vaccines induced the formation of RSV specific functional antibodies in cotton rats as shown by high virus neutralizing antibody titers. The LNP-formulated constructs for pre-fusion stabilization induce higher or comparable responses than F-del. Vaccination schedule see Table 18. Further details are provided in Example 10. 
         FIG. 17  shows the lung histopathology analysis from the RSV cotton rat challenge study. None of the mRNA vaccinated groups displayed enhanced lung pathology as it is the case for the group that was vaccinated using the formalin-inactivated RSV vaccine Vaccination schedule see Table 18. Further details are provided in Example 10. 
         FIG. 18  shows the results of the analysis of lung viral titers ( FIG. 18 a   ) and of nose viral titers ( FIG. 18 b   ) in cotton rats challenged with RSV virus. Vaccination schedule see Table 18. Further details are provided in Example 10. 
         FIG. 19  shows that the used mRNA constructs coding for RSV matrix protein M, phosphoprotein P, nucleoprotein N and matrix protein M2-1 protein led to a detectable protein expression using a rabbit reticulocyte lysate system. Further details are provided in Table 19 and Example 11. 
         FIG. 20  shows the results of the immunogenicity study in mice (ELISA). The humoral immune responses can be seen in  FIG. 20 a   : anti-RSV F IgG and in  FIG. 20 b   : anti-RSV F IgG2a. All groups induced humoral immune responses. In general, the IgG2a titers are 10 times higher than the IgG1 titers, indicating a predominant Th1 response. Vaccination schedule see Table 20. Further details are provided in Example 12. 
         FIG. 21  shows that specific antigen IgGs were detected in sera of immunized mice indicating that the applied mRNA constructs are suitable to induce specific humoral immune responses. Vaccination schedule see Table 20. Further details are provided in Example 12. 
         FIG. 22  shows that all LNP-formulated mRNA vaccines (F, M+F, P+F, N+F, M2-1+F) induced the formation of RSV specific functional antibodies in mice as shown by high virus neutralizing antibody titers. Vaccination schedule see Table 20. Further details are provided in Example 12. 
         FIG. 23  shows that all vaccines containing RSV F, RSV M2-1, or both surprisingly induced a tissue resident memory T cell (TRM) response in the lung upon intramuscular immunization ( FIG. 23 a   ). The splenocyte analysis revealed that an immunization with RSV F and especially RSV M2-1 lead to an increase of antigen-specific CD8+ and CD4+ T cells secreting IFN-γ and TNF indicating the induction of a systemic T cell response in addition to a site-specific response ( FIG. 23 b    and  FIG. 23 c   ). 
     
    
    
     EXAMPLES 
     In the following, particular examples illustrating various embodiments and aspects of the invention are presented. However, the present invention shall not to be limited in scope by the specific embodiments described herein. The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. The present invention, however, is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the invention only, and methods which are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention in addition to those described herein will become readily apparent to those skilled in the art from the foregoing description, accompanying figures and the examples below. All such modifications fall within the scope of the appended claims. 
     Example 1: Preparation of DNA and mRNA Constructs and Compositions for In Vitro and In Vivo Experiments 
     The present Example provides methods of obtaining the artificial RNA of the invention as well as methods of generating a composition or a vaccine of the invention. 
     1.1. Preparation of DNA and mRNA constructs: 
     For the present examples, DNA sequences encoding different RSV F proteins (e.g. F0, F-del, F-del_DSCav1, F-del_DSCav1_mut5, etc.) were prepared and used for subsequent RNA in vitro transcription reactions. Said DNA sequences were prepared by modifying the wild type encoding DNA sequences by introducing a G/C optimized coding sequence (e.g., “cds opt1”) for stabilization. Sequences were introduced into a pUC19 derived vector to comprise stabilizing 3′-UTR sequences derived from a 3′-UTR of a gene selected from PSMB3, ALB7, alpha-globin, CASP1, COX6B1, GNAS, NDUFA1 and RPS9 and 5′-UTR sequences derived from a 5′-UTR of a gene selected from HSD17B4, RPL32, ASAH1, ATP5A1, MP68, NDUFA4, NOSIP, RPL31, SLC7A3, TUBB4B and UBQLN2, additionally comprising, a stretch of adenosines (e.g. 64A or A100), and a histone-stem-loop (hSL) structure, and optionally a stretch of 30 cytosines (e.g. C30) as listed in Table 9. 
     The obtained plasmid DNA constructs were transformed and propagated in bacteria using common protocols known in the art. Eventually, the plasmid DNA constructs were extracted, purified, and used for subsequent RNA in vitro transcription (see section 1.2.). 
     Alternatively, DNA plasmids prepared according to paragraph 1 are used as DNA template for PCR-based amplification. Eventually, the generated PCR products are purified and used for subsequent RNA in vitro transcription (see section 1.3.). 
     1.2. RNA In Vitro Transcription from Plasmid DNA Templates: 
     DNA plasmids prepared according to paragraph 1.1 were enzymatically linearized using EcoRI or SapI and used for DNA dependent RNA in vitro transcription using T7 RNA polymerase in the presence of a nucleotide mixture (ATP/GTP/CTP/UTP) and cap analog (e.g., m7GpppG, m7G(5′)ppp(5′)(2′OMeA)pG, or m7G(5′)ppp(5′)(2′OMeG)pG)) under suitable buffer conditions. The obtained mRNA constructs were purified using RP-HPLC (PureMessenger®, CureVac AG, Tubingen, Germany; WO2008/077592) and used for in vitro and in vivo experiments. RNA for clinical development (see Example 6) is produced under current good manufacturing practice e.g. according to WO2016/180430, implementing various quality control steps on DNA and RNA level. The generated RNA sequences/constructs are provided in Table 9 with the encoded F protein and the respective UTR elements indicated therein. In addition to the information provided in Table 9, further information relating to specific mRNA construct SEQ-ID NOs may be derived from the information provided under &lt;223&gt; identifier provided in the ST.25 sequence listing. 
     Alternatively, EcoRI or SapI linearized DNA is used for DNA dependent RNA in vitro transcription using an RNA polymerase in the presence of a modified nucleotide mixture (ATP, GTP, CTP, N(1)-methylpseudouridine (m14) or pseudouridine (Ψ)) and cap analog (m7GpppG, m7G(5′)ppp(5′)(2′OMeA)pG, or m7G(5′)ppp(5′)(2′OMeG)pG) under suitable buffer conditions. The obtained m1Ψ or Ψ-modified mRNAs are purified using RP-HPLC (PureMessenger®, CureVac, Tobingen, Germany; WO2008/077592) and used for further experiments. 
     Some mRNA constructs are in vitro transcribed in the absence of a cap analog. The cap-structure (cap1) is added enzymatically using Capping enzymes as commonly known in the art. In short, in vitro transcribed mRNA is capped using an m7G capping kit with 2′-O-methyltransferase to obtain cap1-capped mRNA. Cap1-capped mRNA is purified using RP-HPLC (PureMessenger®, CureVac, Tubingen, Germany; WO2008/077592) and used for further experiments. 
     1.3. RNA In Vitro Transcription from PCR Amplified DNA Templates: 
     Purified PCR amplified DNA templates prepared according to paragraph 1.1 are transcribed in vitro using DNA dependent T7 RNA polymerase in the presence of a nucleotide mixture (ATP/GTP/CTP/UTP) and cap analog (m7GpppG) under suitable buffer conditions. Alternatively, PCR amplified DNA is transcribed in vitro using DNA dependent T7 RNA polymerase in the presence of a modified nucleotide mixture (ATP, GTP, CTP, N(1)-methylpseudouridine (m14)) and cap analog (m7GpppG) under suitable buffer conditions. Some mRNA constructs are in vitro transcribed in the absence of a cap analog and the cap-structure (cap1) is added enzymatically using capping enzymes as commonly known in the art e.g. using an m7G capping kit with 2′-O-methyltransferase. The obtained mRNAs are purified e.g. using RP-HPLC (PureMessenger®, CureVac AG, Tübingen, Germany; WO2008/077592) and used for in vitro and in vivo experiments. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 mRNA constructs used in the present examples 
               
            
           
           
               
               
               
               
               
               
            
               
                 RNA 
                   
                 5′-UTR/3′-UTR; 
                 3′-terminal 
                 SEQ ID NO: 
                 SEQ ID NO: 
               
               
                 ID 
                 Antigen Name 
                 UTR Design 
                 Elements (3′-end) 
                 RNA 
                 Protein 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 R6939/ 
                 F0 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 475 
                 68 
               
               
                 R7003 
               
               
                 R3737/ 
                 F0 
                 RPL32/ALB7; i-2 
                 A64-N5-C30-histoneSL-N5 
                 466 
                 68 
               
               
                 R3938 
               
               
                 R6940 
                 F-del 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 890 
                 483 
               
               
                 R3738/ 
                 F-del 
                 RPL32/ALB7; i-2 
                 A64-N5-C30-histoneSL-N5 
                 881 
                 483 
               
               
                 R3939 
               
               
                 R6808 
                 F0_DSCav1 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 1259 
                 898 
               
               
                 R5453 
                 F-del_DSCav1 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 1628 
                 1267 
               
               
                 R6122 
                 F-del_DSCav1 
                 RPL32/ALB7; i-2 
                 A64-N5-C30-histoneSL-N5 
                 1620 
                 1267 
               
               
                 R4745/ 
                 F-del_DSCav1 
                 HSD17B4/ALB7; i-4 
                 A64-N5-C30-histoneSL-N5 
                 8278 
                 1267 
               
               
                 R5717 
               
               
                 R6771 
                 F_DSCav1_mut1 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 1997 
                 1636 
               
               
                 R6774 
                 F-del_DSCav1_mut1 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 2366 
                 2005 
               
               
                 R6772 
                 F_DSCav1_mut2 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 2735 
                 2374 
               
               
                 R6773 
                 F-del_DSCav1_mut2 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 3104 
                 2743 
               
               
                 R6770 
                 F_DSCav1_mut3 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 3473 
                 3112 
               
               
                 R6775 
                 F-del_DSCav1_mut3 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 3842 
                 3481 
               
               
                   
