Influenza virus vaccines

Abstract

The present invention is inter alia directed to immunogenic compositions for use in the treatment or prophylaxis of an infection with an Influenza virus, wherein the immunogenic composition comprises: (a) a first nucleic acid encoding a hemagglutinin (HA) antigen of a strain of a first subtype of Influenza A virus; (b) a second nucleic acid encoding a HA antigen of a strain of a second subtype of Influenza A virus; (c) a third nucleic acid encoding a HA antigen of a first strain of Influenza B virus; and (d) optionally, a fourth nucleic acid encoding a HA antigen of a second strain of Influenza B virus, wherein an immune response is elicited against HA antigens of said strains of first and second subtypes of Influenza A virus, said first and, optionally, second strains of Influenza B virus and at least one further HA antigen subtype of Influenza A virus, being different from any of the HA antigen subtypes of Influenza A virus encoded by a nucleic acid present in the composition.

Description

INFLUENZA VIRUS VACCINESTECHNICAL FIELDThe present invention is inter alia directed to immunogenic compositions, as well as vaccines and kits or kits of parts comprising such, for use in the treatment or prophylaxis of an infection with an Influenza virus comprising nucleic acids, suitably mRNAs, encoding hemagglutinin (HA) antigens derived from strains of Influenza A and B virus. The present invention is also directed to a method of eliciting an immune response against an Influenza virus and to a method of treating or preventing a disorder caused by an Influenza virus.BACKGROUNDInfluenza viruses are RNA viruses belonging to the family Orthomyxoviridae (NCBI Taxonomy ID: 11308), being sub-divided into e.g. AlphaInfluenzavirus (the genus that includes Influenza A viruses) and BetaInfluenzavirus (the genus that includes Influenza B viruses), that circulate in all parts of the world. Influenza viruses cause acute respiratory illness often during local outbreaks or seasonal epidemics and occasionally during pandemics. Typical Influenza epidemics cause increases in incidence of pneumonia and lower respiratory disease by increased rates of hospitalization or mortality. The elderly or those with underlying chronic diseases are most likely to experience such complications, but young infants also may suffer severe disease. Influenza viruses (mainly Influenza A and B viruses) have a significant impact on global public health, causing millions of cases of severe illness each year, thousands of deaths, and considerable economic losses.Influenza viruses, such as Influenza A and B viruses, are enveloped viruses comprising eight pieces of segmented negative-sense RNA, which encode 11 proteins (HA, NA, NP, M1 , M2, NS1 , NEP, PA, PB1 , PB1-F2, PB2). The best-characterized of these viral proteins are hemagglutinin (HA) and neuraminidase (NA), two large glycoproteins found on the outside of the viral particles. NA is an enzyme involved in the release of progeny virus from infected cells. HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell.Currently, there are 18 described HA (H1-H18) subtypes and 11 described NA (N1- N11) subtypes of Influenza A viruses that potentially form 144 HA and NA combinations. Unlike Influenza A viruses that have a wide range of host, the Influenza B viruses almost exclusively infect humans. The Influenza B viruses are categorized into two distinct lineages: BA / ictoria / 2 / 1987-like (B / Victoria lineage) and B / Yamagata / 16 / 1988-like (B / Yamagata lineage)viruses that have been circulating worldwide since 1983. Influenza virus B mutates at a rate 2 to 3 times slower than type A; however, it significantly impacts children and young adults annually.Constant emergence of new strains of Influenza virus through antigenic drift is the virological basis for seasonal epidemics. Due to its constant evolving nature, the periodic update of viruses contained in Influenza (flu) vaccines is necessary for the vaccines to be effective. Public health authorities monitor the Influenza viruses circulating in humans and update the recommended composition of flu vaccines twice a year. The recommendations issued (usually, three or four different strains of Influenza virus) are used by the national vaccine regulatory agencies and pharmaceutical companies to develop, produce, and license Influenza vaccines for the following Influenza season.Vaccination is currently the most widely used method to prevent Influenza outbreaks, particularly in high-risk population. Multivalent live attenuated (FLUMIST, AstraZeneca), inactivated (AFLURIA, FLUAD and FLUCELVAX, Seqirus; FLUARIX and FLULAVAL, GlaxoSmithKline; FLUZONE, Sanofi), or recombinant (FLUBLOK, Sanofi) flu vaccines are already available on the market for active immunization against disease caused by Influenza subtype A viruses and Influenza type B viruses contained in the vaccines.Because HA is the major Influenza virus antigen recognized by neutralizing antibodies, this glycoprotein has been the focus of currently inactivated and recombinant approved flu vaccines. Most of those flu vaccines are quadrivalent vaccines, based on 4 HA derived from each of the four strains of Influenza virus specified by health authorities for inclusion in the annual seasonal vaccine (typically two Influenza subtype A strains and two Influenza type B strains), meaning designed to protect against those four different flu virus strains.Current quadrivalent influenza vaccines only elicit antibody responses to the vaccine strains (e.g. homologous immune response) or to closely related isolates, but rarely extend to more diverged strains within a subtype / lineage (e.g. heterologous immune response) or to strains belonging to different subtypes / lineages (e.g. heterosubtypic immune response).Therefore, there remains a need to provide an immunogenic composition capable of eliciting a broad, rapid and robust immune response against Influenza virus. There particularly remains a need for an influenza vaccine that protects individuals from heterologous and heterosubtypic strains of influenza virus ( / .e. that are not present in the vaccine).SUMMARY OF THE INVENTIONIn a first aspect, the invention provides an immunogenic composition for use in the treatment or prophylaxis of an infection with an Influenza virus, wherein the immunogenic composition comprises:(a) a first nucleic acid encoding a hemagglutinin (HA) antigen of a strain of a first subtype of Influenza A virus;(b) a second nucleic acid encoding a HA antigen of a strain of a second subtype of Influenza A virus;(c) a third nucleic acid encoding a HA antigen of a first strain of Influenza B virus; and(d) optionally, a fourth nucleic acid encoding a HA antigen of a second strain of Influenza B virus, wherein an immune response is elicited against HA antigens of said strains of first and second subtypes of Influenza A virus, said first and, optionally, second strains of Influenza B virus and at least one further HA antigen subtype of Influenza A virus, being different from any of the HA antigen subtypes of Influenza A virus encoded by a nucleic acid present in the composition.In a second aspect, the invention provides a vaccine for use in the treatment or prophylaxis of an infection with an Influenza virus, comprising an immunogenic composition as defined herein, wherein an immune response is elicited as defined herein.In a third aspect, the invention provides a kit or kit of parts for use in the treatment or prophylaxis of an infection with an Influenza virus, wherein the kit or kit of parts comprises the nucleic acids, suitably the mRNAs, as defined herein, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) as defined herein, optionally comprising a liquid vehicle for solubilizing, and, optionally, technical instructions providing information on administration and dosage of the components, wherein an immune response is elicited as defined herein.In a fourth aspect, the invention provides a method of eliciting an immune response against an Influenza virus, wherein the method comprises applying or administering to a subject in need thereof an immunogenic composition as defined herein, and wherein an immune response is elicited as defined herein.In a fifth aspect, the invention provides a method of treating or preventing a disorder caused by an Influenza virus, wherein the method comprises applying or administering to a subject in need thereof an immunogenic composition as defined herein, and wherein an immune response is elicited as defined herein.BRIEF DESCRIPTION OF THE SEQUENCESSEQ ID NO: 1 Amino acid sequence of HA from A / Michigan / 45 / 2015 (H1 N1).SEQ ID NO: 2 Amino acid sequence of NA from A / Michigan / 45 / 2015 (H1 N1).SEQ ID NO: 3 Amino acid sequence of HA from A / Switzerland / 8060 / 2017 (H3N2).SEQ ID NO: 4 Amino acid sequence of NA from A / Switzerland / 8060 / 2017 (H3N2).SEQ ID NO: 5 Amino acid sequence of HA from B / Colorado / 06 / 2017.SEQ ID NO: 6 Amino acid sequence of NA from B / Colorado / 06 / 2017.SEQ ID NO: 7 Amino acid sequence of HA from B / Phuket / 3073 / 2013.SEQ ID NO: 8 Amino acid sequence of NA from B / Phuket / 3073 / 2013.SEQ ID NO: 9 Amino acid sequence of HA from A / Singapore / INFIMH-16-0019 / 2016(H3N2).SEQ ID NO: 10 Amino acid sequence of NA from A / Singapore / INFIMH-16-0019 / 2016(H3N2).SEQ ID NO: 11 Amino acid sequence of HA from A / Brisbane / 02 / 2018 (H1 N1).SEQ ID NO: 12 Amino acid sequence of NA from A / Brisbane / 02 / 2018 (H1 N1).SEQ ID NO: Amino acid sequence of HA from A / Kansas / 14 / 2017 (H3N2).SEQ ID NO: Amino acid sequence of NA from A / Kansas / 14 / 2017 (H3N2).SEQ ID NO: 15 Amino acid sequence of HA from A / South Austral ia / 34 / 2019 (H3N2).SEQ ID NO: 16 Amino acid sequence of NA from A / South Austral ia / 34 / 2019 (H3N2).SEQ ID NO: 17 Amino acid sequence of HA from B / Washington / 02 / 2019.SEQ ID NO: 18 Amino acid sequence of NA from B / Washington / 02 / 2019.SEQ ID NO: 19 Amino acid sequence of HA from A / Guangdong-Maonan / SWL1536 / 2019 (H1 N1).SEQ ID NO: 20 Amino acid sequence of NA from A / Guangdong- Maonan / SWL1536 / 2019 (H1 N1).SEQ ID NO: 21 Amino acid sequence of HA from A / Hong Kong / 2671 / 2019 (H3N2).SEQ ID NO: 22 Amino acid sequence of NA from A / Hong Kong / 2671 / 2019 (H3N2).SEQ ID NO: 23 Amino acid sequence of HA from A / Hawaii / 70 / 2019 (H1 N1).SEQ ID NO: 24 Amino acid sequence of NA from A / Hawaii / 70 / 2019 (H1 N1).SEQ ID NO: 25 Amino acid sequence of HA from A / Hong Kong / 45 / 2019 (H3N2).SEQ ID NO: 26 Amino acid sequence of NA from A / Hong Kong / 45 / 2019 (H3N2).SEQ ID NO: 27 Amino acid sequence of HA from A / Victoria / 2570 / 2019 (H1 N1).SEQ ID NO: 28 Amino acid sequence of NA from A / Victoria / 2570 / 2019 (H1 N1).SEQ ID NO: 29 Amino acid sequence of HA from A / Wisconsin / 588 / 2019 (H1 N1).SEQ ID NO: 30 Amino acid sequence of NA from A / Wisconsin / 588 / 2019 (H1 N1).SEQ ID NO: 31 Amino acid sequence of HA from A / Cambodia / e0826360 / 2020 (H3N2).SEQ ID NO: 32 Amino acid sequence of NA from A / Cambodia / e0826360 / 2020 (H3N2).SEQ ID NO: 33 Amino acid sequence of HA from A / Darwin / 9 / 2021 (H3N2).SEQ ID NO: 34 Amino acid sequence of NA from A / Darwin / 9 / 2021 (H3N2).SEQ ID NO: 35 Amino acid sequence of HA from B / Austria / 1359417 / 2021.SEQ ID NO: 36 Amino acid sequence of NA from B / Austria / 1359417 / 2021.SEQ ID NO: 37 Amino acid sequence of HA from A / Darwin / 6 / 2021 (H3N2).SEQ ID NO: 38 Amino acid sequence of NA from A / Darwin / 6 / 2021 (H3N2).SEQ ID NO: 39 Amino acid sequence of HA from A / Victoria / 4897 / 2022 (H1 N1).SEQ ID NO: 40 Amino acid sequence of NA from A / Victoria / 4897 / 2022 (H1 N1).SEQ ID NO: 41 Amino acid sequence of HA from A / Wisconsin / 67 / 2022 (H1 N1).SEQ ID NO: 42 Amino acid sequence of NA from A / Wisconsin / 67 / 2022 (H1 N1).SEQ ID NO: 43 Amino acid sequence of HA from A / Sydney / 5 / 2021 (H1 N1).SEQ ID NO: 44 Amino acid sequence of NA from A / Sydney / 5 / 2021 (H1 N1).SEQ ID NO: 45 Amino acid sequence of HA from A / Thailand / 8 / 2022 (H3N2).SEQ ID NO: 46 Amino acid sequence of NA from A / Thailand / 8 / 2022 (H3N2).SEQ ID NO: 47 Amino acid sequence of HA from A / Massachusetts / 18 / 2022 (H3N2).SEQ ID NO: 48 Amino acid sequence of NA from A / Massachusetts / 18 / 2022 (H3N2).DESCRIPTION OF THE FIGURESFIG. 1 : Domain structure of the Influenza A virus (IAV) HA protein. Domains in HA1 include fusion (F1), vestigial esterase (VE), and receptor-binding domain (RBD). Domains in HA2 include the HA2 ectodomain, transmembrane region (TM), and cytoplasmic tail (CT). The HA head includes the receptor-binding and vestigial esterase subdomains. The stalk (also known as “stem”) contains the HA1 fusion domains and the HA2 ectodomain.FIG. 2A-B (A) IFN-a release in human PBMCs stimulated with the mRNA-LNP. hPBMC from four donors were incubated each in triplicates with 10 pg / ml of the respective mRNA-LNP encoding the HA protein of influenza virus A / Hawaii / 70 / 2019 (H1 N1 pdmO9) in 96-well flat-bottom plate for 24h. IFNa was measured via ELISA. Values derived from individual donors (dots) are depicted for each group with line representing the geometric mean with 95% confidence interval (Cl). Between groups geometrical mean ratios (GMR) are depicted on graphs and statistical significance is indicated by a *(CI not containing 1), ns: non-significant.(B) HA-encoding mRNA-LNP vaccines containing pseudouridine or N1- methylpseudouridine induce substantially lower IFNa levels compared to unmodified mRNA-LNP vaccine in mice. Female Balb / c mice (n= 10 / group) were vaccinated with 5pg or 0.71 pg of the mRNA-LNP vaccines CVAC21-53- R9973 (unmodified), CVAC21-53-R10736 (pseudouridine) and CVAC21-53- R10737 (N1-methylpseudouridine). Control animals (n= 5 / group) received 0.9% NaCI solution. 18 hours after the immunization, serum IFNa levels were determined using ELISA. Each dot represents an individual animal, lines depict the geometric mean (GM) with 95% confidence interval (Cl). Between groups geometrical mean ratios (GMR) are depicted on graphs and statistical significance is indicated by a *(CI not containing 1), ns: non-significant.FIG. 3A-B (A) IFN-a release in hPBMCs stimulated with the mRNA-LNP vaccines. hPBMC from four donors were incubated each in triplicates with 10 pg / ml of the respective mRNA-LNP vaccines encoding NA protein of influenza virus A / Hong Kong / 45 / 2019 (H3N2) in 96-well flat-bottom plate for 24h. IFNa was measured via ELISA. Values derived from individual donors (dots) are depicted for each group with line representing the geometric mean with 95% confidence interval (Cl). Between groups geometrical mean ratios (GMR) are depicted on graphs and statistical significance is indicated by a *(CI not containing 1), ns: nonsignificant.(B) NA-encoding mRNA-LNP vaccines containing pseudouridine or N1- methylpseudouridine induce substantially lower IFNa levels compared to unmodified mRNA-LNP vaccine in mice. Female Balb / c mice (n= 10 / group) were vaccinated with 5pg or 0.71 pg of the mRNA-LNP vaccines. Control animals (n= 5 / group) received 0.9% NaCI solution. 18 h after the immunization serum IFNa levels were determined using ELISA. Each dot represents an individual animal, lines depict the geometric mean with 95% Cl. Between groups geometrical mean ratios (GMR) are depicted on graphs and statistical significance is indicated by a *(CI not containing 1).FIG. 4A-B (A) IFNa release in hPBMCs stimulated with the seasonal influenza 4- and 7- component mRNA vaccine formulations. hPBMC from four donors were incubated each in triplicates with 10 pg / ml of the seasonal influenza 4- component (4HA; unmodified, ip and N1-mip) and 7-component (4HA+3NA; unmodified, ip and N1-mip) mRNA-LNP vaccines in 96-well flat-bottom plate for 24h. IFNa was measured via ELISA in cell-free supernatants. Values derived from individual donors (dots) are depicted for each group with line representing the geometric mean (GM) with 95% Cl. Between groups geometrical mean ratios (GMR) are depicted on graphs and statistical significance is indicated by a *( Cl not containing 1).(B) Seasonal influenza 4- and 7-component mRNA vaccines containing modified (ip and N1-mip) nucleosides induce substantially lower IFNa levels compared to unmodified mRNA vaccines in mice. Female Balb / c mice (n= 10 / group) were vaccinated with 0.56 pg or 2.84 pg of the 4-component (4HA; unmodified, ip and N1-mip) and 1 pg or 2.84 pg of 7-component (4HA+3NA; unmodified, ip and N1-mip) mRNA vaccines. Control animals (n= 5 / group) received 0.9% NaCI solution. IFNa levels were determined using ELISA in serum samples collected 18 h after the first immunization. Each dot represents an individual animal, lines depict the geometric mean (GM) with 95% confidence interval (Cl). Between groups geometrical mean ratios (GMR) are depicted on graphs and statistical significance is indicated by a *(CI not containing 1).FIG. 5A-D HI titers induced by the 4- or 7-component seasonal influenza mRNA vaccines containing unmodified or modified (ip and N1-mip) nucleosides. Female Balb / c mice (n= 10 / group) were vaccinated with 0.56 pg or 2.84 pg of the 4-component (4HA; unmodified, ip and N1-mip) and 1 pg or 2.84 pg of 7-component (4HA+3NA; unmodified, ip and N1-mip) mRNA-LNP vaccines. Control animals (n= 5 / group) received either 0.9% NaCI solution or one tenth of the human doseof the licensed QIVs FLUARIX or FLUZONE High-Dose. HI titers against influenza A / Wisconsin / 588 / 2019 (H1 N1 pdmO9) (A),A / Cambodia / e0826360 / 2020 (H3N2) (B), B / Washington / 02 / 2019 (C) and B / Phuket / 3073 / 2013 (D) were measured in serum of the mice two weeks post second immunization. Each dot represents an individual animal, lines depict the geometric mean titer (GMT) with 95% confidence interval (Cl). Between groups geometrical mean ratios (GMR) are depicted on graphs and statistical significance is indicated by a *(CI not containing 1). The dashed line indicates the HI titer= 40 defined as a surrogate correlate of protection.FIG. 6A-C Nl titers induced by the 7-component seasonal influenza mRNA vaccines containing unmodified or modified (ip and N1-mip) nucleosides. Female Balb / c mice (n= 10 / group) were vaccinated with 1 pg or 2.84 pg of 7-component (4HA+3NA; unmodified, ip and N1-mip) mRNA vaccines. Control animals (n= 5 / group) received either 0.9% NaCI solution or one tenth of the human dose of the licensed QIVs FLUARIX or FLUZONE High-Dose. Nl titers against influenza A / Wisconsin / 588 / 2019 (H1 N1pdmO9) (A), A / Cambodia / e0826360 / 2020 (H3N2) (B), B / Washington / 02 / 2019 (C) were measured in serum two weeks post second immunization. Each dot represents an individual animal, lines show the geometrical mean titer (GMT) with 95% confidence interval (Cl).FIG. 7A-B 4-component and 7-component seasonal influenza mRNA vaccines induced T cell immune responses after i.m. immunization of mice. Female Balb / c mice (n= 8 / group) were vaccinated i.m. twice on day 0 and 21 with 1.25, 2.5, 5, or 10pg of the 4-component (4HA) or 7-component (4HA+3NA) Flu Seasonal mRNA vaccines. Control animals received physiological saline (NaCI) (n= 5 / group) or one tenth of the human dose of the licensed split-inactivated QIVs FLUARIX (= 6pg) or FLUZONE HD (= 24pg) (n= 8 / group) via i.m. route twice on day 0 and 21. T cell immune responses were analyzed two weeks post second immunization by intracellular cytokine staining in isolated splenocytes restimulated with 15-mer overlapping peptide libraries spanning the full-length HA or NA proteins of influenza A / Wisconsin / 588 / 2019 (H1 N1pdmO9). HA-specific IFNy+TNF+ CD4+ T cells (A) and CD8+ T cells (B) were measured. Each dot represents an individual animal, lines depict the geometrical mean (GM) with 95% confidence interval (Cl). Between groups geometrical mean ratio (GMR) are depicted on graphs and statistical significance is indicated by a * (Cl not containing 1).FIG. 8A-B 4-component and 7-component seasonal influenza mRNA vaccines induced T cell immune responses after i.m. immunization of mice. Female Balb / c mice (n= 8 / group) were vaccinated i.m. twice on day 0 and 21 with 1.25, 2.5, 5, or 1Opg of the 4-component (4HA) or 7-component (4HA+3NA) Flu Seasonal mRNA vaccines. Control animals received physiological saline (NaCI) (n= 5 / group) or one tenth of the human dose of the licensed split-inactivated QIVs FLUARIX (= 6pg) or FLUZONE HD (= 24pg) (n= 8 / group) via i.m. route twice on day 0 and 21. T cell immune responses were analyzed two weeks post second immunization by intracellular cytokine staining in isolated splenocytes restimulated with 15-mer overlapping peptide libraries spanning the full-length HA or NA proteins of influenza A / Wisconsin / 588 / 2019 (H1 N1pdmO9). NA-specific IFNy+TNF+ CD4+(A) T cells and CD8+ T cells (B) were measured. Each dot represents an individual animal, lines depict the geometrical mean (GM) with 95% confidence interval (Cl). Between groups geometrical mean ratio (GMR) are depicted on graphs and statistical significance is indicated by a * (Cl not containing 1).FIG. 9A-D Unmodified and modified 7-component seasonal influenza mRNA vaccines induced HI responses in naive ferrets. Female ferrets (n= 6 / group) were immunized twice by IM route on day 0 and day 28 with 3 pg or 12.5 pg of the 7- component mRNA vaccine containing unmodified nucleosides or 12.5 pg or 50 pg of the 7-component mRNA vaccine containing modified nucleosides (N1mi ). Two groups were immunized twice by IM route on day 0 and day 28 with full human dose of the licensed split-inactivated QIVs, FLUARIX or FLUZONE HD. Animals in the negative control group were injected with physiological saline twice by IM route on day 0 and day 28. HI titers against influenza A / Wisconsin / 588 / 2019 (H1 N1 pdmO9) (A), A / Cambodia / e0826360 / 2020 (B), B / Washington / 02 / 2019 (C), and B / Phuket / 3073 / 2013 (D) were measured in serum of vaccinated ferrets four weeks post second immunization. Each dot represents an individual animal, lines depict the geometrical mean with 95% confidence interval (Cl). Between groups geometrical mean ratio (GMR) are depicted on graphs and statistical significance is indicated by a * (Cl not containing 1). The dashed line indicates the HI titer = 40 defined as a surrogate correlate of protection.FIG.10A-C Unmodified and modified 7-component seasonal influenza mRNA vaccines induced Nl responses in naive ferrets. Female ferrets (n= 6 / group) were immunized twice by IM route on day 0 and day 28 with 3 pg or 12.5 pg of the 7-component mRNA vaccine containing unmodified nucleosides or 12.5 pg or 50 pg of the 7-component mRNA vaccine containing modified nucleosides (N1mi ). Two groups were immunized twice by IM route on day 0 and day 28 with full human dose of the licensed split-inactivated QIVs, FLUARIX or FLUZONE HD. Animals in the negative control group were injected with physiological saline twice by IM route on day 0 and day 28. Nl titers against influenza A / Wisconsin / 588 / 2019 (H1 N1 pdmO9) (A), A / Cambodia / e0826360 / 2020 (B) and B / Washington / 02 / 2019 (C) were measured using the ELLA in serum of vaccinated ferrets four weeks post second immunization. Each dot represents an individual animal, lines depict the geometrical mean with 95% confidence interval (Cl). Between groups geometrical mean ratio (GMR) are depicted on graphs and statistical significance is indicated by a * (Cl not containing 1).FIG. 11 A-D HI responses induced upon i.m. immunization of naive ferrets with 4-component and 8-component seasonal influenza mRNA vaccine formulations. Female ferrets were immunized via i.m. route on Day 0 and 28 with 12.5pg and 25pg of the 4-component and 25pg and 50pg of the 8-component Flu Seasonal N1 mi mRNA vaccines (n=6). Control animals received either 0.9% NaCI solution (n= 6 / group) or full human dose of the licensed split-inactivated QIV FLUARIX (NH22-23) (n= 6 / group) via i.m. route on Day 0 and 28. HI titers against influenza A / Wisconsin / 588 / 2019 (H1 N1pdmO9) (A) , A / Darwin / 6 / 2021 (H3N2) (B), B / Austria / 1359417 / 2021 (C) and B / Phuket / 3073 / 2013 (D) were measured in serum of vaccinated animals collected on Day 55. Each dot represents an individual animal, lines depict the geometrical mean (GM) with 95% confidence interval (Cl). Between groups geometrical mean ratio (GMR) are depicted on graphs and statistical significance is indicated by a *(GMR > 3, confidence interval (Cl) not containing 1). The dashed line indicates the HI titer of 40 defined as a surrogate correlate of protection.FIG. 12A-D MN titers induced upon i.m. immunization of naive ferrets with 4-component and 8-component seasonal influenza mRNA vaccine formulations. Female ferrets were immunized via i.m. route on Day 0 and 28 with 12.5pg and 25pg of the 4- component and 25pg and 50pg of the 8-component Flu Seasonal N1mi mRNA vaccines (n=6). Control animals received either 0.9% NaCI solution (n= 6 / group) or full human dose of the licensed split-inactivated QIV FLUARIX (NH22-23) (n= 6 / group) via i.m. route on Day 0 and 28. MN titers against influenza A / Wisconsin / 588 / 2019 (H1 N1 pdmO9) (A), A / Darwin / 6 / 2021 (H3N2) (B), B / Austria / 1359417 / 2021 (C) and B / Phuket / 3073 / 2013 (D) were measured inserum of vaccinated animals collected on Day 55. Each dot represents an individual animal, lines depict the geometrical mean (GM) with 95% confidence interval (Cl). Between groups geometrical mean ratio (GMR) are depicted on graphs and statistical significance is indicated by a *(GMR > 3, confidence interval (Cl) not containing 1).FIG. 13A-D Nl titers induced upon i.m. immunization of naive ferrets with 8-component seasonal influenza mRNA vaccine formulations. Female ferrets were immunized via i.m. route on Day 0 and 28 with 25pg and 50pg of the 8- component Flu Seasonal N1mi mRNA vaccines (n=6). Control animals received either 0.9% NaCI solution (n= 6 / group) or full human dose of the licensed split-inactivated QIV FLUARIX (NH22-23) (n= 6 / group) via i.m. route on Day 0 and 28. Nl titers against influenza A / Wisconsin / 588 / 2019 (H1 N1pdmO9) (A), A / Darwin / 6 / 2021 (H3N2) (B), B / Austria / 1359417 / 2021 (C) and B / Phuket / 3073 / 2013 (D) were measured in serum of vaccinated animals collected on Day 55. Each dot represents an individual animal, lines depict the geometrical mean (GM) with 95% confidence interval (Cl). Between groups geometrical mean ratio (GMR) are depicted on graphs and statistical significance is indicated by a *(GMR > 3, confidence interval (Cl) not containing 1).FIG. 14A-D Viral load in the respiratory tissues post influenza A / Victoria / 2570 / 2019 (H1 N1pdmO9) challenge in ferrets. Female ferrets (n= 6 / group) were immunized twice by IM route on day 0 and day 28 with 3 pg or 12.5 pg of the 7-component seasonal influenza mRNA vaccine containing unmodified nucleosides or 12.5 pg or 50 pg of the 7-component mRNA vaccine containing modified nucleosides (N1 mi ). Two groups were immunized twice by IM route on day 0 and day 28 with full human dose of the licensed split-inactivated QIVs, FLUARIX or FLUZONE HD. Animals in the negative control group were injected with physiological saline twice by IM route on day 0 and day 28. Four weeks after the last immunization the ferrets were challenged with 10A5 TCID50 of wild type influenza virus A / Victoria / 2570 / 2019 (H1 N1pdmO9) (via the intratracheal and intranasal route) and euthanized 4 days post challenge infection. Titration of lung tissue (A) and nasal turbinates (B) samples collected on day 4 post challenge with A / Victoria / 2570 / 2019 (H1 N1 pdmO9). Individual titers are shown by group with group mean indicated by solid black line. The lower limit of detection (LLOD) for the assay is dependent on the tissue sample weight and the LLOD range is indicated by the dashed lines.Severity of bronchiolitis (C) and alveolitis (D) averaged per group (inflammatory changes in the pulmonary parenchyma of animals). For each animal and lung section four tissues slides were evaluated and each dot represents the mean of an individual animal, lines depict the mean of the particular group with 95% confidence intervals (Cis). Between groups difference are depicted on graphs and statistical significance is indicated by a *.FIG. 15A-B Viral load in the respiratory tissues post influenza A / Victoria / 2570 / 2019 (H1 N1pdmO9) challenge in ferrets. Female ferrets were immunized via i.m. route on Day 0 and 28 with 25pg and 50pg of the 8-component seasonal influenza N1 mi mRNA vaccines (n=6). Control animals received either 0.9% NaCI solution (n= 6 / group) or full human dose of the licensed split-inactivated QIV FLUARIX (NH22-23) (n= 6 / group) via i.m. route on Day 0 and 28. Four weeks after the last immunization the ferrets were challenged with 10A5 TCID50 of wild type influenza virus A / Victoria / 2570 / 2019 (H1 N1pdmO9) (via the intratracheal and intranasal route) and euthanized 4 days post challenge infection. Titration of lung tissue (A) and nasal turbinates (B) samples collected on day 4 post challenge with A / Victoria / 2570 / 2019 (H1 N1 pdmO9). Individual titers are shown by group with group mean indicated by solid black line. The lower limit of detection (LLOD) for the assay is dependent on the tissue sample weight and the LLOD range is indicated by the dashed lines.FIG. 16A-C Body temperature changes post influenza A / Victoria / 2570 / 2019 (H1 N1pdmO9) challenge in ferrets. Female ferrets were immunized via i.m. route on Day 0 and 28 with 25pg and 50pg of the 4- (A) and 8-component (B) seasonal influenza N1mi mRNA vaccines (n=6). Control animals received either 0.9% NaCI solution (n= 6 / group) or full human dose of the licensed split-inactivated QIV FLUARIX (NH22-23) (n= 6 / group) via i.m. route on Day 0 and 28 (C). Four weeks after the last immunization the ferrets were challenged with 10A5 TCID50 of wild type influenza virus A / Victoria / 2570 / 2019 (H1 N1pdmO9) (via the intratracheal and intranasal route). Mean body temperature change (in °C) from day 0 to day 4 post challenge relative to baseline is shown per group.FIG. 17A-F Virus titration of throat swabs (A-C) and nose swabs (D-F) Day 0 (pre-challenge) to Day 4 post challenge with influenza A / Victoria / 2570 / 2019 (H1 N1pdmO9). Female ferrets were immunized via i.m. route on Day 0 and 28 with 25pg and 50pg of the 8-component seasonal influenza N1mi mRNA vaccines (n=6). Control animals received either 0.9% NaCI solution (n= 6 / group) or full human dose of the licensed split-inactivated QIV FLUARIX (NH22-23) (n= 6 / group) viai.m. route on Day 0 and 28. Four weeks after the last immunization the ferrets were challenged with 10A5 TCID50 of wild type influenza virus A / Victoria / 2570 / 2019 (H1 N1pdmO9) (via the intratracheal and intranasal route). Individual values are shown by group with group mean indicated by a solid black line. The lower limit of detection (LLOD) for the assay is indicated by a dashed line.FIG. 18A-D Ferrets immunized with 4- and 8-component seasonal influenza mRNA vaccines show reduced macroscopic and microscopic pathological changes in the lungs. Female ferrets were immunized via i.m. route on Day 0 and 28 with 25pg and 50pg of the 8-component seasonal influenza N1mi mRNA vaccines (n=6). Control animals received either 0.9% NaCI solution (n= 6 / group) or full human dose of the licensed split-inactivated QIV FLUARIX (NH22-23) (n= 6 / group) via i.m. route on Day 0 and 28. Four weeks after the last immunization the ferrets were challenged with 10A5 TCID50 of wild type influenza virus A / Victoria / 2570 / 2019 (H1 N1pdmO9) (via the intratracheal and intranasal route).