INFLUENZA VACCINE FORMULATION

Abstract

nza formulations against influenza are disclosed. The peptides are derived from influenza-based epitopes. The formulations are based on peptide mixtures which may be formulated so that variability is present at particular residues. The formulations can be used to prepare vaccines for preventing influenza, particularly avian influenza.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001]This application is a divisional application from U.S. patent application Ser. No. 11/948,505, filed Nov. 30, 2007, which claims priority from U.S. Provisional Application Ser. No. 60/868,008 filed Nov. 30, 2006, which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002]The present invention relates generally to an anti-viral formulation, and in particular relates to a peptide-based influenza vaccine formulation, more particularly to an avian influenza peptide-based vaccine formulation.

BACKGROUND OF THE INVENTION

[0003]Avian influenza is an infectious disease of birds caused by type A strains of the influenza virus. The disease, which was first identified in Italy more than 100 years ago, occurs worldwide. Sixteen subtypes of influenza virus are known to infect birds, thus providing an extensive reservoir of influenza viruses potentially circulating in bird populations. To date, all known outbreaks of the highly pathogenic form have been caused by influenza A viruses of subtypes H5 and H7.

[0004]Of the 16 avian influenza virus subtypes, H5N1 is of particular concern for several reasons. H5N1 mutates rapidly and has a documented propensity to acquire genes from viruses, thereby facilitating infection of other animal species. Indeed, its ability to cause severe disease in humans has now been documented. Laboratory studies have demonstrated that isolates from this virus have a high pathogenicity and can cause mortality in humans.

[0005]Two other avian influenza viruses have recently been found to cause illness in humans: H7N7 and H9N2.

[0006]All type A influenza viruses are genetically labile and well adapted to elude host defences. Influenza viruses lack mechanisms for the "proofreading" and repair of errors that occur during replication. As a result of these uncorrected errors, the genetic composition of the viruses changes as they replicate in humans and animals, and new antigenic variants emerge. These constant, permanent and usually small changes in the antigenic composition of influenza A viruses are known as antigenic "drift".

[0007]Influenza viruses are typed as A or B on the basis of relatively stable intracellular nucleoproteins and envelope associated matrix proteins. Virus subtypes are based on two proteins in the viral envelope, hemagglutinin (HA) and neuraminidase (NA), which undergo constant antigenic change. 16 distinct subtypes of HA and 9 subtypes of NA are recognized for influenza A viruses. The sudden appearance of a new subtype (antigenic shift) has caused three major pandemics in the past century: 1918 (Spanish Flu, H1N1), 1957 (Asian Flu, H2N2) and 1968 (Hong Kong Flu, H3N2).

[0008]Influenza viruses have a second characteristic of great public health concern: influenza A viruses can swap or "re-assort" genetic materials between subtypes of any species resulting in novel subtypes. This reassortment process, known as antigenic "shift," has resulted in worldwide pandemics in humans.

[0009]Influenza pandemics have occurred, on average, three to four times each century when new virus subtypes have emerged that are readily transmitted from person to person. In the 20th century, the great influenza pandemic of 1918-1919, which caused an estimated 40 to 50 million deaths worldwide, was followed by pandemics in 1957-1958 and 1968-1969. Experts surmise that another influenza pandemic is inevitable and possibly imminent. Given the unpredictable behaviour of influenza viruses, neither the timing nor the severity of the next pandemic can be predicted with any certainty.

[0010]Seven variable B-cell epitopes, and one variable T-cell epitope collectively represent the antigenic drift sites found on the hemagglutinin HA1 protein of Influenza A (subtype H5). Each of the B-cell variable epitopes represents a conformational epitope, and four of them are comprised of two discontinuous stretches of amino acids. There are two extended antigenic sites on the HA1 proteins, and each of them is represented by two distinct peptide sequences. The nonadjacent segments (stretches of amino acids) that are artificially joined together to represent the discontinuous epitopes are selected using the three-dimensional structure of A/duck/Singapore/3/97 hemagglutinin (PDB ID code: 1JSM). Use of crystallographic data aids in design of linear peptides that can mimic the native conformational epitopes of proteins. The T-cell eptiope is represented by a linear peptide sequence which may also be lipidated.