                 F-del_DSCav1 
                 HSD17B4/PSMB3; a-1 
                 A64-N5-C30-histoneSL-N5 
                 1276 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Ndufa4/PSMB3; a-2 
                 A64-N5-C30-histoneSL-N5 
                 1284 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Slc7a3/PSMB3; a-3 
                 A64-N5-C30-histoneSL-N5 
                 1292 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Nosip/PSMB3; a-4 
                 A64-N5-C30-histoneSL-N5 
                 1300 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Mp68/PSMB3; a-5 
                 A64-N5-C30-histoneSL-N5 
                 1308 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Ubqln2/RPS9; b-1 
                 A64-N5-C30-histoneSL-N5 
                 1316 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 ASAH1/RPS9; b-2 
                 A64-N5-C30-histoneSL-N5 
                 1324 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 HSD17B4/RPS9; b-3 
                 A64-N5-C30-histoneSL-N5 
                 1332 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 HSD17B4/CASP1; b-4 
                 A64-N5-C30-histoneSL-N5 
                 1340 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Nosip/COX6B1; b-5 
                 A64-N5-C30-histoneSL-N5 
                 1348 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Ndufa4/RPS9; c-1 
                 A64-N5-C30-histoneSL-N5 
                 1356 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Nosip/Ndufa1; c-2 
                 A64-N5-C30-histoneSL-N5 
                 1364 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Ndufa4/COX6B1; c-3 
                 A64-N5-C30-histoneSL-N5 
                 1372 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Ndufa4/Ndufa1; c-4 
                 A64-N5-C30-histoneSL-N5 
                 1380 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 ATP5A1/PSMB3; c-5 
                 A64-N5-C30-histoneSL-N5 
                 1388 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Rpl31/PSMB3; d-1 
                 A64-N5-C30-histoneSL-N5 
                 1396 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 ATP5A1/CASP1; d-2 
                 A64-N5-C30-histoneSL-N5 
                 1404 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Slc7a3/Gnas; d-3 
                 A64-N5-C30-histoneSL-N5 
                 1412 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 HSD17B4/Ndufa1; d-4 
                 A64-N5-C30-histoneSL-N5 
                 1420 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Slc7a3/Ndufa1; d-5 
                 A64-N5-C30-histoneSL-N5 
                 1428 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 TUBB4B/RPS9; e-1 
                 A64-N5-C30-histoneSL-N5 
                 1436 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Rpl31/RPS9; e-2 
                 A64-N5-C30-histoneSL-N5 
                 1444 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Mp68/RPS9; e-3 
                 A64-N5-C30-histoneSL-N5 
                 1452 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Nosip/RPS9; e-4 
                 A64-N5-C30-histoneSL-N5 
                 1460 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 ATP5A1/RPS9; e-5 
                 A64-N5-C30-histoneSL-N5 
                 1468 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 ATP5A1/COX6B1; e-6 
                 A64-N5-C30-histoneSL-N5 
                 1476 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 ATP5A1/Gnas; f-1 
                 A64-N5-C30-histoneSL-N5 
                 1484 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 ATP5A1/Ndufa1; f-2 
                 A64-N5-C30-histoneSL-N5 
                 1492 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 HSD17B4/COX6B1; f-3 
                 A64-N5-C30-histoneSL-N5 
                 1500 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 HSD17B4/Gnas; f-4 
                 A64-N5-C30-histoneSL-N5 
                 1508 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Mp68/COX6B1; f-5 
                 A64-N5-C30-histoneSL-N5 
                 1516 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Mp68/Ndufa1; g-1 
                 A64-N5-C30-histoneSL-N5 
                 1524 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Ndufa4/CASP1; g-2 
                 A64-N5-C30-histoneSL-N5 
                 1532 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Ndufa4/Gnas; g-3 
                 A64-N5-C30-histoneSL-N5 
                 1540 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Nosip/CASP1; g-4 
                 A64-N5-C30-histoneSL-N5 
                 1548 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Rpl31/CASP1; g-5 
                 A64-N5-C30-histoneSL-N5 
                 1556 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Rpl31/COX6B1; h-1 
                 A64-N5-C30-histoneSL-N5 
                 1564 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Rpl31/Gnas; h-2 
                 A64-N5-C30-histoneSL-N5 
                 1572 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Rpl31/Ndufa1; h-3 
                 A64-N5-C30-histoneSL-N5 
                 1580 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Slc7a3/CASP1; h-4 
                 A64-N5-C30-histoneSL-N5 
                 1588 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Slc7a3/COX6B1; h-5 
                 A64-N5-C30-histoneSL-N5 
                 1596 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 Slc7a3/RPS9; i-1 
                 A64-N5-C30-histoneSL-N5 
                 1604 
                 1267 
               
               
                   
                 F-del_DSCav1 
                 RPL32(32L4)/ALB7; i-2 
                 A64-N5-C30-histoneSL-N5 
                 1612 
                 1267 
               
               
                 R7454 
                 F_DSCav1_mut0 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 4211 
                 3850 
               
               
                 R7455 
                 F-del_DSCav1_mut0 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 4580 
                 4219 
               
               
                 R7458 
                 F_DSCav1_mut4 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 4949 
                 4588 
               
               
                 R7459 
                 F-del_DSCav1_mut4 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 5318 
                 4957 
               
               
                 R7456 
                 F_DSCav1_mut5 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 5687 
                 5326 
               
               
                 R7457 
                 F-del_DSCav1_mut5 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 6056 
                 5695 
               
               
                   
                 F_DSCav1_mut6 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 6425 
                 6064 
               
               
                   
                 F-del_DSCav1_mut6 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 6794 
                 6433 
               
               
                   
                 F_DSCav1_mut7 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 7163 
                 6802 
               
               
                   
                 F-del_DSCav1_mut7 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 7532 
                 7171 
               
               
                   
                 F_DSCav1_mut8 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 7901 
                 7540 
               
               
                   
                 F-del_DSCav1_mut8 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 8270 
                 7909 
               
               
                 R7595 
                 M 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 10046 
                 9684 
               
               
                 R7597 
                 N 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 10496 
                 10134 
               
               
                 R7598 
                 M2-1 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 11545 
                 11183 
               
               
                 R7596 
                 P 
                 —/muag; i-3 
                 A64-N5-C30-histoneSL-N5 
                 10999 
                 10637 
               
               
                   
               
            
           
         
       
     
     1.4. Preparation of an LNP Formulated mRNA Composition: 
     Lipid nanoparticles (LNP), cationic lipids, and polymer conjugated lipids (PEG-lipid) were prepared and tested essentially according to the general procedures described in WO2015/199952, WO2017/004143 and WO2017/075531, the full disclosures of which are incorporated herein by reference. LNP formulated mRNA was prepared using an ionizable amino lipid (cationic lipid), phospholipid, cholesterol and a PEGylated lipid. Briefly, cationic lipid compound of formula III-3, DSPC, cholesterol, and PEG-lipid of formula Va were solubilized in ethanol at a molar ratio (%) of approximately 50:10:38.5:1.5 or 47.4:10:40.9:1.7. LNPs comprising cationic lipid compound of formula III-3 and PEG-lipid compound of formula IVa were prepared at a ratio of mRNA to total Lipid of 0.03-0.04 w/w. The mRNA was diluted to 0.05 mg/mL to 0.2 mg/mL in 10 mM to 50 mM citrate buffer, pH4. Syringe pumps were used to mix the ethanolic lipid solution with the mRNA aqueous solution at a ratio of about 1:5 to 1:3 (vol/vol) with total flow rates above 15 ml/min. The ethanol was then removed and the external buffer replaced with a PBS buffer comprising Sucrose by dialysis. Finally, the lipid nanoparticles were filtered through a 0.2 um pore sterile filter and the LNP-formulated mRNA composition was adjusted to about 1 mg/ml total mRNA. Lipid nanoparticle particle diameter size was 60-90 nm as determined by quasi-elastic light scattering using a Malvern Zetasizer Nano (Malvern, UK). For other cationic lipid compounds mentioned in the present specification, the formulation process is essentially similar. The obtained LNP-formulated mRNA composition (1 mg/ml total mRNA) was diluted to the desired target concentration using Saline before in vivo application. 
     1.5. Preparation of a Protamine Complexed mRNA Composition: 
     mRNA constructs were complexed with protamine prior to use in in vivo immunization experiments. The mRNA formulation consisted of a mixture of 50% free mRNA and 50% mRNA complexed with protamine at a weight ratio of 2:1. First, mRNA was complexed with protamine by addition of protamine-Ringer&#39;s lactate solution to mRNA. After incubation for 10 minutes, when the complexes were stably generated, free mRNA was added, and the final concentration was adjusted with Ringer&#39;s lactate solution. 
     Example 2: Vaccination of Cotton Rats with LNP-Formulated mRNA Encoding RSV-F and RSV Cotton Rat Challenge Study 
     The present Example shows that LNP-formulated mRNA encoding RSV-F induces strong and functional immune responses in cotton rats. 
     For the development of RSV vaccines the cotton rat is an accepted animal model, especially for the challenge infection. Cotton rats that have received formalin-inactivated RSV virus vaccine preparations respond to RSV infection with enhanced lung pathology. This allows the evaluation of the safety of a vaccination in terms of enhanced disease phenomenon. 
     To optimize the RSV-specific immune response, mRNA vaccines encoding the pre-fusion stabilized RSV F protein F-del_DSCav were prepared according to Example 1, formulated either with LNPs (see Example 1.4.) or with protamine (see Example 1.5.) and were applied on days 0 and 28 intramuscularly (i.m.) or intradermally (i.d) with different doses of RNA as shown in Table 10. Control animals received a single vaccination at day 0 with 105 pfu live RSV/A2 virus intranasally or two vaccinations at days 0 and 28 with formalin-inactivated RSV virus (FI-RSV) intramuscularly. Additional control animals received buffer only. For the present example, a UTR combination HSD17B4/ALB7 was used, herein referred to as “i-4”. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Animal groups and vaccination schedule of Example 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Group 
                 Cotton rats 
                 Treatment 
                 mRNA 
                 dose 
                 Route 
                 Volume 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 5 
                 mRNA/LNP 
                 R4745 
                 10 
                 μg 
                 i.m. 
                 1 × 100 
                 uL 
               
               
                 2 
                 5 
                 mRNA/LNP 
                 R4745 
                 2 
                 μg 
                 i.m. 
                 1 × 100 
                 uL 
               
               
                 3 
                 5 
                 mRNA/LNP 
                 R4745 
                 10 
                 μg 
                 i.d. 
                 2 × 50 
                 uL 
               
               
                 4 
                 5 
                 mRNA/LNP 
                 R4745 
                 2 
                 μg 
                 i.d. 
                 2 × 50 
                 uL 
               
               
                 5 
                 5 
                 mRNA/protamine 
                 R5717 
                 80 
                 μg 
                 i.m. 
                 1 × 100 
                 uL 
               
               
                 6 
                 5 
                 mRNA/protamine 
                 R5717 
                 80 
                 μg 
                 i.d. 
                 2 × 50 
                 uL 
               
               
                 7 
                 5 
                 Live RSV/A2 virus 
                   
                 105 
                 pfu 
                 i.n. 
                 1 × 100 
                 uL 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 8 
                 5 
                 FI-RSV 
                   
                 1:100 
                 i.m. 
                 1 × 100 
                 uL 
               
               
                 9 
                 5 
                 Buffer 
                   
                 — 
                 i.m 
                 1 × 100 
                 uL 
               
               
                 10 
                 5 
                 Untreated/uninfected 
                   
                 — 
                 — 
               
               
                   
               
            
           
         
       
     
     Determination of Virus Neutralization Titers: 
     Serum was collected at day 49 and RSV virus neutralization titers (VNTs) were measured using a plaque reduction neutralization test (PRNT). Diluted serum samples were incubated with RSV/A2 for 1 hour at room temperature and inoculated in duplicates onto confluent HEp-2 monolayers in 24 well plates. After one hour incubation at 37° C. in a 5% CO2 incubator, the wells were overlayed with 0.75% Methylcellulose medium. After 4 days of incubation, the overlays were removed and the cells were fixed and stained. The corresponding reciprocal neutralizing antibody titers were determined at the 60% reduction end-point of the virus control. 
     Cotton Rat Challenge Study: 
     The vaccinated animals were challenged intranasally at day 63 with 105 pfu live RSV/A2 virus in 100 uL. One control group remained untreated and uninfected (group 10). All animals were sacrificed at day 68 and nasal tissue and lung were harvested. 
     RSV Titers in the Lungs of Challenged Cotton Rats: 
     Lungs of animals were collected at day 68 (i.e. 5 days after intranasal challenge with 105 pfu live RSV/A2 virus) and RSV/A2 titers were quantified in one lobe by plaque assay. Lung homogenates were clarified by centrifugation and diluted in EMEM. Confluent HEp-2 monolayers were infected in duplicates with diluted homogenates in 24 well plates. After one hour incubation at 37° C. in a 5% CO incubator, the wells were overlayed with 0.75% methylcellulose medium. After 4 days of incubation, the overlays were removed and the cells were fixed and stained with 0.1% crystal violet for one hour and then rinsed and air dried. Plaques were counted and virus titers were expressed as plaque forming units per gram of tissue. Viral titers were calculated as geometric mean±standard error for all animals in a group at a given time. 
     Lung Histopathology of Challenged Cotton Rats: 
     Lungs of animals were collected at day 68 (i.e. 5 days after intranasal challenge with 105 pfu live RSV/A2 virus) and one lobe was analyzed by histopathology. Lungs were dissected and inflated with 10% neutral buffered formalin to their normal volume, and then immersed in the same fixative solution. Following fixation, the lungs were embedded in paraffin, sectioned and stained with hematoxylin and eosin (H&amp;E). Four parameters of pulmonary inflammation were evaluated: peribronchiolitis (inflammatory cell infiltration around the bronchioles), perivasculitis (inflammatory cell infiltration around the small blood vessels), interstitial pneumonia (inflammatory cell infiltration and thickening of alveolar walls), and alveolitis (cells within the alveolar spaces). Slides were scored blindly on a 0-4 severity scale. The scores were subsequently converted to a 0-100% histopathology scale. 
     Results: 
     As can be seen from  FIG. 1 , the LNP formulated RSV-F (F-del_DSCav1) mRNA vaccines induce the formation of RSV specific functional antibodies in cotton rats as shown by high virus neutralizing antibody titers (groups 1-4). Vaccination with protamine-formulated mRNA induces only weak responses. 
     As can be seen from  FIG. 2 , the LNP-formulated RSV-F (F-del_DSCav1) mRNA vaccines reduce lung viral titers in cotton rats challenged with RSV virus and therefore limit RSV infection of the lung (groups 1-4). All the animal groups vaccinated with mRNA formulated in LNPs vaccines showed virus titers below the level of detection of the performed virus titration demonstrating protection of vaccinated cotton rats in terms of viral lung titers. By contrast, the protamine-formulated mRNA vaccines (administrated i.m.) and the Formalin-inactivated virus vaccine reduced only minimally the lung virus titer compared to the buffer control group. 
     As can be seen from  FIG. 3 , the lung histopathology analysis from the RSV cotton rat challenge study reveals different pathology scores for the various animal groups. From the histopathology it can be concluded that none of the mRNA vaccinated groups displayed enhanced lung pathology as it is the case for the group that was vaccinated using the formalin-inactivated RSV vaccine. The average pathology scores for peribronchiolitis, perivasculitis, insterstitial pneumonia and alveolitis are much lower for all groups vaccinated with mRNA (groups 1-6) compared to the group with formalin-inactivated RSV (group 8). 
     Example 3: Vaccination of Cotton Rats with LNP-Formulated mRNA Encoding RSV-F and RSV Cotton Rat Challenge Study 
     The present Example shows that LNP-formulated mRNA encoding different RSV-F antigens induce strong and functional immune responses in cotton rats for mRNA constructs having UTR combination RPL32/ALB7 (i-2). 
     This experiment compared mRNA-LNPs encoding three different RSV-F variants: full-length RSV F0, truncated RSV F-del, and pre-fusion stabilized truncated F-del_DSCav1. The mRNA-LNP vaccines were prepared according to Example 1. Cotton rats received two intramuscular vaccinations with mRNA-LNP vaccines on days 0 and 28. Each dose comprised 10 μg or 100 μg mRNA-LNPs. Control animals received a single vaccination at day 0 with 105 pfu live RSV/A2 virus intranasally or two vaccinations at days 0 and 28 with formalin-inactivated RSV virus (FI RSV) intramuscularly. Additional control animals received buffer only (see Table 11). 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Animal groups and vaccination schedule of Example 3 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 RNA 
                   