(A) Relative lung weight on day 4 post challenge with influenza A / Victoria / 2570 / 2019 (H1 N1pdmO9) virus in ferrets. Relative lung weights (RLW) reflect the extent and severity of lung lesions since inflamed and / or infiltrated lungs are usually heavier than unaffected lungs. In general RLWs < 1 are recorded in healthy or slightly pneumonic ferrets. Individual percentage is shown by group with group mean ± SD indicated. A dashed line indicates relative lung weight of 1 .(B) Percentage affected lung tissue on day 4 post challenge. Macroscopic lung lesion consisted of pulmonary consolidation, characterized by reddening and slightly increased firmness of the lung parenchyma. The extent of pulmonary consolidation was assessed based on visual estimation of the percentage of affected lung. Individual percentage of observed affected lung tissue is shown by group with group mean ± SD indicated.Severity score of conductive system inflammation (C) and of lung inflammation (D) averaged per group. Individual score are shown per group with group mean indicated by a solid black line.FIG. 19A-D 4-component or 7-component seasonal influenza mRNA vaccines induced HI responses against several heterologous influenza strains upon i.m. immunization in mice. Female Balb / c mice (n= 8 / group) were vaccinated i.m. twice on day 0 and 21 with 1.25 or 10pg of the 4-component (4HA) or 7- component (4HA+3NA) Flu Seasonal mRNA vaccines. Control animalsreceived physiological saline (NaCI) (n= 5 / group) or one tenth of the human dose of the licensed split-inactivated QIVs FLUARIX (= 6pg) or FLUZONE HD (= 24pg) (n= 8 / group) via i.m. route twice on day 0 and 21. HI titers induced by 1.25pg and 10pg of the Flu Seasonal mRNA vaccines as well as FLUARIX and FLUZONE HD against influenza A / California / 7 / 2009 (H1 N1 pdmO9) (A), A / Hong Kong / 2671 / 2019 (H3N2) (B), B / Darwin / 7 / 2019 (C) andA / Brisbane / 02 / 2018(H1 N1 pdm09) (D) were measured in serum collected two weeks post second immunization. Each dot represents an individual animal, lines depict the geometrical mean (GM) with 95% confidence interval (Cl). Between groups geometrical mean ratio (GMR) are depicted on graphs and statistical significance is indicated by a *(CI not containing 1). The dashed line indicates the HI titer = 40 defined as a surrogate correlate of protection.FIG. 20A-B 4-component or 7-component seasonal influenza mRNA vaccines induced broad heterologous and heterosubtypic HA-binding antibodies upon i.m. immunization in mice. Female Balb / c mice (n= 8 / group) were vaccinated i.m. twice on day 0 and 21 with 1.25 or 10pg of the 4-component (4HA) or 7- component (4HA+3NA) Flu Seasonal mRNA vaccines. Control animals received physiological saline (NaCI) (n= 5 / group) or one tenth of the human dose of the licensed split-inactivated QIVs FLUARIX (= 6pg) or FLUZONE HD (= 24pg) (n= 8 / group) via i.m. route twice on day 0 and 21. HA-specific antibodies were measured in serum of vaccinated animals two weeks post second immunization using multiplex HA-binding assays including recombinant HA proteins from four H1 , one H2, one H5, six H3, one H7, one H10 (A) , two Yamagata and eight Victoria strains (B). For each panel, a heatmap displayed gray scale as function of intensity of response across vaccinated groups (dark gray=highest response, light gray=lowest response).FIG. 21A-F 7-component seasonal influenza mRNA vaccine induced heterologous and heterosubtypic Nl responses upon i.m. immunization in mice. Female Balb / c mice (n= 8 / group) were vaccinated i.m. twice on day 0 and 21 with 1.25 or 10pg of the 4-component (4HA) or 7-component (4HA+3NA) Flu Seasonal mRNA vaccines. Control animals received physiological saline (NaCI) (n= 5 / group) or one tenth of the human dose of the licensed split-inactivated QIVs FLUARIX (= 6pg) or FLUZONE HD (= 24pg) (n= 8 / group) via i.m. route twice on day 0 and 21. Nl titers against the NA of influenza A / California / 7 / 2009 (H1 N1pdmO9) (A), A / Brevig Mission / 1 / 1918 (H1 N1) (B), A / Washington / 01 / 2007 (H3N2) (C), B / Brisbane / 60 / 2008 (D), A / Vietnam / 1194 / 2004 (H5N1) (E) andB / Phuket / 3073 / 2013 (F) were analyzed using the enzyme-linked lectin assay (ELLA) in the serum of vaccinated mice collected two weeks post second immunization. Each dot represents an individual animal, lines depict the geometrical mean (GM) with 95% confidence interval (Cl). Between groups geometrical mean ratio (GMR) are depicted on graphs and statistical significance is indicated by a * (Cl not containing 1). LLOQ= lower limit of quantification, ULOQ= upper limit of quantification.FIG. 22A-E Heterologous HI responses induced upon i.m. immunization of naive ferrets with 4-component and 8-component Flu Seasonal mRNA vaccine formulations. Female ferrets were immunized via i.m. route on Day 0 and 28 with 12.5pg and 25pg of the 4-component and 25pg and 50pg of the 8-component Flu Seasonal N1mi mRNA vaccines (n=6). Control animals received either 0.9% NaCI solution (n= 6 / group) or full human dose of the licensed split-inactivated QIV FLUARIX (NH22-23) (n= 6 / group) via i.m. route on Day 0 and 28. HI titers against influenza A / Brisbane / 02 / 2018 (A), A / California / 07 / 2009 (B), A / South Australia / 34 / 2019 (C), B / Darwin / 7 / 2019 (D) and A / Hong Kong / 45 / 2019 (E) were measured in serum of vaccinated animals collected on Day 55. Each dot represents an individual animal, lines depict the geometrical mean (GM) with 95% confidence interval (Cl). Between groups geometrical mean ratio (GMR) are depicted on graphs and statistical significance is indicated by a *(GMR > 3, confidence interval (Cl) not containing 1). The dashed line indicates the HI titer of 40 defined as a surrogate correlate of protection.FIG. 23A-G Heterologous Nl responses induced upon i.m. immunization of naive ferrets with 8-component Flu Seasonal mRNA vaccine formulations. Female ferrets were immunized via i.m. route on Day 0 and 28 with 25pg and 50pg of the 8- component Flu Seasonal N1mi mRNA vaccines (n=6). Control animals received either 0.9% NaCI buffer (n= 6 / group) or full human dose of the licensed split-inactivated QIV FLUARIX (NH22-23) (n= 6 / group) via i.m. route on Day 0 and 28. Nl titers against NA of influenza A / California / 07 / 2009 (A), A / Brevig Mission / 1 / 1918 (B), A / Vietnam / 1194 / 2004 (C), A / Cambodia / e0826360 / 2020 (D), A / Washington / 01 / 2007 (E), B / Brisbane / 60 / 2008 (F) and B / Washington / 02 / 2019 (G) were measured in serum of vaccinated animals collected on Day 55. Each dot represents an individual animal, lines depict the geometrical mean (GM) with 95% confidence interval (Cl). Between groups geometrical mean ratio (GMR) are depicted on graphs and statistical significance is indicated by a *(GMR > 3, confidence interval (Cl) not containing1). The dashed line indicates the Nl titer of 40 defined as a surrogate correlate of protection.FIG. 24A-C Reactogenicity assessment of subjects in the CVSQIV Phase I influenza vaccination trial. FIG. 24A, Solicited Adverse Events in subjects at the indicated mRNA dose levels shown at the bottom of the chart. FIG. 24B, Solicited Adverse Events in subjects at the indicated mRNA dose levels separated between younger and older adults. FIG. 24A-B, Grade 0 events at the bottom of the chart above the dose level indication and percentages for increasing grade events arranged vertically. FIG. 24C, Solicited Adverse Events in subjects at the indicated mRNA dose levels separated for younger and older adults and separated between local and systemic events. Grade 0-1 events at the bottom of the chart above the dose level indication. The percentages for Grade 0-1 versus Grade > 2 are shown.FIG. 25A-H Graphs show the Geometric Mean Titer (95% Cl) for Hemagglutinin Inhibition Assay (HAI) Assay. FIG. 25A, C, E and G show the HAI titers for all subjects at Day 1 , Day 22 and Day 183 at the indicated vaccine mRNA dose levels. Data in FIG. 25B, D, F and H are separated between younger adults (YA) and older adults (OA) at the indicated mRNA dose levels. Data are shown separately for each of the HA components encoded by the vaccine mRNA: H1 N1 (FIG. 25A- B); H3N2 (FIG. 25C-D); B / Phuket (FIG. 25E-F); and B / Washington (FIG. 25G- H).FIG. 26 Seroconversion rates (SCR) from HAI assay. The table in upper-left panel shows SCR (is defined as <1 :10 pre-vaccination titers, the post-vaccination titers should be >1 :40; if >1 :10 pre-vaccination titers, the post-vaccination titers should be > four-fold increase from baseline). Data are shown for each encoded HA, at each dose level and either for all subjects or separated between younger and older adults. The graph in the lower left panel shows overall SCR for each encoded HA, at each dose level. The graph in the upper right panel shows SCR for each encoded HA, at each dose level, in younger adults. The graph in the lower right panel shows SCR for each encoded HA, at each dose level, in older adults.FIG. 27 Shows the percentage of study subjects that exhibited a > four-fold increase in anti-HA titer by microneutralization (MN) assay. The table in upper-left panel shows the percentage of subjects with > four-fold increase in anti-HA titer by MN assay. Data are shown for each encoded HA, at each dose level, and eitherfor all subjects or separated between younger and older adults. The graph in the lower left panel shows overall 4-fold anti-HA increase by MN assay for each encoded HA, at each dose level. The graph in the upper right panel shows 4- fold anti-HA increase by MN assay for each encoded HA, at each dose level, in younger adults. The graph in the lower right panel shows 4-fold anti-HA increase by MN assay for each encoded HA, at each dose level, in older adults.FIG. 28 Shows the percentage of study subjects that exhibited a > four-fold increase in anti-NA titer by enzyme linked lectin assay (ELLA) assay. The table in upperleft panel shows the percentage of subjects with > four-fold increase anti-NA titer by ELLA assay. Data are shown for each encoded NA, at each dose level, and either for all subjects or separated between younger and older adults. The graph in the lower left panel shows overall 4-fold anti-NA increase by ELLA assay for each encoded NA, at each dose level. The graph in the upper right panel shows 4-fold anti-NA increase by ELLA assay for each encoded NA, at each dose level, in younger adults. The graph in the lower right panel shows 4- fold anti-NA increase by ELLA assay for each encoded NA, at each dose level, in older adults.FIG. 29A-D Shows HI titers induced upon immunization of human healthy adults (18-50 years old) with 1- component, 4-component and 8-component Flu Seasonal mRNA vaccine formulations. The control is a Flu D-QIV (FLUARIX, NH 2022- 23). HI titers against influenza A / Victoria / 2570 / 2019 (H1 N1pdmO9) (A), A / Darwin / 6 / 2021 (H3N2) (B), B / Connecticut / 01 / 2021 (C) andB / Phuket / 3073 / 2013 (D) were measured on Day 29.FIG. 30A-D Shows Nl titers induced upon immunization of human healthy adults (18-50 years old) with 1- component, 4-component and 8-component Flu Seasonal mRNA vaccine formulations. The control is a Flu D-QIV (FLUARIX, NH 2022- 23). Nl titers against influenza A / Wisconsin / 588 / 2019 (H1 N1pdmO9) (A), Flu A / Cambodia / e0826360 / 2020 (H3N2) (B), Flu B / Austria / 1359417 / 2021 (C) and B / Phuket / 3073 / 2013 (D) were measured on Day 29.FIG. 31A-D Shows the percentage of human healthy adults (18-50 years old) with solicited events (any; A), local events (B) and systemic events (C) within 7 days of immunization with 1- component, 4-component and 8-component Flu Seasonal mRNA vaccine formulations. The control is a Flu D-QIV (FLUARIX, NH 2022- 23). (D) shows the overall summary by event including grade 3 events.FIG. 32 Shows the percentage of human healthy adults (18-50 years old) with related unsolicited events within 7 days of immunization with 1- component, 4- component and 8-component Flu Seasonal mRNA vaccine formulations. The control is a Flu D-QIV (FLUARIX, NH 2022-23).DETAILED DESCRIPTION OF THE INVENTIONThe present application is filed together with a sequence listing in electronic format, which is part of the description (WIPO standard ST.26). The information contained in the sequence listing is incorporated herein by reference in its entirety. Where reference is made herein to a “SEQ ID NO”, the corresponding nucleic acid (n.a.) 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 (NCBI) or GISAID (epi) identifiers, or additional detailed information regarding its coding capacity. Where reference is made to “SEQ ID NOs” of other published patent applications or patents, said sequences, e.g. amino acid sequences or nucleic acid sequences, are explicitly incorporated herein by reference. Accordingly, these sequences constitute an integral part of the underlying description.Immunogenic composition:Protective immune responses induced by vaccination against Influenza viruses are primarily directed to the viral HA protein, which is a glycoprotein on the surface of the virus responsible for interaction of the virus with host cell receptors.HA proteins on the virus surface are homotrimers of HA protein monomers that are enzymatically cleaved to yield amino-terminal HA1 and carboxy-terminal HA2 polypeptides. Structurally, hemagglutinin proteins are comprised of several domains: a globular head domain, a stalk domain (also referred to as a stem domain), a transmembrane domain, and a cytoplasmic domain (see FIG. 1 , Russell et al., 2021).It is generally thought that during infection of a host cell (e.g., a eukaryotic cell such as a human cell) with an Influenza virus, the hemagglutinin protein recognizes and binds to sialic acid of a receptor on the surface of a host cell facilitating attachment of the virus to the host cell. Following endocytosis of the virus and acidification of the endosome, the hemagglutinin protein undergoes a pH-dependent conformational change that allows for the hemagglutinin protein to facilitate fusion of the viral envelope with the endosome membrane of host cell and entry of the viral nucleic acid into the host cell.The globular head consists exclusively of the major portion of the HA1 polypeptide, whereas the stem that anchors the HA protein into the viral lipid envelope is comprised of HA2 and part of HA1 . The globular head of a HA protein includes two domains: the receptor binding domain (RBD), a domain that includes the sialic acid-binding site, and the vestigial esterase domain, a smaller region just below the RBD. In general, Influenza viruses are classified based on the amino acid sequences of the viral hemagglutinin protein and / or the amino acid sequence of the viral neuraminidase (NA). The differences in amino acid sequence between HA proteins of different subtypes are largely found within the sequence of the head domain of the protein. The amino acid sequence of the stalk domain is considered to be more conserved between HA subtypes compared to sequences of the head domain. Domains of the HA protein may be predicted using conventional methods known in the art.Many naturally occurring and experimentally derived antibodies that bind and neutralize the HA protein are thought to bind epitopes within the head domain of HA and prevent or reduce interaction of HA with sialic acid on receptors of host cells, thereby preventing or reducing infection of the cell. Alternatively, or in addition, neutralizing antibodies may prevent or reduce fusion of the virus membrane with the membrane of the endosome. Such antibodies may bind epitopes within the stalk domain, thereby inhibiting the conformations change of the protein. Antibodies against Influenza mainly target variable antigenic sites in the globular head of HA and thus, neutralize only antigenically closely related viruses. Current trivalent and quadrivalent influenza vaccines elicit antibody responses to the vaccine strains (e.g. homologous immune response) or to closely related isolates, but rarely extend to more diverged strains within a subtype / lineage (e.g. heterologous or intrasubtypic immune response) or to strains belonging to different subtypes / lineages (e.g. heterosubtypic immune response).The inventors overcame the drawbacks of the prior art by providing an immunogenic composition for use in the treatment or prophylaxis of an infection with an Influenza virus, wherein the immunogenic composition comprises:(a) a first nucleic acid encoding a hemagglutinin (HA) antigen of a strain of a first subtype of Influenza A virus;(b) a second nucleic acid encoding a HA antigen of a strain of a second subtype of Influenza A virus;(c) a third nucleic acid encoding a HA antigen of a first strain of Influenza B virus; and(d) optionally, a fourth nucleic acid encoding a HA antigen of a second strain of Influenza B virus, wherein an immune response is elicited against HA antigens of said strains of first and second subtypes of Influenza A virus, said first and, optionally, second strains of Influenza B virus andat least one further HA antigen subtype of Influenza A virus, being different from any of the HA antigen subtypes of Influenza A virus encoded by a nucleic acid present in the composition.It has been found that the immunogenic compositions for use according to the invention induce a broad, rapid, and robust cross-reactive immune response against Influenza virus, such as Influenza A and / or B.In particular, or in addition, it has been found that the immunogenic compositions for use according to the invention induce a broad, rapid, and robust homologous, heterologous and heterosubtypic immune response against Influenza virus, such as Influenza A and / or B.In particular, or in addition, it has been found that the immunogenic compositions for use according to the invention elicit antibody responses to the vaccine strains and to closely related strains, but also to further strains belonging either to the same or to a different subtype / lineage.In particular, or in addition, it has been found that the immunogenic compositions for use according to the invention elicit antibody responses to Influenza virus strains that are antigenically distinct from the vaccine strains.In particular, or in addition, it has been found that the immunogenic compositions for use according to the invention elicit antibody responses to Influenza virus strains being different from any of the strains having an HA encoded by an mRNA present in the composition.In particular, or in addition, it has been found that the immunogenic compositions for use according to the invention elicit antibody responses to Influenza viruses with a different geographical origin and / or year of isolation than any of the strains having an HA and / or NA encoded by an mRNA present in the composition.In particular, or in addition, it has been found that the immunogenic compositions for use according to the invention elicit antibody responses to HA antigen subtype of Influenza A virus, being different from any of the HA antigen subtypes of Influenza A virus encoded by a nucleic acid present in the composition.In particular, or in addition, it has been found that the immunogenic compositions for use according to the invention elicit antibody responses to HA antigen subtype of Influenza A virus, being different from any of the HA antigen of a strain of Influenza B virus, being different from any of the HA antigens of a strain of Influenza B virus encoded by a nucleic acid present in the composition.In particular, or in addition, it has been found that the immunogenic compositions for use according to the invention induce cross-reactive binding and functional anti-HA responses.In particular, or in addition, it has been found that the immunogenic compositions for use according to the invention protect individuals from strains of Influenza virus that are not present in the immunogenic composition.In particular, or in addition, it has been found that the immunogenic compositions for use according to the invention protect individuals from homologous, heterologous and heterosubtypic strains of influenza virus.Suitably, the immunogenic compositions for use according to the invention have at least some of the following advantageous features:T ranslation of the first, second, third and fourth nucleic acid, suitably mRNAs, at the site of injection / vaccination (e.g. muscle);Induction of immune responses at a low dosage and / or dosing regimen;Suitability for vaccination of infants and / or newborns or the elderly, in particular the elderly;Suitability of the composition / vaccine for intramuscular administration;Fast onset of immune protection against Influenza virus, suitably Influenza A virus and / or Influenza B virus;Longevity of the induced immune responses against Influenza virus, suitably Influenza A virus and / or Influenza B virus;No enhancement of a virus infection (e.g. Influenza virus infection) due to vaccination or immunopathological effects;No antibody dependent enhancement (ADE) caused by the nucleic acid-based composition / vaccine;No excessive induction of systemic cytokine or chemokine response after application of the composition / vaccine, which could lead to an undesired high reactogenicity upon injection / vaccination;Well tolerability, no side-effects, non-toxicity of the composition / vaccine;Advantageous stability characteristics of the nucleic acid-based composition / vaccine;Speed, adaptability, simplicity and scalability of the nucleic acid-based composition / vaccine production;Advantageous injection / vaccination regimen that only requires a low dose of the composition / vaccine for sufficient protection.Therefore, in a first aspect, the invention relates to an immunogenic composition for use in the treatment or prophylaxis of an infection with an Influenza virus, wherein the immunogenic composition comprises:(a) a first nucleic acid encoding a hemagglutinin (HA) antigen of a strain of a first subtype of Influenza A virus;(b) a second nucleic acid encoding a HA antigen of a strain of a second subtype of Influenza A virus;(c) a third nucleic acid encoding a HA antigen of a first strain of Influenza B virus; and(d) optionally, a fourth nucleic acid encoding a HA antigen of a second strain of Influenza B virus, wherein an immune response is elicited against HA antigens of said strains of first and second subtypes of Influenza A virus, said first and, optionally, second strains of Influenza B virus and at least one further HA antigen subtype of Influenza A virus, being different from any of the HA antigen subtypes of Influenza A virus encoded by a nucleic acid present in the composition.The terms “hemagglutinin”, “hemagglutinin protein”, and “HA” may be used interchangeably throughout and refer to a hemagglutinin protein that may be present on the surface of an Influenza virus.In some embodiments, said strain of said first subtype of Influenza A virus of (a) and said strain of said second subtype of Influenza A virus of (b) are different.As it is known in the art, Influenza A viruses are divided into subtypes based on the antigenic properties of their hemagglutinin (HA) and neuraminidase (NA) surface proteins. Currently, there are 18 described HA subtypes (e.g. H1 , H2, H3, H4, H5, H6, H7, H8, H9, H10, H11 , H12, H13, H14, H15, H16, H17 and H18 subtypes) and 11 described NA subtypes (N1 , N2, N3, N4, N5, N6, N7, N8, N9, N10 and N11 subtypes) that can form potentially 144 combinations e.g. H1 N1 , H2N2, H3N2, H5N1 , H7N9 or H10N8.In some embodiments, said first strain of Influenza B virus of (c) and said second strain of Influenza B virus of (d) are identical.In some embodiments, (c) and (d) are identical.In some embodiments, said first strain of Influenza B virus of (c) and said second strain of Influenza B virus of (d) are different.In some embodiments, (c) and (d) are different.In some embodiments, said first and / or second subtype of Influenza A virus is selected from influenza A viruses characterized by a HA selected from the group consisting of H1 , H2, H3, H4, H5, H6, H7, H8, H9, H10, H11 , H12, H13, H14, H15, H16, H17 and H18, suitably fromthe group consisting of H1 , H3, H5, H7, H9, and H10, more suitably from the group consisting of H1 and H3.In some embodiments, said first and / or second subtype of Influenza A virus is selected from influenza A viruses characterized by a neuraminidase (NA) selected from the group consisting of N1 , N2, N3, N4, N5, N6, N7, N8, N9, N10, and N11 , suitably selected from the group consisting of N1 , N2, and N8, more suitably selected from the group consisting of N1 and N2.The terms “neuraminidase”, “neuraminidase protein”, and “NA” may be used interchangeably throughout and refer to a neuraminidase protein that may be present on the surface of an Influenza virus.In some embodiments, said first and / or second subtype of Influenza A virus is selected from the group consisting of H1 N1 , H1 N2, H2N2, H3N1 , H3N2, H3N8, H5N1 , H5N2, H5N3, H5N8, H5N9, H7N1 , H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N7 and H10N8, suitably H1 N1 and H3N2.In some embodiments, said first subtype of Influenza A virus is a subtype of Influenza A Group 1 , suitably influenza A subtype H1 , H2, H5, H6, H8, H9, H11 , H12, H13, H16, H17 or H18, more suitably H1.In some embodiments, said first subtype of Influenza A virus is Influenza A H1 N1 subtype.In some embodiments, said second subtype of Influenza A virus is a subtype of Influenza A Group 2, suitably influenza A subtype H3, H4, H7, H10, H14 and H15, more suitably H3.In some embodiments, said second subtype of Influenza A virus is Influenza A H3N2 subtype.In some embodiments, said strain of first and / or second subtype of Influenza A virus is selected from the group consisting of A / Thailand / 8 / 2022 (H3N2)-like virus, A / Massachusetts / 18 / 2022 (H3N2)-like virus, AA / ictoria / 4897 / 2022 (H1 N1)pdmO9-like virus, A / Wisconsin / 67 / 2022 (H1 N1)pdmO9-like virus, A / Sydney / 5 / 2021 (H1 N1)pdmO9-like virus, A / Victoria / 2570 / 2019 (H1 N1)pdmO9-like virus, A / Darwin / 9 / 2021 (H3N2)-like virus, A / Wisconsin / 588 / 2019 (H1 N1)pdmO9-like virus, A / Darwin / 6 / 2021 (H3N2)-like virus, A / Cambodia / e0826360 / 2020 (H3N2)-like virus, A / Guangdong-Maonan / SWL1536 / 2019 (H1 N1)pdmO9-like virus, A / Hong Kong / 2671 / 2019 (H3N2)-like virus, A / Hawaii / 70 / 2019 (H1 N1)pdmO9-like virus, A / Hong Kong / 45 / 2019 (H3N2)-like virus, A / Brisbane / 02 / 2018(H1 N1)pdmO9-like virus, A / Kansas / 14 / 2017 (H3N2)-like virus, A / California / 7 / 2009 (H1 N1)pdmO9-like virus, A / Switzerland / 97] 5293 / 2013 (H3N2)-like virus, A / Hong Kong / 4801 / 2014 (H3N2)-like virus, A / Michigan / 45 / 2015 (H1 N1)pdmO9-like virus, A / Singapore / INFIMH-16-0019 / 2016 (H3N2)-like virus, A / Switzerland / 8060 / 2017 (H3N2)-like virus, A / Brisbane / 02 / 2018 (H1 N1)pdmO9-like virus, A / Kansas / 14 / 2017 (H3N2)-like virus, A / South Austral ia / 34 / 2019 (H3N2)-like virus, A / ldaho / 07 / 2018 (H1 N1)pdmO9-like virus, A / Maine / 38 / 2018 (H1 N1)pdmO9-like virus, A / Nebraska / I S / 2018 (H1 N1)pdmO9-like virus, A / Nebraska / 14 / 2019 (H1 N1)pdmO9-like virus, A / lowa / 33 / 2019 H1 N1)pdmO9-like virus, A / Arkansas / 28 / 2019 H1 N1)pdmO9-like virus, A / Virginia / 41 / 2019 H1 N1)pdmO9-like virus, A / Minnesota / 60 / 2019 H1 N1)pdmO9-like virus, A / Alabama / 27 / 2019 H1 N1)pdmO9-like virus, A / lowa / 60 / 2018 (H3N2)-like virus, A / Jamaica / 60361 / 2019 (H3N2)-like virus, A / Florida / 130 / 2019 (H3N2)-like virus, A / Laos / 1789 / 2019 (H3N2)-like virus, A / Vermont / 25 / 2019 (H3N2)-like virus, A / New Jersey / 34 / 2019 (H3N2)-like virus, A / California / 176 / 2019 (H3N2)-like virus, A / Pennsylvania / 1026 / 2019 (H3N2)-like virus, A / Togo / 634 / 2019 (H3N2)-like virus, A / Kenya / 130 / 2019 (H3N2)-like virus, A / Togo / 1307 / 2019 (H3N2)-like virus, A / Ohio / 30 / 2019 (H3N2)-like virus, A / Guatemala / 93 / 2019 (H3N2)-like virus, A / Guatemala / 10 / 2019 (H3N2)-like virus, and A / Hong Kong / 4801 / 2014 (H3N2)-like virus.In some embodiments, first strain of first subtype of Influenza A virus is a strain of H1 N1 and is selected from the group consisting of A / Victoria / 4897 / 2022 (H1 N1)pdmO9-like virus, A / Wisconsin / 67 / 2022 (H1 N1)pdmO9-like virus, A / Sydney / 5 / 2021 (H1 N1)pdmO9-like virus, A / Beijing / 262 / 95(H1 N1)-like virus, A / New Caledonia / 20 / 99(H1 N1)-like virus, A / Solomon lslands / 3 / 2006 (H1 N1)-like virus, A / Brisbane / 59 / 2007 (H1 N1)-like virus, A / California / 7 / 2009 (H1 N1)-like virus, A / California / 7 / 2009 (H1 N1)pdmO9-like virus, A / Michigan / 45 / 2015 (H1 N1)pdm09-like virus, A / Victoria / 2570 / 2019 (H1 N1)pdmO9-like virus, A / Wisconsin / 588 / 2019 (H1 N1)pdmO9-like virus, A / Guangdong-Maonan / SWL1536 / 2019 (H1 N1)pdmO9-like virus, A / Hawaii / 70 / 2019 (H1 N1)pdmO9-like virus, A / Brisbane / 02 / 2018 (H1 N1)pdmO9-like virus, A / Christchurch / 16 / 2010 and A / South Dakota / 6 / 2007, AA / ictoria / 4897 / 2022 (H1 N1)pdm09-like virus, A / Wisconsin / 67 / 2022 (H1 N1)pdmO9-like virus and A / Sydney / 5 / 2021 (H1 N1)pdmO9-like virus.In some embodiments, said second strain of Influenza A virus is H3N2 and is selected from the group consisting of A / Thailand / 8 / 2022 (H3N2)-like virus, A / Massachusetts / 18 / 2022 (H3N2)-like virus, A / Sydney / 5 / 97(H3N2)-like virus, A / Moscow / 10 / 99(H3N2)-like virus, A / Panama / 2007 / 99, A / Fujian / 411 / 2002(H3N2)-like virus, A / Wyoming / 3 / 2003, A / Kumamoto / 102 / 2002, A / Wellington / 1 / 2004 (H3N2)-like virus, A / California / 7 / 2004 (H3N2)-like virus, A / New York / 55 / 2004, A / Wisconsin / 67 / 2005 (H3N2)-like virus, A / Hiroshima / 52 / 2005, A / Brisbane / 10 / 2007 (H3N2)-like virus, A / Uruguay / 716 / 2007, A / Perth / 16 / 2009 (H3N2)-likevirus, A / Wisconsin / 15 / 2009, A / Victoria / 210 / 2009, AA / ictoria / 361 / 2011 (H3N2)-like virus, A / Ohio / 2 / 2012, A / Maryland / 2 / 2012, A / South Australia / 30 / 2012, A / Brisbane / 1 / 2012, A / Brisbane / 6 / 2012, A(H3N2) virus antigenically like the cell-propagated prototype virus AA / ictoria / 361 / 2011 , A / Texas / 50 / 2012 (H3N2)-like virus, A / Darwin / 9 / 2021 (H3N2)-like virus, A / Darwin / 6 / 2021 (H3N2)-like virus, A / Cambodia / e0826360 / 2020 (H3N2)-like virus, A / HongKong / 2671 / 2019 (H3N2)-like virus, A / Hong Kong / 45 / 2019 (H3N2)-like virus, A / Switzerland / 9715293 / 2013 (H3N2)-like virus, A / South Australia / 55 / 2014, A / Norway / 466 / 2014, A / Stockholm / 6 / 2014, A / Hong Kong / 4801 / 2014 (H3N2)-like virus, A / Singapore / INFIMH- 16-0019 / 2016 (H3N2)-like virus, A / Switzerland / 8060 / 2017 (H3N2)-like virus, A / Kansas / 14 / 2017 (H3N2)-like virus and A / South Australia / 34 / 2019 (H3N2)-like virus.In some embodiments, said strain of said first and / or second subtype of Influenza A virus is selected from an Influenza A virus as listed in Table 1 and / or Table 2.In some embodiments, said strain of said first and / or second subtype of Influenza A virus is selected from an Influenza A virus which is recommended for Influenza virus vaccine composition by the WHO (https: / / www.who.int / teams / global-influenza- programme / vaccines / who-recommendations).Table 1 : Recommended composition of Influenza virus vaccines for use in the 1998- 2025 northern hemisphere influenza seasonTable 2: Recommended composition of Influenza virus vaccines for use