[0011]To date, no effective peptide-based vaccine against avian influenza is commercially available.

[0012]Current antiviral therapies may be clinically effective against influenza A virus strains in otherwise healthy adults and children; however, these therapies have limitations. Some of these drugs are expensive and supplies are limited. The vaccine composition must also change each year to account for changes in the virus circulating in the population due to antigenic drift. At least four months of development time is required to produce a new effective vaccine in significant quantities.

[0013]Processes for preparation of an immunogenic peptide mixture are described by Torres in U.S. Pat. No. 7,118,874, and in PCT application PCT/CA06/000891, herein incorporated by reference. According to one of these processes, the variability of immunogenic epitope sequences of a pathogen are evaluated. A peptide mixture is synthesized comprising a plurality of peptides representative of the frequency with which different amino acids are found at variable residues of selected epitopes.

[0014]Thus, there is a need to develop a vaccine formulation effective against multiple subtypes and multiple variants of avian influenza.

SUMMARY OF THE INVENTION

[0015]It is an object of the present invention to obviate or mitigate at least one disadvantage of previous influenza vaccine formulations.

[0016]In a first aspect, the present invention provides a peptide-based anti-influenza formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 1 to 496 and analogues thereof. Particularly, the present invention provides a peptide-based anti-influenza formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 1 to 248 and analogues thereof. In addition, the present invention provides a formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 249 to 496 and analogues thereof. In exemplary embodiments, the present invention provides a formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 1 to 212, a formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 249 to 460, a formulation comprising peptides selected from the group consisting of: a) SEQ ID NOs: 1 to 212, and b) SEQ ID NOs: 249 to 460; a formulation comprising peptides selected from the group consisting of: a) SEQ ID NOs: 213 to 248, and b) SEQ ID NOs: 461 to 496; a formulation comprising peptides selected from the group consisting of: a) SEQ ID NOs: 1 to 248, and b) SEQ ID NOs: 249 to 496; or a formulation comprising peptides selected from the group consisting of: a) SEQ ID NOs: 1 to 40, and b) SEQ ID NOs: 249 to 288.

[0017]In another exemplary embodiment of the present invention, the formulation comprises at least one peptide sequence from at least one of the following groups: a) SEQ ID NOs: 1 to 24; b) SEQ ID NOs: 25 to 40; c) SEQ ID NOs: 41 to 64; d) SEQ ID NOs: 65 to 88; e) SEQ ID NOs: 89 to 120; f) SEQ ID NOs: 121 to 144; g) SEQ ID NOs: 145 to 176, h) SEQ ID NOs: 177 to 212; i) SEQ ID NOs: 249 to 272; j) SEQ ID NOs: 273 to 288; k) SEQ ID NOs: 289 to 312; l) SEQ ID NOs: 313 to 336; m) SEQ ID NOs: 337 to 368; n) SEQ ID NOs: 369 to 392; o) SEQ ID NOs: 393 to 424; or p) SEQ ID NOs: 425 to 460.

[0018]In yet another exemplary embodiment of the present invention, the formulation comprises 2ⁿ peptide sequences from at least one of the following groups: a) SEQ ID NOs: 1 to 24; b) SEQ ID NOs: 25 to 40; c) SEQ ID NOs: 41 to 64; d) SEQ ID NOs: 65 to 88; e) SEQ ID NOs: 89 to 120; f) SEQ ID NOs: 121 to 144; g) SEQ ID NOs: 145 to 176, h) SEQ ID NOs: 177 to 212, i) SEQ ID NOs: 249 to 272; j) SEQ ID NOs: 273 to 288; k) SEQ ID NOs: 289 to 312; l) SEQ ID NOs: 313 to 336; m) SEQ ID NOs: 337 to 368; n) SEQ ID NOs: 369 to 392; o) SEQ ID NOs: 393 to 424; or p) SEQ ID NOs: 425 to 460, wherein n is 1 to 4.