                   
               
               
                 Group 
                 Test item 
                 ID 
                 Dose 
                 Route 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 mRNA encoding F0 
                 R3737 
                 10 
                 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 2 
                 mRNA encoding F0 
                 R3737 
                 100 
                 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 3 
                 mRNA encoding F-del 
                 R3738 
                 10 
                 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 4 
                 mRNA encoding F-del 
                 R3738 
                 100 
                 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 5 
                 mRNA encoding F-delDSCav1 
                 R6122 
                 10 
                 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 6 
                 mRNA encoding F-delDSCav1 
                 R6122 
                 100 
                 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 7 
                 Live RSV/A2 virus 
                   
                 105 
                 pfu 
                 i.n. 
               
            
           
           
               
               
               
               
               
            
               
                 8 
                 FI RSV 
                   
                 1:100 
                 i.m. 
               
               
                 9 
                 Buffer 
                   
                 — 
                 i.m. 
               
               
                 10 
                 untreated/uninfected 
                   
                 — 
                 — 
               
               
                   
               
            
           
         
       
     
     Determination of Anti-RSV F Protein Antibodies by ELISA: 
     Blood samples were collected on days 28, 49, and 63 for the determination of anti-RSV F antibody titers. ELISA plates are coated with recombinant human RSV fusion glycoprotein (Extracellular domain of human RSV Fusion glycoprotein (529) fused with a polyhistidine tag at the C-terminus, expressed in Baculovirus-Insect Cells, provided as lyophilized powder). Coated plates are incubated using given serum dilutions. Binding of specific antibodies to the F protein is detected using biotinylated isotype specific anti-mouse antibodies in combination with streptavidin-HRP (horse radish peroxidase) with ABTS substrate. 
     Determination of Virus Neutralization Titers: 
     Serum was collected at day 49 and RSV virus neutralization titers (VNTs) were measured using a plaque reduction neutralization test (PRNT). Diluted serum samples were incubated with RSV/A2 for 1 hour at room temperature and inoculated in duplicates onto confluent HEp-2 monolayers in 24 well plates. After one hour incubation at 37° C. in a 5% CO2 incubator, the wells were overlayed with 0.75% Methylcellulose medium. After 4 days of incubation, the overlays were removed and the cells were fixed and stained. The corresponding reciprocal neutralizing antibody titers were determined at the 60% reduction end-point of the virus control. 
     Cotton Rat Challenge Study: 
     The vaccinated animals were challenged intranasally at day 63 with 10 5  pfu live RSV/A2 virus in 100 uL. One control group remained untreated and uninfected. All animals were sacrificed at day 68 and nasal tissue and lung were harvested. 
     RSV Titers in the Lungs of Challenged Cotton Rats: 
     Lungs of animals were collected at day 68 (i.e. 5 days after intranasal challenge with 10 5  pfu live RSV/A2 virus) and RSV/A2 titers were quantified in one lobe by plaque assay as described above. 
     RSV Titers in Nasal Tissue of Challenged Cotton Rats 
     Nasal tissue of animals was collected at day 68 (i.e. 5 days after intranasal challenge with 105 pfu live RSV/A2 virus). The nose homogenates were clarified as the lung homogenates by centrifugation and diluted in EMEM. Confluent HEp-2 monolayers were infected in duplicates with diluted homogenates in 24 well plates. After one hour incubation at 37° C. in a 5% CO incubator, the wells were overlayed with 0.75% methylcellulose medium. After 4 days of incubation, the overlays were removed and the cells were fixed and stained with 0.1% crystal violet for one hour and then rinsed and air dried. Plaques were counted and virus titers were expressed as plaque forming units per gram of tissue. Viral titers were calculated as geometric mean±standard error for all animals in a group at a given time. 
     Lung Histopathology of Challenged Cotton Rats: 
     Lungs of animals were collected at day 68 (i.e. 5 days after intranasal challenge with 105 pfu live RSV/A2 virus) and one lobe was analyzed by histopathology as described before. 
     Results: 
     As can be seen from  FIG. 4 , all LNP-formulated RSV-F (F0, F-del, F-del_DSCav1) mRNA vaccines induced the formation of RSV specific functional antibodies in cotton rats as shown by high virus neutralizing antibody titers. 
       FIGS. 5 a , 5 b  and 5 c    show that LNP-formulated mRNA encoding the RSV F-protein (F0, F-del, and F-del_DSCav1) induces humoral immune responses in cotton rats against the RSV-F protein. Antibody total IgG titers were determined by ELISA.  FIG. 5 a   : Antibody titers determined on day 49;  FIGS. 5 b  and 5 c   : time-dependent igG titers in serum with 10 μg mRNA ( FIG. 5 b   ) or 100 μg mRNA ( FIG. 5 c   ) encoding the RSV F-protein (F0, F-del, and F-del_DSCav1). With both doses, 10 μg and 100 μg, F0 and F-del vaccines induce higher titers of RSV-F specific IgGs already after prime vaccination (day 28) compared with the vaccination with the live virus. After boost vaccination all tested LNP-formulated RSV-F (F0, F-del, F-del_DSCav1) mRNA vaccines induces humoral immune responses measured with ELISA which are more prominent then the answers of the control vaccinations. 
     As can be seen from  FIG. 6 , LNP-formulated RSV-F (F0, F-del, F-del_DSCav1) mRNA vaccines reduced lung viral titers in cotton rats challenged with RSV virus and therefore limit RSV infection of the lung. All the animal groups vaccinated with mRNA formulated in LNPs vaccines showed virus titers below the level of detection of the performed virus titration. The results demonstrate protection of vaccinated cotton rats in terms of viral lung titers. By contrast, the formalin-inactivated virus vaccine (FI RSV) reduced only minimally the lung virus titer compared to the buffer control group. 
     As can be seen from  FIG. 7 , the LNP-formulated RSV-F (F0, F-del, F-del_DSCav1) mRNA vaccines strongly reduced viral titers in nasal tissue of cotton rats challenged with RSV virus and therefore reduce RSV infection of the nose. In comparison to the mRNA vaccines the vaccine based on formalin-inactivated virus (F RSV) were not able to reduce the nasal virus titers. 
     As can be seen from  FIG. 8 , the lung histopathology analysis from the RSV cotton rat challenge study reveals different pathology scores for the various animal groups. From the histopathology it can be concluded that none of the mRNA vaccinated groups displayed enhanced lung pathology as it is the case for the group that was vaccinated using the formalin-inactivated RSV vaccine. The average pathology scores for peribronchiolitis, perivasculitis, insterstitial pneumonia and alveolitis are much lower for all groups vaccinated with mRNA compared to the group with formalin-inactivated RSV. 
     To further improve the efficiency of the mRNA-based vaccine, several alternative RSV-F mRNA constructs were designed harboring different UTR combinations to potentially increase translation efficiency of the mRNA. Those mRNA constructs were tested as can be seen in the following Example. 
     Example 4: In Vitro Expression Screen of RSV-F mRNA Constructs 
     The present Example shows that the UTR combinations according to the invention strongly improve the expression performance of said mRNA constructs compared to a reference mRNA construct (harboring RPL32/ALB7 UTRs) used e.g. in Example 3 (UTR combination RPL32/ALB7 (i-2)). 
     To further improve the expression performance of RSV-F mRNA, a screening experiment was conducted to identify advantageous UTR combinations according to the invention. To determine the protein expression performance of RSV-F mRNA constructs comprising different UTR combinations, HEK 293T cells were transfected with different Lipofectamine-formulated mRNA constructs, which all contain the same coding sequence encoding pre-fusion stabilized truncated F-del_DSCav1 but use different 5′- and 3′-UTRs (see Table 12). RSV-F expression was analyzed 24 h after transfection by flow cytometry. 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Overview of mRNA constructs with different 
               
               
                 UTR combinations used in Example 4 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 SEQ ID NO: 
                 SEQ ID NO: 
               
               
                 Antigen 
                 UTR Design 
                 RNA 
                 Protein 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 F-del_DSCav1 
                 HSD17B4/PSMB3; a-1 
                 1276 
                 1267 
               
               
                 F-del_DSCav1 
                 Ndufa4/PSMB3; a-2 
                 1284 
                 1267 
               
               
                 F-del_DSCav1 
                 Slc7a3/PSMB3; a-3 
                 1292 
                 1267 
               
               
                 F-del_DSCav1 
                 Nosip/PSMB3; a-4 
                 1300 
                 1267 
               
               
                 F-del_DSCav1 
                 Mp68/PSMB3; a-5 
                 1308 
                 1267 
               
               
                 F-del_DSCav1 
                 Ubqln2/RPS9; b-1 
                 1316 
                 1267 
               
               
                 F-del_DSCav1 
                 ASAH1/RPS9; b-2 
                 1324 
                 1267 
               
               
                 F-del_DSCav1 
                 HSD17B4/RPS9; b-3 
                 1332 
                 1267 
               
               
                 F-del_DSCav1 
                 HSD17B4/CASP1; b-4 
                 1340 
                 1267 
               
               
                 F-del_DSCav1 
                 Nosip/COX6B1; b-5 
                 1348 
                 1267 
               
               
                 F-del_DSCav1 
                 Ndufa4/RPS9; c-1 
                 1356 
                 1267 
               
               
                 F-del_DSCav1 
                 Nosip/Ndufa1; c-2 
                 1364 
                 1267 
               
               
                 F-del_DSCav1 
                 Ndufa4/COX6B1; c-3 
                 1372 
                 1267 
               
               
                 F-del_DSCav1 
                 Ndufa4/Ndufa1; c-4 
                 1380 
                 1267 
               
               
                 F-del_DSCav1 
                 ATP5A1/PSMB3; c-5 
                 1388 
                 1267 
               
               
                 F-del_DSCav1 
                 Rpl31/PSMB3; d-1 
                 1396 
                 1267 
               
               
                 F-del_DSCav1 
                 ATP5A1/CASP1; d-2 
                 1404 
                 1267 
               
               
                 F-del_DSCav1 
                 Slc7a3/Gnas; d-3 
                 1412 
                 1267 
               
               
                 F-del_DSCav1 
                 HSD17B4/Ndufa1; d-4 
                 1420 
                 1267 
               