in the 1999- 2024 southern hemisphere influenza seasonIn some embodiments, said first strain of Influenza B virus is selected from the group consisting of B / Victoria lineage and B / Yamagata lineage.As it is known in the art, Influenza B viruses are categorized into two distinct lineages: B / Victoria / 2 / 1987-like (B / Victoria lineage) and B / Yamagata / 16 / 1988-like (B / Yamagata lineage) viruses that have been circulating worldwide since 1983. In some embodiments, said first and / or second strain of Influenza B virus is selected from the group consisting of B / Beijing / 184 / 93-like virus, B / Harbin / 94-like virus, B / Shangdong / 7 / 97-like virus, B / Yamanashi / 166 / 98-like virus, B / Sichuan / 379 / 99-like virus, B / Guangdong / 120 / 2000, B / Johannesburg / 5 / 99, B / Victoria / 504 / 2000, B / Hong Kong / 330 / 2001-like virus, B / Hong Kong / 1434 / 2002, B / Brisbane / 32 / 2002, B / Shanghai / 361 / 2002-like virus, B / Jiangsu / 10 / 2003, B / J ilin / 20 / 2003, B / Malaysia / 2506 / 2004-like virus, B / Malaysia / 2506 / 2004 virus, B / Ohio / 1 / 2005, B / Florida / 4 / 2006-like virus, B / Brisbane / 3 / 2007, B / Brisbane / 60 / 2008-like virus, B / Brisbane / 33 / 2008, B / Wisconsin / 1 / 2010-like virus, B / Hubei-Wujiagang / 158 / 2009,B / Texas / 6 / 2011 , B / Massachusetts / 2 / 2012-like virus, B / Phuket / 3073 / 2013-like virus, B / Austria / 1359417 / 2021 -like virus, B / Washington / 02 / 2019-like virus and B / Colorado / 06 / 2017- like virus.In some embodiments, said first strain of Influenza B virus is selected from an Influenza B virus as listed in Table 1 and / or Table 2.In some embodiments, said first strain of Influenza B virus is selected from an Influenza B virus which is recommended for Influenza virus vaccine composition by the WHO (https: / / www.who.int / teams / global-influenza-programme / vaccines / who-recommendations).In some embodiments, said first strain and said second strain of Influenza B are a strain of B / Victoria lineage.In some embodiments, said first strain of Influenza B is a strain of B / Victoria lineage.In some embodiments, said second strain of Influenza B is a strain of B / Yamagata lineage.In some embodiments, said first strain of Influenza B virus is selected from the group consisting of B / Austria / 1359417 / 2021 (B / Victoria lineage)-like virus, B / Washington / 02 / 2019 (B / Victoria lineage)-like virus, B / Colorado / 06 / 2017-like virus (B / Victoria / 2 / 87 lineage), B / Brisbane / 60 / 2008-like virus and B / Colorado / 06 / 2019 (B / Victoria lineage)-like virus.In some embodiments, said first subtype of Influenza A virus is of Influenza A H1 N1 , said second subtype of Influenza A virus is of influenza A H3N2, said first strain of Influenza B virus is of Influenza B / Victoria lineage.In some embodiments, the immunogenic composition further comprises:(d) said fourth nucleic acid encoding a HA antigen of a second strain of Influenza B virus, wherein an immune response is further elicited against said HA antigen of said second strain of Influenza B virus.In some embodiments, said first strain of Influenza B virus of (c) and said second strain of Influenza B virus of (d) are identical.In some embodiments, said first and second strains of Influenza B are a strain of B / Victoria lineage.In some embodiments, (c) and (d) are identical.In some embodiments, said first strain of Influenza B virus of (c) and said second strain of Influenza B virus of (d) are different.In some embodiments, said first strain of Influenza B is a strain of B / Victoria lineage.In some embodiments, said second strain of Influenza B is a strain of B / Yamagata lineage.In some embodiments, (c) and (d) are different.In some embodiments, said second strain of Influenza B virus is B / Phuket / 3073 / 2013 (B / Yamagata lineage)-like virus.In some embodiments, said first subtype of Influenza A virus is of Influenza A H1 N1 , said second subtype of Influenza A virus is of influenza A H3N2, said first strain of Influenza B virus is of influenza B / Victoria lineage and said second strain of Influenza B virus is of Influenza B / Yamagata.Exemplary HA antigens are known in the art and art publicly available, for example, NCBI’s Influenza Virus Resource (https: / / www.ncbi.nlm.nih.gov / genomes / FLU / Database / nph- select.cgi?go=database) and GISRS (https: / / gisaid.org / resources / human-lnfluenza-vaccine- composition / ).In some embodiments, said HA antigen encoded by said first, second, third and / or fourth nucleic acid comprises or consists of an amino acid sequence having at least 90%, 95%, 98% or 99% identity to the amino acid sequence set forth in any one of SEQ ID NO: 1 , 3, 5, 7, 9, 11 , 13, 15, 17, 19, 21 , 23, 25, 27, 29, 31 , 33, 35, 37, 39, 41 , 43, 45 or 47 or fragment or variant thereof.In some embodiments, said HA antigen encoded by said first, second, third and / or fourth nucleic acid antigen comprises or consists of the amino acid sequence set forth in any one of SEQ ID NO: 1 , 3, 5, 7, 9, 11 , 13, 15, 17, 19, 21 , 23, 25, 27, 29, 31 , 33, 35, 37, 39, 41 , 43, 45 or 47 or fragment or variant thereof.In some embodiments, said HA antigen encoded by said third and / or fourth nucleic acid comprises or consists of an amino acid sequence having at least 90%, 95%, 98% or 99% identity to the amino acid sequence set forth in any one of SEQ ID NO: 5, 7, 17 or 35, or fragment or variant thereof.In some embodiments, said HA antigen encoded by said third and / or fourth nucleic acid comprises or consists of an amino acid sequence set forth in any one of SEQ ID NO: 5, 7, 17 or 35, or fragment or variant thereof.In some embodiments, said HA antigen encoded by said first and / or second nucleic acid comprises or consists of an amino acid sequence having at least 90%, 95%, 98% or 99% identity to the amino acid sequence set forth in any one of SEQ ID NO: 1 , 3, 9, 11 , 13, 15, 19, 21 , 23, 25, 27, 29, 31 , 33, 37, 39, 41 , 43, 45 or 47 or fragment or variant thereof.In some embodiments, said HA antigen encoded by said first and / or second nucleic acid comprises or consists of an amino acid sequence set forth in any one of SEQ ID NO: 1 , 3, 9, 11 , 13, 15, 19, 21 , 23, 25, 27, 29, 31 , 33, 37, 39, 41 , 43, 45 or 47 or fragment or variant thereof.In some embodiments, said HA antigen encoded by said first nucleic acid comprises or consists of an amino acid sequence having at least 90%, 95%, 98% or 99% identity to the amino acid sequence set forth in any one of SEQ ID NO: 1 , 11 , 19, 23, 27, 29, 39, 41 or 43, or fragment or variant thereof.In some embodiments, said HA antigen encoded by said first nucleic acid comprises or consists of an amino acid sequence set forth in any one of SEQ ID NO: 1 , 11 , 19, 23, 27, 29, 39, 41 or 43, or fragment or variant thereof.In some embodiments, said HA antigen encoded by said second nucleic acid comprises or consists of an amino acid sequence having at least 90%, 95%, 98% or 99% identity to the amino acid sequence set forth in any one of SEQ ID NO: 3, 9, 13, 15, 21 , 25, 31 , 33, 37, 45 or 47 or fragment or variant thereof.In some embodiments, said HA antigen encoded by said second nucleic acid comprises or consists of an amino acid sequence set forth in any one of SEQ ID NO: 3, 9, 13, 15, 21 , 25, 31 , 33, 37, 45 or 47 or fragment or variant thereof.In some embodiments, said HA antigen encoded by said first, second, third and / or fourth nucleic acid is a polypeptide comprising a full-length Influenza HA protein. Suitably, said HA antigen encoded by said first, second, third and / or fourth nucleic acid is a polypeptide consisting of a full-length Influenza HA protein.In some embodiments, said HA antigen encoded by said first, second, third and / or fourth nucleic acid is a fragment of a hemagglutinin protein, such as a truncated hemagglutinin protein. In some embodiments, the fragment is a headless hemagglutinin, meaning the fragment does not comprise the head domain. In some embodiments, the fragment comprises a portion of the head domain. In some embodiments, the fragment is a stalk domain. In some embodiments, the fragment does not comprise the cytoplasmic domain. In some embodiments, the fragment does not comprise the transmembrane domain. In such embodiments, the fragment may be referred to as a soluble or secreted hemagglutinin protein or fragment.In some embodiments, the composition does not comprise a nucleic acid encoding a HA antigen from an influenza strain which is not recommended by WHO.In some embodiments, the composition does not comprise a nucleic acid encoding a HA antigen identified or designed by machine learning.In some embodiments, the elicited immune response is homologous, heterosubtypic, and optionally heterologous or intrasubtypic.In some embodiments, the elicited immune response is further heterologous or intrasubtypic.In some embodiments, an immune response is elicited against HA antigens that are antigenically distinct from any of the HA antigen encoded by a nucleic acid present in the compositions.Subtypes and lineages of Influenza virus can be further divided into different genetic “’’clades (also called “groups”) and “sub-clades” (also called “sub-groups”) based on the similarity of their HA gene sequences. Clades and sub-clades are shown on phylogenetic trees as groups and sub-groups of viruses that usually have similar genetic changes (i.e. nucleotide or amino acid changes) and have a single common ancestor.Clades and sub-clades that are genetically different from others are not necessarily antigenically different. Viruses from a specific clade or sub-clade may not have a mutation that impacts host immunity in comparison to other clades or sub-clades.The term “antigenic properties” is used to describe the immune response triggered by the antigens, e.g. HA and / or NA, on a particular virus.In some embodiments, said at least one further HA antigen subtype of Influenza A virus is selected from influenza A viruses characterized by a HA selected from the group consisting of H1 , H2, H3, H4, H5, H6, H7, H8, H9, H10, H11 , H12, H13, H14, H15, H16, H17 and H18, suitably from the group consisting of H1 , H2, H3, H5, H7 and H 10, more suitably from the group consisting of H2, H5, H7 and H10.In some embodiments, said at least one further HA antigen subtype of Influenza A virus is selected from influenza A viruses characterized by a neuraminidase (NA) selected from the group consisting of N1 , N2, N3, N4, N5, N6, N7, N8, N9, N10, and N11 , suitably selected from the group consisting of N1 , N2, N8 and N9.In some embodiments, said at least one further HA antigen subtype of Influenza A virus is selected from the group consisting of H1 N1 , H1 N2, H2N2, H3N1 , H3N2, H3N8, H5N1 , H5N2,H5N3, H5N8, H5N9, H7N1 , H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N7 and H10N8, suitably H1 N1 , H2N2, H3N2, H5N1 , H7N9 and H10N8.In some embodiments, said at least one further HA antigen subtype of Influenza A virus is from Influenza A Group 1 , suitably influenza A subtype H1 , H2, H5, H6, H8, H9, H11 , H12, H13, H16, H17 or H18, more suitably H1 , H2 or H5.In some embodiments, said at least one further HA antigen subtype of Influenza A virus is of H2N2 or H5N1.In some embodiments, said at least one further HA antigen subtype of Influenza A virus is from a subtype of Influenza A Group 2, suitably influenza A subtype H3, H4, H7, H10, H14 or H15, more suitably H3, H7 or H10.In some embodiments, said at least one further HA antigen subtype of Influenza A virus is of H7N9 or H10N8.In some embodiment, said strain of said at least one further HA antigen subtype of Influenza A virus is selected from the group consisting of H2 / Singapore 1957, H5A / ietnam / 2004, H7 / Shanghai / 2013 and H10 / Jiangxi Donghu / 2013.In some embodiments, an immune response is elicited against HA antigens of Influenza A subtypes H1 , H3 and at least one, suitably all, HA antigen of Influenza A subtype H2, H5, H7 or H10.In some embodiments, an immune response is further elicited against at least one further HA antigen of a strain of Influenza B virus, being different from any of the HA antigens of a strain of Influenza B virus encoded by a nucleic acid present in the composition.In some embodiments, said at least one further HA antigen of a strain of Influenza B virus is derived from a strain selected from the group consisting of B / Victoria lineage and B / Yamagata lineage.In some embodiments, said at least one further HA antigen of a strain of Influenza B virus is a strain of B / Victoria lineage.In some embodiments, said at least one further HA antigen of a strain of Influenza B virus is a strain of B / Yamagata lineage.In some embodiments, said at least one further HA antigen of a strain of Influenza B virus is selected from the group consisting of B / Austria / 1359417 / 2021 (B / Victoria lineage)-like virus, B / Washington / 02 / 2019 (B / Victoria lineage)-like virus, B / Colorado / 06 / 2017-like virus (B / Victoria / 2 / 87 lineage), B / Brisbane / 60 / 2008-like virus, B / Colorado / 06 / 2019 (B / VictoriaIineage)-like virus, B / lllinois / NHRC_FDX51486 / 2015, B / Oman / 4241 / 2019,B / lllinois / NHRC_18512 / 2017, B / California / BRD12452N / 2017, B / lndia / Pun-1922338 / 2019, B / Japan / 8858 / 2019, B / Washington / 02 / 2019, B / Stockholm / 7 / 2019, B / Phuket / 3073 / 2013 and B / Quebec / 70 / 2015In some embodiments, said at least one further HA antigen of a strain of Influenza B virus is selected from the group consisting of B / Austria / 1359417 / 2021 (B / Victoria lineage)-like virus, B / Washington / 02 / 2019 (B / Victoria lineage)-like virus, B / Colorado / 06 / 2017-like virus (B / Victoria / 2 / 87 lineage), B / Brisbane / 60 / 2008-like virus, B / Colorado / 06 / 2019 (B / Victoria lineage)-like virus, B / lllinois / NHRC_FDX51486 / 2015, B / Oman / 4241 / 2019, B / lllinois / NHRC_18512 / 2017, B / California / BRD12452N / 2017, B / lndia / Pun-1922338 / 2019, B / Japan / 8858 / 2019, B / Washington / 02 / 2019 and B / Stockholm / 7 / 2019.In some embodiments, said at least one further HA antigen of a strain of Influenza B virus is selected from the group consisting of B / Phuket / 3073 / 2013 and B / Quebec / 70 / 2015.In some embodiments, an immune response is further elicited against at least one HA antigen of a heterologous or intrasubtypic strain of Influenza A virus.In some embodiments, said heterologous or intrasubtypic strain of Influenza A virus is selected from the group consisting of H1 / Michigan / 2015, H1 / Hawaii / 2019, H1 / Christchurch / 2010, H1 / California / 2009, H3 / Finland / 2004, H3 / Hong Kong 2019, H3 / Perth / 2009, H3Bejing / 1992, H3 / Philippines / 1982 and H3 / Hong Kong / 1968.In some embodiments, said heterologous or intrasubtypic strain of Influenza A virus is selected from the group consisting of H1 / Michigan / 2015, H1 / Hawaii / 2019, H1 / Christchurch / 2010 and H1 / California / 2009.In some embodiments, said heterologous or intrasubtypic strain of Influenza A virus is selected from the group consisting of H3 / Finland / 2004, H3 / Hong Kong 2019, H3 / Perth / 2009, H3Bejing / 1992, H3 / Philippines / 1982 and H3 / Hong Kong / 1968.In some embodiments, an immune response is elicited against at least three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen HA antigens of at least three, four, five, six, seven, eight, nine, ten subtypes of Influenza A virus, including said first and second subtypes of Influenza A virus and / or at least three four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen HA antigens of Influenza B virus, including against HA antigens of said first strain of Influenza B virus.In some embodiments, an immune response is elicited against at least three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen HA antigens of at leastthree, four, five, six, seven, eight, nine, ten subtypes of Influenza A virus, including said first and second subtypes of Influenza A virus and / or at least three four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen HA antigens of Influenza B virus, including against HA antigens of said first and second strains of Influenza B virus.In some embodiments, an immune response is elicited against at least one HA antigen of Influenza A from each of subtypes H1, H2, H3, H5, H7 and H10 and at least one HA antigen of Influenza B from B / Victoria lineage.In some embodiments, an immune response is elicited against at least one HA antigen of Influenza A from each of subtypes H1, H2, H3, H5, H7 and H10, at least one HA antigen of Influenza B from B / Victoria lineage and at least one strain of Influenza B from B / Yamagata lineage.In some embodiments, the nucleic acids, suitably mRNAs, encoding said HA antigens are present in equimolar proportions.In some embodiments, the ratio of (a):(b):(c) is 1:1:1.In some embodiments, the ratio of (a):(b):(c):(d) is 1:1:1 :1.In some embodiments, the nucleic acids, suitably mRNAs, encoding said HA antigens are not present in equimolar proportions.In some embodiments, the dose (e.g. weight dose or molar dose, suitably weight dose) of (c) and / or (d) is different compared to the dose (e.g. weight dose or molar dose, suitably weight dose) of (a) and / or (b).In some embodiments, the ratio of (a):(b):(c) is comprised between 1:1:1.5 and 1:1:20.In some embodiments, the ratio of (a):(b):(c) is comprised between 1:1:1.5 and 1:1:5, optionally between 1:1:2 and 1:1:5, optionally between 1:1:3 and 1:1:5, optionally between 1:1:4 and 1:1:5, optionally between 1:1:1.5 and 1:1:4, optionally between 1:1:1.5 and 1:1:3, optionally between 1:1:2 and 1:1:4, optionally between 1:1:2 and 1:1:3.In some embodiments, the ratio of (a):(b):(c) is greater than 1:1:5 and lower or equal than 1:1:20, optionally greater than 1:1:5 and lower or equal to 1:1:15, optionally greater than 1:1:5 and lower or equal to 1:1:12, optionally greater than 1:1:5 and lower or equal to 1:1:10, optionally greater than 1:1:5 and lower or equal to 1:1:8. In some embodiments, the ratio of (a):(b):(c) is comprised between 1:1:5.5 and 1:1:20, optionally between 1:1:5.5 and 1:1:15, optionally between 1:1:5.5 and 1:1:12, optionally between 1:1:5.5 and 1:1:10, optionally between 1:1:5.5 and 1:1:8, optionally between 1:1:6 and 1:1:20, optionally between 1:1:6 and 1:1:15, optionally between 1:1:6 and 1:1:12, optionally between 1:1:6 and 1:1:10, optionallybetween 1:1:6 and 1:1:8, optionally between 1:1:8 and 1:1:20, optionally between 1:1:8 and 1:1:15, optionally between 1:1:8 and 1:1:12, optionally between 1:1:8 and 1:1:10.In some embodiments, the ratio of (a):(b):(c) is selected from about 1:1:1.5, about 1:1:2, about 1:1:2.2, about 1:1:2.4:2.4, about 1:1:2.6, about 1:1:2.8, about 1:1:3, about 1:1:3.2, about 1:1:3.4, about 1 :1 :3.6, about 1 :1 :3.8, about 1:1:4, about 1 :1 :4.2, about 1 :1 :4.4, about 1 :1 :4.6, about 1:1:4.8, about 1:1:5, about 1:1:5.5, about 1:1:6, about 1:1:6.5, about 1:1:7, about 1:1:7.5, about 1:1:8, about 1:1:8.5, about 1:1:9, about 1:1:9.5, about 1:1:10, about 1:1:10.5, about 1:1:11, about 1:1:11.5, about 1:1:12, about 1:1:12.5, about 1:1:13, about 1:1:13.5, about 1:1:14, about 1:1:14.5, about 1:1:15, about 1:1:15.5, about 1:1:16, about 1:1:16.5, about 1:1:17, about 1:1:17.5, about 1:1:18, about 1:1:18.5, about 1:1:19, about 1:1:19.5 or about 1:1:20.In some embodiments, the ratio of (a):(b):(c) is 1:1:1.5, 1:1:2, 1:1:2.2, 1:1:2.4, 1:1:2.6, 1:1:2.8, 1:1:3, 1:1:3.2, 1:1:3.4, 1:1:3.6, 1:1:3.8, 1:1:4, 1:1:4.2, 1:1:4.4, 1:1:4.6, 1:1:4.8, 1:1:5, 1:1:5.5, 1:1:6, 1:1:6.5, 1:1:7, 1:1:7.5, 1:1:8, 1:1:8.5, 1:1:9, 1:1:9.5, 1:1:10, 1:1:10.5, 1:1:11, 1:1:11.5, 1:1:12, 1:1:12.5, 1:1:13, 1:1:13.5, 1:1:14, 1:1:14.5, 1:1:15, 1:1:15.5, 1:1:16, 1:1:16.5, 1:1:17, 1:1:17.5, 1:1:18, 1:1:18.5, 1:1:19, 1:1:19.5 or 1:1:20.In some embodiments, the ratio of (a):(b):(c) is comprised between 1:1:2 and 1:1:4, suitably is about 1:1:2, about 1:1:3 or about 1:1:4, suitably is 1:1:2, 1:1:3 or 1:1:4.In some embodiments, the ratio of (a):(b):(c) is comprised between 1:1:5.5 and 1:1:20, suitably between 1:1:6 and 1:1:12, suitably between 1:1:6 and 1:1:10, suitably is about 1:1:6, about 1:1:8 or about 1:1:10, suitably is 1:1:6, 1:1:8 or 1:1:10.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c) is comprised between 1:1.5:1 and 1:20:1, optionally between 1:1.5:1 and 1:5:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c) is comprised between 1:1.5:1 and 1:5:1, optionally between 1:2:1 and 1:5:1, optionally between 1:3:1 and 1:5:1, optionally between 1:4:1 and 1:5:1, optionally between 1:1.5:1 and 1:4:1, optionally between 1:1.5:1 and 1:3:1, optionally between 1:2:1 and 1:4:1, optionally between 1:2:1 and 1:3:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c) is about 1:1.5:1, about 1:2:1, about 1:2.2:1, about 1:2.4:1, about 1:2.6:1, about 1:2.8:1, about 1:3:1, about 1:3.2:1, about 1 :3.4:1 , about 1:3.6:1, about 1 :3.8:1 , about 1:4:1, about 1 :4.2:1 , about 1 :4.4:1 , about 1 :4.6:1 , about 1:4.8:1 or about 1:5:1. In some embodiments, the ratio of (a):(b):(c) is 1:1.5:1, 1:2:1,1:2.2:1, 1 :2.4:1, 1 :2.6:1, 1:2.8:1, 1:3:1, 1 :3.2:1, 1 :3.4:1, 1 :3.6:1, 1 :3.8:1, 1:4:1, 1 :4.2:1, 1 :4.4:1, 1:4.6:1, 1:4.8:1 or 1:5:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c) is comprised between 1:2:1 and 1:4:1, suitably between 1:2:1 and 1:3:1, suitably is 1:2:1 or 1:3:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and said ratio of (a):(b):(c) is greater than 1:3:1 and lower or equal to 1 :20: 1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and said ratio of (a):(b):(c) is greater than 1:3:1 and lower or equal to 1:5:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c) is comprised between 1:1.5: 1.5 and 1:20:5, optionally between 1:1.5: 1.5 and 1:5:5, optionally between 1:2:2 and 1:5:5, optionally between 1:3:3 and 1:5:5, optionally between 1:4:4 and 1:5:5, optionally between 1:1.5: 1.5 and 1:4:4, optionally between 1:1.5: 1.5 and 1:3:3, optionally between 1:2:2 and 1:4:4, optionally between 1:2:2 and 1:3:3, suitably is 1:2:2, 1:2:3, 1:3:2 or 1:3:3.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c) is comprised between 1 : 1.5:5.5 and 1 :20:20, optionally between 1 : 1.5:5.5 and 1 :5:20, optionally between 1 :2:5.5 and 1 :5:20, optionally between 1 :3:5.5 and 1 :5:20, optionally between 1 :4:5.5 and 1 :5:20, optionally between 1:1.5:5.5 and 1:4:20, optionally between 1:1.5:5.5 and 1:3:20, optionally between 1:2:5.5 and 1:4:20, optionally between 1:2:5.5 and 1:3:20, suitably is 1:2:6, 1:2:8, 1:2:10, 1:3:6, 1:3:8 or 1:3:10.In some embodiments, the ratio is a weight / weight ratio or a molar ratio. Suitably, the ratio is a weight / weight ratio.In some embodiments, the ratio of (a):(b):(c):(d) is comprised between 1:1:1.5:1.5 and 1:1:20:20.In some embodiments, the ratio of (a):(b):(c):(d) is comprised between 1:1:1.5:1.5 and 1:1 :5:5.In some embodiments, the ratio of (a):(b):(c):(d) is comprised between 1:1:1.5:1.5 and 1:1:5:5, optionally between 1:1:2:2 and 1:1:5:5, optionally between 1:1:3:3 and 1:1:5:5, optionally between 1:1:4:4 and 1 :1 :5:5, optionally between 1:1:1.5: 1.5 and 1 :1 :4:4, optionallybetween 1:1: 1.5: 1.5 and 1 :1 :3:3, optionally between 1 : 1:2:2 and 1:1 :4:4, optionally between 1:1 :2:2 and 1:1 :3:3.In some embodiments, the ratio of (a):(b):(c) :(d) is greater than 1 : 1 :5:5 and lower or equal than 1:1:20:20, optionally greater than 1 : 1 :5:5 and lower or equal to 1:1:15:15, optionally greater than 1 : 1 :5:5 and lower or equal to 1:1:12:12, optionally greater than 1 : 1 :5:5 and lower or equal to 1:1:10:10, optionally greater than 1 : 1 :5:5 and lower or equal to 1 : 1 :8:8.In some embodiments, the ratio of (a):(b):(c) :(d) is comprised between 1:1:5.5:5.5 and 1:1:20:20, optionally between 1:1:5.5:5.5 and 1:1:15:15, optionally between 1:1:5.5:5.5 and 1:1:12:12, optionally between 1:1:5.5:5.5 and 1:1:10:10, optionally between 1:1:5.5:5.5 and 1:1 :8:8, optionally between 1 :1 :6:6 and 1:1:20:20, optionally between 1:1:6:6 and 1:1:15:15, optionally between 1 : 1 :6:6 and 1:1:12:12, optionally between 1 : 1 :6:6 and 1:1:10:10, optionally between 1:1:6:6 and 1:1:8:8, optionally between 1:1:8:8 and 1:1:20:20, optionally between 1:1 :8:8 and 1:1:15:15, optionally between 1 :1:8:8 and 1:1:12:12, optionally between 1:1:8:8 and 1:1:10:10.In some embodiments, the ratio of (a):(b):(c):(d) is selected from about 1:1:1.5:1.5, about 1 :1 :2:2, about 1:1:2.2:2.2, about 1:1 :2.4:2.4, about 1:1 :2.6:2.6, about 1:1:2.8:2.8, about 1 : 1 :3:3, about 1 : 1 :3.2:3.2, about 1 : 1 :3.4:3.4, about 1 : 1 :3.6:3.6, about 1 :1 :3.8:3.8, about 1 :1 :4:4, about 1:1:4.2:4.2, about 1:1:4.4:4.4, about 1:1:4.6:4.6, about 1:1:4.8:4.8, about 1 :1 :5:5, about 1:1:5.5:5.5, about 1 :1:6:6, about 1:1:6.5:6.5, about 1 :1:7:7, about 1:1:7.5:7.5, about 1 :1:8:8, about 1:1:8.5:8.5, about 1 :1 :9:9, about 1:1:9.5:9.5, about 1:1:10:10, about 1:1:10.5:10.5, about 1:1:11:11, about 1:1:11.5:11.5, about 1:1:12:12, about 1:1:12.5:12.5, about 1:1:13:13, about 1:1:13.5:13.5, about 1:1:14:14, about 1:1:14.5:14.5, about 1:1:15:15, about 1:1:15.5:15.5, about 1:1:16:16, about 1:1:16.5:16.5, about 1:1:17:17, about 1:1:17.5:17.5, about 1:1:18:18, about 1:1:18.5:18.5, about 1:1:19:19, about 1:1:19.5:19.5 or about 1:1:20:20.In some embodiments, the ratio of (a):(b):(c):(d) is 1:1:1.5:1.5, 1:1:2:2, 1:1:2.2:2.2, 1:1:2.4:2.4, 1:1:2.6:2.6, 1:1:2.8:2.8, 1:1:3:3, 1:1:3.2:3.2, 1:1:3.4:3.4, 1:1:3.6:3.6, 1:1:3.8:3.8, 1:1:4:4, 1:1:4.2:4.2, 1:1:4.4:4.4, 1:1:4.6:4.6, 1:1:4.8:4.8, 1:1:5:5, 1:1:5.5:5.5, 1:1:6:6, 1:1:6.5:6.5, 1:1:7:7, 1:1:7.5:7.5, 1:1:8:8, 1:1:8.5:8.5, 1:1:9:9, 1:1:9.5:9.5, 1:1:10:10, 1:1:10.5:10.5, 1:1:11:11, 1:1:11.5:11.5, 1:1:12:12, 1:1:12.5:12.5, 1:1:13:13, 1:1:13.5:13.5, 1:1:14:14, 1:1:14.5:14.5, 1:1:15:15, 1:1:15.5:15.5, 1:1:16:16, 1:1:16.5:16.5, 1:1:17:17, 1:1:17.5:17.5, 1:1:18:18, 1:1:18.5:18.5, 1:1:19:19, 1:1:19.5:19.5 or 1:1:20:20.In some embodiments, the ratio of (a):(b):(c):(d) is comprised between 1 : 1:2:2 and 1 :1 :4:4, suitably between 1 :1 :2:2 and 1 :1 :3:3, suitably is 1 :1 :2:2 or 1 :1 :3:3.In some embodiments, the ratio of (a):(b):(c):(d) is comprised between 1:1:2:2 and 1 :1 :4:4, suitably is about 1 :1 :4:4, suitably is 1 :1 :4:4.In some embodiments, the ratio of (a):(b):(c):(d) is comprised between 1:1:5.5:5.5 and 1:1:20:20, suitably between 1 :1 :6:6 and 1:1:12:12, suitably between 1 :1:6:6 and 1:1:10:10, suitably is 1 :1 :6:6 or 1 :1 :8:8 or 1:1:10:10.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d) is comprised between 1:1.5:1:1 and 1:20:1:1, optionally between 1:1.5:1:1 and 1 :5:1 :1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d) is comprised between 1:1.5:1:1 and 1:20:1:1, optionally between 1:1.5: 1:1 and 1:5:1 :1, optionally between 1:2:1 :1 and 1:5: 1:1, optionally between 1:3:1 :1 and 1:5:1 :1, optionally between 1:4:1 :1 and 1:5:1 :1, optionally between 1:1.5:1:1 and 1:4:1 :1, optionally between 1:1.5:1:1 and 1:3:1 :1, optionally between 1:2:1 :1 and 1:4:1 :1, optionally between 1:2:1 :1 and 1:3: 1:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d) is about 1:1.5:1:1, about 1 :2:1 :1 , about 1:2.2:1:1, about 1:2.4:1:1, about 1 :2.6:1 :1 , about 1:2.8:1:1, about 1 :3:1 :1 , about 1:3.2:1:1, about 1:3.4:1:1, about 1:3.6:1:1, about 1:3.8:1:1, about 1:4:1:1, about 1:4.2:1:1, about 1:4.4:1:1, about 1:4.6:1:1, about 1:4.8:1:1 or about 1 :5:1 :1. In some embodiments, the ratio of (a):(b):(c):(d) is 1:1.5:1:1, 1:2:1:1, 1:2.2:1:1, 1:2.4:1:1, 1:2.6:1:1, 1:2.8:1:1, 1:3:1:1, 1:3.2:1:1, 1:3.4:1:1, 1:3.6:1:1, 1:3.8:1:1, 1:4:1:1, 1:4.2:1:1, 1:4.4:1:1, 1:4.6:1:1, 1:4.8:1:1 or 1:5:1 :1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d) is comprised between 1:2:1 :1 and 1:4:1 :1, suitably between 1:2: 1:1 and 1:3: 1:1, suitably is 1:2:1 :1 or 1:3: 1:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and said ratio of (a):(b):(c):(d) is greater than 1:3:1 :1 and lower or equal to 1 :20: 1:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and said ratio of (a):(b):(c):(d) is greater than 1:3:1 :1 and lower or equal to 1:5: 1:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d) is comprised between1 :1.5: 1.5: 1.5 and 1 :20:5:5, optionally between 1 :1.5: 1.5: 1.5 and 1 :5:5:5, optionally between 1 :2:2:2 and 1 :5:5:5, optionally between 1 :3:3:3 and 1 :5:5:5, optionally between 1 :4:4:4 and 1 :5:5:5, optionally between 1 :1.5:1.5:1.5 and 1 :4:4:4, optionally between 1 :1.5:1.5:1.5 and 1 :3:3:3, optionally between 1 :2:2:2 and 1 :4:4:4, optionally between 1 :2:2:2 and 1 :3:3:3, suitably is 1 :2:2:2, 1 :2:3:3, 1 :3:2:2 or 1 :3:3:3.In some embodiments, said first subtype of Influenza A virus of (a) is H1 , said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d) is comprised between 1 :1.5:5.5:5.5 and 1 :20:20:20, optionally between 1 :1.5:5.5:5.5 and 1 :5:20:20, optionally between 1 :2:5.5:5.5 and 1 :5:20:20, optionally between 1 :3:5.5:5.5 and 1 :5:20:20, optionally between 1 :4:5.5:5.5 and 1 :5:20:20, optionally between 1 :1.5:5.5:5.5 and 1 :4:20:20, optionally between 1 :1.5:5.5:5.5 and 1 :3:20:20, optionally between 1 :2:5.5:5.5 and 1 :4:20:20, optionally between 1 :2:5.5:5.5 and 1 :3:20:20, suitably is 1 :2:6:6, 1 :2:8:8, 1 :2:10:10, 1 :3:6:6, 1 :3:8:8 or 1 :3:10:10.In some embodiments, the ratio is a weight / weight ratio or a molar ratio. Suitably, the ratio is a weight / weight ratio.In some embodiments, the immunogenic composition further comprises:(e) at least one further nucleic acid encoding at least one further antigen, wherein said at least one further antigen is derived from a strain of Influenza virus.In some embodiments, said strain of Influenza virus from which said at least one further antigen (e) is derived is selected from the group consisting of Influenza A virus and Influenza B virus.In some embodiments, said strain of Influenza virus from which said at least one further antigen (e) is derived is selected from the group consisting of said first subtype of Influenza A virus, said second subtype of Influenza A virus, said first strain of Influenza B virus and said second strain of Influenza B virus.In some embodiments, the immunogenic composition is a trivalent composition.In some embodiments, the immunogenic composition is a quadrivalent composition.In some embodiments, said at least one further antigen comprises or consists of a peptide or protein selected or derived from an Influenza virus hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix protein 1 (M1), matrix protein 2 (M2), non- structural protein 1 (NS1), non-structural protein 2 (NS2), nuclear export protein (NEP), polymerase acidic protein (PA), polymerase basic protein PB1 , PB1-F2, and / or polymerase basic protein 2 (PB2), or an immunogenic fragment or an immunogenic variant thereof.In some embodiments, said at least one further antigen comprises or consists of a peptide or protein selected or derived from an Influenza virus NA or an immunogenic fragment or an immunogenic variant thereof.In some embodiments, the immunogenic composition comprises a combination of HA and NA nucleic acids encoding said HA and NA antigens, said at least one further antigen comprising or consisting of a peptide or protein selected or derived from an Influenza virus NA or fragment or variant thereof.Like HA, neuraminidase (NA) is a major surface glycoprotein of Influenza virus. Naturally acquired or vaccine-induced NA-inhibiting (NAI) antibodies have been shown to contribute to influenza disease protection in naturally occurring Influenza or in experimental human challenge studies . NAI antibodies appear to have an independent role in vaccine efficacy / effectiveness as compared to Hemagglutinin inhibition