Influenza virus vaccines

Abstract

The present invention is inter alia directed to hemagglutinin (HA) antigens from Influenza B virus (IBV) or nucleic acids, suitably mRNAs, encoding such, wherein the IBV HA antigens have an amino acid sequence comprising at least one amino acid substitution relative to a reference amino acid sequence. The present invention is also directed to immunogenic compositions, vaccines and kits or kits of parts comprising such. Immunogenic compositions, vaccines and kits-of-parts provided herein are suitable for use as a medicament, in particular, for use in the treatment or prophylaxis of an infection with an Influenza virus, suitably an Influenza A and / or Influenza B virus.

Description

70583W001INFLUENZA VIRUS VACCINESTECHNICAL FIELDThe present invention is inter alia directed to hemagglutinin (HA) antigens from Influenza B virus (IBV). The present invention is also directed to nucleic acids, suitably mRNAs, encoding such as well as immunogenic compositions, vaccines and kits or kits of parts comprising such. Immunogenic compositions, vaccines and kits-of-parts provided herein are suitable for use as a medicament, in particular, for use in the treatment or prophylaxis of an infection with an Influenza virus, suitably an Influenza A and / or Influenza B 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; IAV) and BetaInfluenzavirus (the genus that includes Influenza B viruses; IBV), 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 (IAV) that potentially form 198 HA and NA combinations. Unlike Influenza A viruses that have a wide range of hosts, the Influenza B viruses (IBV) almost exclusively infect humans. The 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)70583W001viruses that have been circulating worldwide since 1983. B / Yamagata lineage has not been detected after March 2020, using global surveillance for actively circulating Influenza viruses. Influenza virus B mutates at a rate 2 to 3 times slower than type A; however, it significantly impacts children and young adults annually.Vaccination is currently the most widely used method to prevent Influenza outbreaks, particularly in high-risk populations. 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.Multivalent live attenuated (FLUMIST, AstraZeneca), inactivated (AFLURIA, FLLIAD 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 A viruses and Influenza 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. Until recently, most of those flu vaccines were 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. Starting for the 2024-2025 season, the recommended flu vaccines will be trivalent as the Influenza B / Yamagata vaccine component is being removed because Influenza B / Yamagata viruses have not been detected in more than 4 years.Clinical studies underlying the currently approved flu vaccines highlight some variabilities in vaccine efficacy against different strains of Influenza virus and in immunogenicity associated with different antigens (e.g. HA) forming the flu vaccine. For example, the efficacy of FLUBLOK against Influenza subtype A is of 54.4% compared to only 23.1% against Influenza type B, both in healthy adults 18-49 years of age. Similarly, the corresponding immunogenicity studies reveal HI GMTs (hemagglutination inhibition geometric mean titers) up to 17-fold higher for HA A antigens than for HA B antigens.70583W001Therefore, there remains a need to provide immunogenic compositions capable of eliciting a broad, rapid and robust immune response against Influenza virus.SUMMARY OF THE INVENTIONIn a first aspect, the invention provides a hemagglutinin (HA) antigen from an influenza B virus (IBV) having an amino acid sequence comprising at least one amino acid substitution relative to a reference amino acid sequence, such as a wild type IBV HA amino acid sequence, wherein said amino acid sequence of said HA antigen comprises one or more of (i)-(xxviii):(i) a leucine (L) or a phenylalanine (F) at position 34;(ii) a phenylalanine (F) or a tyrosine (Y) at position 447;(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;(xvii) an isoleucine (I) at position 450;(xviii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;70583W001(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217,wherein the positions of (i)-(xxviii) are numbered by alignment of the reference to SEQ ID NO: 1.In some embodiments, said at least one amino acid substitution comprises one or more of (i)-(xxviii):(i) A34L or A34F substitution;(ii) R447F or R447Y substitution;(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution;(xix) F110G, F110Y, F110L, F1101 or F110A substitution;(xx) S155A or S155V substitution;(xxi) G156R substitution;(xxii) T194A substitution;(xxiii) H206F substitution;(xxiv) D208E substitution;(xxv) D209E substitution;(xxvi) A214V substitution;(xxvii) L216A substitution; or(xxviii) Y217F substitution.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34.70583W001In some embodiments, said at least one amino acid substitution comprises A34L substitution.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447.In some embodiments, said at least one amino acid substitution comprises R447F substitution.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a phenylalanine (F) at position 447.In some embodiments, said at least one amino acid substitution comprises A34L and R447F substitutions.In some embodiments, said amino acid sequence of said IBV HA antigen further comprises one or more of (iii)-(xxviii):(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;(xvii) an isoleucine (I) at position 450;(xviii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;70583W001(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217.In some embodiments, said at least one amino acid substitution further comprises one or more of (iii)-(xxviii):(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution(xix) F110G, F110Y, F110L, F1101 or F110A substitution;(xx) S155A or S155V substitution;(xxi) G156R substitution;(xxii) T 194A substitution;(xxiii) H206F substitution;(xxiv) D208E substitution;(xxv) D209E substitution;(xxvi) A214V substitution;(xxvii) L216A substitution; or(xxviii) Y217F substitution.In further aspects, the invention provides a nucleic acid, suitably mRNA, encoding the IBV HA antigen as described herein.In some embodiments, the nucleic acid is a mRNA.70583W001In further aspects, the invention provides an immunogenic composition comprising an IBV HA antigen as defined herein or a nucleic acid, suitably mRNA, encoding an IBV HA antigen as described herein, and a pharmaceutically acceptable carrier.In some embodiments, the immunogenic composition comprises:(a) an IBV HA antigen as defined herein ora nucleic acid, suitably mRNA, as described herein; and(b) at least one further antigen or at least one further nucleic acid, suitably mRNA, encoding said at least one further antigen, wherein said at least one further antigen is derived from a strain of Influenza virus.Also described herein is an immunogenic composition comprising:(a) a first nucleic acid, suitably mRNA, encoding an IBV HA antigen as defined herein, optionally the HA antigen is from an influenza B / Victoria lineage virus;(b1) a second nucleic acid, suitably mRNA, encoding a second HA antigen from a first strain of influenza A virus, optionally H1 N1 ; and(b2) a third nucleic acid, suitably mRNA, encoding a third HA antigen from a second strain of influenza A virus, optionally H3N2;In some embodiments, the immunogenic composition further comprises:(b3) a fourth nucleic acid, suitably mRNA, encoding a first NA antigen from said first strain of influenza A virus, optionally H1N1;(b4) fifth nucleic acid, suitably mRNA, encoding a second NA antigen from said second strain of influenza A virus, optionally H3N2;(b5) a sixth nucleic acid, suitably mRNA, encoding a third NA antigen from said first strain of influenza B virus, optionally influenza B / Victoria lineage virus.In further aspects, the invention relates to a vaccine comprising an immunogenic composition as described herein.In further aspects, the invention relates to a kit or kit of parts comprising a HA antigen, or a nucleic acid and / or an mRNA as defined herein, optionally comprising a liquid vehicle for solubilizing, and, optionally, technical instructions providing information on administration and dosage of the components.In further aspects, the invention relates to an immunogenic composition, a vaccine, or a kit or kit of parts as described herein, for use as a medicament.In further aspects, the invention relates to an immunogenic composition, a vaccine, or a kit or kit of parts as described herein, for use in the treatment or prophylaxis of an infection with an Influenza virus, suitably an Influenza A and / or Influenza B virus.70583W001In further aspects, the invention relates to a method of treating or preventing a disorder or disease caused by an Influenza virus, suitably an Influenza A and / or Influenza B virus, wherein the method comprises applying or administering to a subject in need thereof an immunogenic composition, a vaccine or a kit or kit of parts as described herein.In further aspects, the invention also relates to a method of eliciting an immune response wherein the method comprises applying or administering to a subject in need thereof an immunogenic composition, a vaccine or a kit or kit of parts as described herein.The invention further relates to an immunogenic composition, a vaccine, or a kit or kit of parts as described herein, for the preparation or manufacture of a medicament for treating or preventing a disorder or disease caused by an Influenza virus, suitably an Influenza A and / or Influenza B virus, in a subject (e.g., human).BRIEF DESCRIPTION OF THE SEQUENCES SEQ ID NO: 1 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(Wild type) - BHA_0001_FL.SEQ ID NO: 2 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L) - BHA_2001_FL.SEQ ID NO: 3 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34F) - BHA_2303_FL.SEQ ID NO: 4 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F) - BHA_2024_FL.SEQ ID NO: 5 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447Y) - BHA_2321_FL.SEQ ID NO: 6 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F) - BHA_2115_FL (D73).SEQ ID NO: 7 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34F, R447Y) - BHA_2348_FL.SEQ ID NO: 8 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(K420C, D449C) - BHA_1010_FL (D15).SEQ ID NO: 9 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, K420C, D449C) - BHA_2116_FL.70583W001SEQ ID NO: 10 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A428C, E435C) - BHA_1011_FL.SEQ ID NO: 11 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, A428C, E435C) - BHA_2117_FL.SEQ ID NO: 12 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, T450I) - BHA_2118_FL (D81).SEQ ID NO: 13 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, T450I, K420C, D449C) - BHA_2119_FL.SEQ ID NO: 14 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, T450I, A428C, E435C) - BHA_2120_FL.SEQ ID NO: 15 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, A394C, A512C) - BHA_2291_FL.SEQ ID NO: 16 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, A394C, A512C) - BHA_2292_FL.SEQ ID NO: 17 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, A394C, A512C) - BHA_2293_FL.SEQ ID NO: 18 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, G21C, T384C) - BHA_2294_FL.SEQ ID NO: 19 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, G21C, T384C) - BHA_2295_FL.SEQ ID NO: 20 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, G21C, T384C) - BHA_2296_FL (D347).SEQ ID NO: 21 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, A378C, A395C) - BHA_2263_FL.SEQ ID NO: 22 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, A378C, A395C) - BHA_2264_FL.SEQ ID NO: 23 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, A378C, A395C) - BHA_2265_FL.SEQ ID NO: 24 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, H381C, S399C) - BHA_2266_FL.70583W001SEQ ID NO: 25 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, H381C, S399C) - BHA_2267_FL.SEQ ID NO: 26 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, H381C, S399C) - BHA_2268_FL.SEQ ID NO: 27 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C) - BHA_2269_FL (D342).SEQ ID NO: 28 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, N410C, S462C) - BHA_2270_FL.SEQ ID NO: 29 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, N410C, S462C) - BHA_2271_FL.SEQ ID NO: 30 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, A353C, G371C) - BHA_2272_FL.SEQ ID NO: 31 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, A353C, G371C) - BHA_2273_FL.SEQ ID NO: 32 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, A353C, G371C) - BHA_2274_FL.SEQ ID NO: 33 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, A428C, H433C) - BHA_2275_FL.SEQ ID NO: 34 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, A428C, H433C) - BHA_2276_FL.SEQ ID NO: 35 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, A428C, H433C) - BHA_2277_FL.SEQ ID NO: 36 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, K293C, Q423C) - BHA_2278_FL.SEQ ID NO: 37 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, K293C, Q423C) - BHA_2279_FL.SEQ ID NO: 38 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, K293C, Q423C) - BHA_2280_FL.SEQ ID NO: 39 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, L422C, D444C) - BHA_2281_FL.70583W001SEQ ID NO: 40 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, L422C, D444C) - BHA_2282_FL.SEQ ID NO: 41 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, L422C, D444C) - BHA_2283_FL.SEQ ID NO: 42 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, A34C, L460C) - BHA_2284_FL.SEQ ID NO: 43 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, T20C, L477C) - BHA_2285_FL.SEQ ID NO: 44 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, T20C, L477C) - BHA_2286_FL.SEQ ID NO: 45 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, T20C, L477C) - BHA_2287_FL.SEQ ID NO: 46 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, S385C, L508C) - BHA_2288_FL.SEQ ID NO: 47 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, S385C, L508C) - BHA_2289_FL.SEQ ID NO: 48 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(R447F, S385C, L508C) - BHA_2290_FL.SEQ ID NO: 49 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, Q454F) - BHA_2346_FL.SEQ ID NO: 50 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, Q454F) - BHA_2347_FL.SEQ ID NO: 51 Amino acid sequence of HA Full Length from B / Washington / 02 / 2019(Wild type)SEQ ID NO: 52 Amino acid sequence of HA Full Length from B / Colorado / 06 / 2017 (Wild type)SEQ ID NO: 53 Amino acid sequence of HA Full Length from B / Brisbane / 60 / 2008 (Wild type)SEQ ID NO: 54 Amino acid sequence of HA Full Length from B / Phuket / 3073 / 2013 (Wild type)70583W001SEQ ID NO: 55 Amino acid sequence of HA Full Length from B / Massachusetts / 2 / 2012(Wild type)SEQ ID NO: 56 Amino acid sequence of HA Full Length from B / Lee / 1940 (Wild type) SEQ ID NO: 57 Nucleic acid sequence encoding BHA_2269_FL (A34L, R447F, N410C,S462C) - D342_ASEQ ID NO: 58 Nucleic acid sequence encoding BHA_2296_FL (A34L_R447F_G21C_T384C) - D347SEQ ID NO: 59 Nucleic acid sequence encoding BHA_FL (R447F, T450I) - D77 SEQ ID NO: 60 nucleic acid sequence encoding BHA_2281_FL (A34L, R447F, L422C,D444C) - D344Nucleic acid sequence encoding BHA_2293_FL (A34L_R447F_A394C_A512C) - D346SEQ ID NO: 62 Nucleic acid sequence encoding BHA_2266_FL (A34L, R447F, H381C,S399C) - D341SEQ ID NO: 63 Nucleic acid sequence encoding BHA_2278_FL (A34L, R447F, K293C,Q423C) - D327SEQ ID NO: 64 Nucleic acid sequence encoding BHA_2117_FL (A34L, R447F,A428C:E435C) - D338SEQ ID NO: 65 Nucleic acid sequence encoding BHA_2118_FL (A34L, R447F, T450I)- D81SEQ ID NO: 66 Nucleic acid sequence encoding BHA_2115_FL (A34L, R447F) - D73_B SEQ ID NO: 67 Nucleic acid sequence encoding BHA_2116_FL (A34L, R447F,K420C:D449C) - D337SEQ ID NO: 68 Nucleic acid sequence encoding BHA_2272_FL (A34L, R447F, A353C,G371C) - D343SEQ ID NO: 69 Nucleic acid sequence encoding BHA_FL (K420C:D445C) - D15 SEQ ID NO: 70 Nucleic acid sequence encoding BHA_2263_FL (A34L) - D21 SEQ ID NO: 71 Nucleic acid sequence encoding BHA_2024_FL (R447F) - D46 SEQ ID NO: 72 Nucleic acid sequence encoding BHA_FL (R447F, Q454F) - D7870583W001SEQ ID NO: 73 Nucleic acid sequence encoding BHA_WT-2_FLSEQ ID NO: 74 Nucleic acid sequence encoding BHA_FL (R447F, T450I, Q454F) - D79 SEQ ID NO: 75 BHA_0001_ecto: B / Austria / 1359417 / 2021, HA ectodomain | Wild Type SEQ ID NO: 76 BHA_2001_ecto: HA ectodomain | A34LSEQ ID NO: 77 BHA_2303_ecto: HA ectodomain | A34FSEQ ID NO: 78 BHA_2024_ecto: HA ectodomain | R447FSEQ ID NO: 79 BHA_2321_ecto: HA ectodomain | R447YSEQ ID NO: 80 BHA_2115_ecto: HA ectodomain | A34L, R447F (D73)SEQ ID NO: 81 BHA_2348_ecto: HA ectodomain | A34F, R447YSEQ ID NO: 82 BHA_1010_ecto: HA ectodomain | K420C, D449CSEQ ID NO: 83 BHA_2116_ecto: HA ectodomain | A34L, R447F, K420C, D449C SEQ ID NO: 84 BHA_1011_ecto: HA ectodomain | A428C, E435CSEQ ID NO: 85 BHA_2117_ecto: HA ectodomain | A34L, R447F, A428C, E435C SEQ ID NO: 86 BHA_2118_ecto: HA ectodomain | A34L, R447F, T450I (D81) SEQ ID NO: 87 BHA_2119_ecto: HA ectodomain | A34L, R447F, T450I, K420C, D449C SEQ ID NO: 88 BHA_2120_ecto: HA ectodomain | A34L, R447F, T450I, A428C, E435C SEQ ID NO: 89 BHA_2291_ecto: HA ectodomain | A34L, A394C, A512CSEQ ID NO: 90 BHA_2292_ecto: HA ectodomain | R447F, A394C, A512CSEQ ID NO: 91 BHA_2293_ecto: HA ectodomain | A34L, R447F, A394C, A512C SEQ ID NO: 92 BHA_2294_ecto: HA ectodomain | A34L, G21C, T384CSEQ ID NO: 93 BHA_2295_ecto: HA ectodomain | R447F, G21C, T384CSEQ ID NO: 94 BHA_2296_ecto: HA ectodomain | A34L, R447F, G21C, T384C (D347) SEQ ID NO: 95 BHA_2263_ecto: HA ectodomain | A34L, R447F, A378C, A395C SEQ ID NO: 96 BHA_2264_ecto: HA ectodomain | A34L, A378C, A395CSEQ ID NO: 97 BHA_2265_ecto: HA ectodomain | R447F, A378C, A395CSEQ ID NO: 98 BHA_2266_ecto: HA ectodomain I A34L, R447F, H381C, S399C70583W001SEQ ID NO: 99 BHA_2267_ecto: HA ectodomain | A34L, H381C, S399CSEQ ID NO: 100 BHA_2268_ecto: HA ectodomain | R447F, H381C, S399CSEQ ID NO: 101 BHA_2269_ecto: HA ectodomain | A34L, R447F, N410C, S462C (D342) SEQ ID NO: 102 BHA_2270_ecto: HA ectodomain | A34L, N410C, S462CSEQ ID NO: 103 BHA_2271_ecto: HA ectodomain | R447F, N410C, S462CSEQ ID NO: 104 BHA_2272_ecto: HA ectodomain | A34L, R447F, A353C, G371C SEQ ID NO: 105 BHA_2273_ecto: HA ectodomain | A34L, A353C, G371CSEQ ID NO: 106 BHA_2274_ecto: HA ectodomain | R447F, A353C, G371CSEQ ID NO: 107 BHA_2275_ecto: HA ectodomain | A34L, R447F, A428C, H433C SEQ ID NO: 108 BHA_2276_ecto: HA ectodomain | A34L, A428C, H433CSEQ ID NO: 109 BHA_2277_ecto: HA ectodomain | R447F, A428C, H433CSEQ ID NO: 110 BHA_2278_ecto: HA ectodomain | A34L, R447F, K293C, Q423C SEQ ID NO: 111 BHA_2279_ecto: HA ectodomain | A34L, K293C, Q423CSEQ ID NO: 112 BHA_2280_ecto: HA ectodomain | R447F, K293C, Q423CSEQ ID NO: 113 BHA_2281_ecto: HA ectodomain | A34L, R447F, L422C, D444C SEQ ID NO: 114 BHA_2282_ecto: HA ectodomain | A34L, L422C, D444CSEQ ID NO: 115 BHA_2283_ecto: HA ectodomain | R447F, L422C, D444CSEQ ID NO: 116 BHA_2284_ecto: HA ectodomain | R447F, A34C, L460CSEQ ID NO: 117 BHA_2285_ecto: HA ectodomain | A34L, R447F, T20C, L477C SEQ ID NO: 118 BHA_2286_ecto: HA ectodomain | A34L, T20C, L477CSEQ ID NO: 119 BHA_2287_ecto: HA ectodomain | R447F, T20C, L477CSEQ ID NO: 120 BHA_2288_ecto: HA ectodomain | A34L, R447F, S385C, L508C SEQ ID NO: 121 BHA_2289_ecto: HA ectodomain | A34L, S385C, L508CSEQ ID NO: 122 BHA_2290_ecto: HA ectodomain | R447F, S385C, L508CSEQ ID NO: 123 BHA_2346_ecto: HA ectodomain | A34L, Q454FSEQ ID NO: 124 BHA_2347_ecto: HA ectodomain I A34L, R447F, Q454F70583W001SEQ ID NO: 125 5’UTR RNA sequence | 5’-UTR4SEQ ID NO: 126 3’UTR RNA sequence | 3’-UTR4SEQ ID NO: 127 5’UTR RNA sequence | HSD17B45'-UTR SEQ ID NO: 128 5’UTR RNA sequence | HSD17B45'-UTR SEQ ID NO: 129 3’UTR RNA sequence | PSMB33-UTR SEQ ID NO: 130 3’UTR RNA sequence | PSMB33'-UTR SEQ ID NO: 131 5’UTR RNA sequence | 5’UTRSEQ ID NO: 132 5’UTR RNA sequence | synthetic 5'-UTR SEQ ID NO: 133 5’UTR RNA sequence | synthetic 5'-UTR SEQ ID NO: 134 3’UTR RNA sequence | 3’UTRSEQ ID NO: 135 3’UTR RNA sequence | HBA1 3'-UTR SEQ ID NO: 136 3’UTR RNA sequence | HBA1 3'-UTR SEQ ID NO: 137 3’UTR RNA sequence | HBA1 3'-UTR SEQ ID NO: 138 3’UTR RNA sequence | HBA1 3'-UTR SEQ ID NO: 139 5’UTR RNA sequence | 5’UTRSEQ ID NO: 140 5’UTR RNA sequence | HBA1 5'-UTR SEQ ID NO: 141 5’UTR RNA sequence | HBA1 5'-UTR SEQ ID NO: 142 3’UTR RNA sequence | 3’UTRSEQ ID NO: 143 3’UTR RNA sequence | AES-12S 3'-UTR SEQ ID NO: 144 5’UTR RNA sequence | HHV55-UTR SEQ ID NO: 145 5’UTR RNA sequence | HHV55'-UTR SEQ ID NO: 146 3’UTR RNA sequence | GH1 3'-UTR SEQ ID NO: 147 3’UTR RNA sequence | GH1 3'-UTR SEQ ID NO: 148 HSL RNA sequence | Histone stem-loop SEQ ID NO: 149 mRNA 3'-end RNA sequence | HSL-A100 SEQ ID NO: 150 mRNA 3'-end RNA sequence | HSL-A100-N570583W001SEQ ID NO: 151 mRNA 3'-end RNA sequence | A100SEQ ID NO: 152 mRNA 3'-end RNA sequence | A100-N5SEQ ID NO: 153 mRNA 3'-end RNA sequence | A100-N5SEQ ID NO: 154 mRNA 3'-end RNA sequence | A30-N10-A70SEQ ID NO: 155 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, F110A) - Ectodomain: BHA_2352_ectoSEQ ID NO: 156 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, F110A)SEQ ID NO: 157 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, F110G)SEQ ID NO: 158 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, F110G)SEQ ID NO: 159 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, F1101) - Ectodomain: BHA_2351_ectoSEQ ID NO: 160 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, F110I)SEQ ID NO: 161 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, F110L) - Ectodomain: BHA_2350_ectoSEQ ID NO: 162 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, F110L)SEQ ID NO: 163 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, F110Y) - Ectodomain: BHA_2354_ectoSEQ ID NO: 164 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, F110Y)SEQ ID NO: 165 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, S155A)SEQ ID NO: 166 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, S115A)SEQ ID NO: 167 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, S115V)70583W001SEQ ID NO: 168 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, S115V)SEQ ID NO: 169 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, G156R)SEQ ID NO: 170 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, G156R)SEQ ID NO: 171 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, T194A)SEQ ID NO: 172 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, T194A)SEQ ID NO: 173 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, H206F)SEQ ID NO: 174 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, H206F)SEQ ID NO: 175 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, D208E)SEQ ID NO: 176 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, D209E) - Ectodomain: BHA_2353_ectoSEQ ID NO: 177 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, D209E)SEQ ID NO: 178 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, A214V) - Ectodomain: BHA_2349_ectoSEQ ID NO: 179 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, A214V)SEQ ID NO: 180 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, L216A)SEQ ID NO: 181 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, Y217F)SEQ ID NO: 182 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, Y217F)70583W001SEQ ID NO: 183 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, F110A)SEQ ID NO: 184 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, F110A) SEQ ID NO: 185 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, F110G)SEQ ID NO: 186 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, F110G) SEQ ID NO: 187 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, F110I)SEQ ID NO: 188 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, F110I) SEQ ID NO: 189 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, F110L) - D411SEQ ID NO: 190 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, F110L) - D411 SEQ ID NO: 191 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, F110Y)SEQ ID NO: 192 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, F110Y) SEQ ID NO: 193 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, S155A)SEQ ID NO: 194 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, S115A) SEQ ID NO: 195 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, S115V)SEQ ID NO: 196 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, S115V) SEQ ID NO: 197 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, G156R)70583W001SEQ ID NO: 198 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, G156R) SEQ ID NO: 199 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, T194A)SEQ ID NO: 200 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, T194A) SEQ ID NO: 201 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, H206F)SEQ ID NO: 202 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, H206F) SEQ ID NO: 203 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, D208E)SEQ ID NO: 204 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, D209E)SEQ ID NO: 205 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, D209E) SEQ ID NO: 206 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, A214V)SEQ ID NO: 207 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, A214V) SEQ ID NO: 208 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, L216A)SEQ ID NO: 209 Amino acid sequence of HA Full Length from B / Austria / 1359417 / 2021(A34L, R447F, N410C, S462C, Y217F)SEQ ID NO: 210 Nucleic acid sequence encoding HA Full Length from B / Austria / 1359417 / 2021 (A34L, R447F, N410C, S462C, Y217F) SEQ ID NO: 211 Nucleic acid sequence encoding BHA_2115_FL (A34L, R447F) - D73_A SEQ ID NO: 212 Nucleic acid sequence encoding BHA_2115_FL (A34L, R447F) - D73_C70583W001SEQ ID NO: 213 Nucleic acid sequence encoding BHA_2115_FL (A34L, R447F) - D73_DSEQ ID NO: 214 Nucleic acid sequence encoding BHA_2115_FL (A34L, R447F) - D73_E SEQ ID NO: 215 Nucleic acid sequence encoding BHA_2115_FL (A34L, R447F) - D73_F SEQ ID NO: 216 Nucleic acid sequence encoding BHA_2115_FL (A34L, R447F) - D73_GSEQ ID NO: 217 Nucleic acid sequence encoding BHA_2269_FL (A34L, R447F, N410C,S462C) - D342_BSEQ ID NO: 218 Nucleic acid sequence encoding BHA_2269_FL (A34L, R447F, N410C,S462C) - D342_CSEQ ID NO: 219 Nucleic acid sequence encoding BHA_2269_FL (A34L, R447F, N410C,S462C) - D342_DSEQ ID NO: 220 Nucleic acid sequence encoding BHA_2269_FL (A34L, R447F, N410C,S462C) - D342_ESEQ ID NO: 221 Nucleic acid sequence encoding BHA_2269_FL (A34L, R447F, N410C,S462C) - D342_FSEQ ID NO: 222 Nucleic acid sequence encoding BHA_2269_FL (A34L, R447F, N410C,S462C) - D342_GSEQ ID NO: 223 Amino acid sequence of a fusion protein comprising an amino (N)- terminal domain of a SARS-CoV-2 Spike protein and a receptor binding domain (RBD) of a SARS-CoV-2 Spike proteinSEQ ID NO: 224 Nucleic acid sequence encoding BHA_WT-1_FLDESCRIPTION OF THE FIGURES FIG. 