               
                 F-del_DSCav1 
                 Slc7a3/Ndufa1; d-5 
                 1428 
                 1267 
               
               
                 F-del_DSCav1 
                 TUBB4B/RPS9; e-1 
                 1436 
                 1267 
               
               
                 F-del_DSCav1 
                 Rpl31/RPS9; e-2 
                 1444 
                 1267 
               
               
                 F-del_DSCav1 
                 Mp68/RPS9; e-3 
                 1452 
                 1267 
               
               
                 F-del_DSCav1 
                 Nosip/RPS9; e-4 
                 1460 
                 1267 
               
               
                 F-del_DSCav1 
                 ATP5A1/RPS9; e-5 
                 1468 
                 1267 
               
               
                 F-del_DSCav1 
                 ATP5A1/COX6B1; e-6 
                 1476 
                 1267 
               
               
                 F-del_DSCav1 
                 ATP5A1/Gnas; f-1 
                 1484 
                 1267 
               
               
                 F-del_DSCav1 
                 ATP5A1/Ndufa1; f-2 
                 1492 
                 1267 
               
               
                 F-del_DSCav1 
                 HSD17B4/COX6B1; f-3 
                 1500 
                 1267 
               
               
                 F-del_DSCav1 
                 HSD17B4/Gnas; f-4 
                 1508 
                 1267 
               
               
                 F-del_DSCav1 
                 Mp68/COX6B1; f-5 
                 1516 
                 1267 
               
               
                 F-del_DSCav1 
                 Mp68/Ndufa1; g-1 
                 1524 
                 1267 
               
               
                 F-del_DSCav1 
                 Ndufa4/CASP1; g-2 
                 1532 
                 1267 
               
               
                 F-del_DSCav1 
                 Ndufa4/Gnas; g-3 
                 1540 
                 1267 
               
               
                 F-del_DSCav1 
                 Nosip/CASP1; g-4 
                 1548 
                 1267 
               
               
                 F-del_DSCav1 
                 Rpl31/CASP1; g-5 
                 1556 
                 1267 
               
               
                 F-del_DSCav1 
                 Rpl31/COX6B1; h-1 
                 1564 
                 1267 
               
               
                 F-del_DSCav1 
                 Rpl31/Gnas; h-2 
                 1572 
                 1267 
               
               
                 F-del_DSCav1 
                 Rpl31/Ndufa1; h-3 
                 1580 
                 1267 
               
               
                 F-del_DSCav1 
                 Slc7a3/CASP1; h-4 
                 1588 
                 1267 
               
               
                 F-del_DSCav1 
                 Slc7a3/COX6B1; h-5 
                 1596 
                 1267 
               
               
                 F-del_DSCav1 
                 Slc7a3/RPS9; i-1 
                 1604 
                 1267 
               
               
                 F-del_DSCav1 
                 RPL32(32L4)/ALB7; i-2 
                 1612 
                 1267 
               
               
                   
               
            
           
         
       
     
     Detailed Description of the Transfection and Flow Cytometry Analysis: 
     293T cells were seeded at a density of 200000 cells/well (200000 cells/2 ml) in a 6-well plate. Each RNA was complexed with Lipofectamine2000 at a ratio of 1/1.5 (w/v) for 20 minutes in Opti-MEM. Lipocomplexed mRNAs were then added to cells for transfection with 2 μg of RNA per well in a total volume of 500 uL. 4 h post start of transfection the transfection solution was exchanged for 2000 uL/well of complete medium. Cells were further maintained at 37° C., 5% CO2 before performing FACS analysis. 
     24 hours after transfection, expression of antigen of interest was quantified by FACS analysis using standard procedures. Briefly, cells were detached (40 mM Tris HCl pH 7.5 150 mM NaCl, 1 mM EDTA in H20; 5 min at RT), washed with PBS, and stained on the surface with a mouse antibody against the RSV-F (Millipore, Cat: MAB8262) and a fluorescently labeled goat anti-mouse IgG antibody (Sigma, Cat: F5262). Cells were resuspended in 100 uL PFEA buffer (PBS+2% FCS+2 mM EDTA+0.01% NaN3) and analyzed using a BD FACS Canto II. Live/Dead staining was performed with Aqua fluorescent reactive dye (Invitrogen). 
     The results were compared to the expression from a reference construct of Example 3 containing the RPL32/ALB7 UTR-combination (SEQ ID NO: 1612) which was set to a level of 100%. The results of the analysis are shown in  FIG. 9 . 
     Results 
     As can be seen from  FIG. 9 , the expression performances of the mRNA constructs comprising UTR combinations according to the invention were strongly increased compared to the construct comprising the reference UTR combination (RPL32/ALB7; i-2). 
     Example 5: Vaccination of Cotton Rats with LNP-Formulated mRNA Encoding RSV-F and Cotton Rat Challenge Study 
     Based on the results of the UTR screen of Example 4, mRNA constructs having UTR combinations for optimizing mRNA expression are used in vaccination experiments. 
     In this experiment mRNA vaccines encoding RSV-F (F, F-del, or F-del_DSCav1) with different UTR combinations according to the invention are compared. The mRNA-LNP vaccines are prepared according to Example 1. Cotton rats receive two intramuscular vaccinations with mRNA-LNP vaccines on days 0 and 28. Each dose comprises 2 μg or 10 μg mRNA-LNPs. Control animals receive a single vaccination at day 0 with 105 pfu live RSV/A2 virus intranasally or formalin-inactivated RSV virus intramuscularly. Additional control animals receive buffer only (see Table 13). 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Animal groups and vaccination schedule of Example 5 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ ID NO: 
                   
                   
               
               
                 Group 
                 Test Item 
                 5′-UTR/3′-UTR; 
                 RNA 
                 Dose 
                 Route 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1 
                 F0, F-del or F-del_DSCav1 
                 Nosip/RPS9; e-4 
                 286, 701 or 1460 
                 10 
                 μg 
                 i.m. 
               
               
                 2 
                 F0, F-del or F-del_DSCav1 
                 Nosip/RPS9; e-4 
                 286, 701 or 1460 
                 2 
                 μg 
                 i.m. 
               
               
                 3 
                 F0, F-del or F-del_DSCav1 
                 Ndufa4/CASP1; g-2 
                 367, 782 or 1532 
                 10 
                 μg 
                 i.m. 
               
               
                 4 
                 F0, F-del or F-del_DSCav1 
                 Ndufa4/CASP1; g-2 
                 367, 782 or 1532 
                 2 
                 μg 
                 i.m. 
               
               
                 5 
                 F0, F-del or F-del_DSCav1 
                 Ndufa4/RPS9; c-1 
                 169, 584 or 1356 
                 10 
                 μg 
                 i.m. 
               
               
                 6 
                 F0, F-del or F-del_DSCav1 
                 Ndufa4/RPS9; c-1 
                 169, 584 or 1356 
                 2 
                 μg 
                 i.m. 
               
               
                 7 
                 F0, F-del or F-del_DSCav1 
                 Ndufa4/PSMB3; a-2 
                 88, 503 or 1284 
                 10 
                 μg 
                 i.m. 
               
               
                 8 
                 F0, F-del or F-del_DSCav1 
                 Ndufa4/PSMB3; a-2 
                 88, 503 or 1284 
                 2 
                 μg 
                 i.m. 
               
               
                 9 
                 F0, F-del or F-del_DSCav1 
                 HSD17B4/PSMB3; a-1 
                 79, 494 or 1276 
                 10 
                 μg 
                 i.m. 
               
               
                 10 
                 F0, F-del or F-del_DSCav1 
                 HSD17B4/PSMB3; a-1 
                 79, 494 or 1276 
                 2 
                 μg 
                 i.m. 
               
               
                 11 
                 F0, F-del or F-del_DSCav1 
                 —/muag; i-3 
                 475, 890 or 1628 
                 10 
                 μg 
                 i.m. 
               
               
                   
                   
                   
                 (R6939, R6940 or 
               
               
                   
                   
                   
                 R5453) 
               
               
                 12 
                 F0, F-del or F-del_DSCav1 
                 —/muag; i-3 
                 475, 890 or 1628 
                 2 
                 μg 
                 i.m. 
               
               
                   
                   
                   
                 (R6939, R6940 or 
               
               
                   
                   
                   
                 R5453) 
               
            
           
           
               
               
               
               
               
               
            
               
                 13 
                 Live RSV/A2 virus 
                   
                   
                 5.0Log IM 
                 i.n. 
               
               
                 14 
                 UV-Inact. RSV/A2 
                   
                   
                 5.0Log IM 
                 i.m. 
               
               
                 15 
                 FI-RSV 
                   
                   
                 1:100 
                 i.m. 
               
               
                 16 
                 Buffer 
                   
                   
                   
                 i.m. 
               
               
                 17 
                 untreated/uninfected 
               
               
                   
               
            
           
         
       
     
     Determination of Anti-RSV Immune Responses Using ELISA or PRNT 
     The induction of anti-RSV immune responses are determined as described before. 
     Cotton Rat Challenge Study 
     The vaccinated animals are challenged intranasally at day 63 with 10exp5 pfu live RSV/A2 virus in 100 uL. One control group remains untreated and uninfected. All animals are sacrificed at day 68 and nasal tissue and lung tissue are harvested. 
     RSV Titers in the Lungs of Challenged Cotton Rats 
     Lungs of animals are collected at day 68 (i.e. 5 days after intranasal challenge with 10exp5 pfu live RSV/A2 virus) and RSV/A2 titers are quantified in one lobe by plaque assay as described above. In addition, RSV viral genome copy numbers (by measuring copy numbers of the RSV NS-1 gene) and cytokine mRNA levels were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). 
     RSV Titers in Nasal Tissue of Challenged Cotton Rats 
     Nasal tissue of animals are collected at day 68 (i.e. 5 days after intranasal challenge with 105 pfu live RSV/A2 virus). The viral titers are quantified as described above. In addition, RSV viral genome copy numbers (by measuring copy numbers of the RSV NS-1 gene) and cytokine mRNA levels were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). 
     Lung Histopathology of Challenged Cotton Rats 
     Lungs of animals are collected at day 68 (i.e. 5 days after intranasal challenge with 105 pfu live RSV/A2 virus) and one lobe is analyzed by histopathology as described before. 
     Example 6: Vaccination of Cotton Rats with LNP-Formulated mRNA Encoding RSV-F and Cotton Rat Challenge Study 
     In this experiment mRNA vaccines encoding RSV-F (F_DSCav1_mut1, F_DSCav1_mut2, F_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2, F-del_DSCav1_mut3 (and/or additionally with F_DSCav1_mut0, _mut4, _mut5, _mut6, _mut7, _mut8 and/or F-del_DSCav1_mut0, _mut4, _mut5, _mut6, _mut7, _mut8) are compared. The mRNA-LNP vaccines are prepared according to Example 1. Cotton rats receive two intramuscular vaccinations with mRNA-LNP vaccines on days 0 and 28. Each dose comprises 2 μg or 10 μg mRNA-LNPs. Control animals receive a single vaccination at day 0 with 105 pfu live RSV/A2 virus intranasally or formalin-inactivated RSV virus intramuscularly. Additional control animals receive buffer only (see Table 14). 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Animal groups of Example 6 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 RNA 
                 SEQ ID NO: 
                 SEQ ID NO: 
                   
               
               
                 Group 
                 Test Item 
                 ID 
                 RNA 
                 Protein 
                 Route 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 F_DSCav1_mut1 
                 R6771 
                 1997 
                 1636 
                 i.m. 
               
               
                 2 
                 F-del_DSCav1_mut1 
                 R6774 
                 2366 
                 2005 
                 i.m. 
               
               
                 3 
                 F_DSCav1_mut2 
                 R6772 
                 2735 
                 2374 
                 i.m. 
               
               
                 4 
                 F-del_DSCav1_mut2 
                 R6773 
                 3104 
                 2743 
                 i.m. 
               
               
                 5 
                 F_DSCav1_mut3 
                 R6770 
                 3473 
                 3112 
                 i.m. 
               
               
                 6 
                 F-del_DSCav1_mut3 
                 R6775 
                 3842 
                 3481 
                 i.m. 
               
               
                 7 
                 Live RSV/A2 virus 
                   
                   
                   
                 i.n. 
               
               
                 8 
                 UV-Inact. RSV/A2 
                   
                   
                   
                 i.m. 
               