antibodies .In some embodiments, said NA antigen is a polypeptide comprising a full-length Influenza NA protein. Suitably, said NA antigen is a polypeptide consisting of a full-length Influenza NA protein.In some embodiments, said NA antigen is a fragment of a neuraminidase protein, such as a truncated neuraminidase protein.In some embodiments, the composition does not comprise a nucleic acid encoding a NA antigen from an influenza strain which is not recommended by WHO.In some embodiments, the composition does not comprise a nucleic acid encoding a NA antigen identified or designed by machine learning.In some embodiments, the nucleic acids, suitably mRNAs, encoding said HA and NA antigens are present in equimolar proportions.In some embodiments, the nucleic acids, suitably mRNAs, encoding said HA and NA antigens are not present in equimolar proportions.In some embodiments, the dose (e.g. weight dose or molar dose, suitably weight dose) of said at least one further nucleic acid, suitably mRNA, encoding said NA antigen is different compared to the dose (e.g. weight dose or molar dose, suitably weight dose) of said nucleic acids, suitably mRNAs, encoding said HA antigens.In some embodiments, the ratio of HA:NA antigens encoded by nucleic acids, suitably mRNAs, is comprised between 4:1 and 1 :4, suitably, 3:1 and 1 :3, suitably 2:1 and 2:1.In some embodiment, the ratio of HA:NA antigens encoded by nucleic acids, suitably mRNAs, is 4:1 or 1 :4.In some embodiment, the ratio of HA:NA antigens encoded by nucleic acids, suitably mRNAs, is 3:1 or 1 :3.In some embodiment, the ratio of HA:NA antigens encoded by nucleic acids, suitably mRNAs, is 2:1 or 1 :2.In some embodiment, the ratio of HA:NA antigens encoded by nucleic acids, suitably mRNAs, is 3:2 or 2:3.In some embodiment, the ratio of HA:NA antigens encoded by nucleic acids, suitably mRNAs, is 4:3 or 3:4.In some embodiment, the ratio of HA:NA antigens encoded by nucleic acids, suitably mRNAs, is about 1 :1.In some embodiment, the ratio of HA:NA antigens encoded by nucleic acids, suitably mRNAs, is 1 :1.In some embodiments, the ratio is a weight / weight ratio or a molar ratio. Suitably, the ratio is a weight / weight ratio.In some embodiments, said at least one further antigen comprises or consists of an amino acid sequence having at least 90%, 95%, 98% or 99% identity to the amino acid sequence set forth in any one of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46 or 48 or fragment or variant thereof.In some embodiments, said at least one further antigen comprises or consists of the amino acid sequence set forth in any one of SEQ ID NO: SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46 or 48 or fragment or variant thereof.In some embodiments, said at least one further antigen comprises or consists of an amino acid sequence having at least 90%, 95%, 98% or 99% identity to the amino acid sequence set forth in any one of SEQ I D NO: 6, 8, 18, 36, or fragment or variant thereof.In some embodiments, said at least one further antigen comprises or consists of the amino acid sequence set forth in any one of SEQ ID NO: SEQ ID NO: 6, 8, 18, 36, or fragment or variant thereof.In some embodiments, said at least one further antigen comprises or consists of an amino acid sequence having at least 90%, 95%, 98% or 99% identity to the amino acidsequence set forth in any one of SEQ ID NO: 2, 4, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46 or 48 or fragment or variant thereof.In some embodiments, said at least one further antigen comprises or consists of the amino acid sequence set forth in any one of SEQ ID NO: SEQ ID NO: 2, 4, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46 or 48 or fragment or variant thereof.In some embodiments, said at least one further antigen comprises or consists of an amino acid sequence having at least 90%, 95%, 98% or 99% identity to the amino acid sequence set forth in any one of SEQ ID NO: 2, 12, 20, 24, 28, 30, 40, 42 or 44, or fragment or variant thereof.In some embodiments, said at least one further antigen comprises or consists of the amino acid sequence set forth in any one of SEQ ID NO: 2, 12, 20, 24, 28, 30, 40, 42 or 44, or fragment or variant thereof.In some embodiments, said at least one further antigen comprises or consists of an amino acid sequence having at least 90%, 95%, 98% or 99% identity to the amino acid sequence set forth in any one of SEQ ID NO: 4, 10, 14, 16, 22, 26, 32, 34, 38, 46 or 48 or fragment or variant thereof.In some embodiments, said at least one further antigen comprises or consists of the amino acid sequence set forth in any one of SEQ ID NO: SEQ ID NO: 4, 10, 14, 16, 22, 26, 32, 34, 38, 46 or 48 or fragment or variant thereof.In some embodiments, the immunogenic composition comprises a plurality of (e), such as (e1), (e2), (e3) and / or (e4) as defined herein.In some embodiments, the composition comprises at least three, four, five, six, seven or eight nucleic acids, suitably mRNAs, encoding at least three, four, five, six, seven or eight antigens, optionally three to eight nucleic acids, suitably mRNAs, encoding three to eight antigens, optionally five to ten nucleic acids, suitably mRNAs, encoding five to ten antigens, optionally seven or eight nucleic acids, suitably mRNAs, encoding seven or eight antigens.In some embodiments, the composition is a multivalent composition, wherein said antigens of (a), (b), (c), (d) and / or (e) are derived from at least three strains of Influenza virus.In some embodiments, the composition comprises three nucleic acids, suitably mRNAs, encoding three antigens.In some embodiments, the composition comprises six nucleic acids, suitably mRNAs, encoding six antigens.In some embodiments, the immunogenic composition comprises a combination of said first, second and third nucleic acids, suitably mRNAs, encoding said three HA antigens, and three nucleic acids, suitably mRNAs, encoding three NA antigens.In some embodiments, the composition is a multivalent composition, wherein said antigens of (a), (b), (c), (d) and / or (e) are derived from at least four strains of Influenza virus.In some embodiments, the composition comprises seven nucleic acids, suitably mRNAs, encoding seven antigens.In some embodiments, the immunogenic composition comprises a combination of said first, second, third and fourth nucleic acids, suitably mRNAs, encoding said four HA antigens, and three nucleic acids, suitably mRNAs, encoding three NA antigens.In some embodiments, the immunogenic composition further comprises:(e1) a fifth nucleic acid encoding a NA of the first subtype of Influenza A virus;(e2) a sixth nucleic acid encoding a NA of the second subtype of Influenza A virus; and (e3) a seventh nucleic acid encoding a NA of the first strain of Influenza B virus.In some embodiments, the ratio of (a):(b):(c):(e1):(e2):(e3) is comprised between 3:3:9: 1 : 1 : 1 and 1 : 1 :3:3:3:3, suitably between 2:2:6: 1 :1 : 1 and 1 :1 :3:2:2:2, suitably is 2:2:6: 1 : 1 :1 or 1:1:3:2:2:2 or 3:3:6:1:1:1 or 1:1:3:3:3:3.In some embodiments, the ratio of (a):(b):(c):(e1):(e2):(e3) is comprised between 3:3:24:1:1:1 and 1:1:8:3:3:3, suitably between 2:2:16:1:1:1 and 1:1:8:2:2:2, suitably is 2:2:16:1:1:1 or 1:1:8:2:2:2 or 3:3:24:1:1:1 or 1:1:8:3:3:3.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(e1):(e2):(e3) is comprised between 3:9:3:1:1:1 and 1 :3:1 :3:3:3, suitably between 2:6:2:1:1:1 and 1:3:1 :2:2:2, suitably is 2:6:2:1:1:1 or 1:3:1:2:2:2 or 3:9:3:1:1:1 or 1:3:1:3:3:3.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(e1):(e2):(e3) is comprised between 3:15:3:1:1:1 and 1:5:1:3:3:3, suitably is 2:10:2:1:1:1 or 3:15:3:1:1:1 or 2:8:2:1:1:1 or 3:12:3:1:1:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(e1):(e2):(e3) is comprised between 3:9:9:1:1:1 and 1:3:3:3:3:3, suitably between 2:6:6:1:1:1 and 1:3:3:2:2:2, suitably is 2:6:6:1:1:1 or 1:3:3:2:2:2 or 3:9:9:1:1:1 or 1:3:3:3:3:3.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(e1):(e2):(e3) is comprised between 3:15:15:1:1:1 and 1:5:5:3:3:3, suitably is 2:10:10:1:1:1 or 3:15:15:1:1:1 or2:8:8:1:1:1 or 3:12:12:1:1:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(e1):(e2):(e3) is comprised between 3:9:24:1:1:1 and 1:3:8:3:3:3, suitably between 2:6:16:1:1:1 and 1:3:8:2:2:2, suitably is 2:6:16:1:1:1 or 1:3:8:2:2:2 or 3:9:24:1:1:1 or 1:3:8:3:3:3.In some embodiments, the ratio of (a):(b):(c):(d):(e1):(e2):(e3) is comprised between 3:3:9:9: 1 : 1 :1 and 1:1:3:3:3:3:3, suitably between 2:2:6:6:1:1:1 and 1:1:3:3:2:2:2, suitably is 2:2:6:6:1:1:1 or 1:1:3:3:2:2:2 or 3:3:9:9: 1 : 1 : 1 or 1:1:3:3:3:3:3.In some embodiments, the ratio of (a):(b):(c):(d):(e1):(e2):(e3) is comprised between 3:3:24:24:1:1:1 and 1:1:8:8:3:3:3, suitably between 2:2:16:16:1:1:1 and 1:1:8:8:2:2:2, suitably is 2:2:16::161:1:1 or 1:1:8:8:2:2:2 or 3:3:24:24:1:1:1 or 1:1:8:8:3:3:3.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d):(e1):(e2):(e3) is comprised between 3:9:3:3: 1 :1 : 1 and 1 :3: 1 :1 :3:3:3, suitably between 2:6:2:2:1:1:1 and 1 :3: 1 : 1 :2:2:2, suitably is 2:6:2:2:1:1:1 or 1 :3: 1 :1 :2:2:2 or 3:9:3:3: 1 : 1 : 1 or 1 :3: 1 :1 :3:3:3.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d):(e1):(e2):(e3) is comprised between 3:15:3:3:1:1:1 and 1 :5:1 : 1 :3:3:3, suitably is 2:10:2:2:1:1:1 or 3:15:3:3:1:1:1 or 2:8:2:2: 1 : 1 : 1 or 3:12:3:3:1:1:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d):(e1):(e2):(e3) is comprised between 3:9:9:9: 1 :1 : 1 and 1:3:3:3:3:3:3, suitably between 2:6:6:6:1:1:1 and 1:3:3:3:2:2:2, suitably is 2:6:6:6:1:1:1 or 1:3:3:3:2:2:2 or 3:9:9:9: 1 : 1 : 1 or 1:3:3:3:3:3:3.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d):(e1):(e2):(e3) is comprised between 3:15:15:15:1:1:1 and 1:5:5:5:3:3:3, suitably is 2:10:10:10:1:1:1 or 3:15:15:15:1:1:1 or 2:8:8:8:1:1:1 or 3:12:12:12:1:1:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d):(e1):(e2):(e3) is comprisedbetween 3:9:24:24:1:1:1 and 1:3:8:8:3:3:3, suitably between 2:6:16:16:1:1:1 and 1:3:8:8:2:2:2, suitably is 2:6:16:16:1:1:1 or 1:3:8:8:2:2:2 or 3:9:24:24:1:1:1 or 1:3:8:8:3:3:3.In some embodiments, the composition comprises eight nucleic acids, suitably mRNAs, encoding eight antigens.In some embodiments, the immunogenic composition comprises a combination of four HA antigens or four nucleic acids, suitably mRNAs, encoding said four HA antigens, and four NA antigens or four nucleic acids, suitably mRNAs, encoding said four NA antigens.In some embodiments, the composition further comprises:(e4) an eighth nucleic acid encoding a NA of the second strain of Influenza B virus.In some embodiments, the ratio of (a):(b):(c):(d):(e1):(e2):(e3):(e4) is comprised between 3:3:9:9: 1 : 1 :1 :1 and 1:1:3:3:3:3:3:3, suitably between 2:2:6:6: 1 : 1 : 1 : 1 and 1:1:3:3:2:2:2:2, suitably is 2:2:6:6: 1 : 1 : 1 : 1 or 1:1:3:3:2:2:2:2 or 3:3:9:9: 1 :1 : 1 : 1 or 1:1:3:3:3:3:3:3.In some embodiments, the ratio of (a):(b):(c):(d):(e1):(e2):(e3):(e4) is comprised between 3:3:24:24:1:1:1:1 and 1:1:8:8:3:3:3:3, suitably between 2:2:16:16:1:1:1:1 and 1:1:8:8:2:2:2:2, suitably is 2:2:16:16:1:1:1:1 or 1:1:8:8:2:2:2:2 or 3:3:24:24:1:1:1:1 or 1:1:8:8:3:3:3:3.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d):(e1):(e2):(e3):(e4) is comprised between 3:9:3:3: 1 :1 : 1 : 1 and 1 :3: 1 : 1 :3:3:3:3, suitably between 2:6:2:2: 1 : 1 : 1 : 1 and 1:3:1 :1:2:2:2:2, suitably is 2:6:2:2: 1 : 1 : 1 : 1 or 1:3:1:1:2:2:2:2 or3:9:3:3:1:1:1:1 or 1:3:1 :1:3:3:3:3.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d):(e1):(e2):(e3):(e4) is comprised between 3:15:3:3:1:1:1:1 and 1 :5:1 : 1 :3:3:3:3, suitably is 2:10:2:2:1:1:1:1 or 3:15:3:3:1:1:1:1 or2:8:2:2:1:1:1:1 or 3:12:3:3:1:1:1:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d):(e1):(e2):(e3):(e4) is comprised between 3:9:9:9: 1 :1 : 1 : 1 and 1:3:3:3:3:3:3:3, suitably between 2:6:6:6: 1 : 1 : 1 : 1 and 1:3:3:3:2:2:2:2, suitably is 2:6:6:6: 1 : 1 : 1 : 1 or 1:3:3:3:2:2:2:2 or3:9:9:9:1:1:1:1 or 1:3:3:3:3:3:3:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d):(e1):(e2):(e3):(e4) is comprised between 3:15:15:15:1:1:1:1 and 1:5:5:5:3:3:3:3, suitably is 2:10:10:10:1:1:1:1 or 3:15:15:15:1:1:1:1 or2:8:8:8:1:1:1:1 or 3:12:12:12:1:1:1:1.In some embodiments, said first subtype of Influenza A virus of (a) is H1, said second subtype of Influenza A virus of (b) is H3 and the ratio of (a):(b):(c):(d):(e1):(e2):(e3):(e4) iscomprised between 3:9:24:24:1 :1 :1 :1 and 1 :3:8:8:3:3:3:3, suitably between 2:6:16:16:1 :1 :1 :1 and 1 :3:8:8:2:2:2:2, suitably is 2:6:16:16:1 :1 :1 :1 or 1 :3:8:8:2:2:2:2 or 3:9:24:24:1 :1 :1 :1 or 1 :3:8:8:3:3:3:3.In some embodiments, the ratio is a weight / weight ratio or a molar ratio. Suitably, the ratio is a weight / weight ratio.In some embodiments, an immune response is further elicited against NA antigens of said first and second subtypes of Influenza A virus and said first strain of Influenza B virus, and optionally, at least one further NA antigen of a strain of Influenza A virus and / or Influenza B virus, being different from any of the NA antigen encoded by a nucleic acid present in the composition.In some embodiments, an immune response is further elicited against NA antigens of said first and second subtypes of Influenza A virus, said first and second strains of Influenza B virus, and optionally, at least one further NA antigen of a strain of Influenza A virus and / or Influenza B virus, being different from any of the NA antigen encoded by a nucleic acid present in the composition.In some embodiments, an immune response is elicited against NA antigens that are antigenically distinct from any of the NA antigen encoded by a nucleic acid present in the compositions.It has to be noted that specific features and embodiments that are described in the context of the first aspect of the invention, that is the immunogenic composition for use according to the invention, are likewise applicable to the second aspect (vaccine for use according to the invention), the third aspect (kit or kit of parts for use according to the invention), or further aspects including e.g. method of treatments.Nucleic AcidsIn some embodiments, at least one nucleic acid of the immunogenic composition, suitably of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4), is DNA or RNA, suitably mRNA.In some embodiments, as least one nucleic acid of the immunogenic composition, suitably of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4), is a DNA.In some embodiments, at least one nucleic acid of the immunogenic composition, suitably of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4), is an artificial nucleic acid, e.g. an artificial DNA or an artificial RNA, suitably mRNA.Nucleic acid-based vaccination including DNA or RNA, suitably mRNA, represents a promising technique for novel vaccines against emerging viruses and for the provision ofcombination vaccines. Nucleic acids can be genetically engineered and administered to a human subject. Transfected cells directly produce the encoded antigen (e.g. provided by a DNA or an RNA, in particular an mRNA), which results in protective immunological responses.Nucleic acids according to the invention, e.g. DNAs or RNAs, suitably mRNAs, form the basis for a nucleic acid based immunogenic composition or a nucleic acid based vaccine.Such nucleic acid based immunogenic compositions (first aspect) or nucleic acid-based vaccines (second aspect) as provided herein have advantages over classical vaccine approaches.In general, protein-based vaccines, or live attenuated vaccines are suboptimal for use in developing countries due to their high production costs. In addition, protein-based vaccines, or live attenuated vaccines require long development times and are not suitable for rapid responses of epidemic virus outbreaks such as e.g. the Influenza virus outbreaks. Indeed, because traditional methods for producing standard inactivated flu vaccines take a long period of time, the GISRS recommendation is made six to seven months prior the start of the Influenza season, during which the Influenza viruses may continue to evolve.In contrast, the nucleic acid-based immunogenic compositions and vaccines according to the invention allow very fast and cost-effective manufacturing. Therefore, in comparison with known vaccines, compositions / vaccines based on nucleic acids can be produced and manufactured significantly cheaper and faster, which is very advantageous particularly for use in developing countries or in the context of annual epidemics or a global pandemic. The nucleic acid-based compositions / vaccines offer the GISRS additional time to monitor circulating viruses and make its recommendation closer to the Influenza season. This extension of the GISRS monitoring timeline should allow the GISRS predictions to be more accurate, resulting in more effective vaccines designated to target circulating viruses closer to Influenza season. Furthermore, the different nucleic acid encoding different antigens (e.g. of different Influenza strains) can be combined in one immunogenic composition / vaccine to ensure or increase the effectiveness of the immune response against Influenza virus.The use of RNA, suitably mRNA, in or as a vaccine overcomes the disadvantages of conventional genetic vaccination involving incorporating DNA into cells in terms of safeness, feasibility, applicability, and effectiveness to generate immune responses. RNA molecules, suitably mRNAs, are considered to be significantly safer than DNA vaccines, as RNAs, suitably mRNAs, are more easily degraded. They are cleared quickly out of the organism and cannot integrate into the genome and influence the cell's gene expression in an uncontrollable manner. It is also less likely for RNA, suitably mRNA, vaccines to cause severe side effects like the generation of autoimmune disease or anti-DNA antibodies. Transfection with RNA,suitably mRNA, requires only insertion into the cell's cytoplasm, which is easier to achieve than into the nucleus.In some embodiments, at least one nucleic acid of the immunogenic composition, suitably of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4), is an RNA.The term “RNA” is the usual abbreviation for ribonucleic acid. It is a nucleic acid molecule, i.e. a polymer consisting of nucleotide monomers. These nucleotides are usually adenosine-monophosphate (AMP), uridine-monophosphate (UMP), guanosinemonophosphate (GMP) and cytidine-monophosphate (CMP) monomers or analogs thereof, which are connected to each other along a so-called backbone. The backbone is typically formed by phosphodiester bonds between the sugar, i.e. ribose, of a first and a phosphate moiety of a second, adjacent monomer. The specific order of the monomers, i.e. the order of the bases linked to the sugar / phosphate-backbone, is called the RNA sequence.Suitably, the RNA molecule is selected from an antisense RNA, such as an antisense oligonucleotide (ASOs), a small interfering RNA (siRNA), a microRNA (miRNAs), a messenger RNA (mRNA) and an RNA forming part of a single-guide RNA (sgRNA)-mediated CRISPR- Cas system.In some embodiments, (a) is a first RNA, (b) is a second RNA, (c) is a first RNA and / or (d) is a fourth RNA.In some embodiments, (e) is at least one further RNA encoding the at least one further antigen.In some embodiments, the immunogenic composition comprises a plurality of (e) being RNAs.In some embodiments, (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is an RNA.Messenger RNA (mRNA) is a single-stranded RNA molecule that corresponds to the genetic sequence of a gene and is read by ribosomes in the process of producing a protein. mRNA vaccines may utilise non-replicating mRNA or self-replicating RNA (also referred to as self-amplifying mRNA or SAM). Non-replicating mRNA-based vaccines typically encode an antigen of interest and contain 5' and 3' untranslated regions (UTRs), a 5’ cap and a poly(A) tail; whereas self-amplifying RNAs also encode viral replication machinery that enables intracellular RNA amplification.In some embodiments, at least one nucleic acid of the immunogenic composition, suitably of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4), is a mRNA.In some embodiments, said first, second, third and / or fourth nucleic acid is a mRNA.In some embodiments, a dose of each said first, second, third and / or fourth mRNA is 1 to 200 pg, suitably 1 to 60 pg, suitably 2 to 25 pg.In some embodiments, a dose of each said first, second, third and / or fourth mRNA is 2 to 25 pg, optionally 2 to 18 pg, optionally 2 to 9 pg, optionally 2 to 6 pg, optionally 3 to 25 pg, 3 to 18 pg, 3 to 9 pg, optionally 3 to 6 pg.In some embodiments, a dose of each said first, second, third and / or fourth mRNA isI , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 pg, optionally 2, 3, 6, 9 or 18 pg.In some embodiments, a dose of each said first, second, third and / or fourth mRNA is 3, 6, 9, 12 or 18 pg.In some embodiments, a dose of each said first, second, third and / or fourth mRNA is 0.5 to 200 pg, optionally 2 to 25 pg, optionally 2 to 30 pg, optionally 2 to 40 pg, optionally 2 to 45 pg, optionally 2 to 50 pg, optionally 2 to 75 pg.In some embodiments, a dose of each said first, second, third and / or fourth mRNA is 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 30, 35, 36, 37, 38, 39, 40, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 71 , 72, 73, 74 or 75 pg, optionally 3, 6, 9, 24, 36, 48 or 72 pg.In some embodiments, a dose of each said first, second, third and / or fourth mRNA is 3, 6, 9, 24, 36, 48 or 72 pg.In some embodiments, a dose of said first mRNA is comprised between 0.5 and 15 pg, optionally between 2 and 10 pg.In some embodiments, a dose of said first mRNA is 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 or 15 pg.In some embodiments, a dose of said first mRNA is 3, 6 or 9 pg.In some embodiments, a dose of said second mRNA is comprised between 0.5 and 15 pg, optionally between 2 and 10 pg.In some embodiments, a dose of said second mRNA is 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10,I I , 12, 13, 14 or 15 pg.In some embodiments, a dose of said second mRNA is 3, 6 or 9 pg.In some embodiments, a dose of said third mRNA is comprised between 15 and 100 pg, optionally between 20 and 75 pg.In some embodiments, a dose of said third mRNA is 20, 21 , 22, 23, 24, 25, 30, 35, 36, 37, 38, 39, 40, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 71 , 72, 73, 74 or 75 pg.In some embodiments, a dose of said third mRNA is 24, 36, 48 or 72 pg.In some embodiments, a dose of said fourth mRNA is comprised between 15 and 100 pg, optionally between 20 and 75 pg.In some embodiments, a dose of said fourth mRNA is 20, 21 , 22, 23, 24, 25, 30, 35, 36, 37, 38, 39, 40, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 71 , 72, 73, 74 or 75 pg.In some embodiments, a dose of said fourth mRNA is 24, 36, 48 or 72 pg.In some embodiments, said at least one further nucleic acid (e) is an mRNA.In some embodiments, a dose of each said at least one further mRNA is 1 to 200 pg, suitably 1 to 60 pg, suitably 2 to 25 pg.In some embodiments, a dose of each said at least one further mRNA is 2 to 25 pg, optionally 2 to 18 pg, optionally 2 to 9 pg, optionally 2 to 6 pg, optionally 3 to 25 pg, 3 to 18 pg, 3 to 9 pg, optionally 3 to 6 pg.In some embodiments, a dose of each said at least one further mRNA is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 pg, optionally 2, 3, 6, 9 or 18 pg.In some embodiments, a dose of each said at least one further mRNA is 3, 6, 9, 12 or 18 pg.In some embodiments, a dose of each said at least one further mRNA is 0.5 to 200 pg, optionally 2 to 10 pg, 2 to 25 pg, optionally 2 to 30 pg, optionally 2 to 40 pg, optionally 2 to 45 pg, optionally 2 to 50 pg, optionally 2 to 75 pg.In some embodiments, a dose of each said at least one further mRNA is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 30, 35, 36, 37, 38, 39, 40, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 71 , 72, 73, 74or 75 pg, optionally 3, 6, 9, 24, 36, 48 or 72 pg.In some embodiments, a dose of each at least one further mRNA is 3, 6, 9, 24, 36, 48 or 72 pg.In some embodiments, a dose of each at least one further mRNA is comprised between 2 to 10 pg, suitably is 3 pg.In some embodiments, the immunogenic composition comprises a plurality of (e) being mRNAs.In some embodiments, the composition comprises at least three, four, five, six, seven or eight mRNAs, optionally three to eight mRNAs, optionally five to ten mRNAs, optionally seven or eight mRNAs.In some embodiments, the third, fourth, fifth, sixth, seventh and / or eighth nucleic acid is an mRNA.In some embodiments, (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is an mRNA.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 1 to 200 pg, suitably 1 to 60 pg, suitably 1 to 25 pg, suitably 2 to 25 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 1 to 25 pg, optionally 2 to 25 pg, optionally 2 to 18 pg, optionally 2 to 9 pg, optionally 2 to 6 pg, optionally 3 to 25 pg, 3 to 18 pg, 3 to 9 pg, optionally 3 to 6 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 pg, optionally 1 , 2, 3, 6, 9 or 18 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 1 , 2, 3, 6, 9, 12 or 18 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 0.5 to 200 pg, optionally 2 to 10 pg, 2 to 25 pg, optionally 2 to 30 pg, optionally 2 to 40 pg, optionally 2 to 45 pg, optionally 2 to 50 pg, optionally 2 to 75 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 30, 35, 36, 37, 38, 39, 40, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 71 , 72, 73, 74 or 75 pg, optionally 3, 6, 9, 24, 36, 48 or 72 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 3, 6, 9, 24, 36, 48 or 72 pg.Also provided herein is an immunogenic composition for use in the treatment or prophylaxis of an infection with an Influenza virus, wherein the immunogenic composition comprises:(a) a first mRNA encoding a HA antigen of a strain of a first subtype of Influenza A virus;(b) a second mRNA encoding a HA antigen of a strain of a second subtype of Influenza A virus; and(c) a third mRNA encoding a HA antigen of a first strain of Influenza B virus, wherein an immune response is elicited against HA antigens of said strains of first and second subtypes of Influenza A virus, said first strain of Influenza B virus and at least one further HA antigen subtype of Influenza A virus, being different from any of the HA antigen subtypes of Influenza A virus encoded by an mRNA present in the composition.Also provided herein is an immunogenic composition for use in the treatment or prophylaxis of an infection with an Influenza virus, wherein the immunogenic composition comprises:(a) a first mRNA encoding a HA antigen of a strain of a first subtype of Influenza A virus;(b) a second mRNA encoding a HA antigen of a strain of a second subtype of Influenza A virus;(c) a third mRNA encoding a HA antigen of a first strain of Influenza B virus; and(d) a fourth mRNA encoding a HA antigen of a second strain of Influenza B virus, wherein an immune response is elicited against HA antigens of said strains of first and second subtypes of Influenza A virus, said first and second strains of Influenza B virus and at least one further HA antigen subtype of Influenza A virus, being different from any of the HA antigen subtypes of Influenza A virus encoded by an mRNA present in the composition.In some embodiments, said first strain of Influenza B virus of (c) and said second strain of Influenza B virus of (d) are identical.In some embodiments, (c) and (d) are identical.In some embodiments, said first strain of Influenza B virus of (c) and said second strain of Influenza B virus of (d) are different.In some embodiments, (c) and (d) are different.In some embodiments, a dose of each of (c) and (d) is comprised between 15 and 100 pg, optionally between 20 and 75 pg.In some embodiments, a dose of each of (c) and (d) is 20, 21 , 22, 23, 24, 25, 30, 35, 36, 37, 38, 39, 40, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 1 , 72, 73, 74 or 75 pg.In some embodiments, a dose of each of (c) and (d) is 24, 36, 48 or 72 pg.In some embodiments, a dose of (c) and (d) is 5 to 50 pg, optionally 10 to 40 pg, optionally 12 to 36 pg.In some embodiments, a dose of (c) and (d) is 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35,36, 37, 38, 39 or 40 pg.In some embodiments, a dose of (c) and (d) is comprised between 20 and 200 pg, optionally between 40 and 150 pg.In some embodiments, a dose of (c) and (d) is 45, 46, 47, 48, 49, 50, 60, 70, 71 , 72, 73, 74, 75, 80, 90, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 141 , 142, 143, 144, 145 or 150 pg-In some embodiments, a dose of (c) and (d) is 48, 72, 96 or 144 pg.In some embodiments, a dose of each of (a) and (b) is comprised between 0.5 and 15 pg, optionally between 2 and 10 pg.In some embodiments, a dose of each of (a) and (b) is 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 or 15 pg.In some embodiments, a dose of each of (a) and (b) is 3, 6 or 9 pg.In some embodiments, a dose of (a) and (b) is 2 to 20 pg, optionally 5 to 15 pg, optionally 6 to 12 pg.In some embodiments, a dose of (a) and (b) is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 pg.In some embodiments, a dose of (a) and (b) is 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 or 15 pg.In some embodiments, a dose of (a) and (b) is comprised between 2 and 30 pg, optionally between 5 and 20 pg.In some embodiments, a dose of (a) and (b) is 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 pg.In some embodiments, a dose of (a) and (b) is 6, 12 or 18 pg.In some embodiments, a dose of (a), (b), (c) and (d) is 5 to 75 pg, optionally 10 to 60 pg, optionally 12 to 48 pg.In some embodiments, a dose of (a), (b), (c) and (d) is 35 to 75 pg.In some embodiments, a dose of (a), (b), (c) and (d) is 35, 36, 37, 38, 39, 40, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 70, 71 , 72, 73, 74 or 75 pg.In some embodiments, a dose of (a), (b), (c) and (d) is 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 24, 24, 25, 26, 27, 28, 29, 30, 45, 46, 47, 48, 49, 50, 55, 60 pg.In some embodiments, a dose of (a), (b) and (c) is 25 to 150 pg, optionally 25 to 100 pg, optionally 30 to 90 pg.In some embodiments, a dose of (a), (b) and (c) is 25 to 100 pg.In some embodiments, a dose of (a), (b) and (c) is 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 65, 70, 75, 80, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95 or 100 pg.In some embodiments, a dose of (a), (b) and (c) is 30, 36, 54, 60 or 90 pg.In some embodiments, a dose of (c) and (d) is 5 to 50 pg, optionally 10 to 40 pg, optionally 12 to 36 pg, and a dose of (a) and (b) is 2 to 20 pg, optionally 5 to 15 pg, optionally 6 to 12 pg.In some embodiments, a dose of (c) and (d) is 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35,36, 37, 38, 39 or 40 pg, and a dose of (a) and (b) is 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 or 15 pg.In some embodiments, a dose of (c) is comprised between 15 and 100 pg, optionally between 20 and 75 pg, and a dose of (a) and (b) is comprised between 2 and 30 pg, optionally between 5 and 20 pg.In some embodiments, a dose of (c) is 24, 36, 48 or 72 pg, and a dose of (a) and (b) is 6, 12 or 18 pg.In some embodiments, the immunogenic composition further comprises:(e1) a fifth mRNA encoding a NA of the first subtype of Influenza A virus;(e2) a sixth mRNA encoding a NA of the second subtype of Influenza A virus; and(e3) a seventh mRNA encoding a NA of the first strain of Influenza B virus.In some embodiments, a dose of (e1), (e2) and (e3) is 2 to 50 pg, optionally 2 to 30 pg, optionally 5 to 20, optionally 9 to 18 pg.In some