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.70583W001FIG. 2 Multiple alignment of influenza B virus HA amino acid sequences (including SEQ ID NO: 1, 51-56).FIG. 3 Model of the prefusion influenza hemagglutinin (HA) trimer (left), with the head domain (HA1) and fusion subunit (HA2) labeled. Images on the right highlight subdomains that undergo dramatic restructuring from the prefusion structure to the post fusion structure in response to low pH.FIG. 4 HPLC-SEC chromatogram of selected HA ectodomain constructs. Protein peaks with retention times between 4.1 and 4.4 minutes represent HA trimers. The BHA_001 (WT) construct contains a mixture of HA monomers and trimers. HA variants, such as BHA_2001 (A34L) and BHA_2024 (R447F) with specific mutations, demonstrate a significantly improved percentage of trimer content. The BHA_2115 (A34L, R447F) construct shows a more symmetric peak than BHA_001 (WT; wild-type) at the retention time for trimeric HA, indicating a higher proportion of the trimer population.FIG. 5 CryoEM 2D classification of 3 purified HA ectodomain proteins: (1) BLA_0001, wild type; (2) BHA_2115, containing A34L and R447F mutations; and (3) BHA_2116, containing A4L, R447F, and interprotomer disulfide, K420C-D449C. FIG. 6 Binding response (Rll) of receptor binding site knock-out designs to a2,3 (in black) and a2,6 (in gray) -SLNLNLN.FIG. 7 Flu HA Cell Surface Expression, CR9114. All Flu HA constructs were able to express the target antigen after transfection of the target cells. SEM (Standard error of the mean); #1 - no RNA, control; #2 - D338; #3 - D337; #4 - D327; #5 - D347; #6 - D342_A; #7 - D343; #8 - D346; #9 - D341; #10 - D344; #11 - BM2 (benchmark 2); #12 - D73_B; #13- D81; #14- WT-1; #15 - WT-2; #16 - BM1; #17 - WT-1 (Experiment A); #18 - WT-2 (Experiment A); #19 - BM1 (Experiment A).FIG. 8 Flu HA Cell Surface Expression, CR8071. All Flu HA constructs were able to express the target antigen after transfection of the target cells. SEM (Standard error of the mean); #1 - no RNA, control; #2 - D338; #3 - D337; #4 - D327; #5 - D347; #6 - D342_A; #7 - D343; #8 - D346; #9 - D341; #10 - D344; #11 - BM2 (benchmark 2); #12 - D73_B; #13- D81; #14- WT-1; #15 - WT-2; #16 - BM1; #17 - WT-1 (Experiment A); #18 - WT-2 (Experiment A); #19 - BM1 (Experiment A).70583W001FIG. 9 Flu HA Whole Cell Expression, CR8071. All Flu HA constructs were able to express the target antigen after transfection of the target cells. SEM (Standard error of the mean); #1 - no RNA, control; #2 - D338; #3 - D337; #4 - D327; #5 - D347; #6 - D342_A; #7 - D343; #8 - D346; #9 - D341; #10 - D344; #11 - BM2 (benchmark 2); #12 - D73_B; #13- D81; #14- WT-1; #15 - WT-2; #16 - BM1; #17 - WT-1 (Experiment A); #18 - WT-2 (Experiment A); #19 - BM1 (Experiment A).FIG. 10 Flu HA Cell Surface Expression, CR8071. All Flu HA constructs were able to express the target antigen after transfection of the target cells. Each bar shows the mean value. Error bars represent the standard deviation (SD). Each condition was measured in three independent replicates. MAI (Mean Average Intensity (Channel 2); SD (Standard Deviation).FIG. 11 Flu HA Cell Surface Expression, CR9114. All Flu HA constructs were able to express the target antigen after transfection of the target cells. Each bar shows the mean value. Error bars represent the standard deviation (SD). Each condition was measured in three independent replicates. MAI (Mean Average Intensity (Channel 2); SD (Standard Deviation).FIG. 12 In vitro LNP expression assay for in vivo study material after DP (Drug Product) transduction of BJ fibroblast cells for multivalent constituent constructs and D73_B. Indirect immunofluorescent labelling followed by high-content imaging and data analysis to quantify Flu antigen surface expression. BJ cells were transduced with LNP formulated Flu antigen encoding DS (Drug Substance).24h post-transduction, cells were stained for Flu antigen expression using CR9114 (A), CR8071 (B), HL1476 (C), FNI19 (D), 1G01 (E) and analysed by high-content imaging. Data are presented as area under the MFI (Mean Fluorescence Intensity) curve (AUC). SEM (Standard error of the mean).FIG. 13 In vitro LNP expression assay for in vivo study after DP (Drug Product) transduction of BJ fibroblast cells. Indirect immunofluorescent labelling followed by high-content imaging and data analysis to quantify Flu antigen surface expression. BJ cells were transduced with LNP formulated Flu antigen encoding DS (Drug Substance). 24h post-transduction, cells were stained for Flu antigen expression using CR9114 (A), CR8071 (B), and analysed by high-content imaging. Data are presented as area under the MFI (Mean Fluorescence Intensity) curve (AUC). SEM (Standard error of the mean).70583W001FIG. 14 In vitro LNP expression assay for in vivo study material after DP (Drug Product) transduction of BJ fibroblast cells. Indirect immunofluorescent labelling followed by high-content imaging and data analysis to quantify Flu antigen surface expression. BJ cells were transduced with LNP formulated Flu antigen encoding DS (Drug Substance). 24h post-transduction, cells were stained for Flu antigen expression using CR8071 and analysed by high-content imaging. Data are presented as area under the MFI (Mean Fluorescence Intensity) curve (AUG). SEM (Standard error of the mean).FIG. 15 In vitro LNP expression assay for in vivo study after DP (Drug Product) transduction of BJ fibroblast cells. Indirect immunofluorescent labelling followed by high-content imaging and data analysis to quantify Flu antigen surface expression. BJ cells were transduced with LNP formulated Flu antigen encoding DS (Drug Substance). 24h post-transduction, cells were stained for Flu antigen expression using CR9114 and analysed by high-content imaging. Data are presented as area under the MFI (Mean Fluorescence Intensity) curve (AUG). SEM (Standard error of the mean).FIG. 16 HAI titers to B / Connecticut / 01 / 2021at days 21 (D21; Top Panel) and 35 (D35;Bottom Panel) following IM (intramuscular) injection in BALB / c mice at dosages of 1.2, 0.6, and 0.3 pg hemagglutinin on day 0 and on day 21. GMT (Geometrical mean titer); LLOD (Lower limit of detection)FIG. 17 HAI titers to A / Georgia / 12 / 2022 (H1N1) following immunization of mice with the 6-component WT formulation, 6- component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care). Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected two weeks post-dose 2 (Day 35). Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LLOD).FIG. 18 GMRs of HAI titers to A / Georgia / 12 / 2022 (H1N1) following immunization of mice with the 6- component WT formulation, 6- component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care). Female BALB / c mice were immunized IM on Day 0 and Day 21, and ratios were determined on HAI titers from serum collected two weeks post-dose 2 (Day 35). Each symbol represents the GMR with 90% credibility intervals (Cis) for each treatment comparison. LCI>3 (at least 3-fold superior); LCI > 1 / 3 (non-inferior).70583W001FIG. 19 HAI titers to District of Columbia / 27 / 2023 (H3N2) following immunization of mice with the 6- component WT formulation, 6- component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care). Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected two weeks post-dose 2 (Day 35). Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LOD).FIG. 20 GMRs of HAI titers to District of Columbia / 27 / 2023 (H3N2) following immunization of mice with the 6- component WT formulation, 6- component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care). Female BALB / c mice were immunized IM on Day 0 and Day 21, and ratios were determined on HAI titers from serum collected two weeks post-dose 2 (Day 35). Each symbol represents the GMR with 90% credibility intervals (Cis) for each treatment comparison. LCI>3 (at least 3-fold superior); LCI>1 / 3 (non-inferior).FIG. 21 HAI titers to B / Connecticut / 01 / 2021 (B-Victoria) following immunization of mice with the 6- component WT formulation, 6- component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care). Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected three weeks post-dose 1 (Day 21; Top Panel) or two weeks post-dose 2 (Day 35; Bottom Panel). Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LOD).FIG. 22 GMRs of HAI titers to B / Connecticut / 01 / 2021 (B-Victoria) following immunization of mice with the 6- component WT formulation, 6- component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care). Female BALB / c mice were immunized IM on Day 0 and Day 21, and ratios were determined on HAI titers from serum collected three weeks post-dose one (Day 21; Left Panel) or two weeks post-dose 2 (Day 35; Right Panel). Each symbol represents the GMR with 90% credibility intervals (Cis) for each treatment comparison. LCI>3 (at least 3-fold superior); LCI > 1 (superior). FIG. 23 Neuraminidase Antibody titers following immunization of mice with the 6- component WT formulation, 6- component vaccine candidates, and a marketed70583W001inactivated seasonal flu vaccine (SOC; standard of care). Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected two weeks post-dose 2 (Day 35) against A / Georgia / 12 / 2022 (H1N1) (Left Panel), A / Darwin / 11 / 2021 (H3N2) (Middle Panel), or B / Austria / 1359417 / 2021 (B) (Right Panel). Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% confidence (Cis) for each treatment group. The dashed line indicates the limit of detection (LOD).FIG. 24 HAI reciprocal titers to A / Georgia / 12 / 2022 (H1N1) following immunization of mice with the monovalent WT formulation, 6-component WT formulation, 6- component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care) at the administered dosage as indicated above (Note: the marketed inactivated seasonal flu vaccine (SOC; standard of care) (Southern Hemisphere 2025) was administered at 1 / 10 the human dose for all 4 antigens [1.5 pg each HA = 6.0 pg total HA]). Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected two weeks post-dose 2 (Day 35). The number (N) of animals per group is indicated above and ranged from 6 to 15 based on statistical considerations. Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LOD).FIG. 25 GMRs of HAI titers to A / Georgia / 12 / 2022 (H1N1) following immunization of mice with the monovalent WT formulation, 6-component WT formulation, 6- component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care). Female BALB / c mice were immunized IM on Day 0 and Day 21, and ratios were determined on HAI titers from serum collected two weeks post-dose 2 (Day 35). Each symbol represents the GMR with 90% credibility intervals (Cis) for each treatment comparison. LCI>3 (at least 3-fold superior); LCI > 1 / 3 (non-inferior).FIG. 26 HAI reciprocal titers to A / District of Columbia / 27 / 2023 (H3N2) following immunization of mice with the monovalent WT formulation, 6-component WT formulation, the 6-component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care) at the administered dosages as indicated above (Note: the marketed inactivated seasonal flu vaccine (SOC; standard of care) (Southern Hemisphere 2025) was administered at 1 / 10 the human dose for all 4 antigens [1.5 pg each HA = 6.0 pg total HA]). Female70583W001BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected two weeks post-dose 2 (Day 35). The number (N) of animals per group is indicated above and ranged from 10 to 15 based on statistical considerations. Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LCD).FIG. 27 GMRs of HAI titers to A / District of Columbia / 27 / 2023 (H3N2) following immunization of mice with the monovalent WT formulation, 6-component WT formulation, 6-component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care). Female BALB / c mice were immunized IM on Day 0 and Day 21, and ratios were determined on HAI titers from serum collected two weeks post-dose 2 (Day 35). Each symbol represents the GMR with 90% credibility intervals (Cis) for each treatment comparison. LCI>3 (at least 3-fold superior); LCI > 1 / 3 (non-inferior); LCI > 1 (superior).FIG. 28 HAI reciprocal titers to B / Connecticut / 01 / 2021 (B-Victoria) following immunization of mice with the 6-component WT formulation and 6-component vaccine candidates at the administered dosage as indicated above. Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected three weeks post-dose 1 (Day 21). The number (N) of animals per group is indicated above (10 animals per group) based on statistical considerations. Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LOD).FIG. 29 HAI reciprocal titers to B / Connecticut / 01 / 2021 (B-Victoria) following immunization of mice with the 6-component WT formulation, 6-component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care) at the administered dosage as indicated above (Note: the marketed inactivated seasonal flu vaccine (SOC; standard of care) (Southern Hemisphere 2025) was administered at 1 / 10 the human dose for all 4 antigens [1.5 pg each HA = 6.0 pg total HA]) . Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected two weeks post-dose 2 (Day 35). The number (N) of animals per group is indicated above (10 animals per group except for the SOC which had 15 animals) based on statistical considerations. Each symbol represents an individual animal, and the70583W001geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LCD).FIG. 30 GMRs of HAI titers to B / Connecticut / 01 / 2021 (B-Victoria) following immunization of mice with the 6-component WT formulation, 6-component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care). Female BALB / c mice were immunized IM on Day 0 and Day 21, and ratios were determined on HAI titers from serum collected three weeks post-dose 1 (Day 21 ; left side of GMR plot) and two weeks post-dose 2 (Day 35; right side of GMR plot). Each symbol represents the GMR with 90% credibility intervals (Cis) for each treatment comparison. LCI>3 (at least 3-fold superior); LCI>1 (superior).FIG. 31 HAI reciprocal titers to B / Connecticut / 01 / 2021 (B-Victoria) following immunization of mice with the monovalent formulations at the administered dosage as indicated above. Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected three weeks postdose 1 (Day 21). The number (N) of animals per group is indicated above, and ranged from 6 to 10 based on statistical considerations. Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LOD).FIG. 32 HAI reciprocal titers to B / Connecticut / 01 / 2021 (B-Victoria) following immunization of mice with the different monovalent formulations at the administered dosage as indicated above. Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected two weeks post-dose 2 (Day 35). The number (N) of animals per group is indicated above and ranged from 6 to 10 based on statistical considerations. Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LOD).FIG. 33 GMRs of HAI titers to B / Connecticut / 01 / 2021 (B-Victoria) following immunization of mice with the monovalent formulations. Female BALB / c mice were immunized IM on Day 0 and Day 21, and ratios were determined on HAI titers from serum collected three weeks post-dose 1 (Day 21; left side of GMR plot) and two weeks post-dose 2 (Day 35; right side of GMR plot). Each symbol170583W001represents the GMR with 90% credibility intervals (Cis) for each treatment comparison. LCI>1 / 3 (non-inferior)); LCI>1 / 3 (non-inferior).FIG. 34 GMRs of HAI titers to B / Connecticut / 01 / 2021 (B-Victoria) following immunization of mice with the monovalent formulations, 6-component WT formulation, and 6-component vaccine candidates. Female BALB / c mice were immunized IM on Day 0 and Day 21, and ratios were determined on HAI titers from serum collected three weeks post-dose 1 (Day 21; left side of GMR plot) and two weeks post-dose 2 (Day 35; right side of GMR plot). Each symbol represents the GMR with 90% credibility intervals (Cis) for each treatment comparison. LCI>1 / 3 (non-inferior).FIG. 35 Nl reciprocal titers to A / Georgia / 12 / 2022 (H1N1) following immunization of mice with the monovalent WT formulation, the 6-component WT formulation, the 6- component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care) at the administered dosage as indicated above (Note: the marketed inactivated seasonal flu vaccine (SOC; standard of care) (Southern Hemisphere 2025) was administered at 1 / 10 the human dose for all 4 antigens [1.5 pg each HA = 6.0 pg total HA]). Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected two weeks post-dose 2 (Day 35). The number (N) of animals per group is indicated above and ranged from 6 to 15 based on statistical considerations. Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LOD).FIG. 36 GMRs of Nl titers to A / Georgia / 12 / 2022 (H1N1) following immunization of mice with the monovalent WT formulation, the 6-component WT formulation, and the 6-component vaccine candidates. Female BALB / c mice were immunized IM on Day 0 and Day 21 , and ratios were determined on Nl titers from serum collected two weeks post-dose 2 (Day 35). Each symbol represents the GMR with 90% credibility intervals (Cis) for each treatment comparison. LCI>1 / 3 (non-inferior). FIG. 37 Nl reciprocal titers to A / Darwin / 11 / 2021 (H3N2) following immunization of mice with the monovalent WT formulation, the 6-component WT formulation, the 6- component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care) at the administered dosage as indicated above (Note: the marketed inactivated seasonal flu vaccine (SOC; standard of care) (Southern Hemisphere 2025) was administered at 1 / 10 the human dose for all70583W0014 antigens [1.5 g each HA = 6.0 pg total HA]). Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected two weeks post-dose 2 (Day 35). The number (N) of animals per group is indicated above, and ranged from 6 to 15 based on statistical considerations. Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LOD).FIG. 38 GMRs of Nl titers to A / Darwin / 11 / 2021 (H3N2) following immunization of mice with the monovalent WT formulation, the 6-component WT formulation, and the 6-component vaccine candidates. Female BALB / c mice were immunized IM on Day 0 and Day 21 , and ratios were determined on Nl titers from serum collected two weeks post-dose 2 (Day 35). Each symbol represents the GMR with 90% credibility intervals (Cis) for each treatment comparison. LCI>1 / 3 (non-inferior). FIG. 39 Nl reciprocal titers to B / Austria / 1359417 / 2021 (B) following immunization of mice with the monovalent WT formulation, the 6-component WT formulation, the 6-component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care) at the administered dosages as indicated above (Note: the marketed inactivated seasonal flu vaccine (SOC; standard of care) (Southern Hemisphere 2025) was administered at 1 / 10 the human dose for all 4 antigens [1.5 pg each HA = 6.0 pg total HA]). Female BALB / c mice were immunized IM on Day 0 and Day 21, and titers were measured in serum collected two weeks post-dose 2 (Day 35). The number (N) of animals per group is indicated above and ranged from 6 to 15 based on statistical considerations. Each symbol represents an individual animal, and the geometrical mean titers (GMTs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LOD).FIG. 40 GMRs of Nl titers to B / Austria / 1359417 / 2021 (B) following immunization of mice with the monovalent WT formulation, the 6-component WT formulation, the 6- component vaccine candidates, and a marketed inactivated seasonal flu vaccine (SOC; standard of care). Female BALB / c mice were immunized IM on Day 0 and Day 21 , and ratios were determined on Nl titers from serum collected two weeks post-dose 2 (Day 35). Each symbol represents the GMR with 90% credibility intervals (Cis) for each treatment comparison. LCI>3 (at least 3-fold superior); LCI>1 / 3 (non-inferior).70583W001FIG. 41 Systemic innate immune responses following immunization of mice with the 6- component vaccine candidates and the 6-component WT B HA formulation. Female BALB / c mice were immunized IM on Day 0 with either the 6-component vaccine candidates encoding the optimized B HAs, the 6-component WT B HA formulation, or saline, and serum samples were taken 18 hr post-immunization. The number (N) of animals per group is indicated above and is based on statistical considerations. Levels (in pg / mL) of (A) CCL2 (MCP-1), (B) CCL5, (C) CXCL1 (KC), (D) CXCL10 (IP-10), (E) GM_CSF, (F) IFN-a, (G) IFN-p, (H) IFN-Y, (I) IL10, (J) IL12p70, (K) IL-ip, (L) IL6, and (M) TNF-a were determined by cytometric bead array. Each symbol represents an individual animal, and the geometrical means (GMs) are indicated with 95% credibility intervals (Cis) for each treatment group. The dashed line indicates the lower limit of detection (LOD) for each specific cytokine / chemokine.FIG. 42 Systemic innate immune responses following immunization of mice with the 6- component vaccine candidates and the 6-component WT B HA formulation. Female BALB / c mice were immunized IM on Day 0 with either the 6-component vaccine candidates encoding the optimized B HAs, the 6-component WT B HA formulation or saline, and serum samples were taken 18 hr post-dose 1, and ratios were determined. Levels (in pg / mL) of (A) CCL-2 (MCP-1), (B) CCL-5, (C) CXCL-1 (KC), (D) CXCL-10 (IP-10), (E) GM-CSF, (F) IFN-a, (G) IFN-p (H) IFN-y, (I) IL-10, (J) IL-12p70, (K) IL-ip, (L) IL6 and (M) TNF-a were determined by cytometric bead assay. Each symbol represents an individual animal, and the geometrical means (GMs) are indicated with 90% credibility intervals (Cis) for each treatment comparison. Non-superiority between the induced responses is reached if the upper Cl of the geometric mean ratio (GMR) is < 3 (non-superior; UCI<3).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. The sequence listing may also provide additional detailed information, e.g. regarding certain structural features, sequence optimizations, GenBank (NCBI), or additional detailed information70583W001regarding its coding capacity. Where reference is made to “SEQ ID NOs” of other published patent applications or patents, said sequences, e.g. aa or n.a. sequences, are explicitly incorporated herein by reference. Accordingly, these sequences constitute an integral part of the underlying description.Hemagglutinin (HA) antigensProtective 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 etal. Viruses. 2021, 13(5), 746).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 HA 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 HA protein undergoes a pH-dependent conformational change that allows for the HA 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 HA 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 globular 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 globular 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 globular head domain of HA and prevent70583W001or 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 conformational change of the protein. Antibodies against Influenza often target variable antigenic sites in the globular head of HA and thus, neutralize only antigenically closely related viruses. The variability of the HA head is due to the constant antigenic drift ( / .e. changes in the protein sequence) of Influenza viruses and is responsible for seasonal endemics of Influenza.Clinical studies underlying the currently approved flu vaccines highlight some variabilities in vaccine efficacy against different strains of Influenza virus and in immunogenicity associated with different antigens (e.g. HA) forming the flu vaccine. For example, the efficacy of FLU BLOK against Influenza subtype A is of 54.4% compared to only 23.1% against Influenza type B, both in healthy adults 18-49 years of age. Similarly, the corresponding immunogenicity studies reveal HI GMTs (Hemagglutination inhibition geometric mean titers) up to 17-fold higher for HA A antigens than for HA B antigens.The inventors overcame the drawbacks of the prior art by providing a HA antigen from an Influenza B virus (IBV) having an amino acid sequence comprising at least one amino acid substitution relative to a reference amino acid sequence, wherein said amino acid sequence of said HA antigen comprises one or more of (i)-(xxviii):(i) a leucine (L) or a phenylalanine (F) at position 34;(ii) a phenylalanine (F) or a tyrosine (Y) at position 447;(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;(xvii) an isoleucine (I) at position 450;70583W001(xviii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217,wherein the positions of (i)-(xxviii) are numbered by alignment of the reference to SEQ ID NO: 1.In some embodiments, said at least one amino acid substitution comprises one or more of (i)-(xxviii):(i) A34L or A34F substitution;(ii) R447F or R447Y substitution;(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution ;(xix) F110G, F110Y, F110L, F1101 or F110A substitution;(xx) S155A or S155V substitution;70583W001(xxi) G156R substitution;(xxii) T 194A substitution;(xxiii) H206F substitution;(xxiv) D208E substitution;(xxv) D209E substitution;(xxvi) A214V substitution;(xxvii) L216A substitution; or(xxviii) Y217F substitution,wherein the positions of (i)-(xxviii) are numbered by alignment of the reference to SEQ ID NO: 1.Some embodiments relate to HA antigens having an amino acid sequence comprising at least one amino acid substitution relative to a reference amino acid sequence, such as a wild type IBV HA amino acid sequence, and / or numbered according to a listed HA amino acid sequence.For clarity, mutations e.g. amino acid substitutions are described using amino acids numbering corresponding to specific listed HA amino acid sequences {e.g. of a recent vaccine strain B / Austria / 1359417 / 2021; e.g. SEQ ID NO: 1). The skilled person will appreciate that mutations e.g. amino acid substitutions disclosed in relation to a listed HA amino acid sequence may be applied to other HA amino acid sequences of IBV, such as Influenza B / Victoria lineage and / or B / Yamagata lineage virus e.g. SEQ ID NO: 51-56). To apply a mutation e.g. amino acid substitutions disclosed with numbering corresponding to a listed amino acid sequence {e.g. SEQ ID NO: 1) to a different reference, such as a different wild type IBV HA amino acid sequence, the skilled person may align that different reference to the listed amino acid sequence with which the mutation is numbered. For example, to apply a R447F substitution numbered according to SEQ ID NO: 1 ( / .e. the listed amino acid sequence), to a different reference, such as a different wild type IBV HA amino acid sequence, the skilled person would align the different reference to SEQ ID NO: 1, and introduce a phenylalanine (F) at the residue of the different reference that corresponds to R447 of SEQ ID NO: 1. An example of such alignment is presented in FIG. 2, the wild type Influenza B / Phuket / 3073 / 2013 virus HA amino acid sequence of SEQ ID NO: 54, showing that residue R449 of SEQ ID NO: 54 aligns to residue R447 of SEQ ID NO: 1. Accordingly, to apply a R447F substitution to SEQ ID NO: 54, the skilled person would replace residue 449 of SEQ ID NO: 54 with a phenylalanine (F), because residue 449 of SEQ ID NO: 54 aligns to R447 of SEQ ID NO: 1. Other examples are presented in FIG. 2, showing alignments of other references e.g. of wild type B / Washington / 02 / 2019 virus HA amino acid sequence (SEQ ID NO: 51), wild type B / Colorado / 06 / 2017 virus HA amino acid sequence (SEQ ID NO: 52), wild type70583W001B / Brisbane / 60 / 2008 virus HA amino acid sequence (SEQ ID NO: 53), wild type B / Phuket / 3073 / 2013 virus HA amino acid sequence (SEQ ID NO: 54), wild type B / Massachusetts / 2 / 2012 virus HA amino acid sequence (SEQ ID NO: 55) or wild type B / Lee / 1940 virus HA amino acid sequence (SEQ ID NO: 56) to the listed wild type HA amino acid sequence of B / Austria / 1359417 / 2021 virus (SEQ ID NO: 1).Some embodiments relate