               
                 9 
                 FI-RSV 
                   
                   
                   
                 i.m. 
               
               
                 10 
                 Buffer 
                   
                   
                   
                 i.m. 
               
               
                 11 
                 Untreated/uninfected 
               
               
                   
               
            
           
         
       
     
     Determination of Anti-RSV Immune Responses Using ELISA or PRNT 
     The induction of anti-RSV immune responses are determined as described before. 
     Cotton Rat Challenge Study 
     The vaccinated animals are challenged intranasally at day 63 with 10exp5 pfu live RSV/A2 virus in 100 uL. One control group remains untreated and uninfected. All animals are sacrificed at day 68 and nasal tissue and lung tissue are harvested. 
     RSV Titers in the Lungs of Challenged Cotton Rats 
     Lungs of animals are collected at day 68 (i.e. 5 days after intranasal challenge with 10exp5 pfu live RSV/A2 virus) and RSV/A2 titers are quantified in one lobe by plaque assay as described above. In addition, RSV viral genome copy numbers (by measuring copy numbers of the RSV NS-1 gene) and cytokine mRNA levels were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). 
     RSV Titers in Nasal Tissue of Challenged Cotton Rats 
     Nasal tissue of animals are collected at day 68 (i.e. 5 days after intranasal challenge with 105 pfu live RSV/A2 virus). The viral titers are quantified as described above. In addition, RSV viral genome copy numbers (by measuring copy numbers of the RSV NS-1 gene) and cytokine mRNA levels were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). 
     Lung Histopathology of Challenged Cotton Rats Lungs of animals are collected at day 68 (i.e. 5 days after intranasal challenge with 10 5  pfu live RSV/A2 virus) and one lobe is analyzed by histopathology as described before. 
     Example 7: Vaccination of Cotton Rats with SNP-Formulated mRNA Encoding RSV-F and a Further RSV Antigen and Cotton Rat Challenge Study 
     To broaden and optimize the RSV-specific immune response, especially to increase T-cell dependent immune responses, mRNA vaccines encoding different RSV proteins (RSV F (F0, F, F-del, F_DSCav1 F-del_DSCav1, or F_DSCav1 mut0-mut8 or F-del_DSCav1 mut0-mut8) are prepared according to Example 1. In order to assess the effect of single or combined vaccines, these vaccines are administered either alone or in combination as shown in Table 9. Cotton rats receive two intramuscular (i.m.) vaccinations with mRNA-LNP vaccines on days 0 and 28 with 2 μg or 10 μg mRNA for each antigen. Additional groups are immunized intramuscularly (i.m.) with formalin-inactivated RSV and/or live RSV/A2 to compare their immunogenicity to mRNA vaccines. Additional control animals receive buffer only (see Table 15). The RSV-specific immune responses are determined by Elisa or Intracellular cytokine staining (ICS). 
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Animal groups of Example 7 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 SEQ ID NO: 
                   
               
               
                 Group 
                 Test Item 
                 RNA 
                 Route 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1 
                 F 
                 475, 890, 1259, 1628, 1997, 2366, 2735, 3104, 3473, 3842, 4211, 
                 i.m. 
               
               
                   
                   
                 4580, 4949, 5318, 5687, 6056, 6425, 6794, 7163, 7532, 7901, or 
               
               
                   
                   
                 8270 
               
               
                 2 
                 M 
                 10046 
                 i.m. 
               
               
                 3 
                 N 
                 10496 
                 i.m. 
               
               
                 4 
                 M2-1 
                 11545 
                 i.m. 
               
               
                 5 
                 P 
                 10999 
                 i.m. 
               
               
                 6 
                 F + M 
                 F (SEQ ID NOs: 475, 890, 1259, 1628, 1997, 2366, 2735, 3104, 
                 i.m. 
               
               
                   
                   
                 3473, 3842, 4211, 4580, 4949, 5318, 5687, 6056, 6425, 6794, 
               
               
                   
                   
                 7163, 7532, 7901, or 8270) + 
               
               
                   
                   
                 M (SEQ ID NO: 10046) 
               
               
                 7 
                 F + N 
                 F (SEQ ID NOs: 475, 890, 1259, 1628, 1997, 2366, 2735, 3104, 
                 i.m. 
               
               
                   
                   
                 3473, 3842, 4211, 4580, 4949, 5318, 5687, 6056, 6425, 6794, 
               
               
                   
                   
                 7163, 7532, 7901, or 8270) + 
               
               
                   
                   
                 N (SEQ ID NO: 10496) 
               
               
                 8 
                 F + M2-1 
                 F (SEQ ID NOs: 475, 890, 1259, 1628, 1997, 2366, 2735, 3104, 
                 i.m. 
               
               
                   
                   
                 3473, 3842, 4211,4580, 4949, 5318, 5687, 6056, 6425, 6794, 
               
               
                   
                   
                 7163, 7532, 7901, or 8270) + 
               
               
                   
                   
                 M2-1 (SEQ ID NO: 11545) 
               
               
                 9 
                 F + P 
                 F (SEQ ID NOs: 475, 890, 1259, 1628, 1997, 2366, 2735, 3104, 
                 i.m. 
               
               
                   
                   
                 3473, 3842, 4211, 4580, 4949, 5318, 5687, 6056, 6425, 6794, 
               
               
                   
                   
                 7163, 7532, 7901, or 8270) + 
               
               
                   
                   
                 P (SEQ ID NO: 10999) 
               
               
                 10 
                 F + M + P 
                 F (SEQ ID NOs: 475, 890, 1259, 1628, 1997, 2366, 2735, 3104, 
                 i.m. 
               
               
                   
                   
                 3473, 3842, 4211, 4580, 4949, 5318, 5687, 6056, 6425, 6794, 
               
               
                   
                   
                 7163, 7532, 7901, or 8270) + 
               
               
                   
                   
                 P (SEQ ID NO: 10999) + M (SEQ ID NO: 10046). 
               
               
                 11 
                 F + M + N + P 
                 F (SEQ ID NOs: 475, 890, 1259, 1628, 1997, 2366, 2735, 3104, 
                 i.m. 
               
               
                   
                   
                 3473, 3842, 4211, 4580, 4949, 5318, 5687, 6056, 6425, 6794, 
               
               
                   
                   
                 7163, 7532, 7901, or 8270) + P (SEQ ID NO: 10999) + 
               
               
                   
                   
                 M (SEQ ID NO: 10046) + N (SEQ ID NO: 10496) 
               
               
                 12 
                 Live RSV/A2 virus 
                   
                 i.n. 
               
               
                 13 
                 UV-Inact. RSV/A2 
                   
                 i.m. 
               
               
                 14 
                 FI-RSV 
                   
                 i.m. 
               
               
                 15 
                 Buffer 
                   
                 i.m. 
               
               
                 16 
                 Untreated/uninfected 
               
               
                   
               
            
           
         
       
     
     For vaccination experiments of Example 7, polyvalent mRNA compositions/vaccines are produced (e.g. groups 6-10) according to procedures as disclosed in the PCT application WO2017/109134 using at least two different sequence optimized DNA templates (each of which generated as described in Example 1). In short, a DNA construct mixture (each of which comprising a different coding sequences and a T7 promotor) is used as a template for simultaneous RNA in vitro transcription to generate a mixture of mRNA constructs. Subsequently, the obtained RNA mixture is used for co-purification using RP-HPLC. Following that, the obtained purified RNA mixture is formulated in LNPs (as described in section 1.4.) to generate a polyvalent LNP-formulated RNA composition/vaccine. 
     Determination of Anti-RSV Immune Responses Using ELISA PRNT: 
     The induction of anti-RSV immune responses are determined as described before, with suitable recombinant proteins or peptides for its detection. 
     Intracellular Cytokine Staining (ICS): 
     Splenocytes from vaccinated and control mice are isolated according to a standard protocol. Briefly, isolated spleens are grinded through a cell strainer and washed in PBS/1% FBS followed by red blood cell lysis. After an extensive washing step with PBS/1% FBS splenocytes are seeded into 96-well plates (2×106 cells/well). The next day cells are stimulated with a suitable RSV peptide or an irrelevant control peptide and 2.5 μg/ml of an anti-CD28 antibody (BD Biosciences) for 6 hours at 37° C. in the presence of the mixture of GolgiPlug™/GolgiStop™ (Protein transport inhibitors containing Brefeldin A and Monensin, respectively; BD Biosciences). After stimulation cells are washed and stained for intracellular cytokines using the Cytofix/Cytoperm reagent (BD Biosciences) according to the manufacturer&#39;s instructions. The following antibodies are used for staining: CD8-PECy7 (1:200), CD3-FITC (1:200), IL2-PerCP-Cy5.5 (1:100), TNFα-PE (1:100), IFNγ-APC (1:100) (eBioscience), CD4-BD Horizon V450 (1:200) (BD Biosciences) and incubated with Fcy-block diluted 1:100. Aqua Dye is used to distinguish live/dead cells (Invitrogen). Cells are collected using a Canto I flow cytometer (Beckton Dickinson). Flow cytometry data are analysed using FlowJo software (Tree Star, Inc.). 
     Cotton Rat Challenge Study: 
     The vaccinated animals are challenged intranasally at day 63 with 10exp5 pfu live RSV/A2 virus in 100 uL. One control group remains untreated and uninfected. All animals are sacrificed at day 68 and nasal tissue and lung tissue are harvested. 
     Cotton Rat Challenge Study: 
     The vaccinated animals are challenged intranasally at day 63 with 10exp5 pfu live RSV/A2 virus in 100 uL. One control group remains untreated and uninfected. All animals are sacrificed at day 68 and nasal tissue and lung tissue are harvested. Serum is collected at day 49 and RSV virus neutralization titers (VNTs) are measured using a plaque reduction neutralization test (PRNT) as described in Example 2. 
     RSV Titers in the Lungs of Challenged Cotton Rats: 
     Lungs of animals are collected at day 68 (i.e. 5 days after intranasal challenge with 10exp5 pfu live RSV/A2 virus) and RSV/A2 titers are quantified in one lobe by plaque assay as described above. In addition, RSV viral genome copy numbers (by measuring copy numbers of the RSV NS-1 gene) and cytokine mRNA levels were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). 
     RSV Titers in Nasal Tissue of Challenged Cotton Rats: 
     Nasal tissue of animals are collected at day 68 (i.e. 5 days after intranasal challenge with 105 pfu live RSV/A2 virus). The viral titers are quantified as described above. In addition, RSV viral genome copy numbers (by measuring copy numbers of the RSV NS-1 gene) and cytokine mRNA levels were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). 
     Lung Histopathology of Challenged Cotton Rats: 
     Lungs of animals are collected at day 68 (i.e. 5 days after intranasal challenge with 105 pfu live RSV/A2 virus) and one lobe is analyzed by histopathology as described before. 
     Example 8: Expression of Different RSV F Proteins in HeLa Cells and Analysis by FACS 
     To determine in vitro protein expression of the mRNA constructs, HeLa cells were transiently transfected with mRNA encoding RSV F antigens and stained for RSV Fusing a suitable anti-F protein antibodies (raised in mouse), counterstained with a FITC-coupled secondary anti-mouse antibody (F5262 from Sigma). HeLa cells were seeded in a 6-well plate at a density of 400,000 cells/well in cell culture medium (RPMI, 10% FCS, 1% L-Glutamine, 1% Pen/Strep), 24 h prior to transfection. HeLa cells were transfected with 2 μg unformulated mRNA using Lipofectamine 2000 (Invitrogen). The mRNA constructs prepared according to Example 1 and listed in Table 16 were used in the experiment (see also Table 9), including a negative control (water for injection). 24 hours post transfection, HeLa cells were stained with suitable anti RSV-F antibodies (raised in mouse; 1:500) and anti-mouse FITC labelled secondary antibody (1:500) and subsequently analyzed by flow cytometry (FACS) on a BD FACS Canto II using the FACS Diva software. Quantitative analysis of the fluorescent FITC signal was performed using the FlowJo software package (Tree Star, Inc.). Cells were stained intracellularly or alternatively on the cell surface. The results are shown in  FIGS. 10 a  and 10 b   , representing two different independent experiments. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Overview of mRNA constructs used in Example 8 
               
            
           
           
               
               
               
               
               
               
            