embodiments, a dose of (e1), (e2) and (e3) is 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 pg.In some embodiments, a dose of (e1), (e2) and (e3) is 9 to 36 pg.In some embodiments, a dose of (e1), (e2) and (e3) is 9, 18, 27 or 36 pg.In some embodiments, a dose of (e1), (e2) and (e3) is 0.5 to 50 pg, optionally 2 to 20 pg, optionally 5 to 15. In some embodiments, a dose of (e1), (e2) and (e3) is 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 or 15 pg.In some embodiments, a dose of (e1), (e2) and (e3) is 5 to 15 pg.In some embodiments, a dose of (e1), (e2) and (e3) is 9 pg.In some embodiments, a dose of each of (e1), (e2) and (e3) is 0.5 to 20 pg, optionally0.5 to 10 pg, optionally 0.5 to 5, optionally 1 to 5 pg, optionally 2 to 5 pg. In some embodiments, a dose of each of (e1), (e2) and (e3) is 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 pg.In some embodiments, a dose of each of (e1), (e2) and (e3) is 1 to 5 pg.In some embodiments, a dose of each of (e1), (e2) and (e3) is 3 pg.In some embodiments, the immunogenic composition further comprises:(e4) an eighth mRNA encoding a NA of the second strain of Influenza B virus.In some embodiments, a dose of (e1), (e2), (e3) and (e4) is 5 to 50 pg, optionally 10 to 50 pg, optionally 12 to 48 pg.In some embodiments, a dose of (e1), (e2), (e3) and (e4) is 10, 11 , 12, 13, 14, 15, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 36, 37, 38, 39, 40, 45, 46, 47, 48 pg.In some embodiments, a dose of (e1), (e2), (e3) and (e4) is comprised between 0.5 to 50 pg, optionally between 2 to 25 pg, optionally between 5 to 20 pg.In some embodiments, a dose of (e1), (e2), (e3) and (e4) is 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 pg.In some embodiments, a dose of (e1), (e2), (e3) and (e4) is 12 pg.In some embodiments, a dose of each of (e1), (e2), (e3) and (e4) is 0.5 to 20 pg, optionally 0.5 to 10 pg, optionally 0.5 to 5, optionally 1 to 5 pg, optionally 2 to 5 pg. In some embodiments, a dose of each of (e1), (e2) and (e3) is 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 pg.In some embodiments, a dose of each of (e1), (e2), (e3) and (e4) is 1 to 5 pg.In some embodiments, a dose of each of (e1), (e2), (e3) and (e4) is 3 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 1 to 200 pg, suitably 1 to 60 pg, suitably 1 to 25 pg, suitably 2 to 25 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 1 to 25 pg, optionally 2 to 25 pg, optionally 2 to 18 pg, optionally 2 to 9 pg, optionally 2 to 6 pg, optionally 3 to 25 pg, 3 to 18 pg, optionally 3 to 12 pg, optionally 3 to 9 pg, optionally 3 to 6 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 pg, optionally 1 , 2, 3, 6, 9 or 18 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 1 , 2, 3, 6, 9, 12 or 18 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 0.5 to 200 pg, optionally 2 to 10 pg, 2 to 25 pg, optionally 2 to 30 pg, optionally 2 to 40 pg, optionally 2 to 45 pg, optionally 2 to 50 pg, optionally 2 to 75 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 30, 35, 36, 37, 38, 39, 40, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 71 , 72, 73, 74 or 75 pg, optionally 3, 6, 9, 24, 36, 48 or 72 pg.In some embodiments, a dose of each (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) is 3, 6, 9, 24, 36, 48 or 72 pg. mRNAs used herein are suitably provided in purified or substantially purified form i.e. substantially free from proteins (e.g., enzymes), other nucleic acids (e.g. DNA and nucleoside phosphate monomers), and the like, generally being at least about 50% pure (by weight), and usually at least 90% pure, such as at least 95% or at least 98% pure. mRNAs used herein may be prepared in many ways e.g. by chemical synthesis in whole or in part, by digesting longer nucleic acids using nucleases (e.g. restriction enzymes), by joining shorter nucleic acids or nucleotides (e.g. using ligases or polymerases), from genomic or cDNA libraries, etc. In particular, mRNA may be prepared enzymatically using a DNA template. mRNAs used herein may be an artificial nucleic acid. The term “artificial nucleic acid” as used herein is intended to refer to a nucleic acid that does not occur naturally. In other words, an artificial nucleic acid may be understood as a non-natural nucleic acid molecule. Such nucleic acid molecules may be non-natural due to its individual sequence (e.g. G / C content modified coding sequence, UTRs) and / or due to other modifications, e.g. structural modifications of nucleotides. Typically, artificial nucleic acid may be designed and / or generated by genetic engineering to correspond to a desired artificial sequence of nucleotides. In thiscontext, an artificial nucleic acid is a sequence that may not occur naturally, i.e. a sequence that differs from the wild type or reference sequence / the naturally occurring sequence by at least one nucleotide (via e.g. codon modification as further specified below). The term “artificial nucleic acid” is not restricted to mean “one single molecule” but is understood to comprise an ensemble of essentially identical nucleic acid molecules. Accordingly, it may relate to a plurality of essentially identical nucleic acid molecules.In some embodiments, the mRNAs used herein may be a modified and / or stabilized nucleic acid, suitably a modified and / or stabilized artificial mRNA.According to some embodiments, the mRNAs used herein may thus be provided as a “stabilized artificial nucleic acid” or “stabilized coding nucleic acid” that is to say a nucleic acid showing improved resistance to in vivo degradation and / or a nucleic acid showing improved stability in vivo, and / or a nucleic acid showing improved translatability in vivo. In the following, specific suitable modifications / adaptations in this context are described which are suitably to “stabilize” the nucleic acid. mRNAs used herein may also be codon optimized. In some embodiments, the mRNAs used herein comprises at least one codon modified coding sequence. In some embodiments, the coding sequence of the mRNAs used herein is a codon modified coding sequence. Suitably, the amino acid sequence encoded by the codon modified coding sequence is not being modified compared to the amino acid sequence encoded by the corresponding wild type or reference coding sequence.In some embodiments, the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) comprises a coding sequence which is a codon modified coding sequence, wherein the amino acid sequence encoded by the codon modified coding sequence is optionally not being modified compared to the amino acid sequence encoded by the corresponding wild type or reference coding sequence.In some embodiments, mRNAs used herein may be codon optimized for expression in human cells. By “codon optimized” is intended modification with respect to codon usage may increase translation efficacy and / or half-life of the nucleic acid. 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 or reference 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 acidand may be used interchangeably (cf. Table 1 of W02020002525) to optimize / modify the coding sequence for in vivo applications as outlined herein.In embodiments, the mRNAs used herein may be modified, wherein the C content of the at least one coding sequence may be increased, suitably maximized, compared to the C content of the corresponding wild type or reference coding sequence (herein referred to as “C maximized coding sequence”). The amino acid sequence encoded by the C maximized coding sequence of the mRNA is suitably not modified compared to the amino acid sequence encoded by the respective wild type or reference coding sequence. The generation of a C maximized nucleic acid sequences may suitably be carried out using a modification method according to WO20 15 / 062738. In this context, the disclosure of WO2015 / 062738 is included herewith by reference.In some embodiments, the mRNAs used herein may be modified, wherein the codons in the at least one coding sequence 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 humans. Accordingly, the coding sequence of the mRNAs used herein is suitably 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. For example, in the case of the amino acid Ala, the wild type or reference coding sequence is suitably 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 e.g. Table 1 of W02020002525). Accordingly, such a procedure (as exemplified for Ala) is applied for each amino acid encoded by the coding sequence of the RNA to obtain sequences adapted to human codon usage.In embodiments, the mRNAs used herein may be modified, wherein the codon adaptation index (CAI) may be increased or suitably maximised in the at least one coding sequence (herein referred to as “CAI maximized coding sequence”). In some embodiments, all codons of the wild type or reference nucleic acid sequence that are relatively rare in e.g. a human are exchanged for a respective codon that is frequent in the e.g. a human, wherein the frequent codon encodes the same amino acid as the relatively rare codon. Suitably, the most frequent codons are used for each amino acid of the encoded protein (see Table 1 of W02020002525, most frequent human codons are marked with asterisks). Suitably, the mRNAs used herein comprise 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. In some embodiments, the codon adaptation index (CAI) of the at least one coding sequence is 1 (CAI=1). For example, in the case of the amino acid Ala, the wild type orreference coding sequence may be adapted in a way that the most frequent human codon “GCC” is always used for the amino acid. Accordingly, such a procedure (as exemplified for Ala) may be applied for each amino acid encoded by the coding sequence of the mRNA to obtain CAI maximized coding sequences.In embodiments, the mRNAs used herein may be modified, wherein the G / C content of the at least one coding sequence may be modified compared to the G / C content of the corresponding wild type or reference 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 that comprises a modified, suitably an increased number of guanosine and / or cytosine nucleotides as compared to the corresponding wild type or reference coding sequence. Such an increased number may be generated by substitution of codons containing adenosine or thymidine nucleotides by codons containing guanosine or cytosine nucleotides. Suitably, nucleic acid sequences having an increased G / C content are more stable or show a better expression than sequences having an increased A / ll. The amino acid sequence encoded by the G / C content modified coding sequence of the mRNA is suitably not modified as compared to the amino acid sequence encoded by the respective wild type or reference sequence. In some embodiments, the G / C content of the coding sequence of the nucleic acid is increased by at least 10%, 20%, 30%, suitably by at least 40% compared to the G / C content of the coding sequence of the corresponding wild type or reference nucleic acid sequence. The generation of a G / C content optimized mRNA sequence may be carried out using a method according to W02002 / 098443. In this context, the disclosure of W02002 / 098443 is included in its full scope in the present invention.In embodiments, the mRNAs used herein may be modified by altering the number of A and / or II nucleotides in the nucleic acid sequence with respect to the number of A and / or II nucleotides in the original nucleic acid sequence (e.g. the wild type or reference sequence). In some embodiments, such an AU alteration is performed to modify the retention time of the individual nucleic acids in a composition, to (i) allow co-purification using a HPLC method, and / or to allow analysis of the obtained nucleic acid composition. Such a method is described in detail in published PCT application WO2019092153A1. Claims 1 to 70 of WO2019092153A1 herewith incorporated by reference.In some embodiments, the modified RNA sequence is selected from C maximized coding sequence, CAI maximized coding sequence, human codon usage adapted coding sequence, G / C content modified (or optimized) sequence, A / U alteration, or any combination thereof.In some embodiments, the RNA sequence has a G / C content of at least about 45%, 50%, 55%, or 60%. In particular embodiments, the RNA sequence has a G / C content of at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70%.Suitably, when transfected into mammalian host cells, the mRNA comprising a modified sequence has a stability of between 12-18 hours, or greater than 18 hours, e.g., 24, 36, 48, 60, 72, or greater than 72 hours and are capable of being expressed by the mammalian host cell (e.g. a muscle cell).Suitably, when transfected into mammalian host cells, the mRNA comprising a modified RNA sequence is translated into protein, wherein the amount of protein is at least comparable to, or suitably at least 10% more than, or at least 20% more than, or at least 30% more than, or at least 40% more than, or at least 50% more than, or at least 100% more than, or at least 200% or more than the amount of protein obtained by a naturally occurring or wild type or reference coding sequence transfected into mammalian host cells.In some embodiments, the mRNAs used herein comprise at least one poly(N) sequence, e.g. at least one poly(A) sequence, at least one poly(ll) sequence, at least one poly(C) sequence, or combinations thereof.In some embodiments, the mRNAs used herein comprise at least one poly(A) sequence. Suitably, a poly A tail (e.g., of about 30 adenosine residues or more) may be attached to the 3' end of the RNA to increase its half-life.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 e.g. intended to be a sequence of adenosine nucleotides, typically located at the 3’-end of a linear RNA (or in a circular RNA), of up to about 1000 adenosine nucleotides. In some embodiments, the 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 the at least one nucleotide - or a stretch of nucleotides - different from an adenosine nucleotide).The poly(A) sequence may comprise about 10 to about 500 adenosine nucleotides, about 10 to about 200 adenosine nucleotides, about 40 to about 200 adenosine nucleotides, or about 40 to about 150 adenosine nucleotides. In some embodiments, the length of thepoly(A) sequence may be at least about or even more than about 10, 50, 64, 75, 100, 200, 300, 400, or 500 adenosine nucleotides.In some embodiments, the mRNAs used herein comprise at least one poly(A) sequence comprising about 30 to about 200 adenosine nucleotides. In some embodiments, the poly(A) sequence comprises about 64 adenosine nucleotides (A64). In other some embodiments, the poly(A) sequence comprises about 100 adenosine nucleotides (A100). In other embodiments, the poly(A) sequence comprises about 150 adenosine nucleotides.In further embodiments, the mRNAs used herein comprise at least one poly(A) sequence comprising about 100 adenosine nucleotides, wherein the poly(A) sequence is interrupted by non-adenosine nucleotides, suitably by 10 non-adenosine nucleotides (A30- N10-A70).The poly(A) sequence as defined herein may be located directly at the 3’ terminus of the mRNA. In some embodiments, the 3’-terminal nucleotide (that is the last 3’-terminal nucleotide in the polynucleotide chain) is the 3’-terminal A nucleotide of the at least one poly(A) sequence. The term “directly located at the 3’ terminus” has to be understood as being located exactly at the 3’ terminus - in other words, the 3’ terminus of the nucleic acid consists of a poly(A) sequence terminating with an A nucleotide.In an embodiment, the mRNAs used herein comprise a poly(A) sequence of at least 70 adenosine nucleotides, suitably consecutive at least 70 adenosine nucleotides, wherein the 3’- terminal nucleotide is an adenosine nucleotide.In embodiments, the poly(A) sequence of the nucleic acid 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 methods and means as described in WO2016174271.In embodiments, the mRNAs used herein comprise at least one poly(C) sequence.The term “poly(C) sequence” as used herein is intended to be a sequence of cytosine nucleotides of up to about 200 cytosine nucleotides. In embodiments, the poly(C) sequence comprises about 10 to about 200 cytosine nucleotides, about 10 to about 100 cytosine nucleotides, about 20 to about 70 cytosine nucleotides, about 20 to about 60 cytosinenucleotides, or about 10 to about 40 cytosine nucleotides. In an embodiment, the poly(C) sequence comprises about 30 cytosine nucleotides.In embodiments, the mRNAs used herein comprise at least one histone stem-loop (hSL) or histone stem loop structure. In some embodiments, the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) comprises at least one histone stem-loop.The term “histone stem-loop” (abbreviated as “hSL” in e.g. the sequence listing) is intended to refer to nucleic acid sequences that form a stem-loop secondary structure predominantly found in histone mRNAs.Histone stem-loop sequences / structures may suitably be selected from histone stemloop sequences as disclosed in WO2012019780, the disclosure relating to histone stem-loop sequences / histone stem-loop structures incorporated herewith by reference. A histone stemloop sequence that may be used may be derived from formulae (I) or (II) of W02012019780. According to a further embodiment, the mRNA comprises at least one histone stem-loop sequence derived from at least one of the specific formulae (la) or (Ila) of the patent application W02012019780.In other embodiments, the mRNAs used herein does not comprise a hsL as defined herein.The mRNAs used herein may be modified by the addition of a 5’-cap structure, which suitably stabilizes the RNA and / or enhances expression of the encoded antigen and / or reduces the stimulation of the innate immune system (after administration to a subject).The term “5’-cap structure” as used herein will be recognized and understood by the person of ordinary skill in the art, and is e.g. intended to refer to a 5’ modified nucleotide, particularly a guanine nucleotide, positioned at the 5’-end of an RNA, e.g. an mRNA.For example, the 5' end of the RNA may be capped with a modified ribonucleotide with the structure m7G (5') ppp (5') N (cap 0 structure) or a derivative thereof, which can be incorporated during RNA synthesis or can be enzymatically engineered after RNA transcription (e.g., by using Vaccinia Virus Capping Enzyme (VCE) consisting of mRNA triphosphatase, guanylyl-transferase and guanine-7-methytransferase, which catalyzes the construction of NT- monomethylated cap 0 structures). Cap 0 structure plays an important role in maintaining the stability and translational efficacy of the RNA molecule. The 5' cap of the mRNA molecule may be further modified by a 2'-O-Methyltransferase which results in the generation of a cap 1 structure (m7Gppp [m2'-O] N), which may further increase translation efficacy.In some embodiments, the 5’-cap structure is connected via a 5’-5’-triphosphate linkage to the RNA.5’-cap structures which may be suitable are capO (methylation of the first nucleobase, e.g. m7GpppN), 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.In some embodiments, the mRNAs used herein, suitably the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4), comprises a 5’ cap, preferably m7G, capO, cap1 , cap2, a modified capO or a modified cap1 structure, suitably a 5’-cap1 structure.A 5’-cap (capO or cap1) structure may be formed in chemical RNA synthesis or in 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 e.g. intended to refer to a non-polymerizable dinucleotide or tri-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 templatedependent 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 (WG2008016473, WG2008157688, WG2009149253, WO2011015347, and WO2013059475). Further suitable cap analogues in that context are described in WO2017066793, WO2017066781 , WO2017066791 , WO2017066789, WO2017 / 053297, WO2017066782, WO2018075827 and WO2017066797 wherein the disclosures referring to cap analogues are incorporated herewith by reference.In embodiments, a modified cap1 structure is generated using tri-nucleotide cap analogue as disclosed in WO2017053297, WO2017066793, WO2017066781 ,WO2017066791 , WO2017066789, WO2017066782, WO2018075827 and WO2017066797. In particular, any cap structures derivable from the structure disclosed in claim 1-5 of WO2017053297 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.In embodiments, the mRNAs used herein comprises a cap1 structure.In embodiments, the 5’-cap structure may be added co-transcriptionally using trinucleotide cap analogue as defined herein, suitably in an RNA in vitro transcription reaction as defined herein.In embodiments, the cap1 structure of the mRNA is formed using co-transcriptional capping using tri-nucleotide cap analogues m7G(5’)ppp(5’)(2’OMeA)pG or m7G(5’)ppp(5’)(2’OMeG)pG. A suitable cap1 analogues in that context is m7G(5’)ppp(5’)(2’OMeA)pG.In other embodiments, the cap1 structure of the mRNA is formed using co- transcriptional capping using tri-nucleotide cap analogue 3’0Me-m7G(5’)ppp(5’)(2’0MeA)pG.In other embodiments, a capO structure of the mRNAs used herein is formed using co- transcriptional capping using cap analogue 3’0Me-m7G(5’)ppp(5’)G.In other embodiments, the 5’-cap structure is formed via enzymatic capping using capping enzymes (e.g. vaccinia virus capping enzymes and / or cap-dependent 2’-0 methyltransferases) to generate capO or cap1 or cap2 structures. The 5’-cap structure (capO or cap1) may be added using immobilized capping enzymes and / or cap-dependent 2’-0 methyltransferases using methods and means disclosed in WO2016193226.For determining the presence / absence of a capO or a cap1 structure, a capping assay as described in published PCT application W02015101416, in particular, as described in claims 27 to 46 of published PCT application W02015101416 can be used. Other capping assays that may be used to determine the presence / absence of a capO or a cap1 structure of an RNA are described in PCT / EP2018 / 08667, or published PCT applications WO2014152673 and WO2014152659.In embodiments, the mRNAs used herein comprise an m7G(5’)ppp(5’)(2’OMeA) cap structure. In such embodiments, the mRNAs comprise a 5’-terminal m7G cap, and anadditional methylation of the ribose of the adjacent nucleotide of m7GpppN, in that case, a 2’0 methylated Adenosine. In some embodiments, about 70%, 75%, 80%, 85%, 90%, 95% of the RNA (species) comprises such a cap1 structure as determined using a capping assay.In other embodiments, the mRNAs used herein comprise an m7G(5’)ppp(5’)(2’OMeG) cap structure. In such embodiments, the mRNAs comprise a 5’-terminal m7G cap, and an additional methylation of the ribose of the adjacent nucleotide, in that case, a 2’0 methylated guanosine. In some embodiments, about 70%, 75%, 80%, 85%, 90%, 95% of the coding RNA (species) comprises such a cap1 structure as determined using a capping assay.Accordingly, the first nucleotide of the mRNA sequence, that is, the nucleotide downstream of the m7G(5’)ppp structure, may be a 2’0 methylated guanosine or a 2’0 methylated adenosine.Suitably, the mRNAs used herein comprise a ribosome binding site, also referred to as “Kozak sequence”. In embodiments, the A / ll (A / T) content in the environment of the ribosome binding site of the mRNAs used herein may be increased compared to the A / ll (A / T) content in the environment of the ribosome binding site of its respective wild type or reference nucleic acid. This modification (an increased A / ll (A / T) content around the ribosome binding site) increases the efficiency of ribosome binding to the mRNA. An effective binding of the ribosomes to the ribosome binding site in turn has the effect of an efficient translation the mRNA.In some embodiments, the mRNAs used herein may comprise at least one heterologous untranslated region (UTR), e.g. a 5’ UTR and / or a 3’ UTR.The term “untranslated region” or “UTR” or “UTR element” will be recognized and understood by the person of ordinary skill in the art, and are e.g. intended to refer to a part of a nucleic acid molecule typically located 5’ or 3’ of a coding sequence. An UTR is not translated into protein. An UTR may be part of a nucleic acid, e.g. a DNA or an RNA. An UTR may comprise elements for controlling gene expression, also called regulatory elements. Such regulatory elements may be, e.g., ribosomal binding sites, miRNA binding sites, promotor elements etc.In embodiments, the mRNAs used herein comprise a protein-coding region (“coding sequence” or “cds”), and 5’-UTR and / or 3’-UTR. Notably, UTRs may harbor regulatory sequence elements that determine nucleic acid, e.g. RNA turnover, stability, and localization. Moreover, UTRs may harbor sequence elements that enhance translation. In medical application of nucleic acid sequences (including DNA and RNA), translation of the nucleic acid into at least one peptide or protein is of paramount importance to therapeutic efficacy. Certaincombinations of 3’-UTRs and / or 5’-UTRs may enhance the expression of operably linked coding sequences encoding peptides or proteins of the invention. Nucleic acid molecules harboring the UTR combinations advantageously enable rapid and transient expression of antigenic peptides or proteins after administration to a subject, suitably after intramuscular administration. Accordingly, the mRNA comprising certain combinations of 3’-UTRs and / or 5’- UTRs as provided herein is particularly suitable for administration as a vaccine, in particular, suitable for administration into the muscle, the dermis, or the epidermis of a subject.In some embodiments, the mRNAs used herein comprise at least one heterologous 5’- UTR and / or at least one heterologous 3’-UTR. The heterologous 5’-UTRs or 3’-UTRs may be derived from naturally occurring genes or may be synthetically engineered. In embodiments, the mRNA comprises at least one coding sequence as defined herein operably linked to at least one (heterologous) 3’-UTR and / or at least one (heterologous) 5’-UTR.In embodiments, the mRNAs used herein comprise at least one heterologous 3’-UTR.In some embodiments, the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) comprises a 3’ UTR.The term “3’-untranslated region” or “3’-UTR” or “3’-UTR element” will be recognized and understood by the person of ordinary skill in the art, and are e.g. intended to refer to a part of a nucleic acid molecule located 3’ (i.e. downstream) of a coding sequence and which is not translated into protein. A 3’-UTR may be part of a nucleic acid, e.g. a DNA or an RNA, located between a coding sequence and an (optional) terminal poly(A) sequence. A 3’-UTR may comprise elements for controlling gene expression, also called regulatory elements. Such regulatory elements may be, e.g., ribosomal binding sites, miRNA binding sites etc.In some embodiments, the mRNAs used herein comprise a 3’-UTR, which may be derivable from a gene that relates to an RNA with enhanced half-life (i.e. that provides a stable RNA).In some embodiments, a 3’-UTR comprises one or more of a polyadenylation signal, a binding site for proteins that affect a nucleic acid stability of location in a cell, or one or more miRNA or binding sites for miRNAs.In embodiments, the mRNAs used herein comprise at least one heterologous 3’-UTR, wherein the at least one heterologous 3’-UTR comprises a nucleic acid sequence is derived or selected 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.In some embodiments, the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) comprises a 3’ UTR comprising or consisting of a nucleic acid sequence derived from a 3’-UTR of a gene selected from PSMB3, ALB7, CASP1 , COX6B1 , GNAS, NDUFA1 and RPS9, or from a homolog, a fragment or a variant of any one of these genes.Nucleic acid sequences in that context can be derived from published PCT application W02019077001A1 , in particular, claim 9 of WO2019077001 A1. The corresponding 3’-UTR sequences of claim 9 of W02019077001A1 are herewith incorporated by reference.In some embodiments, the mRNAs used herein may comprise a 3’-UTR as described in WO2016107877, the disclosure of WO2016107877 relating to 3’-UTR sequences herewith incorporated by reference. Suitable 3’-UTRs are SEQ ID NOs: 1-24 and SEQ ID NOs: 49-318 of WO2016107877, or fragments or variants of these sequences. In other embodiments, the mRNAs used herein comprise a 3’-UTR as described in WO2017036580, the disclosure of WO2017036580 relating to 3’-UTR sequences herewith incorporated by reference. Suitable 3’-UTRs are SEQ ID NOs: 152-204 of WO2017036580, or fragments or variants of these sequences. In other embodiments, the mRNAs used herein comprise a 3’-UTR as described in WO2016022914, the disclosure of WO2016022914 relating to 3’-UTR sequences herewith incorporated by reference. Particularly suitable 3’-UTRs are nucleic acid sequences according to SEQ ID NOs: 20-36 of WQ2016022914, or fragments or variants of these sequences.In embodiments, the mRNAs used herein comprise at least one heterologous 5’-UTR.In some embodiments, the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) comprises a 5’ untranslated region (UTR).The terms “5’-untranslated region” or “5’-UTR” or “5’-UTR element” will be recognized and understood by the person of ordinary skill in the art, and are e.g. intended to refer to a part of a nucleic acid molecule located 5’ (i.e. “upstream”) of a coding sequence and which is not translated into protein. A 5’-UTR may be part of a nucleic acid located 5’ of the coding sequence. Typically, a 5’-UTR starts with the transcriptional start site and ends before the start codon of the coding sequence. A 5’-UTR may comprise elements for controlling gene expression, also called regulatory elements. Such regulatory elements may be, e.g., ribosomal binding sites, miRNA binding sites etc. The 5’-UTR may be post-transcriptionally modified, e.g. by enzymatic or post-transcriptional addition of a 5’-cap structure (e.g. for mRNA as defined herein).In some embodiments, the mRNAs used herein comprise a 5’-UTR, which may be derivable from a gene that relates to an RNA with enhanced half-life (i.e. that provides a stable RNA).In some embodiments, a 5’-UTR comprises one or more of a binding site for proteins that affect an RNA stability or RNA location in a cell, or one or more miRNA or binding sites for miRNAs.In embodiments, the mRNAs used herein, suitably the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4), comprise at least one heterologous 5’-UTR, wherein the at least one heterologous 5’-UTR comprises a nucleic acid sequence is derived or selected from a 5’-UTR of gene selected from HSD17B4, RPL32, ASAH1 , ATP5A1 , MP68, NDUFA4, NOSIP, RPL31 , SLC7A3, TLIBB4B, and LIBQLN2, or from a homolog, a fragment or variant of any one of these genes.Nucleic acid sequences in that context can be selected from published PCT application W02019077001A1 , in particular, claim 9 of WO2019077001 A1. The corresponding 5’-UTR sequences of claim 9 of WO2019077001 A1 are herewith incorporated by reference (e.g., SEQ ID NOs: 1-20 of WO2019077001 A1 , or fragments or variants thereof).In some embodiments, the mRNAs used herein may comprise a 5’-UTR as described in W02013143700, the disclosure of W02013143700 relating to 5’-UTR sequences herewith incorporated by reference. Particularly suitable 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 WQ2013143700, or fragments or variants of these sequences. In other embodiments, the mRNAs used herein comprise a 5’-UTR as described in WQ2016107877, the disclosure of WQ2016107877 relating