to IBV HA antigens comprising at least one amino acid substitution(s) relative to a reference, such as a wild type IBV HA amino acid sequence. For example, an Influenza B / Victoria lineage virus HA antigen having the amino acid sequence of SEQ ID NO: 6 comprises a leucine (L) substitution and a phenylalanine (F) substitution relative to the wild type Influenza B / Victoria lineage virus HA amino acid sequence of SEQ ID NO: 1 ( / .e. the reference). The skilled person will appreciate the substitutions disclosed in relation to a listed amino acid sequence (e.g. SEQ ID NO: 1) may be referred to in the form X1[#]X2, where X1 is the amino acid at position [#] in a listed amino acid sequence, and X2 is the amino acid introduced by replacement of the X1 at position [#]. For example, a leucine (L) substitution at position 34 may also be referred to as an A34L substitution, when using SEQ ID NO: 1 as a listed amino acid sequence, because the alanine (A) at position 34 of SEQ ID NO: 1 is replaced with a leucine (L). Such a substitution may also be referred to as an “X2 substitution at position [#]”, meaning that a protein comprises an X2 residue at position [#] (numbered by alignment to a listed amino acid sequence), regardless of whether the residue that was present at position [#] in the reference amino acid sequence was X1, or a different residue other than X1. The skilled person will understand that substitutions disclosed in the form X1[#]X2 may also be applied to a reference amino acid sequence in the form of “X2 substitution at position [#]” that is agnostic to the residue present in the reference amino acid sequence (numbered by alignment to a listed amino acid sequence). While the preceding paragraph uses SEQ ID NO: 1 ( / .e. wild type HA amino acid sequence of Influenza B / Austria / 1359417 / 2021 (B / Victoria lineage) virus) as a reference amino acid sequence, a reference amino acid sequence may be a wild type HA amino acid sequence of another Influenza virus isolate (e.g. of B / Washington / 02 / 2019 virus (SEQ ID NO: 51), B / Colorado / 06 / 2017 virus (SEQ ID NO: 52), B / Brisbane / 60 / 2008 virus (SEQ ID NO: 53), B / Phuket / 3073 / 2013 virus (SEQ ID NO: 54), B / Massachusetts / 2 / 2012 virus (SEQ ID NO: 55) or B / Lee / 1940 virus (SEQ ID NO: 56)), or an engineered HA amino acid sequence that is not encoded by a genome of an isolate.Some embodiments relate to IBV HA antigens having an amino acid sequence comprising a specified residue at a specified position, with positions being numbered according to a listed amino acid sequence (e.g. SEQ ID NO: 1). As with determining the positions of substitutions numbered according to a listed amino acid sequence, the skilled person may align the HA antigen amino acid sequence to the listed amino acid sequence, to determine70583W001whether the HA antigen contains the specified residue at that position corresponding to the specified position of the listed amino acid sequence. For example, to determine whether an HA antigen contains a leucine (L) at position 34 and a phenylalanine (F) at position 447, where the positions are numbered by alignment to SEQ ID NO: 1, the skilled person would align the amino acid sequence of the HA antigen to SEQ ID NO: 1, determine whether the amino acid of the HA antigen that aligns to residue 34 of SEQ ID NO: 1 is a leucine (L), and determine whether the amino acid of the HA antigen that aligns to residue 447 of SEQ ID NO: 1 is a phenylalanine (F).Unless otherwise clear from context, mutations e.g. amino acid substitutions described herein are numbered according to full-length amino acid sequences, such as full-length of wild type IBV HA amino acid sequence {e.g. SEQ ID NO: 1) each of which includes the signal peptide ( / .e. residue 1 of each sequence is the methionine encoded by the start codon of an ORF encoding the HA). The skilled person will understand that other numbering schemes exist for reference to other forms or subunits of an HA, such as a post-signal peptide cleavage form (where residue 1 is the N-terminal amino acid after signal peptide cleavage).It has been found that the IBV HA antigens as described herein i.e. comprising at least one amino acid substitution, such as one or more of (i)-(xxviii), are optimized antigens. In particular, or in addition, the IBV HA antigens as described herein exhibit an improved expression, stability e.g. in pre-fusion conformation), and / or trimerization, e.g. as compared to a wild type IBV HA antigen.Therefore, in a first aspect, the invention relates to a hemagglutinin (HA) antigen from Influenza B virus (IBV) having an amino acid sequence comprising at least one amino acid substitution relative to a reference amino acid sequence, wherein said amino acid sequence of said HA antigen comprises one or more of (i)-(xxviii):(i) a leucine (L) or a phenylalanine (F) at position 34;(ii) a phenylalanine (F) or a tyrosine (Y) at position 447;(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;70583W001(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;(xvii) an isoleucine (I) at position 450;(xviii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217.In some embodiments, the positions of (i)-(xxviii) are numbered by alignment of the reference to SEQ ID NO: 1.In some embodiments, said reference amino acid sequence is a wild type IBV HA amino acid sequence, optionally said IBV is from B / Victoria lineage or B / Yamagata lineage, suitably from B / Victoria lineage.In some embodiments, said reference amino acid sequence comprises SEQ ID NO: 1, 51 , 52, 53, 54, 55 or 56. In some embodiments, said reference amino acid sequence comprises SEQ ID NO: 1. In some embodiments, said reference amino acid sequence consists of SEQ ID NO: 1, 51, 52, 53, 54, 55 or 56. In some embodiments, said reference amino acid sequence consists of SEQ ID NO: 1.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 IBV HA antigen comprises or consists of a peptide or protein derived from an IBV HA.In some embodiments, said IBV HA antigen comprises or consists of a recombinant peptide or protein derived from an IBV HA.70583W001A “recombinant peptide or protein” refers to a peptide or protein that is produced in a heterologous organism that does not naturally produce the peptide or protein or a variant thereof. Non-limiting examples of organisms in which recombinant peptides or proteins may be produced include bacteria, yeast and mammalian cells.In some embodiments, said IBV HA antigen is a polypeptide comprising a full-length Influenza HA protein. Suitably, said IBV HA antigen is a polypeptide consisting of a full-length Influenza HA protein.In some embodiments, said IBV HA antigen 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 or consists of the head domain or a portion of the head domain. In some embodiments, the fragment comprises or consists of a stalk (or stem) 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, said at least one amino acid substitution comprises one or more of (i)-(xxviii):(i) A34L or A34F substitution;(ii) R447F or R447Y substitution;(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution;70583W001(xix) F110G, F110Y, F110L, F1101 or F110A substitution;(xx) S155A or S155V substitution;(xxi) G156R substitution;(xxii) T194A substitution;(xxiii) H206F substitution;(xxiv) D208E substitution;(xxv) D209E substitution;(xxvi) A214V substitution;(xxvii) L216A substitution; or(xxviii) Y217F substitution.In some embodiments, the positions of (i)-(xxviii) are numbered by alignment of the reference to SEQ ID NO: 1.In some embodiments, said reference amino acid sequence is a wild type IBV HA amino acid sequence, optionally said IBV is from B / Victoria lineage or B / Yamagata lineage, suitably from B / Victoria lineage.In some embodiments, said reference amino acid sequence comprises SEQ ID NO: 1, 51 , 52, 53, 54, 55 or 56. In some embodiments, said reference amino acid sequence comprises SEQ ID NO: 1. In some embodiments, said reference amino acid sequence consists of SEQ ID NO: 1, 51, 52, 53, 54, 55 or 56. In some embodiments, said reference amino acid sequence consists of SEQ ID NO: 1.In some embodiments, said IBV HA antigen comprises at least one amino acid substitution as described in Table 1.Table 1: Amino acid substitutions comprised in IBV HA antigens as defined herein (e.g. SEQ ID NO: 2-50, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 176, 178, 180, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 204, 206, 208 and 209) relative to a reference (e.g. SEQ ID NO: 1)SEQ ID NO: 1 Reference; Wild type IBV HA amino acid sequenceSEQ ID NO: 2 A34LSEQ ID NO: 3 A34FSEQ ID NO: 4 R447FSEQ ID NO: 5 R447YSEQ ID NO: 6 A34L R447FSEQ ID NO: 7 A34F R447YSEQ ID NO: 8 K420C, D449CSEQ ID NO: 9 A34L R447F K420C, D449CSEQ ID NO: 10 A428C, E435CSEQ ID NO: 11 A34L R447F A428C, E435C70583W001SEQ ID NO 12 A34L R447F T450I SEQ ID NO 13 A34L R447F K420C, D449C T450I SEQ ID NO 14 A34L R447F A428C, E435C T450I SEQ ID NO 15 A34L A394C, A512CSEQ ID NO 16 R447F A394C, A512CSEQ ID NO 17 A34L R447F A394C, A512CSEQ ID NO 18 A34L G21C, T384CSEQ ID NO 19 R447F G21C, T384CSEQ ID NO 20 A34L R447F G21C, T384CSEQ ID NO 21 A34L A378C, A395CSEQ ID NO 22 R447F A378C, A395CSEQ ID NO 23 A34L R447F A378C, A395CSEQ ID NO 24 A34L H381C, S399CSEQ ID NO 25 R447F H381C, S399CSEQ ID NO 26 A34L R447F H381C, S399CSEQ ID NO 27 A34L N410C, S462CSEQ ID NO 28 R447F N410C, S462CSEQ ID NO 29 A34L R447F N410C, S462CSEQ ID NO 30 A34L A353C, G371CSEQ ID NO 31 R447F A353C, G371CSEQ ID NO 32 A34L R447F A353C, G371CSEQ ID NO 33 A34L A428C, H433CSEQ ID NO 34 R447F A428C, H433CSEQ ID NO 35 A34L R447F A428C, H433CSEQ ID NO 36 A34L K293C, Q423CSEQ ID NO 37 R447F K293C, Q423CSEQ ID NO 38 A34L R447F K293C, Q423CSEQ ID NO 39 A34L L422C, D444CSEQ ID NO 40 R447F L422C, D444CSEQ ID NO 41 A34L R447F L422C, D444CSEQ ID NO 42 R447F A34C, L460CSEQ ID NO 43 A34L T20C, L477CSEQ ID NO 44 R447F T20C, L477CSEQ ID NO 45 A34L R447F T20C, L477CSEQ ID NO 46 A34L S385C, L508CSEQ ID NO 47 R447F S385C, L508CSEQ ID NO 48 A34L R447F S385C, L508CSEQ ID NO 49 A34L Q454F SEQ ID NO 50 A34L R447F Q454F SEQ ID NO: 155 A34L R447F F110A SEQ ID NO: 157 A34L R447F F110G SEQ ID NO: 159 A34L R447F F110I SEQ ID NO: 161 A34L R447F F110L SEQ ID NO: 163 A34L R447F F110Y SEQ ID NO: 165 A34L R447F S155A SEQ ID NO: 167 A34L R447F S155V SEQ ID NO: 169 A34L R447F G156R SEQ ID NO: 171 A34L R447F T194A SEQ ID NO: 173 A34L R447F H206F SEQ ID NO: 175 A34L R447F D208E SEQ ID NO: 176 A34L R447F D209E SEQ ID NO: 178 A34L R447F A214VSEQ ID NO: 180 A34L R447F L216A70583W001SEQ ID NO 181 A34L R447F Y217F SEQ ID NO 183 A34L R447F N410C, S462C F110A SEQ ID NO 185 A34L R447F N410C, S462C F110G SEQ ID NO 187 A34L R447F N410C, S462C F110I SEQ ID NO 189 A34L R447F N410C, S462C F110L SEQ ID NO 191 A34L R447F N410C, S462C F110Y SEQ ID NO 193 A34L R447F N410C, S462C S155A SEQ ID NO 195 A34L R447F N410C, S462C S155V SEQ ID NO 197 A34L R447F N410C, S462C G156R SEQ ID NO 199 A34L R447F N410C, S462C T194A SEQ ID NO 201 A34L R447F N410C, S462C H206F SEQ ID NO 203 A34L R447F N410C, S462C D208E SEQ ID NO 204 A34L R447F N410C, S462C D209E SEQ ID NO 206 A34L R447F N410C, S462C A214V SEQ ID NO 208 A34L R447F N410C, S462C L216ASEQ ID NO 209 A34L R447F N410C, S462C Y217FIn some embodiments, said at least one amino acid substitution increases expression, stability {e.g. in pre-fusion conformation) and / or trimerization of said HA antigen.In some embodiments, said at least one amino acid substitution increases expression, of said HA antigen.In some embodiments, said at least one amino acid substitution increases stability (e.g. in pre-fusion conformation) of said HA antigen.In some embodiments, said at least one amino acid substitution increases trimerization of said HA antigen.In some embodiments, said at least one amino acid substitution increases expression, stability (e.g. in pre-fusion conformation) and trimerization of said HA antigen.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 34.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and one or more of (ii)-(xxviii):(ii) a phenylalanine (F) or a tyrosine (Y) at position 447;(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;70583W001(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;(xvii) an isoleucine (I) at position 450;(xviii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217.In some embodiments, said at least one amino acid substitution comprises A34L substitution. In some embodiments, said at least one amino acid substitution consists of A34L substitution.In some embodiments, said at least one amino acid substitution comprises A34F substitution. In some embodiments, said at least one amino acid substitution consists of A34F substitution.In some embodiments, said at least one amino acid substitution comprises A34L substitution and one or more of (ii)-(xxviii):(ii) R447F or R447Y substitution;(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;70583W001(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution;(xix) F110G, F110Y, F110L, F1101 or F110A substitution;(xx) S155A or S155V substitution;(xxi) G156R substitution;(xxii) T194A substitution;(xxiii) H206F substitution;(xxiv) D208E substitution;(xxv) D209E substitution;(xxvi) A214V substitution;(xxvii) L216A substitution; or(xxviii) Y217F substitution.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a tyrosine (Y) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and one or more of (i), (iii)-(xxviii):(i) a leucine (L) or a phenylalanine (F) at position 34;(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;70583W001(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;(xvii) an isoleucine (I) at position 450;(xviii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217.In some embodiments, said at least one amino acid substitution comprises R447F substitution. In some embodiments, said at least one amino acid substitution consists of R447F substitution.In some embodiments, said at least one amino acid substitution comprises R447Y substitution. In some embodiments, said at least one amino acid substitution consists of R447Y substitution.In some embodiments, said at least one amino acid substitution comprises R447F substitution and one or more of (i), (iii)-(xxviii):(i) A34L or A34F substitution;(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;70583W001(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution(xix) F110G, F110Y, F110L, F1101 or F110A substitution;(xx) S155A or S155V substitution;(xxi) G156R substitution;(xxii) T194A substitution;(xxiii) H206F substitution;(xxiv) D208E substitution;(xxv) D209E substitution;(xxvi) A214V substitution;(xxvii) L216A substitution; or(xxviii) Y217F substitution.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a tyrosine (Y) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 34 and a phenylalanine (F) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 34 and a tyrosine (Y) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a phenylalanine (F) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen further comprises one or more of (iii)-(xxviii):(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;70583W001(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;(xvii) an isoleucine (I) at position 450;(xviii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 420 and a cysteine (C) at position 449.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 420 and a cysteine (C) at position 449.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 420 and a cysteine (C) at position 449.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 428 and a cysteine (C) at position 435.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 428 and a cysteine (C) at position 435.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 428 and a cysteine (C) at position 435.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an isoleucine (I) at position 450.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an isoleucine (I) at position 450.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an isoleucine (I) at position 450.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 420 and a cysteine (C) at position 449 and an isoleucine (I) at position 450.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 428 and a cysteine (C) at position 435 and an isoleucine (I) at position 450.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 394 and a cysteine (C) at position 512.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 394 and a cysteine (C) at position 512.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 394 and a cysteine (C) at position 512.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 21 and a cysteine (C) at position 384.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 21 and a cysteine (C) at position 384.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 21 and a cysteine (C) at position 384.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 378 and a cysteine (C) at position 395.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 378 and a cysteine (C) at position 395.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 378 and a cysteine (C) at position 395.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 381 and a cysteine (C) at position 399.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 381 and a cysteine (C) at position 399.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 381 and a cysteine (C) at position 399.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 410 and a cysteine (C) at position 462.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 410 and a cysteine (C) at position 462.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410 and a cysteine (C) at position 462.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 353 and a cysteine (C) at position 371.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 353 and a cysteine (C) at position70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 353 and a cysteine (C) at position 371.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 428 and a cysteine (C) at position 433.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 428 and a cysteine (C) at position 433.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 428 and a cysteine (C) at position 433.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 293 and a cysteine (C) at position 423.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 293 and a cysteine (C) at position 423.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 293 and a cysteine (C) at position 423.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 422 and a cysteine (C) at position 444.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 422 and a cysteine (C) at position 444.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 422 and a cysteine (C) at position 444.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 34 and a cysteine (C) at position 460.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 20 and a cysteine (C) at position 477.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 20 and a cysteine (C) at position 477.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 20 and a cysteine (C) at position 477.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 385 and a cysteine (C) at position 508.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 385 and a cysteine (C) at position 508.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 385 and a cysteine (C) at position 508.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a phenylalanine (F) at position 454.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a phenylalanine (F) at position 454.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a phenylalanine (F) at position 454.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a glycine (G) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a tyrosine (Y) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a leucine (L) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an isoleucine (I) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an alanine (A) at position 110.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a glycine (G) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a tyrosine (Y) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a leucine (L) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an isoleucine (I) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an alanine (A) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a glycine (G) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a tyrosine (Y) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a leucine (L) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an isoleucine (I) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an alanine (A) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an alanine (A) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an alanine (A) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an alanine (A) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a valine (V) at position 155.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a valine (V) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a valine (V) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an arginine (R) at position 156.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an arginine (R) at position 156.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an arginine (R) at position 156.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an alanine (A) at position 194.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an alanine (A) at position 194.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an alanine (A) at position 194.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a phenylalanine (F) at position 206.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a phenylalanine (F) at position 206.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a phenylalanine (F) at position 206.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a glutamic acid (E) at position 208.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a glutamic acid (E) at position 208.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a glutamic acid (E) at position 208.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a glutamic acid (E) at position 209.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a glutamic acid (E) at position 209.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a glutamic acid (E) at position 209.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a valine (V) at position 214.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a valine (V) at position 214.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a valine (V) at position 214.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an alanine (A) at position 216.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an alanine (A) at position 216.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an alanine (A) at position 216.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a phenylalanine (F) at position 217.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a phenylalanine (F) at position 217.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a phenylalanine (F) at position 217.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a glycine (G) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a tyrosine (Y) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a leucine (L) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an isoleucine (I) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an alanine (A) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an alanine (A) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a valine (V) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an arginine (R) at position 156.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an alanine (A) at position 194.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a phenylalanine (F) at position 206.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a glutamic acid (E) at position 208.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a glutamic acid (E) at position 209.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a valine (V) at position 214.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an alanine (A) at position 216.