               
                 RNA 
                   
                   
                 SEQ ID NO: 
                 SEQ ID NO: 
                 see 
               
               
                 ID 
                 Antigen 
                 UTR Design 
                 RNA 
                 Protein 
                 Figure 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 R6939 
                 F0 
                 —/muag; i-3 
                 475 
                 68 
                 10a, 10b 
               
               
                 R6808 
                 F0_DSCav1 
                 —/muag; i-3 
                 1259 
                 898 
                 10a, 10b 
               
               
                 R6770 
                 F_DSCav1_mut3 
                 —/muag; i-3 
                 3473 
                 3112 
                 10a 
               
               
                 R6771 
                 F_DSCav1_mut1 
                 —/muag; i-3 
                 1997 
                 1636 
                 10a 
               
               
                 R6772 
                 F_DSCav1_mut2 
                 —/muag; i-3 
                 2735 
                 2374 
                 10a 
               
               
                 R6940 
                 F-del 
                 —/muag; i-3 
                 890 
                 483 
                 10a, 10b 
               
               
                 R5453 
                 F-del_DSCav1 
                 —/muag; i-3 
                 1628 
                 1267 
                 10a, 10b 
               
               
                 R6775 
                 F-del_DSCav1_mut3 
                 —/muag; i-3 
                 3842 
                 3481 
                 10a 
               
               
                 R6774 
                 F-del_DSCav1_mut1 
                 —/muag; i-3 
                 2366 
                 2005 
                 10a 
               
               
                 R6773 
                 F-del_DSCav1_mut2 
                 —/muag; i-3 
                 3104 
                 2743 
                 10a 
               
               
                 R7454 
                 F_DSCav1_mut0 
                 —/muag; i-3 
                 4211 
                 3850 
                 10b 
               
               
                 R7456 
                 F_DSCav1_mut5 
                 —/muag; i-3 
                 5687 
                 5326 
                 10b 
               
               
                 R7458 
                 F_DSCav1_mut4 
                 —/muag; i-3 
                 4949 
                 4588 
                 10b 
               
               
                 R7455 
                 F-del_DSCav1_mut0 
                 —/muag; i-3 
                 4580 
                 4219 
                 10b 
               
               
                 R7457 
                 F-del_DSCav1_mut5 
                 —/muag; i-3 
                 6056 
                 5695 
                 10b 
               
               
                 R7459 
                 F-del_DSCav1_mut4 
                 —/muag; i-3 
                 5318 
                 4957 
                 10b 
               
               
                   
               
            
           
         
       
     
     Results: 
     The results show that the used mRNA constructs led to a detectable intracellular RSV F protein expression as well as to a detectable protein expression at the cell surface. The RSV F constructs with deleted C-terminus (F-del) (e.g. R6940, R5453, R6775, R6774, R6773, R7455, R7457, R7459) show an increased cell surface protein expression in comparison to F full length constructs. The construct encoding F-del_DSCav1_mut0 (R7455) exhibits the highest expression. 
     The results exemplify that the inventive mRNA encoding F proteins (F0, F-del, F0_DSCav1, F-del_DSCav1, F_DSCav1_mut0, F-del_DSCav1_mut0, F_DSCav1_mut1, F-del_DSCav1_mut1, F_DSCav1_mut2, F-del_DSCav1_mut2, F_DSCav1_mut3, F-del_DSCav1_mut3, F_DSCav1_mut4, F-del_DSCav1_mut4, F_DSCav1_mut5, F-del_DSCav1_mut5) is translated in cells and are present at the cell surface, which is a prerequisite for an mRNA-based RSV vaccine. 
     Example 9: Vaccination of Cotton Rats with LNP-Formulated mRNA Encoding RSV-F and RSV Cotton Rat Challenge Study 
     The present Example shows that LNP-formulated mRNA according to the invention encoding different pre-fusion stabilized RSV-F antigens induce strong, functional and protective immune responses in cotton rats. 
     This experiment compared mRNA-LNPs encoding different pre-fusion stabilized RSV-F variants (mut 1, mut2, mut3) with either full-length F or with the truncated F (F-del). The mRNA-LNP vaccines were prepared according to Example 1. Cotton rats received two intramuscular vaccinations with mRNA-LNP vaccines on days 0 and 28. Each dose comprised 100 μg mRNA-LNPs. Control animals received a single vaccination at day 0 with 105 pfu live RSV/A2 virus or UV inactivated RSV/A2 virus or two vaccinations at days 0 and 28 with formalin-inactivated RSV virus (F1 RSV) intramuscularly. Additional control animals received buffer only (see Table 17). 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Animal groups and vaccination schedule of Example 9 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 RNA 
                 SEQ ID NO: 
                 SEQ ID NO: 
                   
                   
               
               
                 Group 
                 Test item 
                 ID 
                 RNA 
                 Protein 
                 Dose 
                 Route 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1 
                 mRNA encoding F0 
                 R6939 
                 475 
                 68 
                 100 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 2 
                 mRNA encoding 
                 R6808 
                 1259 
                 898 
                 100 μg 
                 i.m. 
               
               
                   
                 F0_DSCav1 
               
               
                   
                 LNP-formulated 
               
               
                 3 
                 mRNA encoding 
                 R6770 
                 3473 
                 3112 
                 100 μg 
                 i.m. 
               
               
                   
                 F_DSCav1_mut3 
               
               
                   
                 LNP-formulated 
               
               
                 4 
                 mRNA encoding 
                 R6771 
                 1997 
                 1636 
                 100 μg 
                 i.m. 
               
               
                   
                 F_DSCav1_mut1 
               
               
                   
                 LNP-formulated 
               
               
                 5 
                 mRNA encoding 
                 R6772 
                 2735 
                 2374 
                 100 μg 
                 i.m. 
               
               
                   
                 F_DSCav1_mut2 
               
               
                   
                 LNP-formulated 
               
               
                 6 
                 mRNA encoding F-del 
                 R6940 
                 890 
                 483 
                 100 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 7 
                 mRNA encoding 
                 R5453 
                 1628 
                 1267 
                 100 μg 
                 i.m. 
               
               
                   
                 F-del_DSCav1 
               
               
                   
                 LNP-formulated 
               
               
                 8 
                 mRNA encoding 
                 R6775 
                 3842 
                 3481 
                 100 μg 
                 i.m. 
               
               
                   
                 F-del_DSCav1_mut3 
               
               
                   
                 LNP-formulated 
               
               
                 9 
                 mRNA encoding 
                 R6774 
                 2366 
                 2005 
                 100 μg 
                 i.m. 
               
               
                   
                 F-del_DSCav1_mut1 
               
               
                   
                 LNP-formulated 
               
               
                 10 
                 mRNA encoding 
                 R6773 
                 3104 
                 2743 
                 100 μg 
                 i.m. 
               
               
                   
                 F-del_DSCav1_mut2 
               
               
                   
                 LNP-formulated 
               
               
                 11 
                 Live RSV/A2 virus 
                   
                   
                   
                 10 5   
                 i.m. 
               
               
                 12 
                 UV-inact. RSV/A2 
                   
                   
                   
                 10 5   
                 i.m. 
               
               
                 13 
                 FI RSV 
                   
                   
                   
                 1:100 
                 i.m. 
               
               
                 14 
                 Buffer 
                   
                   
                   
                   
                 i.m. 
               
               
                 15 
                 untreated/uninfected 
                   
                   
                   
                   
                 i.m. 
               
               
                   
               
            
           
         
       
     
     Determination of Anti-RSV F Protein Antibodies by ELISA: 
     Blood samples were collected on days 0, 28, 49, and 63 for the determination of anti-RSV F antibody titers. ELISA plates were coated with purified F protein extracted from RSV/A2-infected HEp-2 cells or methanol/Acetone fixed RSV/B infected HEp-2 cells. Coated plates were incubated using given serum dilutions. Binding of specific antibodies to the F protein was detected using isotype specific anti-cotton rat antibodies in combination with streptavidin-HRP (horse radish peroxidase) with TMB substrate. 
     Determination of Virus Neutralization Titers: 
     Serum was collected on days 0, 28, 49, and 63 and RSV virus neutralization titers (VNTs) were measured using a plaque reduction neutralization test (PRNT). Diluted serum samples were incubated with RSV/A2 or RSV/B (25-50 PFU) for 1 hour at room temperature and inoculated in duplicates onto confluent HEp-2 monolayers in 24 well plates. After one hour incubation at 37° C. in a 5% CO2 incubator, the wells were overlayed with 0.75% Methylcellulose medium. After 4 days of incubation, the overlays were removed and the cells were fixed and stained. The corresponding reciprocal neutralizing antibody titers were determined at the 60% reduction end point of the virus control. 
     Cotton Rat Challenge Study: 
     The vaccinated animals were challenged intranasally at day 63 with 10 5  pfu live RSV/A2 virus in 100 uL. One control group remained untreated and uninfected. All animals were sacrificed at day 68 and nasal tissue and lung were harvested. 
     RSV Titers in Nasal Tissue of Challenged Cotton Rats 
     Lungs and nasal tissue of animals were collected at day 68 (i.e. 5 days after intranasal challenge with 10 5  pfu live RSV/A2 virus). The nose homogenates were clarified as the lung homogenates by centrifugation and diluted in EMEM. Confluent HEp-2 monolayers were infected in duplicates with diluted homogenates in 24 well plates. After one hour incubation at 37° C. in a 5% CO incubator, the wells were overlayed with 0.75% methylcellulose medium. After 4 days of incubation, the overlays were removed and the cells were fixed and stained with 0.1% crystal violet for one hour and then rinsed and air dried. Plaques were counted and virus titers were expressed as plaque forming units per gram of tissue. 
     Pulmonary Histopathology 
     Lungs were dissected and inflated with 10% neutral buffered formalin to their normal volume, and then immersed in the same fixative solution. Following fixation, the lungs were embedded in paraffin, sectioned and stained with hematoxylin and eosin (H&amp;E). Four parameters of pulmonary inflammation were evaluated: peribronchiolitis (inflammatory cell infiltration around the bronchioles), perivasculitis (inflammatory cell infiltration around the small blood vessels), interstitial pneumonia (inflammatory cell infiltration and thickening of alveolar walls), and alveolitis (cells within the alveolar spaces). Slides are scored blind on a 0-4 severity scale. The scores are subsequently converted to a 0-100% histopathology scale. 
     Results: 
       FIG. 11  shows that all tested LNP-formulated mRNA constructs encoding different RSV F proteins (F0, F0_DSCav1, F_DSCav1_mut3, F_DSCav1_mut1, F_DSCav1_mut2, F-del, F-del_DSCav1, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) according the invention induce humoral immune responses in cotton rats against the RSV-F protein. Antibody total IgG titers were determined by ELISA. 
     The mRNA constructs encoding the truncated F (F-del) (F-del, F-del_DSCav1, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) induced higher and faster responses than the constructs with the full length F sequence on d28, no significant difference is detectable at later time points. Stabilized constructs (F0_DSCav1, F_DSCav1_mut3, F_DSCav1_mut1, F_DSCav1_mut2, F-del_DSCav1, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) initially yield lower ELISA titers than wildtype constructs (F0 and F-del). Levels are not significantly different at later time points. 
     With a dose of 100 μg, the constructs encoding the stabilized and truncated F protein (F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) induce higher titers of RSV-F specific IgGs already after prime vaccination (day 28) compared with the vaccination with the live virus. After boost vaccination all tested LNP-formulated RSV-F mRNA vaccines induces humoral immune responses measured with ELISA which are more prominent then the answers of the control vaccinations. 
     As can be seen from  FIG. 12 , all LNP-formulated RSV-F (F0, F0_DSCav1, F_DSCav1_mut3, F_DSCav1_mut1, F_DSCav1_mut2, F-del, F-del_DSCav1, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) mRNA vaccines induced the formation of RSV specific functional antibodies in cotton rats as shown by high virus neutralizing antibody titers. The LNP-formulated RSV-F truncated constructs (F-del, F-del_DSCav1, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) induced higher and faster responses than F full length constructs. The constructs for pre-fusion stabilization according to the invention (F_DSCav1_mut3, F_DSCav1_mut1, F_DSCav1_mut2, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) induce higher responses than F0, F0_DSCav1, F-del, F-del_DSCav1. 
     As can be seen from  FIG. 13 , the lung histopathology analysis from the RSV cotton rat challenge study reveals different pathology scores for the various animal groups. From the histopathology it can be concluded that none of the mRNA vaccinated groups displayed enhanced lung pathology as it is the case for the group that was vaccinated using the formalin-inactivated RSV vaccine. The average pathology scores for peribronchiolitis are lower for all groups vaccinated with mRNA compared to the group with formalin-inactivated RSV. The LNP-formulated RSV-F truncated constructs (F-del, F-del_DSCav1, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) showed in general lower pathology scores than F full length constructs. The constructs for pre-fusion stabilization according to the invention (F_DSCav1_mut3, F_DSCav1_mut1, F_DSCav1_mut2, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) yielded better responses (lower pathology scores) than F0, F0_DSCav1, F-del, F-del_DSCav1. 
     As can be seen from  FIG. 14 a   , all in this experiment tested LNP-formulated RSV-F mRNA vaccines reduced lung viral titers in cotton rats challenged with RSV virus and therefore limit RSV infection of the lung. All the animal groups vaccinated with mRNA formulated in LNPs vaccines showed virus titers below the level of detection of the performed virus titration. The results demonstrate protection of vaccinated cotton rats in terms of viral lung titers. By contrast, the formalin-inactivated virus vaccine (FI RSV) and the UV-inactivated RSV/A2 virus control reduced only minimally the lung virus titer compared to the buffer control group. 
     As can be seen from  FIG. 14 b   , the LNP-formulated RSV-F mRNA vaccines strongly reduced viral titers in nasal tissue of cotton rats challenged with RSV virus and therefore reduce RSV infection of the nose. In comparison to the mRNA vaccines the vaccine based on formalin-inactivated virus (FI RSV) and the UV-inactivated RSV/A2 virus control were not able to reduce the nasal virus titers. A complete protection of the nose was only achieved by the pre-fusion stabilization according to the invention (F_DSCav1_mut3, F_DSCav1_mut1, F_DSCav1_mut2, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2). 
     To conclude, the results show that LNP-formulated RNA constructs encoding RSV-F truncated proteins (F-del, F-del_DSCav1, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2) are in general more immunogenic than RNA constructs encoding for full length F proteins. Constructs featuring Ds-Cav1 mutations alone (F0_DSCav1 and F-del_DSCav1) are suboptimal as an mRNA based vaccine in comparison with the constructs encoding the further stabilized F proteins according the invention (F_DSCav1_mut3, F_DSCav1_mut1, F_DSCav1_mut2, F-del_DSCav1_mut3, F-del_DSCav1_mut1, F-del_DSCav1_mut2). 
     To further improve the efficiency of the mRNA-based vaccine, several alternative RSV-F mRNA constructs were designed harboring further mutations stabilizing the pre-fusion conformation in combination with the beneficial truncated F-del protein. Those mRNA constructs were tested as can be seen in the following Example. 
     Example 10: Vaccination of Cotton Rats with LNP-Formulated mRNA Encoding RSV-F and RSV Cotton Rat Challenge Study 
     The present Example shows that LNP-formulated mRNA according to the invention encoding different pre-fusion stabilized RSV-F antigens induce strong, functional and protective immune responses in cotton rats. 
     The mRNA-LNP vaccines were prepared according to Example 1. Cotton rats received either one or two intramuscular vaccinations with mRNA-LNP vaccines on day 0 or on days 0 and 28. Each dose comprised 100 μg mRNA-LNPs. Control animals received a single vaccination at day 28 with 10 5  pfu live RSV/A2 virus or formalin-inactivated RSV virus (FI RSV) intramuscularly. Additional control animals received buffer only (see Table 18). 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Animal groups and vaccination schedule of Example 10 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                 RNA 
                 SEQ ID NO: 
                 SEQ ID NO: 
                   