to 5’-UTR sequences herewith incorporated by reference. Particularly suitable 5’-UTRs are nucleic acid sequences according to SEQ ID NOs: 25-30 and SEQ ID NOs: 319-382 of WQ2016107877, or fragments or variants of these sequences. In other embodiments, the nucleic acid comprises a 5’-UTR as described in WQ2017036580, the disclosure of WQ2017036580 relating to 5’-UTR sequences herewith incorporated by reference. Particularly suitable 5’-UTRs are nucleic acid sequences according to SEQ ID NOs: 1-151 of WQ2017036580, or fragments or variants of these sequences. In other embodiments, the nucleic acid comprises a 5’-UTR as described in WQ2016022914, the disclosure of WQ2016022914 relating to 5’-UTR sequences herewith incorporated by reference. Particularly suitable 5’-UTRs are nucleic acid sequences according to SEQ ID NOs: 3-19 of WQ2016022914, or fragments or variants of these sequences.In some embodiments, the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) comprises an heterologous 5’-UTR that comprises or consists of a nucleic acid sequence derived from a 5’-UTR from HSD17B4 and at least one heterologous 3’-UTR comprises or consists of a nucleic acid sequence derived from a 3’-UTR of PSMB3.In some embodiments, the mRNAs used herein, suitably the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4), comprises from 5’ to 3’: i) 5’-cap1 structure; ii) 5’-UTR derived from a 5’-UTR of a HSD17B4 gene; iii) the coding sequence; iv) 3’-UTR derived from a 3’-UTR of a PSMB3 gene; v) optionally, a histone stem-loop sequence; and vi) poly(A) sequence comprising about 100 A nucleotides, wherein the 3’ terminal nucleotide of said RNA is an adenosine.In embodiments, RNA, suitably mRNA, of the composition has an RNA integrity ranging from about 40% to about 100%.The term “RNA integrity” generally describes whether the complete RNA sequence is present in the composition. Low RNA integrity could be due to, amongst others, RNA degradation, RNA cleavage, incorrect or incomplete chemical synthesis of the RNA, incorrect base pairing, integration of modified nucleotides or the modification of already integrated nucleotides, lack of capping or incomplete capping, lack of polyadenylation or incomplete polyadenylation, or incomplete RNA in vitro transcription. RNA is a fragile molecule that can easily degrade, which may be caused e.g. by temperature, ribonucleases, pH or other factors (e.g. nucleophilic attacks, hydrolysis etc.), which may reduce the RNA integrity and, consequently, the functionality of the RNA.The skilled person can choose from a variety of different chromatographic or electrophoretic methods for determining an RNA integrity. Chromatographic and electrophoretic methods are well-known in the art. In case chromatography is used (e.g. RP- HPLC), the analysis of the integrity of the RNA may be based on determining the peak area (or “area under the peak”) of the full length RNA in a corresponding chromatogram. The peak area may be determined by any suitable software which evaluates the signals of the detector system. The process of determining the peak area is also referred to as integration. The peak area representing the full-length RNA is typically set in relation to the peak area of the total RNA in a respective sample. The RNA integrity may be expressed in % RNA integrity.In the context of aspects of the invention, RNA integrity may be determined using analytical (RP)HPLC. Typically, a test sample of the composition comprising lipid based carrier encapsulating RNA may be treated with a detergent (e.g. about 2% Triton X100) to dissociate the lipid based carrier and to release the encapsulated RNA. The released RNA may be captured using suitable binding compounds, e.g. Agencourt AMPure XP beads (Beckman Coulter, Brea, CA, USA) essentially according to the manufacturer’s instructions. Followingpreparation of the RNA sample, analytical (RP)HPLC may be performed to determine the integrity of RNA. Typically, for determining RNA integrity, the RNA samples may be diluted to a concentration of 0.1 g / l using e.g. water for injection (WFI). About 10pl of the diluted RNA sample may be injected into an HPLC column (e.g. a monolithic poly(styrene-divinylbenzene) matrix). Analytical (RP)HPLC may be performed using standard conditions, for example: Gradient 1 : Buffer A (0.1 M TEAA (pH 7.0)); Buffer B (0.1 M TEAA (pH 7.0) containing 25% acetonitrile). Starting at 30% buffer B the gradient extended to 32% buffer B in 2min, followed by an extension to 55% buffer B over 15 minutes at a flow rate of 1ml / min. HPLC chromatograms are typically recorded at a wavelength of 260nm. The obtained chromatograms may be evaluated using a software and the relative peak area may be determined in percent (%) as commonly known in the art. The relative peak area indicates the amount of RNA that has 100% RNA integrity. Since the amount of the RNA injected into the HPLC is typically known, the analysis of the relative peak area provides information on the integrity of the RNA. Thus, if e.g. 100ng RNA have been injected in total, and 100ng are determined as the relative peak area, the RNA integrity would be 100%. If, for example, the relative peak area would correspond to 80ng, the RNA integrity would be 80%. Accordingly, RNA integrity in the context of the invention is determined using analytical HPLC, suitably analytical RP-HPLC.In embodiments, RNA, suitably mRNA, of the composition has an RNA integrity ranging from about 40% to about 100%. In embodiments, the RNA, suitably mRNA, has an RNA integrity ranging from about 50% to about 100%. In embodiments, the RNA, suitably mRNA, has an RNA integrity ranging from about 60% to about 100%. In embodiments, the RNA, suitably mRNA, has an RNA integrity ranging from about 70% to about 100%. In embodiments, the RNA, suitably mRNA, integrity is for example about 50%, about 60%, about 70%, about 80%, or about 90%. RNA integrity is suitably determined using analytical HPLC, suitably analytical RP-HPLC.In embodiments, the RNA, suitably mRNA, of the composition has an RNA integrity of at least about 50%, suitably of at least about 60%, more suitably of at least about 70%, most suitably of at least about 80% or about 90%. RNA integrity is suitably determined using analytical HPLC, more suitably analytical RP-HPLC.In some embodiments, the RNAs, suitably mRNAs, used herein does not comprise a replicase element (e.g. a nucleic acid encoding a replicase).In some embodiments, the RNAs used herein, suitably the mRNAs used herein, suitably the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4), optionally each, are not self-replicating.In some embodiments, the RNAs used herein, suitably the mRNA used herein, suitably the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4), optionally each, are self-replicating.Chemical ModificationsIn some embodiments, the RNA, suitably mRNA, comprises a coding sequence that consists only of G, C, A and II nucleotides and therefore does not comprise modified nucleotides (except of the 5’ terminal cap structure (capO, cap1 , cap2)).In some embodiments, the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) does not comprise chemically modified nucleotides.In some embodiments, the RNAs, suitably the mRNAs, used herein are modified RNAs, suitably mRNAs, wherein the modification refers to chemical modifications comprising backbone modifications as well as sugar modifications or base modifications.A modified RNA, suitably mRNA, may comprise one or more nucleotide analogs or modified nucleotides (nucleotide analogues / modifications, e.g. backbone modifications, sugar modifications or base modifications). As used herein, "nucleotide analog" or "modified nucleotide" refers to a nucleotide that contains one or more chemical modifications (e.g., substitutions) in or on the nitrogenous base of the nucleoside (e.g. cytosine (C), thymine (T) or uracil (II)), adenine (A) or guanine (G)) and / or one or more chemical modifications in or one the phosphates of the backbone. A nucleotide analog can contain further chemical modifications in or on the sugar moiety of the nucleoside (e.g. ribose, modified ribose, sixmembered sugar analog, or open-chain sugar analog), or the phosphate. The preparation of nucleotides and modified nucleotides and nucleosides are well-known in the art, see the following references: US Patent Numbers 4373071 , 4458066, 4500707, 4668777, 4973679, 5047524, 5132418, 5153319, 5262530, 5700642. Many modified nucleosides and modified nucleotides are commercially available.A backbone modification as described herein is a modification, in which phosphates of the backbone of the nucleotides of the RNA, suitably the mRNA, are chemically modified. A sugar modification as described herein is a chemical modification of the sugar of the nucleotides of the RNA, suitably mRNA. Furthermore, a base modification as described herein is a chemical modification of the base moiety of the nucleotides of the RNA, suitably mRNA. In this context, nucleotide analogues or modifications are suitably selected from nucleotide analogues which are applicable for transcription and / or translation.In some embodiments, the RNAs, suitably the mRNAs, used herein comprise at least one chemical modification.In some embodiments, the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) comprises at least one chemical modification.Modified nucleobases (chemical modifications) which can be incorporated into modified nucleosides and nucleotides and be present in the RNA, suitably mRNA, molecules include: m5C (5-methylcytidine), m5U (5-methyluridine), m6A (N6-methyladenosine), s2U (2- thiouridine), Um (2'-O-methyluridine), m1A (1-methyladenosine); m2A (2-methyladenosine); Am (2-1-O-methyladenosine); ms2m6A (2-methylthio-N6-methyladenosine); i6A (N6- isopentenyladenosine); ms2i6A (2-methylthio-N6isopentenyladenosine); io6A (N6-(cis- hydroxyisopentenyl)adenosine); ms2io6A (2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine); g6A (N6-glycinylcarbamoyladenosine); t6A (N6-threonyl carbamoyladenosine); ms2t6A (2-methylthio-N6-threonyl carbamoyladenosine); m6t6A (N6-methyl-N6- threonylcarbamoyladenosine); hn6A(N6-hydroxynorvalylcarbamoyl adenosine); ms2hn6A (2- methylthio-N6-hydroxynorvalyl carbamoyladenosine); Ar(p) (2'-O-ribosyladenosine (phosphate)); I (inosine); mil (1-methylinosine); m'lm (I ,2'-O-dimethylinosine); m3C (3- methylcytidine); Cm (2’-O-methylcytidine); s2C (2-thiocytidine); ac4C (N4-acetylcytidine); f5C (5-fonnylcytidine); m5Cm (5,2-O-dimethylcytidine); ac4Cm (N4-acetyl-2-O-methylcytidine); k2C (lysidine); m1G (1-methylguanosine); m2G (N2-methylguanosine); m7G (7- methylguanosine); Gm (2'-O-methylguanosine); m22G (N2,N2-dimethylguanosine); m2Gm (N2,2'-O-dimethylguanosine); m22Gm (N2,N2,2'-O-trimethylguanosine); Gr(p) (2'-O- ribosylguanosine (phosphate)); yW (wybutosine); o2yW (peroxywybutosine); OHyW (hydroxywybutosine); OHyW* (undermodified hydroxywybutosine); imG (wyosine); mimG (methylguanosine); Q (queuosine); oQ (epoxyqueuosine); galQ (galtactosyl-queuosine); manQ (mannosyl-queuosine); preQo (7-cyano-7-deazaguanosine); preQi (7-aminomethyl-7- deazaguanosine); G* (archaeosine); D (dihydrouridine); m5Um (5,2'-O-dimethyluridine); s4U (4-thiouridine); m5s2U (5-methyl-2-thiouridine); s2Um (2-thio-2'-O-methyluridine); acp3U (3- (3-amino-3-carboxypropyl)uridine); ho5U (5-hydroxyuridine); mo5U (5-methoxyuridine); cmo5U (uridine 5-oxyacetic acid); mcmo5U (uridine 5-oxyacetic acid methyl ester); chm5U (5- (carboxyhydroxymethyl)uridine)); mchm5U (5-(carboxyhydroxymethyl)uridine methyl ester); mcm5U (5-methoxycarbonyl methyluridine); mcm5Um (S-methoxycarbonylmethyl-2-O- methyluridine); mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine); nm5s2U (5-aminomethyl- 2-thiouridine); mnm5U (5-methylaminomethyluridine); mnm5s2U (5-methylaminomethyl-2- thiouridine); mnm5se2U (5-methylaminomethyl-2-selenouridine); ncm5U (5-carbamoylmethyl uridine); ncm5Um (5-carbamoylmethyl-2'-0-methyluridine); cmnm5U (5- carboxymethylaminomethyluridine); cnmm5Um (5-carboxymethy 1 aminomethyl-2-L-O-methyl uridine); cmnm5s2U (5-carboxymethylaminomethyl-2-thiouridine); m62A (N6,N6- dimethyladenosine); Tm (2'-O-methylinosine); m4C (N4-methylcytidine); m4Cm (N4.2-O-dimethylcytidine); hm5C (5-hydroxymethylcytidine); m3U (3-methyluridine); cm5U (5- carboxymethyluridine); m6Am (N6,2’-O-dimethyladenosine); rn62Am (N6,N6,0-2- trimethyladenosine); m2'7G (N2,7-dimethylguanosine); m2'2'7G (N2,N2,7- trimethylguanosine); m3Um (3,2’-O-dimethyluridine); m5D (5-methyldihydrouridine); f5Cm (5- formyl-2'-O-methylcytidine); mIGm (I ,2'-0-dimethylguanosine); m'Am (1 ,2-O-dimethyl adenosine) irinomethyluridine); tm5s2U (S-taurinomethyl-2-thiouridine)); iniG-14 (4-demethyl guanosine); imG2 (isoguanosine); ac6A (N6-acetyladenosine), hypoxanthine, inosine, 8-oxo- adenine, 7-substituted derivatives thereof, dihydrouracil, pseudouracil, 2-thiouracil, 4- thiouracil, 5-aminouracil, 5-(Ci-Ce)-alkyluracil, 5-methyluracil, 5-(C2-Ce)-alkenyluracil, 5-(C2- Ce)-alkynyluracil, 5-(hydroxymethyl)uracil, 5-chlorouracil, 5-fluorouracil, 5-bromouracil, 5- hydroxycytosine, 5-(Ci-Ce)-alkylcytosine, 5-methylcytosine, 5-(C2-Ce)-alkenylcytosine, 5-(C2- Ce)-alkynylcytosine, 5-chlorocytosine, 5-fluorocytosine, 5-bromocytosine, N2- dimethylguanine, 7-deazaguanine, 8-azaguanine, 7-deaza-7-substituted guanine, 7-deaza-7- (C2-Ce)alkynylguanine, 7-deaza-8-substituted guanine, 8-hydroxyguanine, 6-thioguanine, 8- oxoguanine, 2-aminopurine, 2-amino-6-chloropurine, 2,4-diaminopurine, 2,6-diaminopurine, 8- azapurine, substituted 7-deazapurine, 7-deaza-7-substituted purine, 7-deaza-8-substituted purine, hydrogen (abasic residue), m5C, m5U, m6A, s2U, W, or 2'-O-methyl-U. Many of these modified nucleobases and their corresponding ribonucleosides are available from commercial suppliers.In some embodiments, the nucleotide analogues / modifications which may be incorporated into a modified RNA, suitably mRNA, are 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-lodo-2’-deoxycytidine-5’-triphosphate, 5- iodouridine-5’-triphosphate, 5-lodo-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, N 1 -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, deoxythymidine, 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.In some embodiments, the chemical modification is selected from pseudouridine, N1- methylpseudouridine, N1-ethylpseudouridine, 2-thiouridine, 4'-thiouridine, 5-methylcytosine, 5- methyluridine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio- 5-aza-uridine , 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4- methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4- thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine and 2'-O-methyl uridine.Particularly suitable in that context are pseudouridine (qj), N1-methylpseudouridine (m1 ip), 5-methylcytosine, and 5-methoxyuridine, more suitably pseudouridine (ip) and N1- methylpseudouridine (m1 ip), still more suitably N1 -methylpseudouridine (m1 ip).In some embodiments, essentially all, e.g. essentially 100% of the uracil in the coding sequence of the RNAs, suitably mRNAs, used herein have a chemical modification, suitably a chemical modification is in the 5-position of the uracil.In some embodiments, the RNAs, suitably mRNAs, used herein comprise the chemical modification being a uridine modification, preferably wherein 100% of the uridine positions in the mRNA are modified.Incorporating modified nucleotides such as e.g. pseudouridine (qj), N1- methylpseudouridine (m1 ip), 5-methylcytosine, and / or 5-methoxyuridine into the coding sequence of the RNAs, suitably mRNAs, used herein may be advantageous as unwanted innate immune responses (upon administration of the coding mRNA or the vaccine) may be adjusted or reduced (if required).In embodiments, the coding sequence of the RNAs, suitably mRNAs, used herein comprise at least one modified nucleotide selected from pseudouridine (ip) and N1- methylpseudouridine (m1 ip), suitably wherein all uracil nucleotides are replaced by pseudouridine (ip) nucleotides and / or N1-methylpseudouridine (m1 ip) nucleotides, optionally wherein all uracil nucleotides are replaced by pseudouridine (^P) nucleotides and / or N1- methylpseudouridine (ml ^P) nucleotides.In some embodiments, the RNAs, suitably mRNAs, used herein do not comprise N1- methylpseudouridine (ml^P) substituted positions. In further embodiments, the RNAs, suitably mRNAs, used herein do not comprise pseudouridine (ip), N1 -methylpseudouridine (m1 ip), 5- methylcytosine, and 5-methoxyuridine substituted position.In some embodiments, the chemical modification is N1 -methylpseudouridine and / or pseudouridine. In some embodiments, the chemical modification is N1 -methylpseudouridine.In the context of nucleic acid-based vaccine or therapeutic production, it may be required to provide GMP-grade nucleic acid, e.g. a GMP grade RNA or DNA. GMP-grade RNA or DNA may be produced using a manufacturing process approved by regulatory authorities. Accordingly, in some embodiments, RNA production is performed under current good manufacturing practice (GMP), implementing various quality control steps on DNA and RNA level, suitably according to W02016180430. In embodiments, the RNA, suitably mRNA of the invention is a GMP-grade RNA.RNA synthesisIn some embodiments, the RNA, suitably mRNA, 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.Suitably, the RNA, suitably mRNA, used herein is 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 may be 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 an 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; 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; MgCI2, 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 W02017109161.In embodiments, the nucleotide mixture used in RNA in vitro transcription may additionally comprise modified nucleotides as defined herein. In that context, suitable modified nucleotides may in particular be selected from pseudouridine (i ), N1-methylpseudouridine (m1 i ), 5-methylcytosine, and 5-methoxyuridine. In embodiments, uracil nucleotides in the nucleotide mixture are replaced (either partially or completely) by pseudouridine (i ) and / or N1- methylpseudouridine (m1 ip) to obtain a modified RNA.In other embodiments, the nucleotide mixture used in RNA in vitro transcription does not comprise modified nucleotides as defined herein. In embodiments, the nucleotide mixture used in RNA in vitro transcription only comprises G, C, A and II nucleotides, and, optionally, a cap analog as defined herein.In some 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, suitably as described in WO2015188933.In this context, the in vitro transcription has been performed in the presence of a sequence optimized nucleotide mixture and optionally a cap analog.RNA purificationIn embodiments, the RNA, suitably mRNA, used herein is a purified RNA, suitably mRNA.The term “purified RNA (or 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, MgCI2) 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 (or mRNA)” 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 puritymay 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.In some embodiments, the RNA is purified using RP-HPLC, suitably using Reversed- Phase High pressure liquid chromatography (RP-HPLC) with a macroporous styrene / divinylbenzene column (e.g. particle size 30pm, pore size 4000 A) and additionally using a filter cassette with a cellulose based membrane with a molecular weight cutoff of about 100kDa. The RNA may in particular be purified using PUREMESSENGER (CureVac, Tubingen, Germany; RP-HPLC according to W02008077592) and / or tangential flow filtration (as described in WO2016193206) and / or oligo d(T) purification (see WO2016180430).In some embodiments, the RNA, suitably mRNA, is purified by RP-HPLC and / or TFF to remove double-stranded RNA, non-capped RNA and / or RNA fragments.The formation of double stranded RNA as side products during e.g. RNA in vitro transcription can lead to an induction of the innate immune response, particularly IFNalpha which is the main factor of inducing fever in vaccinated subjects, which is of course an unwanted side effect. Current techniques for immunoblotting of dsRNA (via dot Blot, serological specific electron microscopy (SSEM) or ELISA for example) are used for detecting and sizing dsRNA species from a mixture of nucleic acids.In embodiments, the RNA, suitably mRNA, comprises about 5%, 10%, or 20% less double stranded RNA side products as an RNA, suitably mRNA, that has not been purified with RP-HPLC and / or TFF.In some embodiments, the RP-HPLC and / or TFF purified RNA, suitably mRNA, comprises about 5%, 10%, or 20% less double stranded RNA side products as an RNA, suitably mRNA, that has been purified with Oligo dT purification, precipitation, filtration and / or A EX.CarriersA range of carrier systems have been described which can be used to encapsulate (or complex) RNA, suitbaly mRNA, in order to protect it and facilitate its delivery to target cells. The present invention may utilise any suitable carrier system. Particular carrier systems of note are further described below.In embodiments, the RNAs, suitably mRNAs, used herein are complexed, encapsulated, partially encapsulated, or associated with one or more lipids (e.g. cationic lipids and / or neutral lipids), thereby forming lipid-based carriers such as liposomes, lipid nanoparticles (LNPs), lipoplexes, and / or nanoliposomes, suitably lipid nanoparticles.In some embodiments, the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) are formulated in a lipid nanoparticle (LNP), either separately or together.In some embodiments, the RNAs, suitably mRNAs, used herein are formulated separately (in any formulation or complexation agent defined herein), suitably wherein the RNAs, suitably mRNAs, used herein are formulated in separate liposomes, lipid nanoparticles (LNP), lipoplexes, and / or nanoliposomes.In some embodiments, the RNAs used herein, suitably the mRNAs used herein, suitably the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) are formulated separately.In embodiments, the RNAs, suitably mRNAs, used herein are co-formulated (in any formulation or complexation agent defined herein), suitably wherein the RNAs, suitably mRNAs, used herein are formulated in separate liposomes, lipid nanoparticles (LNP), lipoplexes, and / or nanoliposomes.In some embodiments, the RNAs used herein, suitably the mRNAs used herein, suitably the mRNAs of (a), (b), (c), (d), (e), (e1), (e2), (e3) and / or (e4) are co-formulated, i.e. formulated together.LNPsThe term “lipid nanoparticle” (or “LNP”) refers to a non-virion particle in which nucleic acid molecules, such as RNA, can be encapsulated. LNPs are not restricted to any particular morphology, and include any morphology generated when an ionizable (or cationic) lipid and optionally one or more further lipids are combined, e.g. in an aqueous environment and / or in the presence of a nucleic acid, e.g. an RNA. For example, a liposome, a lipid complex, a lipoplex and the like are within the scope of a lipid nanoparticle (LNP). LNP delivery systems and methods for their preparation are known in the art.The particles can include some external RNA, suitably mRNA, (e.g. on the surface of the particles), but desirably at least half of the RNA, suitably mRNA, (and suitably at least 85%, especially at least 95%, such as all of it) is encapsulated.In some embodiments, LNPs are suitable for intramuscular and / or intradermal administration.In embodiments, at least about 80%, 85%, 90%, 95% of lipid-based carriers, suitably the LNPs, have a spherical morphology.LNPs typically comprise a cationic lipid and one or more excipients selected from neutral lipids, charged lipids, steroids and polymer conjugated lipids (e.g. PEGylated lipid). The RNAs, suitably mRNAs, 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 RNAs, suitably mRNAs, 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. In some embodiments, the LNP comprising nucleic acids, suitably RNAs, more suitably mRNAs, comprises one or more cationic lipids, and one or more stabilizing lipids. Stabilizing lipids include neutral lipids and PEGylated lipids.In some embodiments, the LNP comprises a PEG-modified lipid, a non-cationic lipid, a sterol, and a cationic lipid.LNP can, for example, be formed of a mixture of (i) a PEG-modified lipid (ii) a noncationic lipid (iii) a sterol (iv) an ionisable cationic lipid. Alternatively, LNP can for example be formed of a mixture of (i) a PEG-modified lipid (ii) a non-cationic lipid (iii) a sterol (iv) a non- ionisable cationic lipid.In some embodiments, the non-cationic lipid is a neutral lipid.In some embodiments, the cationic lipid is ionizable.In vivo characteristics and behavior of LNPs 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 (or liposomes, nanoliposomes, lipoplexes) 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 or PEGylated cholesterol).In an embodiment, the RNA, suitably mRNA, is complexed with one or more lipids thereby forming lipid nanoparticles, wherein the LNP (or liposomes, nanoliposomes, lipoplexes) comprises a polymer conjugated lipid, suitably a PEGylated lipid / PEG lipid.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” or “PEG-modified lipid” refers to a molecule comprising both a lipid portion and apolyethylene glycol portion. PEGylated lipids are known in the art and include 1- (monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-s-DMG) and the like. The terms “PEGylated lipid” and “PEG-modified lipid” are used interchangeably herein.A polymer conjugated lipid as defined herein, e.g. a PEG-lipid, may serve as an aggregation reducing lipid.In certain embodiments, the LNP comprises a 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 some embodiments, 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 as4-O-(2’,3’-di(tetradecanoyloxy)propyl-1-O-(w-methoxy(polyethoxy)ethyl)butanedioate (PEG-5-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 some embodiments, the PEG-modified lipid comprises PEG-DMG or PEG-cDMA.In embodiments, the PEGylated lipid is suitably derived from formula (IV) of published PCT patent application W02018078053A1. Accordingly, PEGylated lipids derived from formula (IV) of published PCT patent application W02018078053A1 , and the respective disclosure relating thereto, are herewith incorporated by reference.In some embodiments, the PEG-modified lipid has the formula IV:wherein R8and R9are 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 a mean value ranging from 30 to 60.In some embodiments, the PEG-modified lipid R8and R9are saturated alkyl chains.In some embodiments, the RNA, suitably mRNA, is complexed with one or more lipids thereby forming LNPs, wherein the LNP comprises a polymer conjugated lipid, suitably a PEGylated lipid, wherein the PEG lipid is suitably derived from formula (IVa) of published PCT patent application W02018078053A1. Accordingly, PEGylated lipid derived from formula (IVa) of published PCT patent application W02018078053A1 , and the respective disclosure relating thereto, is herewith incorporated by reference.In some embodiments, the PEG lipid or PEGylated lipid is of formula (IVa):wherein n has a mean value ranging from 30 to 60, such as about 30±2, 32±2, 34±2, 36±2, 38±2, 40±2, 42±2, 44±2, 46±2, 48±2, 50±2, 52±2, 54±2, 56±2, 58±2, or 60±2. In an embodiment n is about 49. In another embodiment n is about 45. In further embodiments, the PEG lipid is of formula (IVa) wherein n is an integer selected such that the average molecular weight of the PEG lipid is about 2000g / mol to about 3000 g / mol or about 2300g / mol to about 2700g / mol, suitably about 2500g / mol.In some embodiments, the PEG-modified lipid has the formula IVa:wherein n has a mean value ranging from 30 to 60, suitably wherein n has a mean value of about 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, most suitably wherein n has a mean value of 49 or 45; or wherein n is an integer selected such that the average molecular weight of the PEG lipid is about 2500g / mol.The lipid of formula IVa as suitably used herein has the chemical term 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, also referred to as ALC-0159.Further examples of PEG-lipids suitable in that context are provided in LIS20150376115A1 and WO2015199952, 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 15%, 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 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 suitably 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 some embodiments, the LNP comprises a PEG-modified lipid at around 0.5 to 10 molar %, optionally 0.5 to 5 molar % or 0.5 to 3 molar %.In embodiments, the LNP comprises one or more additional lipids, which stabilize the formation of particles during their formulation or during the manufacturing process (e.g. 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 some embodiments, the non-cationic lipid is a neutral lipid, such as 1 ,2-distearoyl- sn-glycero-3-phosphocholine (DSPC), 1 ,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1 ,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE) or sphingomyelin (SM), preferably the neutral lipid is DSPC.In embodiments, the LNP (or liposome, nanoliposome, lipoplex) 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- Icarboxylate (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), or mixtures thereof.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 embodiments, the neutral lipid is 1 ,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). Suitably, the molar ratio of the cationic lipid to DSPC may be in the range from about 2:1 to about 8:1.In some embodiments, the steroid is sterol, suitably cholesterol.In embodiments, the steroid is cholesterol. Suitably, the molar ratio of the cationic lipid to cholesterol may be in the range from about 2:1 to about 1 :1. In some embodiments, the cholesterol may be PEGylated.The sterol can be about 10mol% to about 60mol% or about 25mol% to about 55mol% or about 25mol% to about 40mol% of the lipid particle. In one embodiment, the sterol is about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or about 60mol% 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).The cationic lipid of an LNP may be ionizable, 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.Such cationic lipids (for liposomes, lipid nanoparticles (LNP), lipoplexes, and / or nanoliposomes) include, but are not limited to, DSDMA, 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), ckk-E12, ckk, 1 ,2- DiLinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1 ,2-Dilinolenyloxy-N,N- dimethylaminopropane (DLenDMA), 1 ,2-di-y-linolenyloxy-N,N-dimethylaminopropane (y- DLenDMA), 98N12-5, 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), ICE (Imidazol-based), HGT5000, HGT5001 , DMDMA, CLinDMA, CpLinDMA, DMOBA, DOcarbDAP, DLincarbDAP, DLinCDAP, KLin-K-DMA, DLin-K-XTC2- DMA, XTC (2,2-Dilinoleyl-4-dimethylaminoethyl-[1 ,3]-dioxolane) HGT4003, 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), ALNY-100 ((3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9,12-dienyl)tetrahydro-3aH- cyclopenta[d] [1 ,3]dioxol-5-amine)), 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), NC98-5 (4,7, 13-tris(3-oxo-3-(undecylamino)propyl)-N ,N 16-diundecyl-4,7, 10,13-tetraazahexadecane-l,16-diamide), (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. Further suitable cationic lipids for use in the compositions and methods of the invention include those described in international patent publications WO2010053572(and particularly, Cl 2-200 described at paragraph