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a phenylalanine (F) at position 217. In some embodiments, said at least one amino acid substitution comprises A34L and R447Y substitutions. In some embodiments, said at least one amino acid substitution consists of A34L and R447Y substitutions.In some embodiments, said at least one amino acid substitution comprises A34F and R447F substitutions. In some embodiments, said at least one amino acid substitution consists of A34F and R447F substitutions.In some embodiments, said at least one amino acid substitution comprises A34F and R447Y substitutions. In some embodiments, said at least one amino acid substitution consists of A34F and R447Y substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and R447F substitutions. In some embodiments, said at least one amino acid substitution consists of A34L and R447F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and R447F substitutions and one or more of (iii)-(xxviii):(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;70583W001(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217.In some embodiments, said at least one amino acid substitution comprises A34L, K420C and D449C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, K420C and D449C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, K420C and D449C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, A428C and E435C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A428C and E435C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A428C and E435C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and T450I substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises R447F and T450I substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and T450I substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, K420C, D449C and T450I substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A428C, E435C and T450I substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, A394C and A512C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A394C and A512C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A394C and A512C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, G21 C and T384C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, G21C and T384C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, G21C and T384C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, A378C and A395C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A378C and A395C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A378C and A395C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, H381C and S399C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, H381C and S399C substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises A34L, R447F, H381C and S399C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, N410C and S462C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, N410C and S462C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C and S462C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, A353C and G371C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A353C and G371C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A353C and G371C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, A428C and H433C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A428C and H433C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A428C and H433C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, K293C and Q423C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, K293C and Q423C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, K293C and Q423C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, L422C and D444C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, L422C and D444C substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises A34L, R447F, L422C and D444C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A34C and L460C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, T20C and L477C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, T20C and L477C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, T20C and L477C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, S385C and L508C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, S385C and L508C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, S385C and L508C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and Q454F substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and Q454F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and Q454F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and F110G substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and F110G substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and F110G substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and F110Y substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises R447F and F110Y substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and F110Y substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and F110L substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and F110L substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and F110L substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and F1101 substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and F1101 substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and F110I substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and F110A substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and F110A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and F110A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and S155A substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and S155A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and S155A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and S155V substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises R447F and S155V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and S155V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and G156R substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and G156R substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and G156R substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and T194A substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and T194A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and T194A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and H206F substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and H206F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and H206F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and D208E substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and D208E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and D208E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and D209E substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises R447F and D209E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and D209E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and A214V substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and A214V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and A214V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and L216A substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and L216A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and L216A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and Y217F substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and Y217F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and Y217F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and F110G substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and F110Y substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and F11OL substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and F110I substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and F110A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and S155A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and S155V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and G156R substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and T194A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and H206F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and D208E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and D209E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and 214V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and L216V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and Y217F substitutions.In some embodiments, said A34 substitutions, such as A34L and / or A34F, suitably A34L, increase trimerization of said HA antigen.In some embodiments, said R447 substitutions, such as R447F and / or R447Y, suitably R447F, increase stability (e.g. in pre-fusion conformation) and / or trimerization of said HA antigen.In some embodiments, a combination of A34 and R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and R447F, shows a synergic effect.In some embodiments, K420C and D449C substitutions increase stability (e.g. in prefusion conformation) and / or trimerization of said HA antigen, optionally via an inter-protomer70583W001disulfide bond. In some embodiments, K420C and D449C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, A428C and E435C substitutions increase stability (e.g. in prefusion conformation) and / or trimerization of said HA antigen, optionally via an inter-protomer disulfide bond. In some embodiments, A428C and E435C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, A394C and A512C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, A394C and A512C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, G21C and T384C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, G21C and T384C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, A378C and A395C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, A378C and A395C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, H381C and S399C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, H381C and S399C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, N410C and S462C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, N410C and S462C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, A353C and G371C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, A353C and G371C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.70583W001In some embodiments, A428C and H433C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, A428C and H433C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, K293C and Q423C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, K293C and Q423C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, L422C and D444C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, L422C and D444C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, A34C and L460C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, A34C and L460C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, T20C and L477C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, T20C and L477C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, S385C and L508C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, S385C and L508C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, T450I substitution increases expression of said HA antigen, optionally via a polar-to-nonpolar substitution. In some embodiments, T450I substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, G454F substitution increases expression of said HA antigen, optionally via a polar-to-nonpolar substitution. In some embodiments, G454F substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.70583W001In some embodiments, F110G substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, F110G substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, F110G substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, F110Y substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, F110Y substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, F110Y substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, F110L substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, F110L substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, F110L substitution is in combination withA34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, F110I substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, F110I substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. F1101 substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.ln some embodiments, F110A substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, F110A substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F,70583W001R447F and / or R447Y, suitably A34L and / or R447F. F110A substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, S155A substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, S155A substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, S155A substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, S155V substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, S155V substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, S155V substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, G156R substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, G156R substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, G156R substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, T194A substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, T194A substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, T194A substitution is in combination with A34, R447, N410 and / or S46270583W001substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, H206F substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, H206F substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, H206F substitution is in combination withA34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, D208E substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, D208E substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, D208E substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, D209E substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, D209E substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. D209E substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, A214V substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, A214V substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. A214V substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.70583W001In some embodiments, L216A substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, L216A substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, L216A substitution is in combination withA34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, Y217F substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, Y217F substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, Y217F substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 2, 3, 4, 5, 6, 7, 8, 9, 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, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 176, 178, 180, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 204, 206, 208 or 209. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 2, 3, 4, 5, 6, 7, 8, 9, 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, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 176, 178, 180, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 204, 206, 208 or 209.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 2. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 2.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 3. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 3.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 4. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 4.70583W001In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 5. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 5.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 6. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 6.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 7. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 7.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 8. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 8.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 9. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 9.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 10. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 10.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 11. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 11.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 12. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 12.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 13. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 13.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 14. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 14.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 15. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 15.70583W001In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 16. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 16.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 17. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 17.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 18. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 18.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 19. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 19.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 20. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 20.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 21.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 22. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 22.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 23. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 23.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 24. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 24.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 25. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 25.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 26. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 26.70583W001In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 27. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 27.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 28. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 28.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 29. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 29.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 30. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 30.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 31. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 31.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 32. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 32.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 33. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 33.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 34. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 34.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 35. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 35.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 36. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 36.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 37. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 37.70583W001In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 38. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 38.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 39. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 39.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 40. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 40.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 41. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 41.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 42. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 42.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 43. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 43.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 44. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 44.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 45. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 45.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 46. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 46.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 47. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 47.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 48. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 48.70583W001In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 49. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 49.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 50. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 50.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 155. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 155.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 157. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 157.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 159. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 159.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 161. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 161.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 163. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 163.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 165. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 165.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 167. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 167.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 169. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 169.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 171. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 171.70583W001In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 173. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 173.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 175. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 175.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 176. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 176.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 178. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 178.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 180. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 180.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 181. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 181.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 183. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 183.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 185. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 185.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 187. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 187.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 189. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 189.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 191. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 191.70583W001In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 193. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 193.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 195. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 195.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 197. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 197.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 199. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 199.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 201. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 201.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 203. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 203.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 204. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 204.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 206. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 206.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 208. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 208.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 209. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 209.In some embodiments, said amino acid sequence of said IBV HA antigen comprises an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 1 , 51 , 52, 53, 54, 55 or 56. In some embodiments,70583W001said amino acid sequence of said IBV HA antigen consists of an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 1, 51, 52, 53, 54, 55 or 56.In some embodiments, said amino acid sequence of said IBV HA antigen comprises an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 1. In some embodiments, said amino acid sequence of said IBV HA antigen consists of an amino acid sequence with at least 90, 91 , 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 1.In some embodiments, said amino acid sequence of said IBV HA antigen comprises an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 51. In some embodiments, said amino acid sequence of said IBV HA antigen consists of an amino acid sequence with at least 90, 91 , 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 51.In some embodiments, said amino acid sequence of said IBV HA antigen comprises an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 52. In some embodiments, said amino acid sequence of said IBV HA antigen consists of an amino acid sequence with at least 90, 91 , 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 52.In some embodiments, said amino acid sequence of said IBV HA antigen comprises an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 53. In some embodiments, said amino acid sequence of said IBV HA antigen consists of an amino acid sequence with at least 90, 91 , 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 53.In some embodiments, said amino acid sequence of said IBV HA antigen comprises an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 54. In some embodiments, said amino acid sequence of said IBV HA antigen consists of an amino acid sequence with at least 90, 91 , 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 54.In some embodiments, said amino acid sequence of said IBV HA antigen comprises an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity70583W001to the amino acid sequence of SEQ ID NO: 55. In some embodiments, said amino acid sequence of said IBV HA antigen consists of an amino acid sequence with at least 90, 91 , 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 55.In some embodiments, said amino acid sequence of said IBV HA antigen comprises an amino acid sequence with at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 56. In some embodiments, said amino acid sequence of said IBV HA antigen consists of an amino acid sequence with at least 90, 91 , 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity to the amino acid sequence of SEQ ID NO: 56.The reference amino acid sequence, optionally said wild type IBV HA amino acid sequence, optionally said IBV is from BA / ictoria lineage or B / Yamagata lineage, suitably from B / Victoria lineage, may be an HA protein or peptide of an IBV isolate. The reference, such as the wild type IBV HA amino acid sequence, may be an engineered IBV HA protein or peptide.Table 2: Recommended composition of Influenza virus vaccines for use in the 1998-2027 northern hemisphere Influenza season70583W001Year H1N1 strain H3N2 strain B strain B strain (for quadrivalent vaccines) 1998- A / Beijing / 262 / 95 A / Sydney / 5 / 97(H3N2)- B / Beijing / 184 / 93-like / 1999 (H1N1)-like virus like virus virus (The most widelyused vaccine virus is B / Harbin / 7 / 94)1999- A / Beijing / 262 / 95 A / Sydney / 5 / 97(H3N2)- B / Beijing / 184 / 93-like / 2000 (H1N1)-like virus like virus virus (The most widelyused vaccine virus is B / Harbin / 7 / 94) or B / Shangdong / 7 / 97-likevirus2000- A / New A / Moscow / 10 / 99 B / Beijing / 184 / 93-like / 2001 Caledonia / 20 / 99 (H3N2)-like virus virus (The most widely(H1N1)-like virus (A / Panama / 2007 / 99 is used vaccine strain isan A / Moscow / 10 / 99 B / Y amanashi / 166 / 98)(H3N2)-like virus)2001- A / New A / Moscow / 10 / 99 B / Sichuan / 379 / 99-like / 2002 Caledonia / 20 / 99 (H3N2)-like virus virus(H1N1)-like virus (A / Panama / 2007 / 99 is (B / Johannesburg / 5 / 99an A / Moscow / 10 / 99 and B / Victoria / 504 / (H3N2)-like virus) 2000 areB / Sichuan / 379 / 99-likeviruses)2002- A / New A / Moscow / 10 / 99 B / Hong / 2003 Caledonia / 20 / 99 (H3N2)-like virus Kong / 330 / 2001-like(H1N1)-like virus (A / Panama / 2007 / 99 is virusan A / Moscow / 10 / 99(H3N2)-like virus)2003- A / New A / Moscow / 10 / 99 B / Hong / 2004 Caledonia / 20 / 99 (H3N2)-like virus Kong / 330 / 2001-like(H1N1)-like virus (A / Panama / 2007 / 99 is virus (Used vaccinean A / Moscow / 10 / 99 strains include(H3N2)-like virus) B / Shandong / 7 / 97,B / HongKong / 330 / 2001,B / HongKong / 1434 / 2002)2004- A / New A / Fujian / 411 / 2002(H3 B / Shanghai / 361 / 2002- / 2005 Caledonia / 20 / 99 N2)-like virus (Used like virus (Candidate(H1N1)-like virus vaccine virus is vaccine viruses include A / Wyoming / 3 / 2003. A / B / Shanghai / 361 / 2002 Kumamoto / 102 / 2002 and B / Jilin / 20 / 2003is also available as a / which is avaccine virus) B / Shanghai / 361 / 2002- like virus)2005- A / New A / California / 7 / B / Shanghai / 361 / 2002- / 2006 Caledonia / 20 / 99 2004(H3N2)-like virus like virus (Candidate(H1N1)-like virus (A / New York / 55 / 2004 vaccine viruses includeis available as a B / Shanghai / 361 / 2002vaccine virus) and B / Jilin / 20 / 2003which is aB / Shanghai / 361 / 2002- like virus)2006- A / New A / Wisconsin / 67 / 2005 B / Malaysia / 2506 / / 2007 Caledonia / 20 / 99 (H3N2)-like virus 2004-like virus(H1N1)-like virus (A / Wisconsin / 67 / 2005 (B / Malaysia / 2506 / 2004(H3N2) and virus and A / Hiroshima / 52 / 2005) B / Ohio / 1 / 2005)2007- A / Solomon A / Wisconsin / 67 / 2005 B / Malaysia / 2506 / / 2008 lslands / 3 / 2006 (H3N2)-like virus 2004-like virus(H1N1)-like virus (A / Wisconsin / 67 / 200570583W001(H3N2) andA / Hiroshima / 52 / 2005)2008- A / Brisbane / 59 / 2007 A / Brisbane / 10 / 2007 B / Florida / 4 / 2006-like / 2009 (H1N1)-like virus (H3N2)-like virus virus (B / Florida / 4 / 2006and B / Brisbane / 3 / 2007)2009- A / Brisbane / 59 / 2007 A / Brisbane / 10 / 2007 B / Brisbane / 60 / 2008- / 2010 (H1N1)-like virus (H3N2)-like virus like virus(A / Brisbane / 10 / 2007 (B / Brisbane / 33 / 2008and A / Uruguay / 716 / is a B / Brisbane / 60 / 2007) 2008-like virus)2010- A / California / 7 / 2009 A / Perth / 16 / 2009 B / Brisbane / 60 / 2008- / 2011 (H1N1)-like virus (H3N2)-like virus like virus(A / Wisconsin / 15 / 2009is an A / Perth / 16 / 2009(H3N2)-like virus andis a 2010 southernhemisphere vaccinevirus)2011- A / California / 7 / 2009 A / Perth / 16 / 2009 B / Brisbane / 60 / 2008- / 2012 (H1N1)-like virus (H3N2)-like virus like virus2012- A / California / 7 / 2009 AA / ictoria / 361 / 2011 B / Wisconsin / 1 / 201 fl / 2013 (H1N1)pdmO9-like (H3N2)-like virus like virusvirus2013- A / California / 7 / 2009 A(H3N2) virus B / Massachusetts / 2 / 20 B / Brisbane / 60 / 2008- 2014 (H1N1)pdmO9-like antigenically like the 12-like virus like virusvirus (A / Christchurch / cell-propagated (B / Brisbane / 33 / 2008 16 / 2010 is an prototype virus is a B / Brisbane / 60 / A / California / 7 / 2009- AA / ictoria / 361 / 2011 2008-like virus) like virus) (A / Texas / 50 / 2012 is anA(H3N2) virusantigenically like thecell-propagatedprototype virusAA / ictoria / 361 / 2011)2014- A / California / 7 / 2009 A / Texas / 50 / 2012 B / Massachusetts / 2 / 20 B / Brisbane / 60 / 2008- 2015 (H1N1)pdmO9-like (H3N2)-like virus 12-like virus like virusvirus2015- A / California / 7 / 2009 A / Switzerland / 9715293 B / Phuket / 3073 / 2013- B / Brisbane / 60 / 2008- 2016 (H1N1)pdmO9-like / 2013 (H3N2)-like virus like virus like virusvirus2016- A / California / 7 / 2009 A / Hong B / Brisbane / 60 / 2008- B / Phuket / 3073 / 2013- 2017 (H1N1)pdmO9-like Kong / 4801 / 2014 like virus like virusvirus (H3N2)-like virus2017- A / Michigan / 45 / 2015 A / Hong B / Brisbane / 60 / 2008- B / Phuket / 3073 / 2013- 2018 (H1N1)pdmO9-like Kong / 4801 / 2014 like virus like virusvirus (H3N2)-like virus2018- A / Michigan / 45 / 2015 A / Singapore / INFIMH- B / Colorado / 06 / 2017- B / Phuket / 3073 / 2013- 2019 (H1N1)pdmO9-like 16-0019 / 2016 (H3N2)- like virus like virusvirus like virus (BA / ictoria / 2 / 87 (B / Yamagata / 16 / 88 lineage) lineage)2019- A / Brisbane / 02 / 2018 A / Kansas / 14 / 2017 B / Colorado / 06 / 2017- B / Phuket / 3073 / 2013- 2020 (H1N1)pdmO9-like (H3N2)-like virus like virus like virusvirus (BA / ictoria / 2 / 87 (B / Yamagata / 16 / 88 lineage) lineage)2020- A / Guangdong- A / Hong B / Washington / 02 / 2019 B / Phuket / 3073 / 2013 2021 Maonan / SWL1536 / 201 Kong / 2671 / 2019 (BA / ictoria lineage)-like (B / Yamagata lineage)- 9 (H1N1)pdmO9-like (H3N2)-like virus or virus like virus virus or A / Hong Kong / 45 / 2019A / Hawaii / 70 / 2019 (H3N2)-like virus(H1N1)pdmO9-likevirus2021- A / Victoria / 2570 / 2019 A / Cambodia / e0826360 B / Washington / 02 / 2019 B / Phuket / 3073 / 2013 2022 (H1N1)pdmO9-like / 2020 (H3N2)-like virus (BA / ictoria lineage)-like (B / Yamagata lineage)- virus or virus like virusA / Wisconsin / 588 / 201970583W001(H1N1)pdmO9-likevirus2022- A / Victoria / 2570 / 2019 A / Darwin / 9 / 2021 B / Austria / 1359417 / 202 B / Phuket / 3073 / 2013 2023 (H1N1)pdmO9-like (H3N2)-like virus or 1 (B / Victoria lineage)- (B / Yamagata lineage)- virus or A / Darwin / 6 / 2021 like virus like virus A / Wisconsin / 588 / 2019 (H3N2)-like virus(H1N1)pdmO9-likevirus2023- A / Victoria / 4897 / 2022 A / Darwin / 9 / 2021 B / Austria / 1359417 / 202 B / Phuket / 3073 / 2013 2024 (H1N1) pdm09-like (H3N2)-like virus or 1 (B / Victoria lineage)- (B / Yamagata lineage)- virus or A / Darwin / 6 / 2021 like virus like virus A / Wisconsin 767 / (H3N2)-like virus2022(H1N1) pdm09- like virus2024- A / Victoria / 4897 / 2022 A / Thailand / 8 / 2022 B / Austria / 1359417 / 202 / 2025 (H1N1) pdm09-like (H3N2)-like virus or 1 (B / Victoria lineage)- virus or A / Massachusetts / 18 / 2 like virusA / Wisconsin 767 / 022 (H3N2)-like virus2022(H1N1) pdm09- like virus2025- A / Victoria / 4897 / 2022 A / Croatia / 10136RV / 20 B / Austria / 1359417 / 202 / 2026 (H1N1)pdmO9-like 23 (H3N2)-like virus or 1 (B / Victoria lineage)- virus or A / District of like virusA / Wisconsin / 67 / 2022 Columbia / 27 / 2023(H1N1)pdmO9-like (H3N2)-like virusvirus2026- A / Missouri / 11 / 2025 A / Darwin / 1454 / 2025 B / Tokyo / EIS13- / 2027 (H1N1)pdmO9-like (H3N2)-like virus 175 / 2025 (B / Victoriavirus lineage)-like virus orB / Pennsylvania / 14 / 2025 (B / Victoria lineage)-like virusTable 3: Recommended composition of Influenza virus vaccines for use in the 1999-2026 southern hemisphere Influenza season70583W001Year H1N1 strain H3N2 strain B strain B strain (for quadrivalent vaccines) 1999 A / Beijing / 262 / 95(H1N1 A / Sydney / 5 / 97(H3N2)- B / Beijing / 184 / 93-like / )-like virus like virus virus (The most widelyused vaccine virus is B / Harbin / 7 / 94)2000 A / New A / Moscow / 10 / 99 B / Beijing / 184 / 93-like / Caledonia / 20 / 99 (H3N2)-like virus virus (The most widely(H1N1)-like virus used vaccine strain is B / Yamanashi / 166 / 98)or B / Shangdong / 7 / 97- like virus2001 A / New A / Moscow / 10 / 99 B / Sichuan / 379 / 99-like / Caledonia / 20 / 99 (H3N2)-like virus virus(H1N1)-like virus (A / Panama / 2007 / 99 isan A / Moscow / 10 / 99(H3N2)-like virus)2002 A / New A / Moscow / 10 / 99 B / Sichuan / 379 / 99-like / Caledonia / 20 / 99 (H3N2)-like virus virus(H1N1)-like virus (A / Panama / 2007 / 99 is (B / Guangdong / 120 / 20an A / Moscow / 10 / 99 oo,(H3N2)-like virus) B / Johannesburg / 5 / 99and B / Victoria / 504 / 2000 areB / Sichuan / 379 / 99-likeviruses)2003 A / New A / Moscow / 10 / 99 B / Hong / Caledonia / 20 / 99 (H3N2)-like virus Kong / 330 / 2001 -like(H1N1)-like virus (A / Panama / 2007 / 99 is virus (Used vaccinean A / Moscow / 10 / 99 strains include(H3N2)-like virus) B / Shandong / 7 / 97,B / HongKong / 330 / 2001,B / HongKong / 1434 / 2002.B / Brisbane / 32 / 2002 isalso available as avaccine virus)2004 A / New A / Fujian / 411 / 2002(H3 B / Hong / Caledonia / 20 / 99 N2)-like virus (Used Kong / 330 / 2001 -like(H1N1)-like virus vaccine virus is virus (Used vaccine A / Wyoming / 3 / 2003. A strains include / Kumamoto / 102 / 2002 B / Shandong / 7 / 97,is also available as a B / Hongvaccine virus) Kong / 330 / 2001,B / HongKong / 1434 / 2002.B / Brisbane / 32 / 2002 isalso available as avaccine virus)2005 A / New A / Wellington / 1 / B / Shanghai / 361 / 2002- / Caledonia / 20 / 99 2004(H3N2)-like virus like virus (Candidate(H1N1)-like virus vaccine virusesincludeB / Shanghai / 361 / 2002, B / Jiangsu / 10 / 2003 and B / Jilin / 20 / 2003)2006 A / New A / California / 7 / B / Malaysia / 2506 / / Caledonia / 20 / 99 2004(H3N2)-like virus 2004-like virus(H1N1)-like virus (A / New York / 55 / 2004is available as avaccine virus)70583W0012007 A / New A / Wisconsin / 67 / 2005 B / Malaysia / 2506 / / Caledonia / 20 / 99 (H3N2)-like virus 2004-like virus(H1N1)-like virus (A / Wisconsin / 67 / 2005(H3N2) andA / Hiroshima / 52 / 2005)2008 A / Solomon A / Brisbane / 10 / 2007 B / Florida / 4 / 2006-like / lslands / 3 / 2006 (H3N2)-like virus virus(H1N1)-like virus2009 A / Brisbane / 59 / 2007 A / Brisbane / 10 / 2007 B / Florida / 4 / 2006-like / (H1N1)-like virus (H3N2)-like virus virus(A / South (A / Brisbane / 10 / 2007Dakota / 6 / 2007 (an and A / Uruguay / 716 / A / Brisbane / 59 / 2007- 2007)like virus) is a vaccinevirus used in liveatenuated vaccines)2010 A / California / 7 / 2009 A / Perth / 16 / 2009 B / Brisbane / 60 / 2008- / (H1N1)-like virus (H3N2)-like virus like virus2011 A / California / 7 / 2009 A / Perth / 16 / 2009 B / Brisbane / 60 / 2008- / (H1N1)-like virus (H3N2)-like virus like virus(A / Wisconsin / 15 / 2009and A / Victoria / 210 / 2009 areA / Perth / 16 / 2009-likeviruses)2012 A / California / 7 / 2009 A / Perth / 16 / 2009 B / Brisbane / 60 / 2008- / (H1N1)pdmO9-like (H3N2)-like virus like virusvirus2013 A / California / 7 / 2009 AA / ictoria / 361 / 2011 B / Wisconsin / 1 / 2010- B / Brisbane / 60 / 2008- (H1N1)pdmO9-like (H3N2)-like virus like virus (B / Hubei- like virus virus (A / Ohio / 2 / 2012, Wujiagang / 158 / 2009 (B / Brisbane / 33 / 2008 (A / Christchurch / 16 / 201 A / Maryland / 2 / 2012, and B / Texas / 6 / 2011 is a B / Brisbane / 60 / 0 is an A / California / 7 / A / South are B / Wisconsin / 1 / 2008-like virus) 2009-like virus) Australia / 30 / 2012, 2010-like viruses)A / Brisbane / 1 / 2012 andA / Brisbane / 6 / 2012 areA / Victoria / 361 / 2011- like viruses)2014 A / California / 7 / 2009 A / Texas / 50 / 2012 B / Massachusets / 2 / 20 B / Brisbane / 60 / 2008- (H1N1)pdmO9-like (H3N2)-like virus 12-like virus like virus virus (A / Texas / 50 / 2012 is(A / Christchurch / 16 / 201 an A(H3N2) virus that0 is an A / California / 7 / following adaptation to2009-like virus) growth in eggs hasmaintained antigenicproperties similar tothe majority of recentlycirculating cell- propagated A(H3N2)viruses includingA / Victoria / 361 / 2011)2015 A / California / 7 / 2009 A / Switzerland / 971529 B / Phuket / 3073 / 2013- B / Brisbane / 60 / 2008- (H1N1)pdmO9-like 3 / 2013 (H3N2)-like like virus like virus virus virus (A / SouthAustralia / 55 / 2014,A / Norway / 466 / 2014and A / Stockholm / 6 / 2014 areA / Switzerland / 9715293 / 2013-like viruses)2016 A / California / 7 / 2009 A / Hong B / Brisbane / 60 / 2008- B / Phuket / 3073 / 2013- (H1N1)pdmO9-like Kong / 4801 / 2014 like virus like virus virus (H3N2)-like virus2017 A / Michigan / 45 / 2015 A / Hong B / Brisbane / 60 / 2008- B / Phuket / 3073 / 2013- (H1N1)pdmO9-like Kong / 4801 / 2014 like virus like virusvirus (H3N2)-like virus70583W0012018 A / Michigan / 45 / 2015 A / Singapore / INFIMH- B / Phuket / 3073 / 2013- B / Brisbane / 60 / 2008- (H1N1)pdmO9-like 16-0019 / 2016 (H3N2)- like virus like virusvirus like virus2019 A / Michigan / 45 / 2015 A / Switzerland / 8060 / 20 B / Colorado / 06 / 2017- B / Phuket / 3073 / 2013- (H1N1)pdmO9-like 17 (H3N2)-like virus or like virus like virusvirus A / Singapore / INFIMH- (B / Victoria / 2 / 87 (B / Yamagata / 16 / 8816-0019 / 2016-like lineage) lineage)virus2020 A / Brisbane / 02 / 2018 A / South B / Washington / 02 / 2019 B / Phuket / 3073 / 2013- (H1N1)pdmO9-like Australia / 34 / 2019 -like (B / Victoria like (B / Yamagata virus (H3N2)-like virus lineage) virus lineage) virus 2021 A / Victoria / 2570 / 2019 A / Hong B / Washington / 02 / 2019 B / Phuket / 3073 / 2013 (H1N1)pdmO9-like Kong / 2671 / 2019 (B / Victoria lineage)- (B / Yamagata lineage)- virus or (H3N2)-like virus or like virus like virus A / Wisconsin / 588 / 2019 A / Hong Kong / 45 / 2019(H1N1)pdmO9-like (H3N2)-like virusvirus2022 A / Victoria / 2570 / 2019 A / Darwin / 9 / 2021 B / Austria / 1359417 / 202 B / Phuket / 3073 / 2013 (H1N1)pdmO9-like (H3N2)-like virus or 1 (B / Victoria lineage)- (B / Yamagata lineage)- virus or A / Darwin / 6 / 2021 like virus like virus A / Wisconsin / 588 / 2019 (H3N2)-like virus(H1N1)pdmO9-likevirus2023 A / Sydney / 5 / 2021 A / Darwin / 9 / 2021 B / Austria / 1359417 / 202 B / Phuket / 3073 / 2013 (H1N1)pdmO9-like (H3N2)-like virus or 1 (B / Victoria lineage)- (B / Yamagata lineage)- virus A / Darwin / 6 / 2021 like virus like virus(H3N2)-like virus2024 A / Victoria / 4897 / 2022 A / Thailand / 8 / 2022 B / Austria / 1359417 / 202 B / Phuket / 3073 / 2013 (H1N1)pdmO9-like (H3N2)-like virus or 1 (B / Victoria lineage)- (B / Yamagata lineage)- virus or A / Massachusetts / 18 / 2 like virus like virus A / Wisconsin / 67 / 2022 022 (H3N2)-like virus(H1N1)pdmO9-likevirus2025 A / Victoria / 4897 / 2022 A / Croatia / 10136RV / 20 B / Austria / 1359417 / 202 / (H1N1)pdmO9-like 23 (H3N2)-like virus 1 (B / Victoria lineage)- virus or or A / District of like virusA / Wisconsin / 67 / 2022 Columbia / 27 / 2023(H1N1)pdmO9-like (H3N2)-like virusvirus2026 A / Missouri / 11 / 2025 A / Singapore / GP20238 B / Austria / 1359417 / 202 / (H1N1)pdmO9-like / 2024 (H3N2)-like virus 1 (B / Victoria lineage)- virus or like virusA / Sydney / 1359 / 2024(H3N2)-like virusIn some embodiments, said IBV is selected from the group consisting of B / Victoria lineage and B / Yamagata lineage.In some embodiments, said IBV is selected from the group consisting of B / Tokyo / EIS13-175 / 2025 (B / Victoria lineage)-like virus, B / Pennsylvania / 14 / 2025 (B / Victoria lineage)-like virus, 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 / Jilin / 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 / 2009,70583W001B / 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 IBV is an Influenza B / Victoria lineage virus.In some embodiments, said IBV is selected from an Influenza B virus as listed in Table 2 and / or Table 3.In some embodiments, said IBV is selected from an IBV which is recommended for Influenza virus vaccine composition by the WHO (https: / / www.who.int / teams / global-lnfluenza-programme / vaccines / who-recommendations).Exemplary reference amino acid sequences, such as wild type IBV HA amino acid sequences, are known in the art and are publicly available, for example, NCBI’s Influenza Virus Resource (https: / / www.ncbi.nlm.nih.gov / genomes / FLU / Database / nph-select.cgi?go=database).The skilled person will appreciate that mutations, e.g. amino acid substitutions, described in the context of IBV, such as Influenza B / Yamagata lineage and / or B / Victoria lineage viruses, HA may be applied to extant or later-arising IBV HA.comIn further aspects, the invention relates to an immunogenic composition comprising an IBV HA antigen as described herein.It has been found that the immunogenic compositions as defined herein i.e. comprising an HA antigen as described herein e.g. an HA antigen from an IBV having an amino acid sequence comprising at least one amino acid substitution, such as one or more of (i)-(xxviii), induce an improved immune response against Influenza B viruses, such as Influenza B / Victoria lineage viruses and / or Influenza B / Yamagata lineage viruses. In particular, or in addition, the immune response is improved as compared to a wild-type IBV HA antigen.In particular, or in addition, it has been found that the efficacy against Influenza B viruses, such as Influenza B / Victoria lineage viruses and / or Influenza B / Yamagata lineage viruses, is enhanced when the IBV HA antigen comprises at least one amino acid substitution, such as one or more of (i)-(xxviii). In particular, or in addition, the efficacy is enhanced as compared to a wild-type IBV HA antigen.70583W001In particular, or in addition, it has been found that the immunogenicity associated with IBV HA antigens is enhanced, when the IBV HA antigen comprises at least one amino acid substitution, such as one or more of (i)-(xxviii). In particular, or in addition, the immunogenicity is enhanced as compared to a wild-type IBV HA antigen.In some embodiments, the immunogenic composition comprises:(a) an IBV HA antigen as described herein; and(b) at least one further antigen wherein said at least one further antigen is derived from a strain of Influenza virus.In some embodiments, (a) and (b) are different.In some embodiments, said strain of Influenza virus of (b) is selected from the group consisting of Influenza A virus and Influenza B virus.In some embodiments, said strain of Influenza virus of (b) is a strain of Influenza A virus.In some embodiments, said strain of Influenza A virus is selected from Influenza A viruses characterized by a hemagglutinin (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.In some embodiments, said strain 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.In some embodiments, said strain of Influenza A virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N7and H10N8, suitably H1N1 and H3N2.In some embodiments, said strain of Influenza A virus is selected from the group consisting of H1N1 and H3N2.In some embodiments, said strain of Influenza A virus is selected from the group consisting of A / Darwin / 1454 / 2025 (H3N2)-like virus, A / Missouri / 11 / 2025 (H1N1)pdmO9-like virus, A / Croatia / 10136RV / 2023 (H3N2)-like virus, A / District of Columbia / 27 / 2023 (H3N2)-like virus, A / Singapore / GP20238 / 2024 (H3N2)-like virus, A / Sydney / 1359 / 2024 (H3N2)-like virus, A / Thailand / 8 / 2022 (H3N2)-like virus, A / Massachusetts / 18 / 2022 (H3N2)-like virus, A / Beijing / 262 / 95(H1N1)-like virus, A / New Caledonia / 20 / 99(H1N1)-like virus, A / Solomon70583W001lslands / 3 / 2006 (H1N1)-like virus, A / Brisbane / 59 / 2007 (H1N1)-like virus, A / Victoria / 4897 / 2022 (H1N1)pdmO9-like virus, A / Wisconsin / 67 / 2022 (H1N1)pdmO9-like virus, A / Sydney / 5 / 2021 (H1N1)pdmO9-like virus, A / California / 7 / 2009 (H 1 N 1 )-like virus, A / California / 7 / 2009 (H1N1)pdmO9-like virus, A / Michigan / 45 / 2015 (H1N1)pdmO9-like virus, AA / ictoria / 2570 / 2019 (H1N1)pdmO9-like virus, A / Wisconsin / 588 / 2019 (H1N1)pdmO9-like virus, A / Guangdong-Maonan / SWL1536 / 2019 (H1N1)pdmO9-like virus, A / Hawaii / 70 / 2019 (H1N1)pdmO9-like virus, A / Brisbane / 02 / 2018 (H1N1)pdmO9-like virus, A / Christchurch / 16 / 2010, A / South Dakota / 6 / 2007, 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)-like virus, A / Wisconsin / 15 / 2009, A / Victoria / 210 / 2009, A / Victoria / 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 A / Victoria / 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 / Hong Kong / 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 Austral ia / 34 / 2019 (H3N2)-like virus.In some embodiments, said strain of Influenza A virus is H1N1.In some embodiments, said strain of Influenza A H1N1 virus is selected from the group consisting of A / Missouri / 11 / 2025 (H1N1)pdmO9-like virus, A / Victoria / 4897 / 2022 (H1N1)pdmO9-like virus, A / Wisconsin / 67 / 2022 (H1N1)pdmO9-like virus, A / Sydney / 5 / 2021 (H1N1)pdmO9-like virus, A / Beijing / 262 / 95(H1N1)-like virus, A / New Caledonia / 20 / 99(H1N1)-like virus, A / Solomon lslands / 3 / 2006 (H1N1)-like virus, A / Brisbane / 59 / 2007 (H1N1)-like virus, A / California / 7 / 2009 (H1N1)-like virus, A / California / 7 / 2009 (H1N1)pdmO9-like virus, A / Michigan / 45 / 2015 (H1N1)pdmO9-like virus, AA / ictoria / 2570 / 2019 (H1N1)pdmO9-like virus, A / Wisconsin / 588 / 2019 (H1N1)pdmO9-like virus, A / Guangdong-Maonan / SWL1536 / 2019 (H1N1)pdmO9-like virus, A / Hawaii / 70 / 2019 (H1N1)pdmO9-like virus, A / Brisbane / 02 / 2018 (H1N1)pdmO9-like virus, A / Christchurch / 16 / 2010 and A / South Dakota / 6 / 2007.In some embodiments, said strain of Influenza A virus is H3N2.70583W001In some embodiments, said strain of Influenza A H3N2 virus is selected from the group consisting of A / Darwin / 1454 / 2025 (H3N2)-like virus, A / Croatia / 10136RV / 2023 (H3N2)-like virus, A / District of Columbia / 27 / 2023 (H3N2)-like virus, A / Singapore / GP20238 / 2024 (H3N2)-like virus, A / Sydney / 1359 / 2024 (H3N2)-like virus, 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)-like virus, A / Wisconsin / 15 / 2009, AA / ictoria / 210 / 2009, A / Victoria / 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 A / Victoria / 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 / Hong Kong / 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 Influenza A virus is selected from an Influenza A virus as listed in Table 2 and / or Table 3.In some embodiments, said strain 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).In some embodiments, said strain of Influenza virus of (b) is a strain of Influenza B virus.In some embodiments, said strain of Influenza B virus is selected from the group consisting of B / Victoria lineage and B / Yamagata lineage.In some embodiments, said strain of Influenza B virus is selected from the group consisting of B / Tokyo / EIS13-175 / 2025 (B / Victoria lineage)-like virus, B / Pennsylvania / 14 / 2025 (B / Victoria lineage)-like virus, 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,70583W001B / Jiangsu / 10 / 2003, B / Jilin / 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 strain of Influenza B virus is a strain from B / Victoria lineage. In some embodiments, said strain of Influenza B virus is a strain from B / Yamagata lineage.In some embodiments, said strain of Influenza B virus is selected from an Influenza B virus as listed in Table 2 and / or Table 3.In some embodiments, said 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 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 hemagglutinin (HA) or neuraminidase (NA) or an immunogenic fragment or an immunogenic variant thereof.In some embodiments, the immunogenic composition comprises a combination of HA antigens, said at least one further antigen comprising or consisting of a peptide or protein selected or derived from an Influenza virus HA or fragment or variant thereof.In some embodiments, the immunogenic composition comprises:(a) an IBV HA antigen as described herein; and(b) at least one further HA antigen wherein said at least one further antigen is derived from a strain of Influenza virus A, optionally from subtype H1N1 or H3N2.In some embodiments, the HA antigens of (a) and (b) are present in equimolar proportions i.e. the ratio of (a):(b) is 1:1 or about 1:1.70583W001In some embodiments, the HA antigens of (a) and (b) are not present in equimolar proportions, i.e. the ratio of (a):(b) is different than 1:1.In some embodiments, the dose (e.g. weight dose or molar dose, suitably weight dose) of (a) is different compared to the dose (e.g. weight dose or molar dose, suitably weight dose) of (b).In some embodiments, the ratio of (a):(b) is greater than 1:1.In some embodiments, the ratio of (a):(b) is 20:1 or lower. In some embodiments, the ratio of (a):(b) is 1 :20 or lower.In some embodiments, the ratio of (a):(b) is greater than 1:1 and lower or equal to 20:1. In some embodiments, the ratio of (a):(b) is greater than 1:1 and lower or equal to 1:20.In some embodiments, the ratio of (a):(b) is greater than 1:1 and lower or equal to 10:1. In some embodiments, the ratio of (a):(b) is greater than 1:1 and lower or equal to 1:10.In some embodiments, the ratio of (a):(b) is greater than 1:1 and lower or equal to 5:1. In some embodiments, the ratio of (a):(b) is greater than 1:1 and lower or equal to 1:5.In some embodiments, the ratio of (a):(b) is about 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10. In some embodiments, the ratio of (a):(b) is 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10.In some embodiments, the ratio of (a):(b) is about 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, 10:1. In some embodiments, the ratio of (a):(b) is 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, 10:1.In some embodiments, the ratio of (a):(b) is about 1:2. In some embodiments, the ratio of (a):(b) is 1:2. In some embodiments, the ratio of (a):(b) is about 2:1. In some embodiments, the ratio of (a):(b) is 2:1.In some embodiments, the ratio of (a):(b) is about 1:3. In some embodiments, the ratio of (a):(b) is 1:3.In some embodiments, the ratio of (a):(b) is about 3:1. In some embodiments, the ratio of (a):(b) is 3:1.In some embodiments, the ratio of (a):(b) is about 1:4. In some embodiments, the ratio of (a):(b) is 1:4.70583W001In some embodiments, the ratio of (a):(b) is about 4:1. In some embodiments, the ratio of (a):(b) is 4:1.In some embodiments, the ratio of (a):(b) is about 1:5. In some embodiments, the ratio of (a):(b) is 1:5.In some embodiments, the ratio of (a):(b) is about 5:1. In some embodiments, the ratio of (a):(b) is 5:1.In some embodiments, the immunogenic composition comprises a combination of HA and NA antigens, said at least one further antigen of (b) 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. Antigenic drifts of HA and NA have been reported to be independent suggesting that NA-specific immunity is likely to provide a level of protection when drift in HA occurs.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 HA antigen is a polypeptide comprising a full-length Influenza HA protein. Suitably, said HA antigen is a polypeptide consisting of a full-length Influenza HA protein.In some embodiments, said HA antigen 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 or consists of the head domain or a portion of the head domain. In some embodiments, the fragment comprises or consists of a stalk (or stem) 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.70583W001In 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 HA and NA antigens are present in equimolar proportions i.e. the ratio of HA: NA antigens is 1:1 or about 1:1.In some embodiments, the HA and NA antigens are not present in equimolar proportions, i.e. the ratio of HA: NA antigens is different than 1:1.In some embodiments, the dose (e.g. weight dose or molar dose, suitably weight dose) of said at least one NA antigen is different compared to the dose (e.g. weight dose or molar dose, suitably weight dose) of the HA antigens.In some embodiments, the ratio of HA:NA antigens is greater than 1:1.In some embodiments, the ratio of HA:NA antigens is 20:1 or lower. In some embodiments, the ratio of HA: NA antigens is 1:20 or lower.In some embodiments, the ratio of HA:NA antigens is greater than 1:1 and lower or equal to 20:1. In some embodiments, the ratio of HA:NA antigens is greater than 1:1 and lower or equal to 1:20.In some embodiments, the ratio of HA:NA antigens is greater than 1:1 and lower or equal to 10:1. In some embodiments, the ratio of HA: NA antigens is greater than 1:1 and lower or equal to 1:10.In some embodiments, the ratio of HA:NA antigens is greater than 1:1 and lower or equal to 5:1. In some embodiments, the ratio of HA:NA antigens is greater than 1:1 and lower or equal to 1:5.In some embodiment, the ratio of HA:NA antigens is about 4:1 or 1:4. In some embodiment, the ratio of HA: NA antigens is 4:1 or 1:4.In some embodiment, the ratio of HA:NA antigens is about 4:1. In some embodiment, the ratio of HA: NA antigens is 4:1.In some embodiment, the ratio of HA:NA antigens is about 3:1 or 1:3. In some embodiment, the ratio of HA: NA antigens is 3:1 or 1:3.70583W001In some embodiment, the ratio of HA:NA antigens is about 3:1. In some embodiment, the ratio of HA: NA antigens is 3:1.In some embodiment, the ratio of HA:NA antigens is about 2:1 or 1:2. In some embodiment, the ratio of HA: NA antigens is 2:1 or 1:2.In some embodiment, the ratio of HA:NA antigens is about 2:1. In some embodiment, the ratio of HA: NA antigens is 2:1.In some embodiment, the ratio of HA:NA antigens is about 4:3 or 3:4. In some embodiment, the ratio of HA: NA antigens is 4:3 or 3:4.In some embodiment, the ratio of HA:NA antigens is about 4:3. In some embodiment, the ratio of HA: NA antigens is 4:3.In some embodiment, the ratio of HA:NA antigens is about 1:1. In some embodiment, the ratio of HA: NA antigens 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 embodiment, the HA of the ratio of HA:NA antigens is an HA derived from a strain of Influenza A virus, suitably H1N1 and / or H3N2.In some embodiments, the composition is a multivalent composition, said strain of Influenza virus of (a) and / or said strain of Influenza virus of (b) being different.In some embodiments, the composition comprises a plurality of (b), such as (b1), (b2), (b3), (b4), (b5), (b6) and / or (b7) as defined herein.In some embodiments, the composition comprises at least three, four, five, six, seven or eight antigens, optionally three to ten antigens, optionally three, four, six, seven or eight antigens.In some embodiments, said antigens of (a) and / or (b) are derived from at least two, three or four strains of Influenza virus.In some embodiments, the composition comprises a combination of three antigens. In some embodiments, the composition comprises a combination of three HA antigens.In some embodiments, the immunogenic composition comprises:(a) an IBV HA antigen as described herein, optionally wherein said IBV is from B / Victoria lineage;70583W001(b1) a second HA antigen from a first strain of Influenza A virus, optionally from H1N1; and(b2) a third HA antigen from a second strain of Influenza A