                   
                   
               
               
                 Group 
                 Test item 
                 ID 
                 RNA 
                 Protein 
                 Dose 
                 Immunization 
                 Route 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                 (1) mRNA encoding F-del 
                 R6940 
                 890 
                 483 
                 100 μg 
                 day 0, day 28 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 2 
                 (2) mRNA encoding 
                 R6773 
                 3104 
                 2743 
                 100 μg 
                 day 0, day 28 
                 i.m. 
               
               
                   
                 F-del_DSCav1_mut2 
               
               
                   
                 LNP-formulated 
               
               
                 3 
                 (3) mRNA encoding 
                 R7455 
                 4580 
                 4219 
                 100 μg 
                 day 0, day 28 
                 i.m. 
               
               
                   
                 F-del_DSCav1_mut0 
               
               
                   
                 LNP-formulated 
               
               
                 4 
                 (4) mRNA encoding 
                 R7457 
                 6056 
                 5695 
                 100 μg 
                 day 0, day 28 
                 i.m. 
               
               
                   
                 F-del_DSCav1_mut5 
               
               
                   
                 LNP-formulated 
               
               
                 5 
                 (5) mRNA encoding 
                 R7459 
                 5318 
                 4957 
                 100 μg 
                 day 0, day 28 
                 i.m. 
               
               
                   
                 F-del_DSCav1_mut4 
               
               
                   
                 LNP-formulated 
               
               
                 6 
                 (1) mRNA encoding F-del 
                 R6940 
                 890 
                 483 
                 100 μg 
                 day 28 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 7 
                 (2) mRNA encoding 
                 R6773 
                 3104 
                 2743 
                 100 μg 
                 day 28 
                 i.m. 
               
               
                   
                 F-del_DSCav1_mut2 
               
               
                   
                 LNP-formulated 
               
               
                 8 
                 (3) mRNA encoding 
                 R7455 
                 4580 
                 4219 
                 100 μg 
                 day 28 
                 i.m. 
               
               
                   
                 F-del_DSCav1_mut0 
               
               
                   
                 LNP-formulated 
               
               
                 9 
                 (4) mRNA encoding 
                 R7457 
                 6056 
                 5695 
                 100 μg 
                 day 28 
                 i.m. 
               
               
                   
                 F-del_DSCav1_mut5 
               
               
                   
                 LNP-formulated 
               
               
                 10 
                 (5) mRNA encoding 
                 R7459 
                 5318 
                 4957 
                 100 μg 
                 day 28 
                 i.m. 
               
               
                   
                 F-del_DSCav1_mut4 
               
               
                   
                 LNP-formulated 
               
               
                 11 
                 Live RSV/A2 virus 
                   
                   
                   
                 10 5   
                 day 28 
                 i.m. 
               
               
                 12 
                 FI RSV 
                   
                   
                   
                 1:100 
                 day 28 
                 i.m. 
               
               
                 13 
                 Buffer 
                   
                   
                   
                   
                 day 0, day 28 
                 i.m. 
               
               
                 14 
                 untreated/uninfected 
                   
                   
                   
                   
                   
                 i.m. 
               
               
                   
               
            
           
         
       
     
     Determination of Anti-RSV F Protein Antibodies by ELISA and Virus Neutralization Titers 
     Blood samples were collected on days 0, 28, 49, and 63 for the determination of anti-RSV F antibody titers and RSV virus neutralization titers (VNTs) measured using the plaque reduction neutralization test (PRNT) as described before (see Example 9). 
     Cotton Rat Challenge Study: 
     The vaccinated animals were challenged intranasally at day 63 with 10 5  pfu live RSV/A2 virus in 100 uL. One control group remained untreated and uninfected. All animals were sacrificed at day 68 and nasal tissue and lung were harvested. The RSV titers in nasal tissue of challenged cotton rats and the pulmonary histopathology are analyzed as described before (see Example 9). 
     Results: 
       FIG. 15  shows that all tested LNP-formulated mRNA constructs encoding different RSV F proteins (F-del, F-del_DSCav1_mut2, F-del_DSCav1_mut0, F-del_DSCav1_mut5, F-del_DSCav1_mut4) according the invention induce humoral immune responses in cotton rats against the RSV-F protein. Antibody total IgG titers were determined by ELISA. RNA constructs encoding stabilized F proteins (F-del_DSCav1_mut2, F-del_DSCav1_mut0, F-del_DSCav1_mut5, F-del_DSCav1_mut4) initially yield lower ELISA titers than the construct encoding the truncated wildtype F protein, F-del. This trend is also detectable at later time points by using higher serum dilutions for the ELISA (data not shown). The IgG response can be significantly boosted by a second immunization. 
     As can be seen from  FIG. 16 , all LNP-formulated RSV-F (F-del, F-del_DSCav1_mut2, F-del_DSCav1_mut0, F-del_DSCav1_mut5, F-del_DSCav1_mut4) mRNA vaccines induced the formation of RSV specific functional antibodies in cotton rats as shown by high virus neutralizing antibody titers. The LNP-formulated constructs for pre-fusion stabilization according to the invention (F-del_DSCav1_mut2, F-del_DSCav1_mut0, F-del_DSCav1_mut5, F-del_DSCav1_mut4) induce higher or comparable responses than F-del. The RNA construct R7457 coding for the pre-fusion stabilized protein F-del_DSCav1_mut5 induces the highest VNTs (comparable to the best results induced by best pre-fusion stabilized construct in the previous experiment (Example 9, R6773). 
     The lung histopathology analysis shows that none of the mRNA vaccinated groups displayed enhanced lung pathology as it is the case for the group that was vaccinated using the formalin-inactivated RSV vaccine (see  FIG. 17 a    (for Peribronciolitis and Perivasculitis) and  FIG. 17 b    (for Interstitial Pneumonia and Alveolitis)). The constructs for pre-fusion stabilization according to the invention (F-del_DSCav1_mut2, F-del_DSCav1_mut0, F-del_DSCav1_mut5, F-del_DSCav1_mut4) yielded better responses (lower pathology scores) than F-del. Animals received two vaccinations showed a lower pathology score in comparison to animals only received one vaccination. 
     As can be seen from  FIG. 18 a   , all in this experiment tested LNP-formulated RSV-F mRNA vaccines reduced lung viral titers in cotton rats challenged with RSV virus and therefore limit RSV infection of the lung. This is true even for groups receiving only one vaccination. The results demonstrate protection of vaccinated cotton rats in terms of viral lung titers. By contrast, the formalin-inactivated virus vaccine (FI RSV) reduced only minimally the lung virus titer compared to the buffer control group. 
     As can be seen from  FIG. 18 b   , the LNP-formulated RSV-F mRNA vaccines strongly reduced viral titers in nasal tissue of cotton rats challenged with RSV virus and therefore reduce RSV infection of the nose. In comparison to the mRNA vaccines the vaccine based on formalin-inactivated virus (FI RSV) was not able to reduce the nasal virus titers. A complete protection of the nose was only achieved for some groups received two vaccinations (e.g. for R7457 (F-del_DSCav_mut4) and R7459 (F-del_DSCav_mut5)). 
     To conclude, the results show that LNP-formulated RNA constructs encoding pre-fusion stabilized RSV-F truncated proteins (F-del_DSCav1_mut2, F-del_DSCav1_mut0, F-del_DSCav1_mut5, F-del_DSCav1_mut4) raised in general higher functional titers and achieved a more pronounced protection against infection in comparison with the RNA construct coding for the wildtype truncated F protein F_del. The best results were reached by RNA constructs encoding F-del_DSCav1_mut2 or F-del_DSCav1_mut5 (R6773, R7457). 
     Example 11: Expression of Different RSV T-Cell Antigens Using a Rabbit Reticulocyte Lysate System 
     To determine in vitro protein expression of the mRNA constructs according to the second aspect of the invention (mRNA constructs coding for RSV matrix protein M, phosphoprotein P, nucleoprotein N and matrix protein M2-1 protein), unformulated RNAs (prepared according to Example 1) were mixed with components of Promega Rabbit Reticulocyte Lysate System according to manufacture protocol. The lysate contains the cellular components necessary for protein synthesis (tRNA, ribosomes, amino acids, initiation, elongation and termination factors). As positive control Luciferase RNA from Lysate System Kit was used. The translation result was analyzed by SDS-Page and Western Blot analysis (IRDye 800CW streptavidin antibody (1:2000)). Table 19 summarizes the tested RNA constructs. 
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Overview of mRNA constructs used in Example 11 
               
            
           
           
               
               
               
               
               
               
            
               
                 RNA 
                   
                   
                 SEQ ID NO: 
                 SEQ ID NO: 
                 Predicted 
               
               
                 ID 
                 Antigen 
                 UTR Design 
                 RNA 
                 Protein 
                 kDa 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 R7595 
                 M 
                 —/muag; i-3 
                 10046 
                 9684 
                   