[0225] ) and WO2012170930, both of which are incorporated herein by reference, HGT4003, HGT5000, HGTS001 , HGT5001 , HGT5002 (see US20150140070A1).In embodiments, the cationic lipid of the liposomes, lipid nanoparticles (LNP), lipoplexes, and / or nanoliposomes may be 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 embodiments, the cationic lipid of the liposomes, lipid nanoparticles (LNP), lipoplexes, and / or nanoliposomes may an aminoalcohol lipidoid.Aminoalcohol lipidoids may be prepared by the methods described in U.S. Patent 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 WO2017075531A1 , hereby incorporated by reference.In another embodiment, suitable lipids can also be the compounds as disclosed in W02015074085A1 ( / .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. Patent Nos. 9,593,077 and 9,567,296 hereby incorporated by reference in their entirety.In other embodiments, suitable cationic lipids can also be the compounds as disclosed in WO2017117530A1 ( / .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 some embodiments, ionizable or cationic lipids may also be selected from the lipids disclosed in W02018078053A1 ( / .e. lipids derived from formula I, II, and III of W02018078053A1 , or lipids as specified in Claims 1 to 12 of W02018078053A1), the disclosure of W02018078053A1 hereby incorporated by reference in its entirety. In thatcontext, lipids disclosed in Table 7 of W02018078053A1 (e.g. lipids derived from formula 1-1 to 1-41) and lipids disclosed in Table 8 of W02018078053A1 (e.g. lipids derived from formula 11-1 to II-36) may be suitably used in the context of the invention. Accordingly, formula 1-1 to formula 1-41 and formula 11-1 to formula II-36 of W02018078053A1 , and the specific disclosure relating thereto, are herewith incorporated by reference.In some embodiments, cationic lipids may be derived from formula III of published PCT patent application W02018078053A1. Accordingly, formula III of W02018078053A1 , and the specific disclosure relating thereto, are herewith incorporated by reference.In some embodiments, the RNA, suitably mRNA, is complexed with one or more lipids thereby forming LNPs (or liposomes, nanoliposomes, lipoplexes), wherein the cationic lipid of the LNP is selected from structures 111-1 to HI-36 of Table 9 of published PCT patent application W02018078053A1. Accordingly, formula 111-1 to HI-36 of W02018078053A1 , and the specific disclosure relating thereto, are herewith incorporated by reference.In some embodiments, the ionizable cationic lipid has the formula HI:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:L1or L2is each independently -O(C=O)- or -(C=O)O-;G1and G2are each independently unsubstituted C1-C12 alkylene or C1-C12 alkenylene;G3is CI-C24 alkylene, C1-C24 alkenylene, Cs-Cs cycloalkylene, or Cs-Cs cycloalkenylene;R1and R2are each independently, branched or linear, C6-C24 alkyl or C6-C24 alkenyl;R3is H, OR5, CN, -C(=O)OR4, -OC(=O)R4or -NR5C(=O)R4;R4is C1-C12 alkyl;R5is H or C1-C6 alkyl.In some embodiments, the ionizable cationic lipid has the formula HI:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:L1or L2is each independently -O(C=O)- or -(C=O)O-;G1and G2are each independently unsubstituted C1-C12 alkylene;G3is C1-C24 alkylene;R1and R2are each independently, branched or linear, C6-C24 alkyl;R3is OR5; andR5is H.In some embodiments, the ionizable cationic lipid has the formula III and wherein R1, R2or both R1and R2have one of the following structures:In some embodiments, R2has the structure:In some embodiments, the cationic lipid has the formula:In some embodiments, the ionizable cationic lipid has the formula:In some embodiments, the ionizable cationic lipid has the formula 111-3:The lipid of formula 111-3 as suitably used herein has the chemical term ((4- hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), also referred to as ALC- 0315 i.e. CAS Number 2036272-55-4.In certain embodiments, the cationic lipid as defined herein, more suitably cationic lipid compound 111-3 ((4-hydroxybutyl) azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate)), is present in the LNP in an amount from about 30 mol% to about 80 mol%, suitably about 30 mol% to about 60 mol%, more suitably about 40 mol% to about 55 mol%, more suitably about 47.4 mol%, 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 some embodiments, the cationic lipid as defined herein is present in the LNP in an amount from about 20 mol% to about 60 mol%.In some embodiments, the LNP comprises a cationic lipid having the following structure:In embodiments, the cationic lipid is present in the LNP in an amount from about 30 mol% to about 70 mol%. In one embodiment, the cationic lipid is present in the LNP in an amount from about 40 mol% to about 60 mol%, 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 mol%, respectively. In embodiments, the cationic lipid is present in the LNP in an amount from about 47 mol% to about 48 mol%, 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 mol%, respectively, wherein 47.4 mol% are particularly suitable.In some embodiments, the cationic lipid is present in a ratio of from about 20 mol% to about 70 mol% or 75 mol% or from about 45 mol% 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, suitably RNA, more suitably mRNA, is from about 3 to about 15, such as from about 5 to about 13 or from about 7 to about 11.Other suitable (cationic or ionizable) lipids are disclosed in W02009086558, W02009127060, W02010048536, W02010054406, W02010088537, W02010129709, WO2011153493, WO 2013063468, US20110256175, US20120128760, US20120027803, US8158601 , WO2016118724, WO2016118725, W02017070613, W02017070620, WO2017099823, WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638, WO2010080724, W0201021865, W02008103276, WO2013086373, WO2013086354, US Patent Nos. 7,893,302, 7,404,969, 8,283,333, 8,466,122 and 8,569,256 and US Patent Publication No. US20100036115, US20120202871 , US20130064894, US20130129785, US20130150625, US20130178541 , US20130225836, US20140039032 and WO2017112865. In that context, the disclosures of W02009086558, W02009127060, W02010048536,W02010054406, W02010088537, W02010129709, WO2011153493, WO 2013063468, US20110256175, US20120128760, US20120027803, US8158601, WO2016118724, WO2016118725, W02017070613, W02017070620, WO2017099823, W02012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638, W02010080724, W0201021865,W02008103276, WO2013086373, WO2013086354, US Patent Nos. 7,893,302, 7,404,969, 8,283,333, 8,466,122 and 8,569,256 and US Patent Publication No. US20100036115, US20120202871 , US20130064894, US20130129785, US20130150625, US20130178541, US20130225836 and US20140039032 and WO2017112865 specifically relating to (cationic) lipids suitable for LNPs (or liposomes, nanoliposomes, lipoplexes) are incorporated herewith by reference.In other embodiments, the cationic or ionizable lipid isIn 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, suitably 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 (or liposomes, nanoliposomes, lipoplexes) can comprise two or more (different) cationic lipids as defined herein. Cationic lipids may be selected to contribute to 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 (or liposomes, nanoliposomes, lipoplexes). 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, or(i) at an amount such as to achieve an N / P ratio in the range of about 1 to about 20, suitably about 2 to about 15, more suitably about 3 to about 10, even more suitably about 4 to about 9, most suitably about 6;(ii) at an amount such as to achieve an N / P ratio in the range of about 5 to about 20, more suitably about 10 to about 18, even more suitably about 12 to about 16, most suitably about 14;(iii) at an amount such as to achieve a lipid : mRNA weight ratio in the range of 20 to 60, suitably from about 3 to about 15, 5 to about 13, about 4 to about 8 or from about 7 to about 11 ; or(iv) at an amount such as to achieve an N / P ratio in the range of about 6 for a lipid nanoparticle according to the invention, especially a lipid nanoparticle comprising the cationic lipid HI-3.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 nucleic acid which is used as cargo. The N / P ratio may be calculated on the basis that, for example, 1 pg RNA typically contains about 3 nmol phosphate residues, provided that the RNA exhibits a statistical distribution of bases. The “N”-value of the cationic 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. If more than one cationic lipid is present, the N-value should be calculated on the basis of all cationic lipids comprised in the lipid nanoparticles.In some embodiments, the composition has a lipid to RNA molar ratio (N / P ratio) of about 2 to about 12, optionally a N / P ratio of 3 to about 8.In one embodiment the lipid nanoparticles comprise about 40% cationic lipid LKY750, about 10% zwitterionic lipid DSPC, about 48% cholesterol, and about 2% PEGylated lipid DMG (w / w).In some embodiments, LNPs comprise: (a) the RNAs, suitably mRNAs, used herein, (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 cationic lipids (as defined above), non-cationic lipids (as defined above), cholesterol (as defined above), and / or PEG-modified lipids (as defined above) may be combined at various relative molar ratios. For example, the ratio of cationic lipid to noncationic lipid to cholesterol-based lipid to PEGylated lipid may be between about 30-60:20- 35:20-30:1-15, or at a ratio of about 40:30:25:5, 50:25:20:5, 50:27:20:3, 40:30:20:10, 40:32:20:8, 40:32:25:3 or 40:33:25:2, or at a ratio of about 50:25:20:5, 50:20:25:5, 50:27:20:3 40:30:20: 10,40:30:25:5 or 40:32:20:8, 40:32:25:3 or 40:33:25:2, respectively.In some embodiments, the LNPs (or liposomes, nanoliposomes, lipoplexes) comprise ALC-0315, the RNAs, suitably mRNAs, used herein, a neutral lipid which is DSPC, a steroid which is cholesterol and a PEGylated lipid which is ALC-0159.In some embodiments, the LNP comprises a PEG-modified lipid at around 0.5 to 15 molar %, a non-cationic lipid at around 5 to 25 molar %, a sterol at around 25 to 55 molar % and an ionisable cationic lipid at around 20 to 60 molar %.In an embodiment, 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 some embodiments, the RNA, suitably mRNA, is complexed with one or more lipids thereby forming lipid nanoparticles, wherein the LNP comprisesI. at least one cationic lipid as defined herein, suitably lipid of formula 111-3 (ALC- 0315);II. at least one neutral lipid as defined herein, suitably 1 ,2-distearoyl-sn-glycero-3- phosphocholine (DSPC);III. at least one steroid or steroid analogue as defined herein, suitably cholesterol; andIV. at least one polymer conjugated lipid, suitably a PEG-lipid as defined herein, e.g.PEG-DMG or PEG-cDMA, suitably a PEGylated lipid that is or is derived from formula (I a - ALC-0159).In some embodiments, the mRNA is complexed with one or more lipids thereby forming lipid nanoparticles (LNP), wherein the LNP comprises (i) to (iv) in a molar ratio of about 20- 60% cationic lipid: 5-25% neutral lipid: 25-55% sterol; 0.5-15% polymer conjugated lipid, suitably PEG-lipid.In some embodiments, the lipid nanoparticle (or liposome, nanoliposome, lipoplexe) comprises: a cationic lipid with formula (III-3) and / or PEG lipid with formula (IVa), optionally a neutral lipid, suitably 1 ,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and optionally a steroid, suitably 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 an embodiment, the composition comprises the RNA, suitably mRNA, lipid nanoparticles (LNPs), which have a molar ratio of approximately 50:10:38.5:1.5, suitably 47.5:10:40.8:1.7 or more suitably 47.4:10:40.9:1.7 (i.e. proportion (mol%) of cationic lipid (suitably lipid of formula III-3 (ALC-0315)), DSPC, cholesterol and polymer conjugated lipid, suitably PEG-lipid (suitably PEG-lipid of formula (IVa) with n = 49, even more suitably PEG- lipid of formula (IVa) with n = 45; ALC-0159); solubilized in ethanol).Other useful LNPs are described in the following references: WO2012 / 006376; WO20 12 / 030901 ; WO2012 / 031046; WO2012 / 031043; WO2012 / 006378; WO2011 / 076807; WO20 13 / 033563; WO2013 / 006825; WO2014 / 136086; WO2015 / 095340; WO2015 / 095346; W02016 / 037053, which are also incorporated herein by reference.Suitably, LNPs have a mean diameter of from about 50nm to about 200nm, from about 60nm to about 200nm, from about 70nm to about 200nm, from about 80nm to about 200nm, from about 90nm to about 200nm, from about 90nm to about 190nm, from about 90nm to about 180nm, from about 90nm to about 170nm, from about 90nm to about 160nm, from about 90nmto about 150nm, from about 90nm to about 140nm, from about 90nm to about 130nm, from about 90nm to about 120nm, from about 90nm to about 100nm, from about 70nm to about 90nm, from about 80nm to about 90nm, from about 70nm to about 80nm, or about 30nm, 35nm, 40nm, 45nm, 50nm, 55nm, 60nm, 65nm, 70nm, 75nm, 80nm, 85nm, 90nm, 95nm, 100nm, 105nm, 110nm, 115nm, 120nm, 125nm, 130nm, 135nm, 140nm, 145nm, 150nm, 160nm, 170nm, 180nm, 190nm, or 200nm and are substantially non-toxic. As used herein, the mean diameter may be represented by the z-average size as determined by dynamic light scattering as commonly known in the art.Suitably the LNPs have a polydispersity of 0.4 or less, such as 0.3 or less. Typically, the PDI is determined by dynamic light scattering.In some embodiments, the composition has a polydispersity index (PDI) value of less than about 0.4, suitably of less than about 0.3, more suitably of less than about 0.2, most suitably of less than about 0.1.Suitably, at least 50%, more suitably at least 60%, 70% 80%, 85%, 90% or 95% of the RNA is encapsulated in the LNP. In this context, “encapsulated RNA” is understood as RNA (suitably mRNA) that is complexed with the lipids forming the LNP and / or that is contained within the interior space of the LNP. The proportion of encapsulated RNA can typically be determined using a RiboGreen assay.Suitably, the composition contains less than about 30%, suitably less than 20%, 15%, 10% or 5% non-encapsulated RNA (or free RNA). In this context, the term “free RNA” or “nonencapsulated RNA” is understood as RNA (suitably mRNA) that is not encapsulated in the LNPs as defined herein. In a therapeutic composition, free RNA, may represent a contamination or an impurity.Also provided herein is an immunogenic composition comprising:(a) a first nucleic acid encoding a hemagglutinin (HA) antigen of a strain of a first subtype of Influenza A virus;(b) a second nucleic acid encoding a HA antigen of a strain of a second subtype of Influenza A virus;(c) a third nucleic acid encoding a HA antigen of a first strain of Influenza B virus; and(d) optionally, a fourth nucleic acid encoding a HA antigen of a second strain of Influenza B virus.In some embodiments, said immunogenic composition further comprises (d).In some embodiments, said first subtype of Influenza A virus is a subtype of Influenza A Group 1 , suitably influenza A subtype H1 , H2, H5, H6, H8, H9, H11 , H12, H13, H16, H17 or H18, more suitably H1.In some embodiments, said first subtype of Influenza A virus is Influenza A H1 N1 subtype.In some embodiments, said second subtype of Influenza A virus is a subtype of Influenza A Group 2, suitably influenza A subtype H3, H4, H7, H10, H14 and H15, more suitably H3.In some embodiments, said second strain subtype of Influenza A virus is Influenza A H3N2 subtype.In some embodiments, said first strain of Influenza B is a strain of B / Victoria lineage.In some embodiments, said second strain of Influenza B is a strain of B / Yamagata lineage.In some embodiments, said first, second, third and / or fourth nucleic acid is a messenger ribonucleic acid (mRNA).In some embodiments, the immunogenic composition further comprises:(e) at least one further nucleic acid, suitably mRNA, encoding at least one further antigen, wherein said at least one further antigen is derived from a strain of Influenza virus, suitably is selected from the group consisting of Influenza A virus and Influenza B virus, more suitably is selected from the group consisting of said strain of said first subtype of Influenza A virus, said strain of said second subtype of Influenza A virus, said first strain of Influenza B virus and, optionally, said second strain of Influenza B virus.In some embodiments, said at least one further antigen comprises or consists of a peptide or protein selected or derived from an Influenza virus NA or an immunogenic fragment or an immunogenic variant thereof.In some embodiments, the composition comprises a plurality of (e).In some embodiments, the immunogenic composition further comprises:(e1) a fifth nucleic acid, suitably an mRNA, encoding a NA of the first subtype of Influenza A virus;(e2) a sixth nucleic acid, suitably an mRNA, encoding a NA of the second subtype of Influenza A virus;(e3) a seventh nucleic acid, suitably an mRNA, encoding a NA of the first strain of Influenza B virus; and optionally(e4) an eighth nucleic acid, suitably an mRNA, encoding a NA of the second strain of Influenza B virus.In some embodiments, the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) are formulated in a lipid nanoparticle (LNP), each separately or together.In some embodiments, the LNP comprises a PEG-modified lipid, suitably at around 0.5 to 15 molar %, a non-cationic lipid, suitably at around 5 to 25 molar %, a sterol, suitably at around 25 to 55 molar %, and a cationic lipid, suitably an ionizable cationic lipid at around 20 to 60 molar %.In some embodiments, the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4), optionally each, are not self-replicating.In some embodiments, the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) comprises a 5’ untranslated region (UTR), suitably the 5’ UTR comprises or consists of a nucleic acid sequence derived from a 5’-UTR of a 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.In some embodiments, the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) comprises a 3’ UTR, suitably the 3’ UTR comprises or consists of a nucleic acid sequence derived from a 3’-UTR of a gene selected from PSMB3, ALB7, CASP1 , COX6B1 , GNAS, NDUFA1 and RPS9, or from a homolog, a fragment or a variant of any one of these genes.In some embodiments, the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) comprises at least one chemical modification, suitably wherein the chemical modification is N1 -methylpseudouridine and / or pseudouridine, suitably N1-methylpseudouridine.Vaccines and Combination vaccinesIn a second aspect, the invention relates to a vaccine for use in the treatment or prophylaxis of an infection with an Influenza virus, comprising an immunogenic composition as defined herein, wherein an immune response is elicited as defined herein.The vaccine is a nucleic acid-based vaccine, suitably an mRNA-based vaccine.In some embodiments, the vaccine is a multivalent vaccine.In some embodiments, the vaccine is a trivalent Influenza virus vaccine (i.e. comprising immunogenic components derived from 3 strains of Influenza virus).In some embodiments, the trivalent Influenza virus vaccine comprises 3 different nucleic acids, suitably mRNAs, encoding 3 HA antigens.In some embodiments, the trivalent Influenza virus vaccine comprises 2 different nucleic acids, suitably mRNAs, encoding 2 HA antigens derived from a strain of Influenza A virus, suitably from H1 N1 and / or H3N2, and 1 nucleic acid, suitably mRNA, encoding 1 HA antigen derived from a strain of Influenza B virus, suitably from B / Victoria lineage.In some embodiments, the trivalent Influenza virus vaccine comprises 6 different nucleic acids, suitably mRNAs, encoding 3 HA and 3 NA antigens.In some embodiments, the trivalent Influenza virus vaccine comprises 4 different nucleic acids, suitably mRNAs, encoding 2 HA and 2 NA antigens derived from a strain of Influenza A virus, suitably from H1 N1 and / or H3N2, and 2 different nucleic acids, suitably mRNAs, encoding 1 HA and 1 NA antigen derived from a strain of Influenza B virus, suitably from B / Victoria lineage.In some embodiments, the trivalent Influenza virus vaccine comprises (a), (b) and (c) as defined herein.In some embodiments, the trivalent Influenza virus vaccine comprises (a), (b), (c), (e1), (e2) and (e3) as defined herein.In some embodiments, the vaccine is a quadrivalent Influenza virus vaccine (i.e. comprising immunogenic components derived from 4 strains of Influenza virus).In some embodiments, the quadrivalent Influenza virus vaccine comprises 4 mRNAs encoding 4 HA antigens.In some embodiments the quadrivalent Influenza virus vaccine comprises(a) a first mRNA encoding a hemagglutinin (HA) antigen of a strain of a first subtype of Influenza A virus;(b) a second mRNA encoding a HA antigen of a strain of a second subtype of Influenza A virus;(c) a third mRNA encoding a HA antigen of a first strain of Influenza B virus; and(d) a fourth mRNA encoding a HA antigen of a second strain of Influenza B virus.In some embodiments, the quadrivalent Influenza virus vaccine comprises 4 mRNAs encoding 4 HA antigens and 3 mRNAs encoding 3 NA antigens (i.e. seven components quadrivalent Influenza virus vaccine).In some embodiments the quadrivalent Influenza virus vaccine further comprises(e1) a fifth mRNA encoding a NA of the first subtype of Influenza A virus;(e2) a sixth mRNA encoding a NA of the second subtype of Influenza A virus; and(e3) a seventh mRNA encoding a NA of the first strain of Influenza B virus.In some embodiments, the quadrivalent Influenza virus vaccine comprises 4 mRNAs encoding 4 HA antigens and 4 mRNAs encoding 4 NA antigens (i.e. eight components quadrivalent Influenza virus vaccine).In some embodiments the quadrivalent Influenza virus vaccine further comprises(e4) an eighth mRNA encoding a NA of the second strain of Influenza B virus.In some embodiments, the vaccine further comprises at least one antigen or at least one nucleic acid encoding said at least one antigen, such as at least one mRNA encoding an antigen from a further pathogen, suitably the pathogen being a virus, suitably a respiratory virus.In some embodiments, said antigen is from further virus is selected from the group consisting of Coronavirus (e.g. SARS-CoV-1 , SARS-CoV-2, MERS-CoV), Pneumoviridae virus (e.g. Respiratory syncytial virus, Metapneumovirus) and Paramyxovidirae virus (e.g. Parainfluenza virus, Henipavirus), suitably said antigen from a further virus is a spike protein, or an antigenic fragment thereof, from a SARS-CoV-2 virus or a mRNA encoding a spike protein, or an antigenic fragment thereof, from a SARS-CoV-2 virus. For instance, the antigen can be a SARS-CoV- 2 virus spike protein or an antigenic fragment thereof selected from those provided in Table 1 of published PCT application WO2021156267A1 or in Table 1 of published PCT application WO2022137133A1 , each of which is incorporated herein by reference.Also provided herein is a vaccine comprising an immunogenic composition as defined herein.Kit or Kit of partsIn a third aspect, the invention relates to a kit or kit of parts for use in the treatment or prophylaxis of an infection with an Influenza virus, wherein the kit or kit of parts comprises the nucleic acids, suitably the mRNAs, as defined herein, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) as defined herein, optionally comprising a liquid vehicle forsolubilizing, and, optionally, technical instructions providing information on administration and dosage of the components, wherein an immune response is elicited as defined herein.The technical instructions of the kit may contain information about administration and dosage and patient groups. Such kits, suitably kits of parts, may be applied e.g. for any of the applications or uses mentioned herein, suitably for the use of the immunogenic composition or the vaccine for the treatment or prophylaxis of an infection or diseases caused by an Influenza virus, suitably Influenza A and / or B virus.In some embodiments, the immunogenic composition or the vaccine is provided in a separate part of the kit, wherein the immunogenic composition or the vaccine is suitably lyophilised or spray-dried or spray-freeze dried.The kit may further contain as a part, a vehicle (e.g. buffer solution) for solubilising the dried or lyophilized nucleic composition or the vaccine.In some embodiments, the nucleic acids and / or the mRNAs, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4), as defined herein are formulated separately.In some embodiments, the nucleic acids and / or the mRNAs, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4), as defined herein are provided as one part of the kit.In some embodiments, the nucleic acids and / or the mRNAs, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4), as defined herein are each provided as a separate part of the kit. Suitably, the kit or kit of parts comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight parts, each containing at least one of the nucleic acids and / or the mRNAs, suitably the mRNAs (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4), as defined herein.In some embodiments, the kit or kit of parts as defined herein comprises a multi-dose container for administration of the composition / the vaccine and / or an administration device (e.g. an injector for intramuscular and / or intradermal injection).Also provided herein is kit or kit of parts comprising the nucleic acids, suitably the mRNAs, as defined herein, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) as defined herein, optionally comprising a liquid vehicle for solubilizing, and, optionally, technical instructions providing information on administration and dosage of the components, wherein an immune response is elicited as defined herein.Formulation and administrationIn some embodiments, the nucleic acids, suitably mRNAs, as defined herein are coformulated. Suitably, the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4), as defined herein are co-formulated, i.e. formulated together.In some embodiments, the the nucleic acids, suitably mRNAs, as defined herein of the kit or kit of parts are formulated separately. In some embodiments, the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4), as defined herein are formulated separately.In some embodiments, the antigens or the nucleic acids, suitably mRNAs, as defined herein are co-filled. Suitably, the mRNAs of (a), (b), (c), (c1), (c2), (c3), (c4), (c5) and / or (c6), as defined herein are co-filled, i.e. filled together, optionally after being formulated separately.In some embodiments, the nucleic acids, suitably mRNAs, as defined herein are formulated as a bedside mixing formulation. Suitably, the mRNAs, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4), as defined herein are formulated as a bedside mixing formulation.As described herein, a “bedside mixing formulation” must be understood as a formulation wherein some (such as one or more) of the immunogenic components (e.g. mRNA), suitably each, have been formulated (e.g. in LNPs) independently before being mixed to form the bedside mixing formulation.In some embodiments, the bedside mixing formulation is obtained by a process comprising (1) formulating (e.g. in LNPs) each nucleic acid, suitably mRNAs, independently and (2) mixing each (LN Reformulated nucleic acid, suitably mRNAs.In some embodiments, the bedside mixing formulation is obtained by a process comprising (1) co-formulating (e.g. in LNPs) said nucleic acid, suitably mRNAs, encoding such derived from a strain of Influenza A virus (2) co-formulating said nucleic acid, suitably mRNAs, encoding such derived from a strain of Influenza B virus, and (3) mixing (LNP-)co-formulated nucleic acids, suitably mRNAs encoding such derived from a strain of Influenza A virus with (LNP-)co-formulated nucleic acids, suitably mRNAs encoding such derived from a strain of Influenza B virus.In some embodiments, the bedside mixing formulation is obtained by a process comprising (1) co-formulating (e.g. in LNPs) said nucleic acid, suitably mRNAs, encoding such derived from a strain of Influenza A virus (2) formulating each nucleic acid, suitably mRNAs, encoding such derived from a strain of Influenza B virus independently, and (3) mixing (LNP- )co-formulated nucleic acids, suitably mRNAs encoding such derived from a strain of InfluenzaA virus and each (LNP-)formulated nucleic acids, suitably mRNAs encoding such derived from a strain of Influenza B virus.The immunogenic composition may be administered via various suitable routes, including parenteral, such as intramuscular, intradermal, intranasal, or subcutaneous administration. Suitably the immunogenic composition, the vaccine or the kit or kit of parts as described herein is administered intramuscularly and / or intradermally.In some embodiments, intramuscular administration of the immunogenic composition as described herein results in expression of the encoded antigen construct in a subject. Administration of the immunogenic composition as described herein results in translation of the mRNA and to a production of the encoded antigen in a subject.The immunogenic composition described herein may be provided in liquid or dry (e.g. lyophilised) form.In some embodiments, the immunogenic composition is provided in liquid form.In some embodiments, the immunogenic composition is a dry composition.The term “dry composition” as used herein may be a composition that has been lyophilized (e.g. according to WO2016165831 , WO2011069586, WO2022 / 232585, W02022 / 101461 , WO2022 / 076562, WO2012 / 170889 or W02022 / 036170), or spray-dried, or freeze-dried (e.g. according to WO2016184575, WO2016184576 or WO2021 / 216541) to obtain a dry composition, suitably a temperature stable composition, for example in the form of a powder.In one embodiment, the composition according to the invention is a lyophilized, freeze- dried or spray-dried dry composition comprising one or more further excipients selected from cryoprotectants, plasticizers and polymers. Suitably, the lyophilized, freeze-dried or spray- dried dry composition is mixed with a liquid, suitably an aqueous liquid such as sterile water or saline, to form a “reconstituted liquid formulation” prior to administration to a patient.In embodiments, lyophilized or spray-dried composition has a water content of less than about 10%.In some embodiments, lyophilized, freeze-dried or spray-dried composition has a water content of between about 0.5% and 5%.In some embodiments, the lyophilized, freeze-dried or spray-dried composition is stable for at least 2 months after storage at about 5 °C, suitably for at least 3 months, 4 months, 5 months, 6 months.Liquids used for reconstitution will be substantially aqueous, such as water for injection, phosphate buffered saline and the like. The requirement for buffer and / or tonicity modifying agents will depend on the on both the contents of the container being reconstituted and the subsequent use of the reconstituted contents. Buffers may be selected from acetate, citrate, histidine, maleate, phosphate, succinate, tartrate and TRIS. The buffer may be a phosphate buffer such as Na / Na2PO4, Na / K2PO4 or K / K2PO4.Suitably, the formulations used in the present invention have a dose volume of between 0.05 ml and 1 ml, such as between 0.1 and 0.6 ml, in particular a dose volume of 0.45 to 0.55 ml, such as 0.5 ml. The volumes of the compositions used may depend on the subject, delivery route and location, with smaller doses being given by the intradermal route. A typical human dose for administration through routes such as intramuscular, is in the region of 200 pl to 750 pl, such as 400 to 600 pl, in particular about 500 pl, such as 500 pl.The immunogenic composition as described herein may be provided in various physical containers such as vials or pre-filled syringes.In some embodiments, the immunogenic composition is provided in the form of a single dose. In other embodiments, the immunogenic composition, the vaccine or the kit or kit of parts is provided in multidose form such containing 2, 5 or 10 doses.It is common where liquids are to be transferred between containers, such as from a vial to a syringe, to provide ‘an overage’ which ensures that the full volume required can be conveniently transferred. The level of overage required will depend on the circumstances, but excessive overage should be avoided to reduce wastage and insufficient overage may cause practical difficulties. Overages may be of the order of 20 to 100 pl per dose, such as 30 pl or 50 pl.Stabilisers may be present. Stabilisers may be of particular relevance where multidose containers are provided as doses of the final formulation(s) may be administered to subjects over a period of time.Formulations are suitably sterile.Approaches for establishing strong and lasting immunity often include repeated immunisation, i.e. boosting an immune response by administration of one or more further doses.Administration of the immunogenic composition as described herein may therefore be part of a multi-dose administration regime. For example, the immunogenic composition as described herein may be provided as a priming dose in a multidose regime, especially a two-or three-dose regime, in particular a two-dose regime. The immunogenic composition as described herein may be provided as a boosting dose in a multidose regime, especially a two- or three-dose regime, such as a two-dose regime.The time between doses may be two weeks to six months, such as three weeks to three months. Periodic longer-term booster doses may also be provided, such as every 2 to 10 years.In some embodiments, the immunogenic composition further comprises at least one pharmaceutically acceptable carrier.The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein suitably includes the liquid or non-liquid basis of the composition for administration. If the composition is provided in liquid form, the carrier may be water, e.g. pyrogen-free water; isotonic saline or buffered (aqueous) solutions, e.g. phosphate, citrate etc. buffered solutions. Water or suitably a buffer, more suitably an aqueous buffer, may be used, containing a sodium salt, suitably at least 50mM of a sodium salt, a calcium salt, suitably at least 0.01 mM of a calcium salt, and optionally a potassium salt, suitably at least 3mM of a potassium salt. According to some embodiments, 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. Examples of sodium salts include NaCI, Nal, NaBr, Na2COs, NaHCOs, Na2SC , examples of the optional potassium salts include KCI, KI, KBr, K2CO3, KHCO3, K2SO4, and examples of calcium salts include CaCh, Cal2, CaBr2, CaCOs, CaSC , Ca(OH)2.Furthermore, organic anions of the aforementioned cations may be in the buffer. Accordingly, in embodiments, the immunogenic composition may comprise pharmaceutically acceptable carriers or excipients using one or more pharmaceutically acceptable carriers or excipients to e.g. increase stability, increase cell transfection, permit the sustained or delayed, increase the translation of encoded antigenic peptides or proteins in vivo, and / or alter the release profile of encoded antigenic peptides or proteins protein in vivo. In addition to traditional excipients such as any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, excipients can include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, cells transfected with polynucleotides, hyaluronidase, nanoparticle mimics and combinations thereof. In embodiments, 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 subject. The term “compatible” as used herein means that the constituents of the compositionare capable of being mixed with the at least one nucleic acid of component A and / or component B and, optionally, a plurality of nucleic acids 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 (e.g., intramuscular or intradermal administration). Pharmaceutically acceptable carriers or excipients must have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to a subject to be treated. Compounds which may be used as pharmaceutically acceptable carriers or excipients may be sugars, such as, for example, lactose, glucose, trehalose, mannose, 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.Subjects to which administration of the immunogenic compositions is contemplated include, but are not limited to, humans and / or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and / or rats; and / or birds, including commercially relevant birds such as poultry, chickens, ducks, geese, and / or turkeys.In various embodiments, the immunogenic composition does not exceed a certain proportion of free RNA, suitably mRNA.In this context, the term “free RNA, suitably mRNA” or “non-complexed RNA, suitably mRNA” or “non-encapsulated RNA, suitably mRNA” comprise the RNA, suitably mRNA molecules that are not encapsulated in the lipid-based carriers as defined herein. During formulation of the composition (e.g. during encapsulation of the RNA, suitably mRNA, into the lipid-based carriers), free RNA, suitably mRNA may represent a contamination or an impurity.In embodiments, the immunogenic composition comprises free RNA, suitably mRNA, ranging from about 30% to about 0%. In embodiments, the composition comprises about 20% free RNA, suitably mRNA (and about 80% encapsulated RNA, suitably mRNA), about 15% free RNA, suitably mRNA (and about 85% encapsulated RNA, suitably mRNA), about 10% free RNA, suitably mRNA (and about 90% encapsulated RNA, suitably mRNA), or about 5% free RNA, suitably mRNA (and about 95% encapsulated RNA, suitably mRNA). In some embodiments, the composition comprises less than about 20% free RNA, suitably mRNA,suitably less than about 15% free RNA, suitably mRNA, more suitably less than about 10% free RNA, suitably mRNA, most suitably less than about 5% free RNA, suitably mRNA.The term “encapsulated RNA, suitably mRNA” comprises the RNA, suitably mRNA, molecules that are encapsulated in the lipid-based carriers as defined herein. The proportion of encapsulated RNA, suitably mRNA, in the context of the invention is typically determined using a RiboGreen assay.In some embodiments, a single dose of the immunogenic composition is 0.1 to 1000 pg, especially 1 to 500 pg, especially 2 to 500 pg, in particular 10 to 250 pg, suitably 10 to 150 pg of total mRNA.In some embodiments, a single dose of the immunogenic composition is 10 to 150 pg, optionally 20 to 100 pg, optionally 35 to 100 pg of total mRNA.In some embodiments, a single dose of the immunogenic composition is 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99 or 100 pg of total mRNA.In some embodiments, a single dose of the immunogenic composition is 39, 45, 63, 69 or 99 pg of total mRNA.In further embodiments, a single dose of the immunogenic composition comprises a mixture of 2, 3, 4, 5, 6, 7, 8, 9 or 10 different mRNA and is 1 to 200 pg, suitably 1 to 60 pg, suitably 1 to 25 pg, suitably 2 to 25 pg, suitably 3 to 18 pg of each mRNA.In some embodiments, a single dose of the immunogenic composition comprises a mixture of 2, 3, 4, 5, 6, 7, 8, 9 or 10, suitably of 6, different mRNA and is 0.5 to 100 pg, suitably 0.5 to 75 pg, suitably 2 to 75 pg of each mRNA.In some embodiment, a single dose of the composition is 2 to 500 pg, especially 10 to 250 pg of total mRNA, such as 10 to 75 pg of total mRNA.In some embodiments, a single dose of the immunogenic composition is 10 to 100 pg of total mRNA.In some embodiment, a single dose of the composition is 6, 12, 15, 16, 18, 24, 32, 36, 48, 54, 60, 72, 84, 96 or 120 pg of total mRNA.In some embodiments, a single dose of the composition is 1 to 10 pg of each mRNA for younger adult e.g. 18 to 64 years old.In some embodiments, a single dose of the composition is 1 , 2, 3, 6 or 9 pg of each mRNA for younger adult e.g. 18 to 64 years old.In some embodiments, a single dose of the composition is 15 to 50 pg of total mRNA for younger adult e.g. 18 to 64 years old.In some embodiment, a single dose of the composition is 16, 32 or 48 pg of total mRNA for younger adult e.g. 18 to 64 years old.In some embodiments, a single dose of the composition is 0.5 to 50 pg of each mRNA for younger adult e.g. 18 to 64 years old.In some embodiments, a single dose of the composition is 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 20, 21 , 22, 23, 24, 25, 30, 35, 36, 37, 38, 39, 40, 45, 46, 47, 48, 49 or 50 pg of each mRNA for younger adult e.g. 18 to 64 years old.In some embodiments, a single dose of the composition is 25 to 75 pg of total mRNA for younger adult e.g. 18 to 64 years old.In some embodiment, a single dose of the composition is 25, 30, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 66, 67, 68, 69, 70 or 75 pg of total mRNA for younger adult e.g. 18 to 64 years old.In some embodiments, a single dose of the composition is 2 to 20 pg of each mRNA for older adult e.g. 65 years old and above.In some embodiments, a single dose of the composition is 2, 3, 6, 9 or 18 pg of each mRNA for older adult e.g. 65 years old and above.In some embodiments, a single dose of the composition is 30 to 100 pg of total mRNA for older adult e.g. 65 years old and above.In some embodiments, a single dose of the composition is 32, 48 or 96 pg of total mRNA for older adult e.g. 65 years old and above.In some embodiments, a single dose of the composition is 0.5 to 100 pg of each mRNA for older adult e.g. 65 years old and above.In some embodiments, a single dose of the composition is 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 20, 21 , 22, 23, 24, 25, 30, 35, 36, 37, 38, 39, 40, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 71 , 72, 73, 74, 75, 80, 85, 90, 95 or 100 pg of each mRNA for older adult e.g. 65 years old and above.In some embodiments, a single dose of the composition is 35 to 150 pg of total mRNA for older adult e.g. 65 years old and above.In some embodiments, a single dose of the composition is 35, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140 or 150 pg of total mRNA for older adult e.g. 65 years old and above.In some embodiments, the the nucleic acids and / or the mRNAs, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) as described herein are administered at different sites of injection.In some embodiments, the nucleic acids and / or the mRNAs derived from a strain of Influenza A virus are administered at a site of injection which is different to the site of injection where the nucleic acids and / or the mRNAs derived from a strain of Influenza B virus are administered.In some embodiments, the nucleic acids and / or the mRNAs derived from a strain of Influenza B virus are administered separately, suitably at different sites of injection.Methods of treatmentIn a fourth aspect, the invention relates to a method of eliciting an immune response against an Influenza virus, wherein the method comprises applying or administering to a subject in need thereof an immunogenic composition as defined herein, and wherein an immune response is elicited as defined herein.In some embodiments, the elicited immune response is an adaptative immune response, suitably a protective adaptative immune response against an Influenza virus, suitably against an Influenza A virus and / or an Influenza B virus.In some embodiments, the elicited immune response comprises functional antibodies that can effectively neutralize the respective viruses.In some embodiments, the elicited immune response is a cross-reactive immune response, wherein the functional antibodies that can effectively neutralize the respective viruses further neutralize viruses belonging to same and other Influenza A subtypes and / or Influenza B lineages.In some embodiments, the cross-reactive immune response is homologous, heterologous and / or heterosubtypic.The term “homologous” in the context of an elicited immune response will be recognized and understood by the person of ordinary skill in the art, and is e.g. an immune response whichis elicited against the same strain, such as the same Influenza A strain or the same Influenza B strain. E.g. the immunogenic composition may comprise a HA antigen (or nucleic acid, suitably RNA, suitably mRNA, encoding such) derived from A / Michigan / 45 / 2015 (H1 N1 pdm9) which may elicit an immune response against A / Michigan / 45 / 2015 (H1 N1 pdm9) strain.The term “heterologous” or “intrasubtypic” in the context of an elicited immune response will be recognized and understood by the person of ordinary skill in the art, and is e.g. an immune response which is elicited against different strains within a subtype (for Influenza A virus) or lineage (for Influenza B virus), such as different Influenza A strains within a subtype such as H1 or H3 subtypes. E.g. the immunogenic composition may comprise a HA antigen (or nucleic acid, suitably RNA, suitably mRNA, encoding such) derived from A / Michigan / 45 / 2015 (H1 N1 pdm9) which may elicit an immune response against A / New Caledonia / 20 / 1999 (H1 N1) strain.The term “heterosubtypic” in the context of an elicited immune response will be recognized and understood by the person of ordinary skill in the art, and is e.g. an immune response which is elicited against different strains within one or more different subtypes (for Influenza A virus) or lineages (for Influenza B virus). E.g. the immunogenic composition may comprise a HA antigen (or nucleic acid, suitably RNA, suitably mRNA, encoding such) derived from A / Michigan / 45 / 2015 (H1 N1pdm9) which may elicit an immune response against HongKong / 4801 / 2014 (H3N2).In some embodiments, an immune response is elicited against at least three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen HA antigens of at least three, four, five, six, seven, eight, nine, ten subtypes of Influenza A virus, including said first and second subtypes of Influenza A virus and / or at least three four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen HA antigens of Influenza B virus, including against HA antigens of said first and second strains of Influenza B virus.In some embodiments, an immune response is elicited against at least one HA antigen of Influenza A from each of subtypes H1 , H2, H3, H5, H7 and H10, at least one HA antigen of Influenza B from B / Victoria lineage and at least one strain of Influenza B from B / Yamagata lineage.In further embodiments, the elicited immune response comprises broad, functional cellular T-cell responses against the respective viruses. In particular, the elicited immune response comprises a CD4+ T cell immune response and / or a CD8+ T cell immune response.In further embodiments, the elicited immune response comprises a well-balanced B cell and T cell response against the respective viruses.In some embodiments, the elicited immune response comprises antigen-specific immune responses.In some embodiments, the elicited immune response reduces partially or completely the severity of one or more symptoms and / or time over which one or more symptoms of Influenza virus infection are experienced by the subject.In some embodiments, the elicited immune response reduces the likelihood of developing an established Influenza virus infection after challenge.In some embodiments, the elicited immune response slows progression of Influenza, suitably Influenza A and / or B.In some embodiments, the subject in need is a mammalian subject, suitably a human subject.In some embodiments, the composition, the vaccine or the kit or kit of parts as described herein is administered in an amount effective to induce a T cell response against Influenza A subtypes selected from the group consisting of H1 N1 , H2N2, H3N2, H5N1 , H7N9, H10N8 and any combination thereof.In some embodiments, the composition, the vaccine or the kit or kit of parts as described herein is administered in an amount effective to induce a T cell response against Influenza A subtypes selected from the group consisting of H1 N1 , H2N2, H3N2, H5N1 , H7N9, H10N8 and any combination thereof.In some embodiments, the composition, the vaccine or the kit or kit of parts as described herein is administered in an amount effective to induce a T cell response against Influenza B lineages selected from Influenza B / Yamagata lineage, Influenza B / Victoria lineage and any combination thereof.In some embodiments, the composition, the vaccine or the kit or kit of parts as described is administered in an amount effective to induce a neutralizing antibody response against Influenza A subtypes selected from the group consisting of H1 N1 , H2N2, H3N2, H5N1 , H7N9, H10N8 and any combination thereof.In some embodiments, the composition, the vaccine or the kit or kit of parts as described is administered in an amount effective to induce a neutralizing antibody response against Influenza B lineages selected from Influenza B / Yamagata lineage, Influenza B / Victoria lineage and any combination thereof.In some embodiments, an immune response is elicited against HA antigens that are antigenically distinct from any of the HA antigen encoded by a nucleic acid present in the compositions.In some embodiments, an immune response is elicited against NA antigens that are antigenically distinct from any of the NA antigen encoded by a nucleic acid present in the compositions.In some embodiments, an immune response is elicited against HA and NA antigens that are antigenically distinct from any of the HA and NA antigen encoded by a nucleic acid present in the compositions.In some embodiments, an immune response is elicited against Influenza viruses with a different geographical origin and / or year of isolation than any of the strains having an HA and / or NA encoded by an mRNA present in the composition.In embodiments, administration of the immunogenic composition, the vaccine or the kit or kit to a subject elicits neutralizing antibodies and does not elicit disease enhancing antibodies. In particular, administration of the immunogenic composition, the vaccine or the kit or kit to a subject does not elicit immunopathological effects, like e.g. enhanced disease and / or antibody dependent enhancement (ADE).In a fifth aspect, the invention relates to a method of treating or preventing a disorder caused by an Influenza virus, suitably an Influenza A and / or Influenza B, wherein the method comprises applying or administering to a subject in need thereof an immunogenic composition as defined herein, and wherein an immune response is elicited as defined herein.Preventing (Inhibiting) or treating a disease, in particular a virus infection relates to inhibiting the full development of a disease or condition, for example, in a subject who is at risk for a disease such as a virus infection. “Treatment” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. The term “ameliorating”, with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment. Inhibiting a disease can include preventing or reducing the risk of the disease, such as preventing or reducing the risk of viral infection. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptomsof the disease, a slower progression of the disease, a reduction in the viral load, an improvement in the overall health or well-being of the subject, or by other parameters that are specific to the particular disease. A “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing pathology.In some embodiments, the composition, the vaccine or the kit or kit of parts is administered at a therapeutically effective amount.In some embodiments, the subject in need is a mammalian subject, suitably a human subject.Further definitionsFor 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.Throughout the specification, including the claims, where the context permits, the term “comprising” and variants thereof such as “comprises” are to be interpreted as including the stated element (e.g., integer) or elements (e.g., integers) without necessarily excluding any other elements (e.g., integers). Thus, a composition “comprising” X may consist exclusively of X or may include something additional e.g. X + Y.The word “substantially” does not exclude “completely” e.g. a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the definition of the invention.As used herein, the singular forms “a,” “an” and “the” include plural references unless the content clearly dictates otherwise.Unless specifically stated, a process comprising a step of mixing two or more components does not require any specific order of mixing. Thus, components can be mixed in any order. Where there are three components then two components can be combined with each other, and then the combination may be combined with the third component, etc.The term “immunogenic fragment” or “immunogenic variant” has to be understood as any fragment / variant of the corresponding Influenza antigen that is capable of raising an immune response in a subject.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.-%).About: The term “about” is used when determinants or values do not need to be identical, i.e. 100% the same. Accordingly, “about” means, that a determinant or values may diverge by 1 % to 20%, for example by 1 % to 10%; in particular, by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%. The skilled person knows that e.g. certain parameters or determinants can slightly vary based on the method how the parameter has been determined. For example, if a certain determinants or value is defined herein to have e.g. a length of “about 100 nucleotides”, the length may diverge by 1 % to 20%. Accordingly, the skilled person knows that in that specific example, the length may diverge by 1 to 20 nucleotides. Accordingly, a length of “about 100 nucleotides” may encompass sequences ranging from 80 to 120 nucleotides.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 e.g. 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).Antigen: The term “antigen” as used herein will be recognized and understood by the person of ordinary skill in the art, and is e.g. intended to refer to a substance which may be recognized by the immune system, for example 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 comprising at least one epitope are understood as antigens.Antigenic peptide, polypeptide or protein: The term “antigenic peptide or protein” or “immunogenic peptide or protein” will be recognized and understood by the person of ordinary skill in the art, and is e.g. intended to refer to a peptide, protein derived from a (antigenic or immunogenic) protein which stimulates the body’s adaptive immune system to provide an adaptive immune response. Therefore an antigenic / immunogenic peptide or protein comprises at least one epitope (as defined herein) or antigen (as defined herein) of the protein it is derived from.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”. The term “permanently cationic” means, e.g., 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 results from the presence of a quaternary nitrogen atom.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. E.g., in some embodiments, if a compound or moiety is cationisable, it is suitable 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, for example of a pH value of or below 9, of or below 8, of or below 7, for example 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 suitable 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 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 e.g. 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 may be an RNA sequence consisting of a number of nucleotides that may be divided by three, which starts with a start codon and which for example terminates with a stop codon.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 e.g. at least 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 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 (II) by thymines (T) throughout the sequence) or, vice versa, the DNA sequence is converted into the corresponding RNA sequence (in particular by replacing the T by II throughout the sequence). Thereafter, the sequence identity of the DNA sequences or the sequence identity of the RNA sequences is determined. For example, 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. 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, shares e.g. at least 60%, 70%, 75%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence from which it is derived.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 e.g. intended to refer to T cell epitopes and B cell epitopes. T cell epitopes or parts of the antigenic peptides or proteins and 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. 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 epitopes 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.Fragment: The term “fragment” as used throughout the present specification in the context of a nucleic acid sequence (e.g. RNA or a DNA) 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 particular 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 40%, 50%, 60%, 70%, 80%, 90%, 95% of the total (i.e. full-length) molecule from which the fragment is derived (e.g. a virus 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, N-terminally and / or C-terminally truncated compared to the amino acid sequence of the original protein. The term “fragment” as used throughout the present specification in the context of RNA sequences may, typically, comprise an RNA sequence that is 5’-terminally and / or 3’-terminally truncated compared to the reference RNA sequence. 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 for example refer to the entire protein or peptide as defined herein or to the entire (coding) nucleic acid molecule of such a protein or peptide. Fragments of proteins or peptides may comprise at least one epitope of those proteins or peptides.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. RNA, DNA, amino acid) has to be understood as a sequence that is derived from another gene, another allele, or e.g. another species or virus. Two sequences are typically understood to be “heterologous” if they are not derivable from the same gene or from the same allele. I.e., although heterologous sequences may be derivable from the same organism or virus, in nature, they do not occur in the same nucleic acid or 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 e.g. 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 may also 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 e.g. 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 (aa) sequences as defined herein, for example the aa sequences encoded by the nucleic acid sequence as defined herein or the aa 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 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 an algorithm, e.g. an algorithm integrated in the BLAST program. Sequence identity can be determined by using the EMBOSS Water sequence alignment tool at the EMBL-EBI website https: / / www.ebi.ac.uk / Tools / psa / emboss_water / with the parameters gap open=12, gap extend=1 and matrix=BLOSUM62 for protein sequences or matrix=fullDNA for DNA / RNA sequences, or by using the EMBOSS Needle sequence alignment tool at the EMBL-EBI website https: / / www.ebi.ac.uk / Tools / psa / emboss_needle / with default parameters (e.g. gap open=10, gap extend=0.5, end gap penalty=false, end gap open=10 and end gap extend=0.5 and matrix=BLOSUM62 for protein sequences or matrix=fullDNA for DNA / RNA sequences). Unless specified otherwise, where the application refers to sequence identity to a particular reference sequence, the identity is intended to be calculated over the entire length of that reference sequence.Immunogen, Immunogen: The terms “immunogen” or “immunogenic” will be recognized and understood by the person of ordinary skill in the art, and are e.g. intended to refer to a compound that is able to stimulate / induce an (adaptive) immune response. An immunogen may be a peptide, polypeptide, or protein.Immune response: The term “immune response” will be recognized and understood by the person of ordinary skill in the art, and is e.g. 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.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 e.g. 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 activated by ligands of pattern recognition receptor e.g. Toll-like receptors, NOD-like receptors, or RIG-1 like receptors etc..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.Nucleic acid, nucleic acid molecule: The terms “nucleic acid” or “nucleic acid molecule” as used herein, will be recognized and understood by the person of ordinary skill in the art. The terms “nucleic acid” or “nucleic acid molecule” particularly refers to DNA (molecules) or RNA molecules). The term is used synonymously with the term polynucleotide. For example, a nucleic acid or a nucleic acid molecule is a polymer comprising or consisting of nucleotide monomers that are covalently linked to each other by phosphodiester-bonds of a sugar / phosphate-backbone. The terms “nucleic acid” or “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, DNA sequence, RNA sequence: The terms “nucleic acid sequence”, “DNA sequence”, “RNA sequence” will be recognized and understood by the person of ordinary skill in the art, and e.g. refer to a particular and individual order of the succession of its nucleotides.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, e.g., 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 results from the presence of aquaternary nitrogen atom. Where a compound carries a plurality of such positive charges, it may be referred to as permanently polycationic.Stabilized RNA: The term “stabilized RNA” refer to an RNA that is modified such, that it is more stable to disintegration or degradation, e.g., by environmental factors or enzymatic digest, such as by exo- or endonuclease degradation, compared to an RNA without such modification. Preferably, a 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., e.g., for storage of a composition comprising the stabilized RNA.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.RNA: The term “RNA” is the usual abbreviation for ribonucleic acid. It is a nucleic acid molecule, i.e. a polymer consisting of nucleotide monomers. These nucleotides are usually adenosine-monophosphate (AMP), uridine-monophosphate (UMP), guanosinemonophosphate (GMP) and cytidine-monophosphate (CMP) monomers or analogs thereof, which are connected to each other along a so-called backbone. The backbone is typically formed by phosphodiester bonds between the sugar, i.e. ribose, of a first and a phosphate moiety of a second, adjacent monomer. The specific order of the monomers, i.e. the order of the bases linked to the sugar / phosphate-backbone, is called the RNA sequence. In general, RNA can be obtained by transcription of a DNA sequence, e.g. inside a cell or in vitro. In the context of the invention, the RNA may be obtained by RNA in vitro transcription. Alternatively, RNA may be obtained by chemical synthesis.RNA in vitro transcription: 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 is typically a linear DNA template (e.g. linearized plasmid DNA or PCR product). 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 one 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 typically used in RNA in vitro transcription 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; optionally, 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, pyrophosphatase; MgCh; 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.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 e.g. intended to refer to a variant of a nucleic acid sequence derived from another nucleic acid sequence. E.g., a variant of a 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. A variant of a nucleic acid sequence may at least 50%, 60%, 70%, 80%, 90%, or 95% identical to the nucleic acid sequence the variant is derived from. The variant is a functional variant in the sense that the variant has retained at least 50%, 60%, 70%, 80%, 90%, or 95% or more of the function of the sequence where it is derived from. 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 at least 10, 20, 30, 50, 75 or 100 nucleotides of such nucleic acid sequence.The term “variant” as used throughout the present specification in the context of proteins or peptides is e.g. 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) / substitution(s), such as one or more substituted, inserted and / or deleted amino acid(s). Suitably, these fragments and / or variants have the same, or a comparable specific antigenic property (immunogenic variants, antigenic variants). 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 at least 10, 20, 30, 50, 75 or 100 amino acids of such protein or peptide. Alternatively, a “variant” of a protein or polypeptide may havefrom 1 to 20, for example from 1 to 10 single amino acid mutations compared to such protein or peptide, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 15, 16, 17, 18, 19 or 20 single amino acid mutations. For mutations we mean or include substitution, insertion or deletion. In one embodiment, a variant of a protein comprises a functional variant of the protein, which means, in the context of the invention, that the variant exerts essentially the same, or at least 40%, 50%, 60%, 70%, 80%, 90% of the immunogenicity as the protein it is derived from.Multivalent vaccine / composition: the multivalent vaccine or combination of the invention provides more than one valence (e.g. an antigen) derived from more than one virus (e.g. at least one Influenza virus as defined herein and at least one further Influenza virus as defined herein).NUMBERED EMBODIMENTSIn the following, embodiments of the present invention are provided as a numbered embodiments list (Embodiment 1 to Embodiment 100).Embodiment 1. An immunogenic composition for use in the treatment or prophylaxis of an infection with an Influenza virus, wherein the immunogenic composition comprises:(a) a first nucleic acid encoding a hemagglutinin (HA) antigen of a strain of a first subtype of Influenza A virus;(b) a second nucleic acid encoding a HA antigen of a strain of a second subtype of Influenza A virus;(c) a third nucleic acid encoding a HA antigen of a first strain of Influenza B virus; and(d) optionally, a fourth nucleic acid encoding a HA antigen of a second strain of Influenza B virus, wherein an immune response is elicited against HA antigens of said strains of first and second subtypes of Influenza A virus, said first and, optionally, second strains of Influenza B virus and at least one further HA antigen subtype of Influenza A virus, being different from any of the HA antigen subtypes of Influenza A virus encoded by a nucleic acid present in the composition.Embodiment 2. The immunogenic composition for use according to embodiment 1 , wherein the composition further comprises (d) said fourth nucleic acid encoding a HA antigen of a second strain of Influenza B virus and wherein an immune response is further elicited against said HA antigen of said second strain of Influenza B virus.Embodiment 3. The immunogenic composition for use according to embodiment 1 or 2, wherein said first and / or second subtype of Influenza A virus is selected from influenza Aviruses characterized by a HA selected from the group consisting of H1 , H2, H3, H4, H5, H6, H7, H8, H9, H10, H11 , H12, H13, H14, H15, H16, H17 and H18, suitably from the group consisting of H1 , H3, H5, H7, H9, and H10, more suitably from the group consisting of H1 and H3.Embodiment 4. The immunogenic composition for use according to any of embodiments 1 to3, wherein said first and / or second subtype of Influenza A virus is selected from influenza A viruses characterized by a neuraminidase (NA) selected from the group consisting of N1 , N2, N3, N4, N5, N6, N7, N8, N9, N10, and N11 , suitably selected from the group consisting of N1 , N2, and N8, more suitably selected from the group consisting of N1 and N2.Embodiment 5. The immunogenic composition for use according to any of embodiments 1 to4, wherein said first and / or second subtype of Influenza A virus is selected from the group consisting of H1 N1 , H1 N2, H2N2, H3N1 , H3N2, H3N8, H5N1 , H5N2, H5N3, H5N8, H5N9, H7N1 , H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N7 and H10N8, suitably H1 N1 and H3N2.Embodiment 6. The immunogenic composition for use according to any of embodiments 1 to5, wherein said first subtype of Influenza A virus is a subtype of Influenza A Group 1 , suitably influenza A subtype H1 , H2, H5, H6, H8, H9, H11 , H12, H13, H16, H17 or H18, more suitably H1.Embodiment 7. The immunogenic composition for use according to any of embodiments 1 to6, wherein said first subtype of Influenza A virus is Influenza A H1 N1 subtype.Embodiment 8. The immunogenic composition for use according to any of embodiments 1 to7, wherein said second subtype of Influenza A virus is a subtype of Influenza A Group 2, suitably influenza A subtype H3, H4, H7, H10, H14 and H15, more suitably H3.Embodiment 9. The immunogenic composition for use according to any of embodiments 1 to8, wherein said second strain subtype of Influenza A virus is Influenza A H3N2 subtype.Embodiment 10. The immunogenic composition for use according to any of embodiments 1 to9, wherein said strain of first and / or second subtype of Influenza A virus is selected from the group consisting of A / Thailand / 8 / 2022 (H3N2)-like virus, A / Massachusetts / 18 / 2022 (H3N2)- like v...