virus, optionally from H3N2. In some embodiments, the composition is a multivalent composition, HA antigens of (a), (b1) and (b2) being different.In some embodiments, the composition is a trivalent composition, said strain of Influenza virus of (a), (b1) and / or (b2) being different.In some embodiments, said strain of Influenza A virus of (b1) and / or (b2) is selected from Influenza A viruses characterized by a hemagglutinin (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.In some embodiments, said strain of Influenza A virus of (b1) and / or (b2) 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.In some embodiments, said strain of Influenza A virus of (b1) and / or (b2) is selected from the group consisting of H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N7 and H10N8, suitably H1N1 and H3N2.In some embodiments, said strain of Influenza A virus of (b1) and / or (b2) is selected from the group consisting of H1N1 and H3N2.In some embodiments, said strain of Influenza A virus of (b1) and / or (b2) is selected from the group consisting of A / Darwin / 1454 / 2025 (H3N2)-like virus, A / Missouri / 11 / 2025 (H1N1)pdmO9-like virus, A / Croatia / 10136RV / 2023 (H3N2)-like virus, A / District of Columbia / 27 / 2023 (H3N2)-like virus, A / Singapore / GP20238 / 2024 (H3N2)-like virus, A / Sydney / 1359 / 2024 (H3N2)-like virus, A / Thailand / 8 / 2022 (H3N2)-like virus, A / Massachusetts / 18 / 2022 (H3N2)-like virus, A / Victoria / 4897 / 2022 (H1N1)pdmO9-like virus, A / Wisconsin / 67 / 2022 (H1N1)pdmO9-like virus, A / Sydney / 5 / 2021 (H1N1)pdmO9-like virus, A / Beijing / 262 / 95(H1N1)-like virus, A / New Caledonia / 20 / 99(H1N1)-like virus, A / Solomon lslands / 3 / 2006 (H1N1)-like virus, A / Brisbane / 59 / 2007 (H1N1)-like virus, A / California / 7 / 2009 (H1N1)-like virus, A / California / 7 / 2009 (H1N1)pdmO9-like virus, A / Michigan / 45 / 2015 (H 1 N 1 )pdm09-like virus, A / Victoria / 2570 / 2019 (H 1 N 1 )pdm09-like virus, A / Wisconsin / 588 / 201970583W001(H1N1)pdmO9-like virus, A / Guangdong-Maonan / SWL1536 / 2019 (H1N1)pdmO9-like virus, A / Hawaii / 70 / 2019 (H1N1)pdmO9-like virus, A / Brisbane / 02 / 2018 (H1N1)pdmO9-like virus, A / Christchurch / 16 / 2010, A / South Dakota / 6 / 2007, 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)-like virus, A / Wisconsin / 15 / 2009, AA / ictoria / 210 / 2009, A / Victoria / 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 A / Victoria / 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 / Hong Kong / 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 Influenza A virus of (b1) is H1N1.In some embodiments, said strain of Influenza A H1N1 virus of (b1) is selected from the group consisting of A / Missouri / 11 / 2025 (H1N1)pdmO9-like virus, A / Beijing / 262 / 95(H1N1)-like virus, A / New Caledonia / 20 / 99(H1N1)-like virus, A / Solomon lslands / 3 / 2006 (H1 N 1 )-like virus, A / Brisbane / 59 / 2007 (H1N1)-like virus, A / California / 7 / 2009 (H1N1)-like virus, A / California / 7 / 2009 (H1N1)pdmO9-like virus, A / Michigan / 45 / 2015 (H1N1)pdmO9-like virus, A / Victoria / 2570 / 2019 (H 1 N 1 )pdm09-like virus, A / Wisconsin / 588 / 2019 (H 1 N 1 )pdm09-like virus, A / Guangdong-Maonan / SWL1536 / 2019 (H1N1)pdmO9-like virus, A / Hawaii / 70 / 2019 (H1N1)pdmO9-like virus, A / Brisbane / 02 / 2018 (H1N1)pdmO9-like virus, A / Christchurch / 16 / 2010 and A / South Dakota / 6 / 2007, AA / ictoria / 4897 / 2022 (H1N1)pdmO9-like virus, A / Wisconsin / 67 / 2022 (H1N1)pdmO9-like virus and A / Sydney / 5 / 2021 (H1N1)pdmO9-like virus.In some embodiments, said strain of Influenza A virus of (b2) is H3N2.In some embodiments, said strain of Influenza A H3N2 virus of (b2) is selected from the group consisting of A / Darwin / 1454 / 2025 (H3N2)-like virus, A / Croatia / 10136RV / 2023 (H3N2)-like virus, A / District of Columbia / 27 / 2023 (H3N2)-like virus, A / Singapore / GP20238 / 2024 (H3N2)-like virus, A / Sydney / 1359 / 2024 (H3N2)-like virus, A / Thailand / 8 / 2022 (H3N2)-like virus, A / Massachusetts / 18 / 2022 (H3N2)-like virus, A / Sydney / 5 / 97(H3N2)-like virus,70583W001A / 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)-like virus, A / Wisconsin / 15 / 2009, AA / ictoria / 210 / 2009, A / Victoria / 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 A / Victoria / 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 / Hong Kong / 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 Influenza A virus of (b1) and / or (b2) is selected from an Influenza A virus as listed in Table 2 and / or Table 3.In some embodiments, said strain of Influenza A virus of (b1) and / or (b2) is selected from an Influenza A virus which is recommended for Influenza virus vaccine composition by the WHO (https: / / www.who.int / teams / global-lnfluenza-programme / vaccines / who recommendations).In some embodiments, said IBV of (a) is an Influenza B / Victoria lineage virus, said strain of Influenza A virus of (b1) is from H1N1 and said strain of Influenza A virus of (b2) is from H3N2.In some embodiments, the HA antigens of (a), (b1) and (b2) are present in equimolar proportions i.e. the ratio of (a):(b1):(b2) is 1:1:1 or about 1:1:1.In some embodiments, the HA antigens of (a), (b1) and (b2) are not present in equimolar proportions, i.e. the ratio of (a):(b1):(b2) is different than 1:1:1.In some embodiments, the dose (e.g. weight dose or molar dose, suitably weight dose) of (a) is different compared to the dose (e.g. weight dose or molar dose, suitably weight dose) of (b1) and / or (b2).In some embodiments, the ratio of (a):(b1):(b2) is greater than 1:1:1.70583W001In some embodiments, the ratio of (a):(b1):(b2) is 20:1:1 or lower. In some embodiments, the ratio of (a):(b1):(b2) is 1:20:20 or lower.In some embodiments, the ratio of (a):(b1):(b2) is greater than 1:1:1 and lower or equal to 20:1:1. In some embodiments, the ratio of (a):(b1):(b2) is greater than 1:1:1 and lower or equal to 1:20:20.In some embodiments, the ratio of (a):(b1):(b2) is greater than 1:1:1 and lower or equal to 10:1:1. In some embodiments, the ratio of (a):(b1):(b2) is greater than 1:1:1 and lower or equal to 1:10:10.In some embodiments, the ratio of (a):(b1):(b2) is greater than 1:1:1 and lower or equal to 5:1:1. In some embodiments, the ratio of (a):(b1):(b2) is greater than 1:1:1 and lower or equal to 1:5:5.In some embodiments, the ratio of (a):(b1):(b2) is about 1:1.5:1.5, 1:2:2, 1:2.5:2.5, 1:3:3, 1:3.5:3.5, 1:4:4, 1:4.5:4.5, 1:5:5, 1:5.5:5.5, 1:6:6, 1:6.5:6.5, 1:7:7, 1:7.5:7.5, 1:8:8, 1:8.5:8.5, 1:9:9, 1:9.5:9.5, 1:10:10. In some embodiments, the ratio of (a):(b1):(b2) is 1:1.5:1.5, 1:2:2, 1:2.5:2.5, 1:3:3, 1:3.5:3.5, 1:4:4, 1:4.5:4.5, 1:5:5, 1:5.5:5.5, 1:6:6, 1:6.5:6.5, 1:7:7, 1:7.5:7.5, 1:8:8, 1:8.5:8.5, 1:9:9, 1:9.5:9.5, 1:10:10.In some embodiments, the ratio of (a):(b1):(b2) is about 1.5:1:1, 2:1:1, 2.5:1:1, 3:1:1, 3.5:1 :1, 4:1:1, 4.5:1 :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. In some embodiments, the ratio of (a):(b1):(b2) is 1.5:1 :1, 2:1:1, 2.5: 1:1, 3:1:1, 3.5:1 :1, 4:1:1, 4.5:1 :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.In some embodiments, the ratio of (a):(b1):(b2) is about 1:2:2. In some embodiments, the ratio of (a):(b1):(b2) is 1:2:2.In some embodiments, the ratio of (a):(b1):(b2) is about 2:1:1. In some embodiments, the ratio of (a):(b1):(b2) is 2:1:1.In some embodiments, the ratio of (a):(b1):(b2) is about 1:3:3. In some embodiments, the ratio of (a):(b1):(b2) is 1:3:3.In some embodiments, the ratio of (a):(b1):(b2) is about 3:1:1. In some embodiments, the ratio of (a):(b1):(b2) is 3:1:1.In some embodiments, the ratio of (a):(b1):(b2) is about 1:4:4. In some embodiments, the ratio of (a):(b1):(b2) is 1:4:4.In some embodiments, the ratio of (a):(b1):(b2) is about 4:1:1. In some embodiments, the ratio of (a):(b1):(b2) is 4:1:1.70583W001In some embodiments, the ratio of (a):(b1):(b2) is about 1:5:5. In some embodiments, the ratio of (a):(b1):(b2) is 1:5:5.In some embodiments, the ratio of (a):(b1):(b2) is about 5:1:1. In some embodiments, the ratio of (a):(b1):(b2) is 5:1:1.In some embodiments, the composition comprises six antigens.In some embodiments, the immunogenic composition comprises a combination of three HA antigens and three NA antigens.In some embodiments, the immunogenic composition comprises:(a), (b1) and (b2) as defined herein;wherein the composition further comprises:(b3) a first NA antigen wherein the first NA antigen is derived from the first strain of Influenza A virus;(b4) a second NA antigen wherein the second NA antigen is derived from the second strain of Influenza A virus; and(b5) a third NA antigen wherein the third NA antigen is derived from said I BV, optionally from an Influenza B / Victoria lineage virus.In some embodiments, the antigens of (a), (b1), (b2), (b3), (b4) and (b5) are present in equimolar proportions i.e. the ratio of (a):(b1):(b2):(b3):(b4):(b5) is 1:1:1:1:1:1 or about 1 :1:1:1 :1:1.In some embodiments, the antigens of (a), (b1), (b2), (b3), (b4) and (b5) are not present in equimolar proportions, i.e. the ratio of (a):(b1):(b2):(b3):(b4):(b5) is different than 1:1:1:1:1:1.In some embodiments, the ratio of (a):(b1):(b2):(b3):(b4):(b5) is greater than 1:1:1:1:1:1. In some embodiments, the ratio of (a):(b1):(b2):(b3):(b4):(b5) is 25:5:5:1:1:1 or lower. In some embodiments, the ratio of (a):(b1):(b2):(b3):(b4):(b5) is greater than 1 :1:1 :1:1:1 and lower or equal to 25:5:5:1:1:1.In some embodiments, the ratio of (a):(b1):(b2):(b3):(b4):(b5) is greater than 2:4:4: 1 : 1 : 1 and lower or equal to 8:4:4: 1 : 1 : 1.In some embodiments, the ratio of (a):(b1):(b2):(b3):(b4):(b5) is about 2:4:4: 1 : 1 : 1. In some embodiments, the ratio of (a):(b1):(b2):(b3):(b4):(b5) is 2:4:4: 1 :1 : 1.In some embodiments, the ratio of (a):(b1):(b2):(b3):(b4):(b5) is about 4:4:4: 1:1:1. In some embodiments, the ratio of (a):(b1):(b2):(b3):(b4):(b5) is 4:4:4: 1 :1 : 1.70583W001In some embodiments, the ratio of (a):(b1):(b2):(b3):(b4):(b5) is about 8:4:4:1 : 1 : 1. In some embodiments, the ratio of (a):(b1):(b2):(b3):(b4):(b5) is 8:4:4:1 : 1 : 1.In some embodiments, the composition comprises seven antigens.In some embodiments, the immunogenic composition comprises a combination of four HA antigens and three NA antigens.In some embodiments, the immunogenic composition further comprises:(b6) a fourth HA antigen wherein the fourth HA antigen is derived from an additional strain of Influenza B virus, optionally from an Influenza B / Yamagata lineage virus.In some embodiments, the composition comprises eight antigens.In some embodiments, the immunogenic composition comprises a combination of four HA antigens and four NA antigens.In some embodiments, the composition further comprises:(b7) a fourth NA antigen wherein the fourth NA antigen is derived from said additional strain of Influenza B virus, optionally from an Influenza B / Yamagata lineage virus.In some embodiments, the composition comprises four antigens.In some embodiments, the immunogenic composition comprises a combination of four HA antigens.In some embodiments, the immunogenic composition comprises (a), (b1), (b2) and (b6) as defined herein.Nucleic AcidsThe skilled person will appreciate that Influenza virus antigens, e.g. said IBV HA antigens, as defined herein are useful in multiple types of immunogenic compositions (e.g. suitable for use as vaccines). Thus, discussion of Influenza virus antigens can also be applied to nucleic acids, including mRNAs, encoding said Influenza virus antigens, such as nucleic acids, including mRNAs, encoding Influenza virus antigens of (a), (b1), (b2), (b3), (b4), (b5), (b6) and / or (b7) as defined herein, and vice versa unless otherwise clear from context. Thus, disclosure related to particular antigen mutations, e.g. amino acid substitutions, is also relevant to nucleic acids, including mRNAs, encoding such antigens with such mutations, e.g. amino acid substitutions, unless otherwise clear from context. Likewise, disclosure related to nucleic acids, including mRNAs, encoding mutated Influenza virus antigens may also be relevant to the mutated Influenza virus antigens. Thus, when a composition comprising an mRNA70583W001encoding an Influenza virus antigen having a particular mutation, e.g. amino acid substitution, is disclosed, the skilled person can infer that the Influenza virus antigen per se, and compositions comprising the Influenza virus antigen are also disclosed.Nucleic acid-based vaccination including DNA or RNA, suitably messengerRNA (mRNA), represents a promising technique for novel vaccines e.g. against emerging viruses and for the provision of combination 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 as described herein, 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, or nucleic acid-based vaccines as provided herein have advantages over classical vaccine approaches.In general, protein-based vaccines, inactivated vaccines or live attenuated vaccines require long development times and are less 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 (Global Influenza Surveillance and Response System) 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 provided herein allow very fast manufacturing. Therefore, in comparison with known vaccines, immunogenic compositions or vaccines based on nucleic acids can be produced and manufactured significantly 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 immunogenic compositions or 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 or 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,70583W001feasibility, applicability, and effectiveness to generate immune responses. RNA molecules, suitably mRNAs, are considered to be significantly safer than DNA-based vaccines (or 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 further aspects, the invention relates to a nucleic acid, suitably an mRNA, encoding an IBV HA antigen as described herein.In some embodiments, said nucleic acid is a DNA or an RNA, suitably mRNA.In some embodiments, said nucleic acid is a DNA.In some embodiments, said nucleic acid is an artificial nucleic acid, e.g. an artificial DNA or an artificial RNA, suitably an artificial mRNA.In some embodiments, said nucleic acid is an RNA, suitably an mRNA.RNA is the usual abbreviation for ribonucleic acid. It is a nucleic acid molecule, i.e. a polymer consisting of nucleotides. These nucleotides are usually adenosine-monophosphate, uridine-monophosphate, guanosine-monophosphate and cytidine-monophosphate monomers which are connected to each other along a so-called backbone. The backbone is formed by phosphodiester bonds between the sugar, i.e. ribose, of a first and a phosphate moiety of a second, adjacent monomer. The specific succession of the monomers is called the RNA sequence. Usually, RNA may be obtainable by transcription of a DNA sequence, e.g. inside a cell. In eukaryotic cells, transcription is typically performed inside the nucleus or the mitochondria. Typically, transcription of DNA usually results in the so-called premature RNA which has to be processed into so-called messenger RNA, usually abbreviated as mRNA. Processing of the premature RNA, e.g. in eukaryotic organisms, comprises a variety of different posttranscriptional modifications such as splicing, 5'-capping, polyadenylation, export from the nucleus or the mitochondria and the like. The sum of these processes is also called maturation of RNA. The mature messenger RNA usually provides the nucleotide sequence that may be translated into an amino acid sequence of a particular peptide or protein. Typically, a mature mRNA comprises a 5'-cap, a 5'-UTR, a coding region, a 3'-UTR and a poly(A) sequence. Aside from messenger RNA, several non-coding types of RNA exist which may be involved in regulation of transcription and / or translation.]In some embodiments, said nucleic acid is an mRNA.70583W001In some embodiments, the RNA is selected from the group consisting of a selfamplifying (or self-replicating) mRNA (sometimes also referred to as “SAM” or “samRNA”), a non-amplifying mRNA (sometimes also referred to as a conventional mRNA), and a transamplifying mRNA.In some embodiments, the RNA may be a circular mRNA.In some embodiments, the RNA, such as the conventional mRNA, the SAM, and / or the trans-amplifying mRNA, is linear.In some embodiments, the RNA is a self-amplifying (or self-replicating) mRNA. In some embodiments, the RNA is a self-amplifying (or self-replicating) linear mRNA.A "self-amplifying (or self-replicating) mRNA” (sometimes also referred to as “SAM” or “samRNA”) is an RNA molecule which can direct its own amplification once it is introduced into the intracellular environment. The RNA replicon or SAM encodes one or more proteins that are capable of amplifying the RNA replicon or SAM in an intracellular environment. For instance, an RNA replicon or SAM may be constructed from an alphavirus so that it encodes nsP1-4 (e.g. non-structural protein 1 (nsP1 or non-structural alphavirus protein 1), nsP2, nsP3, and nsP4, e.g. further alphavirus nsP1-4). “Capable” is used to refer to the ability of these proteins to co-opt intracellular proteins to thereby amplifying the RNA replicon or SAM once said RNA replicon or SAM are introduced into the cell, and the cell’s transcriptional and translational machinery causes expression of said proteins. “Capable” is also used to refer to the requirement that the cell provide the nucleotides necessary to produce the new strand of SAM or RNA replicon. These one or more proteins that amplify the RNA replicon or SAM are encoded together or separately on one or more sequences of the SAM or RNA replicon. These one or more RNA sequences that together encode the one or more proteins that amplify the RNA are, as RNA sequences, cis-acting RNA sequences. The one or more proteins that amplify the RNA replicon or SAM are cis-acting proteins.In some embodiments, provided are a first RNA molecule and a second RNA molecule which are collectively called trans-amplifying mRNA. The first RNA molecule and second RNA molecule together are able to direct their own amplification once introduced into the intracellular environment. Therefore, that which is encoded in individual sequences of the SAM or the RNA replicon can be divided out into discrete RNA molecules and introduced together into the cell, and together these first and second RNA molecules encode one or more proteins capable of amplifying the first and / or second RNA molecules in an intracellular environment. This plurality of RNA molecules are collectively called trans-amplifying mRNA.70583W001In some embodiments, the RNA does not comprise a replicase element (e.g. a nucleic acid encoding a replicase).In some embodiments, the RNA is not a self-amplifying (or self-replicating) mRNA. In some embodiments, the RNA is a conventional mRNA ( / .e. a non-amplifying mRNA). In some embodiments, the RNA is a conventional linear mRNA (i.e. a non-amplifying linear mRNA).In some embodiments, the nucleic acid, suitably mRNA, encodes an HA antigen from Influenza B virus (IBV) having an amino acid sequence comprising at least one amino acid substitution relative to a reference amino acid sequence, wherein said amino acid sequence of said HA antigen comprises one or more of (i)-(xxviii):(i) a leucine (L) or a phenylalanine (F) at position 34;(ii) a phenylalanine (F) or a tyrosine (Y) at position 447;(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;(xvii) an isoleucine (I) at position 450;(xviii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;70583W001(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217.In some embodiments, the positions of (i)-(xxviii) are numbered by alignment of the reference to SEQ ID NO: 1.In some embodiments, said reference amino acid sequence is a wild type IBV HA amino acid sequence, optionally said IBV is from B / Victoria lineage or B / Yamagata lineage, suitably from B / Victoria lineage.In some embodiments, said reference amino acid sequence comprises SEQ ID NO: 1, 51 , 52, 53, 54, 55 or 56. In some embodiments, said reference amino acid sequence comprises SEQ ID NO: 1. In some embodiments, said reference amino acid sequence consists of SEQ ID NO: 1, 51, 52, 53, 54, 55 or 56. In some embodiments, said reference amino acid sequence consists of SEQ ID NO: 1.In some embodiments, said IBV HA antigen comprises or consists of a peptide or protein derived from an IBV HA.In some embodiments, said IBV HA antigen comprises or consists of a recombinant peptide or protein derived from an IBV HA.In some embodiments, said IBV HA antigen is a polypeptide comprising a full-length Influenza HA protein. Suitably, said IBV HA antigen is a polypeptide consisting of a full-length Influenza HA protein.In some embodiments, said IBV HA antigen 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 or consists of the head domain or a portion of the head domain. In some embodiments, the fragment comprises or consists of a stalk (or stem) 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, said at least one amino acid substitution comprises one or more of (i)-(xxviii):(i) A34L or A34F substitution;(ii) R447F or R447Y substitution;70583W001(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution ;(xix) F110G, F110Y, F110L, F1101 or F110A substitution;(xx) S155A or S155V substitution;(xxi) G156R substitution;(xxii) T194A substitution;(xxiii) H206F substitution;(xxiv) D208E substitution;(xxv) D209E substitution;(xxvi) A214V substitution;(xxvii) L216A substitution; or(xxviii) Y217F substitution.In some embodiments, the positions of (i)-(xxviii) are numbered by alignment of the reference to SEQ ID NO: 1.In some embodiments, said reference amino acid sequence is a wild type IBV HA amino acid sequence, optionally said IBV is from B / Victoria lineage or B / Yamagata lineage, suitably from B / Victoria lineage.In some embodiments, said reference amino acid sequence comprises SEQ ID NO: 1, 51 , 52, 53, 54, 55 or 56. In some embodiments, said reference amino acid sequence comprises SEQ ID NO: 1. In some embodiments, said reference amino acid sequence consists of SEQ70583W001ID NO: 1, 51, 52, 53, 54, 55 or 56. In some embodiments, said reference amino acid sequence consists of SEQ ID NO: 1.In some embodiments, said IBV HA antigen comprises at least one amino acid substitution as described in Table 1.In some embodiments, said at least one amino acid substitutions increases expression, stability {e.g. in pre-fusion conformation) and / or tri merization of said HA antigen.In some embodiments, said at least one amino acid substitutions increases expression of said HA antigen.In some embodiments, said at least one amino acid substitutions increases stability (e.g. in pre-fusion conformation) of said HA antigen.In some embodiments, said at least one amino acid substitutions increases trimerization of said HA antigen.In some embodiments, said at least one amino acid substitutions increases expression, stability (e.g. in pre-fusion conformation) and trimerization of said HA antigen.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 34.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and one or more of (ii)-(xxviii):(ii) a phenylalanine (F) or a tyrosine (Y) at position 447;(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;70583W001(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;(xvii) an isoleucine (I) at position 450;(xviii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217.In some embodiments, said at least one amino acid substitution comprises A34L substitution. In some embodiments, said at least one amino acid substitution consists of A34L substitution.In some embodiments, said at least one amino acid substitution comprises A34F substitution. In some embodiments, said at least one amino acid substitution consists of A34F substitution.In some embodiments, said at least one amino acid substitution comprises A34L substitution and one or more of (ii)-(xxviii):(ii) R447F or R447Y substitution;(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;70583W001(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution;xix) F110G, F110Y, F110L, F1101 or F110A substitution;(xx) S155A or S155V substitution;(xxi) G156R substitution;(xxii) T194A substitution;(xxiii) H206F substitution;(xxiv) D208E substitution;(xxv) D209E substitution;(xxvi) A214V substitution;(xxvii) L216A substitution; or(xxviii) Y217F substitution.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a tyrosine (Y) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and one or more of (i), (iii)-(xxviii):(i) a leucine (L) or a phenylalanine (F) at position 34;(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;70583W001(xvii) an isoleucine (I) at position 450;(xviii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217.In some embodiments, said at least one amino acid substitution comprises R447F substitution. In some embodiments, said at least one amino acid substitution consists of R447F substitution.In some embodiments, said at least one amino acid substitution comprises R447Y substitution. In some embodiments, said at least one amino acid substitution consists of R447Y substitution.In some embodiments, said at least one amino acid substitution comprises R447F substitution and one or more of (i), (iii)-(xxviii):(i) A34L or A34F substitution;(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;70583W001(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution;(xix) F110G, F110Y, F110L, F1101 or F110A substitution;(xx) S155A or S155V substitution;(xxi) G156R substitution;(xxii) T194A substitution;(xxiii) H206F substitution;(xxiv) D208E substitution;(xxv) D209E substitution;(xxvi) A214V substitution;(xxvii) L216A substitution; or(xxviii) Y217F substitution.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a tyrosine (Y) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 34 and a phenylalanine (F) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 34 and a tyrosine (Y) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a phenylalanine (F) at position 447.In some embodiments, said amino acid sequence of said IBV HA antigen further comprises one or more of (iii)-(xxviii):(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;70583W001(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;(xvii) an isoleucine (I) at position 450;(xviii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 420 and a cysteine (C) at position 449.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 420 and a cysteine (C) at position 449.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 420 and a cysteine (C) at position 449.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 428 and a cysteine (C) at position 435.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 428 and a cysteine (C) at position 435.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 428 and a cysteine (C) at position 435.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an isoleucine (I) at position 450.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an isoleucine (I) at position 450.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an isoleucine (I) at position 450.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 420 and a cysteine (C) at position 449 and an isoleucine (I) at position 450.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 428 and a cysteine (C) at position 435 and an isoleucine (I) at position 450.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 394 and a cysteine (C) at position 512.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 394 and a cysteine (C) at position 512.