               
               
                 R7596 
                 P 
                 —/muag; i-3 
                 10999 
                 10637 
                 27.1 
               
               
                 R7597 
                 N 
                 —/muag; i-3 
                 10496 
                 10134 
                 43.4 
               
               
                 R7598 
                 M2-1 
                 —/muag; i-3 
                 11545 
                 11183 
                 22.1 
               
               
                   
                 Luc 
                   
                   
                   
                 61 
               
               
                   
               
            
           
         
       
     
     Results: 
     The results (see  FIG. 19 ) show that the used mRNA constructs led to a detectable protein expression, which is a prerequisite for an mRNA-based RSV vaccine (size shifts of RSV P and M2-1 on the gel may be due to phosphorylation as described e.g. in Richard et al., 2018 or in Hardy and Wertz, 2000 PMIDs: 29489893 and 10846068). 
     Example 12: Vaccination of Mice with LNP-Formulated mRNA Encoding Different RSV T-Cell Antigens Alone and in the Combination with RSV F (F-Del) 
     The present Example analyses LNP-formulated mRNA encoding different RSV T-cell antigens according to the second aspect of the invention (RSV M, P, N, and M2-1) alone or in combination with LNP formulated mRNA encoding the truncated RSV F (F-del). The mRNA-LNP vaccines were prepared according to Example 1. Balb/c mice received two intramuscular vaccinations with mRNA-LNP vaccines on days 0 and 28. Each dose comprised 5 μg, 2.5 μg or 2.5 μg+2.5 μg mRNA-LNPs (for groups receiving mRNAs encoding different antigens the LNPs were separately formulated and mixed before administration). Control animals received buffer only (see Table 20).). Humoral, as well as cellular immune responses and neutralizing antibodies were analyzed by ELISA, FACS, PRNT and ICS. 
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 Animal groups and vaccination schedule of Example 12 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 RNA 
                 SEQ ID NO: 
                 SEQ ID NO: 
                   
                   
               
               
                 Group 
                 Test item 
                 ID 
                 RNA 
                 Protein 
                 Dose 
                 Route 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                 NaCl buffer 
                 — 
                 — 
                 — 
                   
                   
                 i.m. 
               
               
                 2 
                 M: mRNA encoding RSV M 
                 R7595 
                 10046 
                  9684 
                 5 
                 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 3 
                 P: mRNA encoding RSV P 
                 R7596 
                 10999 
                 10637 
                 5 
                 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 4 
                 N: mRNA encoding RSV N 
                 R7597 
                 10496 
                 10134 
                 5 
                 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 5 
                 M2-1: mRNA encoding M2-1 
                 R7598 
                 11545 
                 11183 
                 5 
                 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
               
                 6 
                 F: mRNA encoding F-del 
                 R6940 
                  890 
                  483 
                 2.5 
                 μg 
                 i.m. 
               
               
                   
                 LNP-formulated 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 7 
                 F + M: mRNA encoding F-del + 
                 R7595 + 
                 890 + 
                 483 + 
                 2.5 μg + 
                 i.m. 
               
               
                   
                 mRNA encoding RSV M 
                 R6940 
                 10046 
                 9684 
                 2.5 μg 
               
               
                   
                 LNP-formulated 
               
               
                 8 
                 F + P: mRNA encoding F-del + 
                 R7596 + 
                 890 + 
                 483 + 
                 2.5 μg + 
                 i.m. 
               
               
                   
                 mRNA encoding RSV P 
                 R6940 
                 10999 
                 10637 
                 2.5 μg 
               
               
                   
                 LNP-formulated 
               
               
                 9 
                 F + N: mRNA encoding F-del + 
                 R7597 + 
                 890 + 
                 483 + 
                 2.5 μg + 
                 i.m. 
               
               
                   
                 mRNA encoding RSV N 
                 R6940 
                 10496 
                 10134 
                 2.5 μg 
               
               
                   
                 LNP-formulated 
               
               
                 10 
                 F + M2-1: mRNA encoding F-del + 
                 R7598 + 
                 890 + 
                 483 + 
                 2.5 μg + 
                 i.m. 
               
               
                   
                 mRNA encoding RSV M2-1 
                 R6940 
                 11545 
                 11183 
                 2.5 μg 
               
               
                   
                 LNP-formulated 
               
               
                   
               
            
           
         
       
     
     Determination of Anti-RSV F Protein Antibodies by ELISA: 
     Blood samples were collected on days 0, 14, 28, and 49 for the determination of anti-RSV F antibody titers. ELISA plates were coated with recombinant human RSV fusion glycoprotein (hRSV F Protein (A2; His-tag; Sino Biological; Cat: 11049-V08B)). Coated plates were incubated using given serum dilutions. Binding of specific antibodies to the F protein was detected using isotype specific anti-mouse rat antibodies in combination with streptavidin-HRP (horse radish peroxidase) and the Amplex® UltraRed Reagent (Invitrogen (Ref. No. A36006). 
     Detection of Antigen-Specific Humoral Antibody Responses Measured by FAGS 
     Hela cells were transfected with 2 μg RSV mRNA constructs (R7595, R7596, R7597, R7598) using lipofectamine. The cells were harvested 20 h post transfection, and seeded at 1×10 5  per well into a 96 well plate. The cells were incubated with corresponding sera of vaccinated mice (serum of day 28 and 49, diluted 1:50) followed by a FITC-conjugated anti-mouse IgG antibody staining. Cells were acquired on BD FACS Canto II using DIVA software and analyzed by FlowJo. The results are shown in  FIG. 21 a    (day 28) and  FIG. 21 b    (day 49). As read out the percentage of FITC-positive cells (out of live cells) was used. 
     Determination of Virus Neutralization Titers: 
     Serum was collected on day 49 and RSV virus neutralization titers (VNTs) were measured using a plaque reduction neutralization test (PRNT). Diluted serum samples were incubated with RSV/A2 (25-50 PFU) for 1 hour at room temperature and inoculated in duplicates onto confluent HEp-2 monolayers in 24 well plates. After one hour incubation at 37° C. in a 5% CO2 incubator, the wells were overlayed with 0.75% Methylcellulose medium. After 4 days of incubation, the overlays were removed and the cells were fixed and stained. The corresponding reciprocal neutralizing antibody titers were determined at the 60% reduction end-point of the virus control. 
     Determination of Cellular Immune Responses in Mice by ICS Using FACS 
     Splenocytes and lung cells from vaccinated and control mice were isolated according to standard protocols. Briefly, isolated spleens were grinded through a cell strainer and washed in PBS (1% FCS). After centrifugation, the cell pellet was resuspended with the remaining supernatant, treated with red cell lysis buffer and washed repeatedly with PBS (1% FCS). Finally, splenocytes were resuspended in FCS/10% DMSO, transferred into a cryovial and stored at −80° C. Lungs were perfused using RPMI-1640 medium (10% FCS; 2 mM glutamine; 1% Pen/Strep), harvested, and then stored in RPMI-1640 medium (10% FCS; 2 mM glutamine; 1% Pen/Strep) at 4° C. until lung cells were isolated using the Lung Dissociation Kit mouse from Miltenyi Biotec according to the manufacturer&#39;s instructions. For ICS, 2×10 6  cells (splenocytes or lung cells) were seed in duplicates in round-bottom plates and stimulated with RSV M2-1-specific (VYNTVISYI, SYIGSINNI, SYIESNRKN, KSIDTLSEI), RSV F-specific (FYQSTCSAV, TYMLTNSEL, KYKNAVTEL, KIMTSKTDV), RSF M-specific (KHTATRFAI, AQMPSKFTI, KYIKPQSQF, TYLRSISVR), RSV P-specific (SPITSNSTI, SYEEINDQT), or RSV N-specific (SYKKMLKEM, FYHILNNPK, KYTIQRSTG, GYHVKANGV) peptides. After Golgi block (GolgiPlug 1/1000) and incubation for intracellular cytokine accumulation, cells were subjected to live/dead staining using Aqua-dye. Then, cells were surface stained using the antibodies α-CD8-APC-H7 (1/100), α-CD4-BD-Horizon V450 (1/200), α-Thy1.2-FITC (1/300), and α-CD107a PE-Cy7 (1/100) for splenocytes and α-CD8-APC-H7 (1/100), α-CD4-BD-Horizon V450 (1/200), α-Thy1.2-FITC (1/300), α-CD69-PE (1/100), and α-CD103-PE-Cy7 (1/60) for lung cells. After treatment with Cytofix/Cytoperm, lung cells were intracellularly stained with α-IFNg-APC (1/100) and splenocytes additionally with α-TNFα-PE (1/100). Finally, cells were acquired on BD FACS Canto II using DIVA software and analyzed by FlowJo. 
     Results: 
     The results of the immunogenicity study in mice, e.g. the humoral immune responses can be seen in  FIG. 20  ( FIG. 20 a   : anti-RSV F IgG,  FIG. 20 b   : anti-RSV F IgG2a). In general, all groups induced humoral immune responses without significant differences between F-del alone and the F-del+ T-cell antigen groups. The addition of the T-cell antigens M, P, N, and M2-1 to the mRNA vaccine encoding RSV F-del did not influence or disturb the immune response against RSV F. These findings indicate that the co-expression of T cell antigens does not affect antibody responses induced by RSV F. The immune responses could be boosted by the second immunization (see responses on day 49). In general, the IgG2a titers are 10 times higher than the IgG1 titers, indicating a predominant Th1 response. A Th1-biased immune response is considered to be an important prerequisite for a potential RSV vaccine, as Th2-biased responses have been associated with enhanced respiratory disease (ERD) in animal models. 
     As shown in  FIG. 21 a    and  FIG. 21 b    specific antigen IgGs were detected in sera of immunized mice indicating that the applied mRNA constructs are suitable to induce specific humoral immune responses. Furthermore, the results reveal that the induction of antigen-specific antibody responses for N and M2-1 can already be detected at day 28, while for M and P immunization a boost vaccination is necessary. The decreased antigen-specific antibody responses after RSV F co-immunization are likely due to different immunization doses (5 μg vs, 2.5 μg). 
     As can be seen from  FIG. 22 , all LNP-formulated mRNA vaccines (F, M+F, P+F, N+F, M2-1+F) induced the formation of RSV specific functional antibodies in mice as shown by high virus neutralizing antibody titers. The serum neutralizing antibody titer assays against RSV/A2 revealed no significant differences between the immunization groups. 
     As can be seen from  FIG. 23  ( FIG. 23 a    lung ICS CD8,  FIG. 23 b   , spleen ICS CD8,  FIG. 23 c    spleen ICS CD4), all vaccines containing RSV F, RSV M2-1, or both surprisingly induced a tissue resident memory T cell (T RM ) response in the lung upon intramuscular immunization, as an increase of CD8 +  T RM  cells specific for F or especially for M2-1 could be observed. The induction of a T RM  cell response in the lung might be favorable for a potential RSV vaccine, since lung T RM  cells (CD69 +  and CD103 + ) are proposed to protect against RSV infection. The splenocyte analysis revealed that an immunization with RSV F and especially RSV M2-1 lead to an increase of antigen-specific CD8 +  and CD4 +  T cells secreting IFNγ and TNF indicating the induction of a systemic T cell response in addition to a site-specific response. 
     To conclude, the results show that RSV M2-1 induces the most promising T cell immune responses without affecting antibody responses induced by RSV F. Thus, a vaccine containing mRNAs encoding for RSV F in combination with RSV M2-1 might increase the protective efficacy against RSV infection. 
     Example 13: Clinical Development of a RSV mRNA Vaccine Composition 
     To demonstrate safety and efficiency of the RSV mRNA vaccine composition, a clinical trial (phase 1) is initiated. For clinical development, RNA is used that has been produced under GMP conditions (e.g. using a procedure as described in WO2016/180430). 
     In the clinical trial, a cohort of healthy human volunteers is intramuscularly injected with respective LNP formulated vaccine compositions comprising favorable UTR combinations. 
     In order to assess the safety profile of the vaccine compositions according to the invention, subjects are monitored after administration (vital signals, vaccination site tolerability assessments, hematologic analysis). 
     The efficacy of the immunization is analyzed by determination of virus neutralizing titers (VNT) in sera from vaccinated subjects. Blood samples are collected on day 0 as baseline and after completed vaccination. Sera are analyzed for virus neutralizing antibodies.