Claims

CLAIMS1. Immunogenic composition for use in the treatment or prophylaxis of an infection with an Influenza virus, wherein the immunogenic composition comprises:(a) a first nucleic acid encoding a hemagglutinin (HA) antigen of a strain of a first subtype of Influenza A virus;(b) a second nucleic acid encoding a HA antigen of a strain of a second subtype of Influenza A virus;(c) a third nucleic acid encoding a HA antigen of a first strain of Influenza B virus; and(d) optionally, a fourth nucleic acid encoding a HA antigen of a second strain of Influenza B virus, wherein an immune response is elicited against HA antigens of said strains of first and second subtypes of Influenza A virus, said first and, optionally, second strains of Influenza B virus and at least one further HA antigen subtype of Influenza A virus, being different from any of the HA antigen subtypes of Influenza A virus encoded by a nucleic acid present in the composition.

2. The immunogenic composition for use according to claim 1 , wherein the composition further comprises (d) said fourth nucleic acid encoding a HA antigen of a second strain of Influenza B virus and wherein an immune response is further elicited against said HA antigen of said second strain of Influenza B virus.

3. The immunogenic composition for use according to claim 1 or 2, wherein said first subtype of Influenza A virus is a subtype of Influenza A Group 1 , suitably influenza A subtype H1 , H2, H5, H6, H8, H9, H11 , H12, H13, H16, H17 or H18, more suitably H1.

4. The immunogenic composition for use according to any of claims 1 to 3, wherein said first subtype of Influenza A virus is Influenza A H1 N1 subtype.

5. The immunogenic composition for use according to any of claims 1 to 4, wherein said second subtype of Influenza A virus is a subtype of Influenza A Group 2, suitably influenza A subtype H3, H4, H7, H10, H14 and H15, more suitably H3.

6. The immunogenic composition for use according to any of claims 1 to 5, wherein said second strain subtype of Influenza A virus is Influenza A H3N2 subtype.

7. The immunogenic composition for use according to any of claims 1 to 6, wherein said first strain of Influenza B is a strain of B / Victoria lineage.

8. The immunogenic composition for use according to any of claims 2 to 7, wherein said second strain of Influenza B is a strain of B / Yamagata lineage.

9. The immunogenic composition for use according to any of claims 1 to 8, wherein the elicited immune response is homologous, heterosubtypic, and optionally heterologous or intrasubtypic.

10. The immunogenic composition for use according to any of claims 1 to 9, wherein said at least one further HA antigen subtype of Influenza A virus is from Influenza A Group 1 , suitably influenza A subtype H1 , H2, H5, H6, H8, H9, H11 , H12, H13, H16, H17 or H18, more suitably H1 , H2 or H5.11 . The immunogenic composition for use according to any of claims 1 to 10, wherein said at least one further HA antigen subtype of Influenza A virus is derived from a strain of Influenza A Group 2, suitably influenza A subtype H3, H4, H7, H10, H14 or H15, more suitably H3, H7 or H10.

12. The immunogenic composition for use according to any of claims 1 to 11 , wherein an immune response is elicited against HA antigens of Influenza A subtypes H1 , H3 and at least one, suitably all, HA antigen of Influenza A subtype H2, H5, H7 or H10.

13. The immunogenic composition for use according to any of claims 1 to 12, wherein an immune response is further elicited against at least one further HA antigen of a strain of Influenza B virus, being different from any of the HA antigens of a strain of Influenza B virus encoded by a nucleic acid present in the composition.

14. The immunogenic composition for use according to claim 13, wherein said at least one further HA antigen of a strain of Influenza B virus is derived from a strain selected from the group consisting of B / Victoria lineage and B / Yamagata lineage.

15. The immunogenic composition for use according to any of claims 1 to 14, wherein said first, second, third and / or fourth nucleic acid is a messenger ribonucleic acid (mRNA).

16. The immunogenic composition for use according to any of claims 1 to 15, the immunogenic composition further comprising:(e) at least one further nucleic acid, suitably mRNA, encoding at least one further antigen, wherein said at least one further antigen is derived from a strain of Influenza virus, suitably is selected from the group consisting of Influenza A virus and Influenza B virus, more suitably is selected from the group consisting of said strain of said first subtype of Influenza A virus, said strain of said second subtype of Influenza A virus, said first strain of Influenza B virus and, optionally, said second strain of Influenza B virus.

17. The immunogenic composition for use according to claim 16, wherein said at least one further antigen comprises or consists of a peptide or protein selected or derived from an Influenza virus NA or an immunogenic fragment or an immunogenic variant thereof.

18. The immunogenic composition for use according to claim 16 or 17, wherein the composition comprises a plurality of (e).

19. The immunogenic composition for use according to any of claims 16 to 18, further comprising:(e1) a fifth nucleic acid, suitably an mRNA, encoding a NA of the first subtype of Influenza A virus;(e2) a sixth nucleic acid, suitably an mRNA, encoding a NA of the second subtype of Influenza A virus;(e3) a seventh nucleic acid, suitably an mRNA, encoding a NA of the first strain of Influenza B virus; and optionally(e4) an eighth nucleic acid, suitably an mRNA, encoding a NA of the second strain of Influenza B virus.

20. The immunogenic composition for use according to any of claims 1 to 19, wherein an immune response is further elicited against NA antigens of said strains of said first and second subtypes of Influenza A virus, said first and, optionally, second strains of Influenza B virus, and optionally, at least one further NA antigen of a strain of Influenza A virus and / or Influenza B virus, being different from any of the NA antigens encoded by a nucleic acid present in the composition.21 . The immunogenic composition for use according to any of claims 15 to 20, wherein the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) are formulated in a lipid nanoparticle (LNP), each separately or together.

22. The immunogenic composition for use according to claim 21 , wherein the LNP comprises a PEG-modified lipid, suitably at around 0.5 to 15 molar %, a non-cationic lipid, suitably at around 5 to 25 molar %, a sterol, suitably at around 25 to 55 molar %, and a cationic lipid, suitably an ionizable cationic lipid at around 20 to 60 molar %.

23. The immunogenic composition for use according to any of claims 15 to 22, wherein the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4), optionally each, are not selfreplicating.

24. The immunogenic composition for use according to any of claims 15 to 23, wherein the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) comprises a 5’ untranslated region (UTR), suitably the 5’ UTR comprises or consists of a nucleic acid sequence derived from a 5’-UTR of a 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.

25. The immunogenic composition for use according to any of claims 15 to 24, wherein the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) comprises a 3’ UTR, suitably the 3’ UTR comprises or consists of a nucleic acid sequence derived from a 3’-UTR of a gene selected from PSMB3, ALB7, CASP1 , COX6B1 , GNAS, NDUFA1 and RPS9, or from a homolog, a fragment or a variant of any one of these genes.

26. The immunogenic composition for use according to any of claims 15 to 25, wherein the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) comprises at least one chemical modification, suitably wherein the chemical modification is N1-methylpseudouridine and / or pseudouridine, suitably N1 -methylpseudouridine.

27. Vaccine for use in the treatment or prophylaxis of an infection with an Influenza virus, comprising an immunogenic composition as defined in any of claims 1 to 26, wherein an immune response is elicited as defined in any of claims 1 to 26.

28. The vaccine for use according to claim 27, the vaccine further comprising at least one antigen or at least one nucleic acid encoding said at least one antigen, such as at least one mRNA encoding an antigen from a further pathogen, suitably the pathogen being a virus such as Coronavirus (e.g. SARS-CoV-1 , SARS-CoV-2, MERS-CoV), Pneumoviridae virus (e.g. Respiratory syncytial virus, Metapneumovirus) and / or Paramyxovidirae virus (e.g. Parainfluenza virus, Henipavirus).

29. Kit or kit of parts for use in the treatment or prophylaxis of an infection with an Influenza virus, wherein the kit or kit of parts comprises the nucleic acids, suitably the mRNAs, as defined in any of claims 1 to 26, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) as defined in any of claims 15 to 26, optionally comprising a liquid vehicle for solubilizing, and, optionally, technical instructions providing information on administration and dosage of the components, wherein an immune response is elicited as defined in any of claims 1 to 26.

30. The kit or kit of parts for use according to claim 29, wherein the nucleic acids or the mRNAs, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) are formulated separately.31 . The immunogenic composition for use according to any of claims 1 to 26 or the vaccine for use according to claim 27 or 28, or the kit or kit of parts for use according to claim 29 or 30, wherein the nucleic acids or the mRNAs, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) are formulated as a bedside mixing formulation.

32. The immunogenic composition for use according to any of claims 1 to 26 or the vaccine for use according to claim 27 or 28, or the kit or kit of parts for use according to claim 29 or 30, wherein the antigens or the nucleic acids or the mRNAs, suitably the mRNAs of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) are co-formulated.

33. The immunogenic composition for use according to any of claims 1 to 26 or the vaccine for use according to claim 27 or 28, or the kit or kit of parts for use according to claim 29 or 30, wherein a dose of each mRNA of (a), (b), (c), (d), (e1), (e2), (e3) and / or (e4) is 1 to 200 pg, suitably 1 to 60 pg, suitably 2 to 25 pg.

34. The immunogenic composition for use according to any of claims 1 to 26 or the vaccine for use according to claim 27 or 28, or the kit or kit of parts for use according to claim 29 or 30, wherein a single dose of the composition is 2 to 500 pg, especially 10 to 250 pg of total mRNA, such as 10 to 150 pg of total mRNA.

35. Method of eliciting an immune response against an Influenza virus, wherein the method comprises applying or administering to a subject in need thereof an immunogenic composition as defined in any of claims 1 to 26, and wherein an immune response is elicited as defined in any of claims 1 to 26.

36. Method of treating or preventing a disorder caused by an Influenza virus, wherein the method comprises applying or administering to a subject in need thereof animmunogenic composition as defined in any of claims 1 to 26, and wherein an immune response is elicited as defined in any of claims 1 to 26.

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