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 394 and a cysteine (C) at position 512.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 21 and a cysteine (C) at position 384.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 21 and a cysteine (C) at position 384.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 21 and a cysteine (C) at position 384.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 378 and a cysteine (C) at position 395.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 378 and a cysteine (C) at position 395.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 378 and a cysteine (C) at position 395.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 381 and a cysteine (C) at position 399.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 381 and a cysteine (C) at position 399.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 381 and a cysteine (C) at position 399.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 410 and a cysteine (C) at position 462.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 410 and a cysteine (C) at position 462.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410 and a cysteine (C) at position 462.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 353 and a cysteine (C) at position 371.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 353 and a cysteine (C) at position 371.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 353 and a cysteine (C) at position 371.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 428 and a cysteine (C) at position 433.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 428 and a cysteine (C) at position 433.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 428 and a cysteine (C) at position 433.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 293 and a cysteine (C) at position 423.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 293 and a cysteine (C) at position 423.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 293 and a cysteine (C) at position 423.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 422 and a cysteine (C) at position 444.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 422 and a cysteine (C) at position 444.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 422 and a cysteine (C) at position 444.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 34 and a cysteine (C) at position 460.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 20 and a cysteine (C) at position 477.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 20 and a cysteine (C) at position 477.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 20 and a cysteine (C) at position 477.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a cysteine (C) at position 385 and a cysteine (C) at position 508.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447, a cysteine (C) at position 385 and a cysteine (C) at position 508.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 385 and a cysteine (C) at position 508.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a phenylalanine (F) at position 454.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a phenylalanine (F) at position 454.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a phenylalanine (F) at position 454.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a glycine (G) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a tyrosine (Y) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a leucine (L) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an isoleucine (I) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an alanine (A) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a glycine (G) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a tyrosine (Y) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a leucine (L) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an isoleucine (I) at position 110.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an alanine (A) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a glycine (G) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a tyrosine (Y) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a leucine (L) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an isoleucine (I) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an alanine (A) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an alanine (A) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an alanine (A) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an alanine (A) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a valine (V) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a valine (V) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a valine (V) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an arginine (R) at position 156.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an arginine (R) at position 156.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an arginine (R) at position 156.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an alanine (A) at position 194.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an alanine (A) at position 194.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an alanine (A) at position 194.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a phenylalanine (F) at position 206.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a phenylalanine (F) at position 206.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a phenylalanine (F) at position 206.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a glutamic acid (E) at position 208.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a glutamic acid (E) at position 208.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a glutamic acid (E) at position 208.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a glutamic acid (E) at position 209.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a glutamic acid (E) at position 209.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a glutamic acid (E) at position 209.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a valine (V) at position 214.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a valine (V) at position 214.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a valine (V) at position 214.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and an alanine (A) at position 216.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and an alanine (A) at position 216.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and an alanine (A) at position 216.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a phenylalanine (F) at position 217.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447 and a phenylalanine (F) at position 217.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447 and a phenylalanine (F) at position 217.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a glycine (G) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a tyrosine (Y) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a leucine (L) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an isoleucine (I) at position 110.70583W001In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an alanine (A) at position 110.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an alanine (A) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a valine (V) at position 155.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an arginine (R) at position 156.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an alanine (A) at position 194.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a phenylalanine (F) at position 206.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a glutamic acid (E) at position 208.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a glutamic acid (E) at position 209.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a valine (V) at position 214.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and an alanine (A) at position 216.In some embodiments, said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34, a phenylalanine (F) at position 447, a cysteine (C) at position 410, a cysteine (C) at position 462, and a phenylalanine (F) at position 217.70583W001In some embodiments, said at least one amino acid substitution comprises A34L and R447Y substitutions. In some embodiments, said at least one amino acid substitution consists of A34L and R447Y substitutions.In some embodiments, said at least one amino acid substitution comprises A34F and R447F substitutions. In some embodiments, said at least one amino acid substitution consists of A34F and R447F substitutions.In some embodiments, said at least one amino acid substitution comprises A34F and R447Y substitutions. In some embodiments, said at least one amino acid substitution consists of A34F and R447Y substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and R447F substitutions. In some embodiments, said at least one amino acid substitution consists of A34L and R447F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and R447F substitutions and one or more of (iii)-(xxviii):(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution:(xix) F110G, F110Y, F110L, F1101 or F110A substitution;(xx) S155A or S155V substitution;(xxi) G156R substitution;(xxii) T194A substitution;(xxiii) H206F substitution;70583W001(xxiv) D208E substitution;(xxv) D209E substitution;(xxvi) A214V substitution;(xxvii) L216A substitution; or(xxviii) Y217F substitution.In some embodiments, said at least one amino acid substitution comprises A34L, K420C and D449C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, K420C and D449C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, K420C and D449C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, A428C and E435C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A428C and E435C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A428C and E435C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and T450I substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and T450I substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and T450I substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, K420C, D449C and T450I substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A428C, E435C and T450I substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, A394C and A512C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A394C and A512C substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A394C and A512C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, G21 C and T384C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, G21C and T384C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, G21C and T384C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, A378C and A395C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A378C and A395C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A378C and A395C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, H381C and S399C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, H381C and S399C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, H381C and S399C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, N410C and S462C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, N410C and S462C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C and S462C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, A353C and G371C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A353C and G371C substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A353C and G371C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, A428C and H433C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A428C and H433C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, A428C and H433C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, K293C and Q423C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, K293C and Q423C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, K293C and Q423C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, L422C and D444C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, L422C and D444C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, L422C and D444C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, A34C and L460C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, T20C and L477C substitutions.In some embodiments, said at least one amino acid substitution comprises R447F, T20C and L477C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, T20C and L477C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, S385C and L508C substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises R447F, S385C and L508C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, S385C and L508C substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and Q454F substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and Q454F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and Q454F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and F110G substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and F110G substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and F110G substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and F110Y substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and F110Y substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and F110Y substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and F110L substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and F110L substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and F110L substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and F1101 substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises R447F and F1101 substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and F110I substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and F110A substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and F110A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and F110A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and S155A substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and S155A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and S155A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and S155V substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and S155V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and S155V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and G156R substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and G156R substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and G156R substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and T194A substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises R447F and T194A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and T194A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and H206F substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and H206F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and H206F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and D208E substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and D208E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and D208E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and D209E substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and D209E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and D209E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and A214V substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and A214V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and A214V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and L216A substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises R447F and L216A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and L216A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L and Y217F substitutions.In some embodiments, said at least one amino acid substitution comprises R447F and Y217F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F and Y217F substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and F110G substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and F110Y substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and F110L substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and F110I substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and F110A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and S155A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and S155V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and G156R substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and T194A substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and H206F substitutions.70583W001In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and D208E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and D209E substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and 214V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and L216V substitutions.In some embodiments, said at least one amino acid substitution comprises A34L, R447F, N410C, S462C and Y217F substitutions.In some embodiments, said A34 substitutions, such as A34L and / or A34F, suitably A34L, increase trimerization of said HA antigen.In some embodiments, said R447 substitutions, such as R447F and / or R447Y, suitably R447F, increase stability (e.g. in pre-fusion conformation) and / or trimerization of said HA antigen.In some embodiments, a combination of A34 and R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and R447F, show a synergic effect.In some embodiments, K420C and D449C substitutions increase stability (e.g. in prefusion conformation) and / or trimerization of said HA antigen, optionally via an inter-protomer disulfide bond. In some embodiments, K420C and D449C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, A428C and E435C substitutions increase stability (e.g. in prefusion conformation) and / or trimerization of said HA antigen, optionally via an inter-protomer disulfide bond. In some embodiments, A428C and E435C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, A394C and A512C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, A394C and A512C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.70583W001In some embodiments, G21C and T384C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, G21C and T384C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, A378C and A395C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, A378C and A395C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, H381C and S399C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, H381C and S399C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, N410C and S462C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, N410C and S462C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, A353C and G371C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, A353C and G371C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, A428C and H433C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, A428C and H433C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, K293C and Q423C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, K293C and Q423C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, L422C and D444C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, L422C and D444C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.70583W001In some embodiments, A34C and L460C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, A34C and L460C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, T20C and L477C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, T20C and L477C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, S385C and L508C substitutions increase expression of said HA antigen, optionally via an intra-protomer disulfide bond. In some embodiments, S385C and L508C substitutions are in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, T450I substitution increases expression of said HA antigen, optionally via a polar-to-nonpolar substitution. In some embodiments, T450I substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, G454F substitution increases expression of said HA antigen, optionally via a polar-to-nonpolar substitution. In some embodiments, G454F substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F.In some embodiments, F110G substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, F110G substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, F110G substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, F110Y substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, F110Y substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, F110Y substitution is in combination with A34, R447, N410 and / or S46270583W001substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, F110L substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, F110L substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, F110L substitution is in combination withA34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, F110I substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, F110I substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. F1101 substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, F110A substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, F110A substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. F110A substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, S155A substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, S155A substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, S155A substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.70583W001In some embodiments, S155V substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, S155V substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, S155V substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, G156R substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, G156R substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, G156R substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, T194A substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, T194A substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, T194A substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, H206F substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, H206F substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, H206F substitution is in combination withA34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, D208E substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid70583W001binding ability. In some embodiments, D208E substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, D208E substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, D209E substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, D209E substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. D209E substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, A214V substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, A214V substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. A214V substitution is in combination with A34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, L216A substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, L216A substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, L216A substitution is in combination withA34, R447, N410 and / or S462 substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, Y217F substitution increases expression of said HA antigen, optionally via a removal of a sialic acid receptor binding, optionally by modifying one or more residues in the sialic acid binding pocket, optionally by eliminating a(2, 6) and a(2, 3) sialic acid binding ability. In some embodiments, Y217F substitution is in combination with A34 and / or R447 substitutions, such as A34L, A34F, R447F and / or R447Y, suitably A34L and / or R447F. In some embodiments, Y217F substitution is in combination with A34, R447, N410 and / or S46270583W001substitutions, such as A34L, A34F, R447F, R447Y, N410C and / or S462C, suitably A34L, R447F, N410C and / or S462C, more suitably A34L, R447F, N410C and S462C.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 2, 3, 4, 5, 6, 7, 8, 9, 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, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 176, 178, 180, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 204, 206, 208 or 209. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 2, 3, 4, 5, 6, 7, 8, 9, 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, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 176, 178, 180, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 204, 206, 208 or 209.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 2. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 2.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 3. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 3.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 4. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 4.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 5. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 5.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 6. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 6.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 7. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 7.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 8. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 8.70583W001In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 9. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 9.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 10. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 10.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 11. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 11.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 12. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 12.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 13. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 13.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 14. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 14.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 15. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 15.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 16. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 16.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 17. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 17.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 18. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 18.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 19. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 19.70583W001In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 20. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 20.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 21.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 22. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 22.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 23. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 23.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 24. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 24.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 25. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 25.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 26. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 26.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 27. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid sequence of SEQ ID NO: 27.In some embodiments, said amino acid sequence of said IBV HA protein comprises an amino acid sequence of SEQ ID NO: 28. In some embodiments, said amino acid sequence of said IBV HA protein consists of an amino acid seque...

Claims

1. 70583W001CLAIMS1. A hemagglutinin (HA) antigen from an influenza B virus (IBV) having an amino acid sequence comprising at least one amino acid substitution relative to a reference amino acid sequence, wherein said amino acid sequence of said HA antigen comprises:(i) a leucine (L) or a phenylalanine (F) at position 34; and / or(ii) a phenylalanine (F) or a tyrosine (Y) at position 447,wherein the positions of (i)-(ii) are numbered by alignment of the reference to SEQ ID NO: 1, suitably wherein said reference amino acid sequence is a wild type IBV HA amino acid sequence, optionally said IBV is from B / Victoria lineage.

2. The HA antigen of claim 1 , wherein said at least one amino acid substitution comprises:(i) A34L or A34F substitution; and / or(ii) R447F or R447Y substitution.

3. The HA antigen of claim 1 or 2, wherein said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34.

4. The HA antigen of any claim 1 to 3, wherein said at least one amino acid substitution comprises A34L substitution.

5. The HA antigen of any claim 1 to 4, wherein said amino acid sequence of said IBV HA antigen comprises a phenylalanine (F) at position 447.

6. The HA antigen of any claim 1 to 5, wherein said at least one amino acid substitution comprises R447F substitution.

7. The HA antigen of any claim 1 to 6, wherein said amino acid sequence of said IBV HA antigen comprises a leucine (L) at position 34 and a phenylalanine (F) at position 447.

8. The HA antigen of any claim 1 to 7, wherein said at least one amino acid substitution comprises A34L and R447F substitutions.

9. The HA antigen of any claim 3 to 8, wherein said amino acid sequence of said IBV HA antigen further comprises one or more of (iii)-(xxviii):(iii) a cysteine (C) at position 420 and a cysteine (C) at position 449;32670583W001(iv) a cysteine (C) at position 428 and a cysteine (C) at position 435;(v) a cysteine (C) at position 394 and a cysteine (C) at position 512;(vi) a cysteine (C) at position 21 and a cysteine (C) at position 384;(vii) a cysteine (C) at position 378 and a cysteine (C) at position 395;(viii) a cysteine (C) at position 381 and a cysteine (C) at position 399;(ix) a cysteine (C) at position 410 and a cysteine (C) at position 462;(x) a cysteine (C) at position 353 and a cysteine (C) at position 371 ;(xi) a cysteine (C) at position 428 and a cysteine (C) at position 433;(xii) a cysteine (C) at position 293 and a cysteine (C) at position 423;(xiii) a cysteine (C) at position 422 and a cysteine (C) at position 444;(xiv) a cysteine (C) at position 34 and a cysteine (C) at position 460;(xv) a cysteine (C) at position 20 and a cysteine (C) at position 477;(xvi) a cysteine (C) at position 385 and a cysteine (C) at position 508;(xvii) an isoleucine (I) at position 450;(xvii) a phenylalanine (F) at position 454;(xix) a glycine (G), a tyrosine (Y), a leucine (L) or an isoleucine (I) or an alanine (A) at position 110;(xx) an alanine (A) or a valine (V) at position 155;(xxi) an arginine (R) at position 156;(xxii) an alanine (A) at position 194;(xxiii) a phenylalanine (F) at position 206;(xxiv) a glutamic acid (E) at position 208;(xxv) a glutamic acid (E) at position 209;(xxvi) a valine (V) at position 214;(xxvii) an alanine (A) at position 216; or(xxviii) a phenylalanine (F) at position 217.

10. The HA antigen of any claim 3 to 9, wherein said at least one amino acid substitution further comprises one or more of (iii)-(xxviii):(iii) K420C and D449C substitutions;(iv) A428C and E435C substitutions;(v) A394C and A512C substitutions;(vi) G21C and T384C substitutions;(vii) A378C and A395C substitutions;(viii) H381C and S399C substitutions;(ix) N410C and S462C substitutions;(x) A353C and G371C substitutions;70583W001(xi) A428C and H433C substitutions;(xii) K293C and Q423C substitutions;(xiii) L422C and D444C substitutions;(xiv) A34C and L460C substitutions;(xv) T20C and L477C substitutions;(xvi) S385C and L508C substitutions;(xvii) T450I substitution;(xviii) Q454F substitution;(xix) F110G, F110Y, F110L, F1101 or F110A substitution;(xx) S155A or S155V substitution;(xxi) G156R substitution;(xxii) T194A substitution;(xxiii) H206F substitution;(xxiv) D208E substitution;(xxv) D209E substitution;(xxvi) A214V substitution;(xxvii) L216A substitution; or(xxviii) Y217F substitution.

11. The HA antigen of any claim 1 to 10, wherein said HA antigen is a polypeptide comprising a full-length HA protein.

12. A nucleic acid encoding an IBV HA antigen of any claim 1 to 11, wherein the nucleic acid is suitably an mRNA.

13. An immunogenic composition comprising an IBV HA antigen of any claim 1 to 11 or a nucleic acid, suitably mRNA, of claim 12 or 13, and a pharmaceutically acceptable carrier.

14. An immunogenic composition comprising:(a) a first nucleic acid, suitably mRNA, encoding an IBV HA antigen of any claim 1 to 11 , optionally the HA antigen is from an influenza B / Victoria lineage virus;(b1) a second nucleic acid, suitably mRNA, encoding a second HA antigen from a first strain of influenza A virus, optionally H1 N1 ; and(b2) a third nucleic acid, suitably mRNA, encoding a third HA antigen from a second strain of influenza A virus, optionally H3N2;15. The immunogenic composition of claim 14 further comprising:70583W001(b3) a fourth nucleic acid, suitably mRNA, encoding a first NA antigen from said first strain of influenza A virus, optionally H1N1;(b4) fifth nucleic acid, suitably mRNA, encoding a second NA antigen from said second strain of influenza A virus, optionally H3N2;(b5) a sixth nucleic acid, suitably mRNA, encoding a third NA antigen from said first strain of influenza B virus, optionally influenza B / Victoria lineage virus.

16. The immunogenic composition of any claim 13 to 15, wherein the mRNAs, suitably the mRNAs of (a), (b), (b1), (b2), (b3), (b4) and / or (b5), optionally each, are formulated in a lipid nanoparticle (LNP), each separately or not.

17. The immunogenic composition of any claim 13 to 16, wherein the mRNAs, suitably the mRNAs of (a), (b), (b1), (b2), (b3), (b4) and / or (b5), optionally each, are not selfamplifying.

18. The immunogenic composition of any claim 13 to 17, wherein the mRNAs, suitably the mRNAs of (a), (b), (b1), (b2), (b3), (b4) and / or (b5), optionally each, comprises at least one chemical modification, wherein the chemical modification is N1 methylpseudouridine.

19. A vaccine comprising the immunogenic composition according to any claim 13 to 18.

20. The immunogenic composition according to any claim 13 to 18 or the vaccine according to claim 19, for use as a medicament.

21. The immunogenic composition according to any claim 13 to 18 or the vaccine according to claim 19, for use in the treatment or prophylaxis of an infection with an influenza virus, suitably an influenza A and / or influenza B.

22. The immunogenic composition or the vaccinefor use of any claim 20 or 21 , wherein an immune response is elicited, suitably an adaptative immune response, more suitably a protective adaptative immune response against an influenza virus, suitably an influenza A and / or influenza B.

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