[0019]The formulation can further comprise at least one peptide sequence from SEQ ID NOs: 213 to 248, or SEQ ID NOs: 461 to 496.

[0020]In a further aspect of the present invention there is provided a vaccine comprising the formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 1 to 496 and analogues thereof, together with a pharmaceutically-acceptable diluent or carrier. The vaccine can further comprise an adjuvant. In one example, the adjuvant is alum.

[0021]The anti-viral formulation can be an anti-influenza formulation. More particularly, the anti-influenza formulation can be an avian anti-influenza formulation.

[0022]In a further aspect of the present invention, there is provided a use of the formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 1 to 496 and analogues thereof, for the preparation of a vaccine. The vaccine can be used for preventing or treating influenza in an animal in need thereof. In one exemplary embodiment, the influenza is avian influenza. The present invention further relates to a method for inducing an immune response in humans or animals and conferring protection against avian influenza, or novel subtypes of influenza derived from avian influenza, which comprises administering to humans or other animals a peptide-based vaccine as described herein.

[0023]In a further aspect of the present invention, there is provided a method for preparing an anti-viral formulation, such as the anti-viral formulation as described herein. According to one embodiment, there is provided a method for preparing a peptide from SEQ ID NOs: 1 to 212 comprising the steps of determining a linear sequence representative of primary sequences of discontinuous epitopes of an avian influenza viral protein, wherein the epitopes are in proximity to each other when the protein is in a folded conformation; and synthesizing a peptide representative of the linear sequence. In another embodiment, there is provided method for preparing a peptide mixture comprising any two peptide sequences from SEQ ID NOs: 1 to 212 comprising the steps of: determining a linear sequence representative of primary sequences of discontinuous epitopes of an avian influenza viral protein, the epitopes being in proximity to each other when the protein is in a folded conformation; said discontinuous epitopes comprising variable residues, and synthesizing a peptide mixture including at least two different amino acids at a variable residue.

[0024]In yet another aspect, the present invention relates generally to an anti-influenza vaccine comprising a mixture of peptides containing at least one hemagglutinin (HA) antigen of influenza virus. Hemagglutinin (HA) is a potent immunogen, and viral neutralizing antibodies are directed against the variable regions of HA. The isolated peptide mixture represents variants of multiple variable regions of hemagglutinin. Thus, in accordance with one aspect of the present invention, there is provided an anti-viral formulation comprising a mixture of isolated peptides, said mixture being formulated on the basis of the variable region of the avian influenza virus HA protein and said isolated peptide mixture representing variants of a variable region of the HA or HA1 protein, wherein each of said variable regions comprising a plurality of variable amino acid residues, at least one of which is represented by two or more amino acids.

[0025]In one embodiment, the plurality of variable amino acid residues in the anti-viral formulation comprises three or more residues. One or more of said Avian influenza proteins can be an HA or HA1.

[0026]Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying Figures.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027]Embodiments of the present invention will now be described, by way of example only, with reference to the attached Figures, wherein:

[0028]FIG. 1 shows an analytical HPLC chromatogram of crude INFA-H5-1-V1 peptide sequences (corresponding to SEQ ID NOs: 249 to 272).

[0029]FIG. 2 shows an analytical HPLC chromatogram of crude INFA-H5-1-V2 peptide sequences (corresponding SEQ ID NOs: 273 to 288).

[0030]FIG. 3 shows an analytical HPLC chromatogram of crude INFA-H5-1-V3 peptide sequences (corresponding to SEQ ID NOs: 289 to 312).

[0031]FIG. 4 shows an analytical HPLC chromatogram of crude INFA-H5-1-V4 peptide sequences (corresponding to SEQ ID NOs: 313 to 336).

[0032]FIG. 5 shows an analytical HPLC chromatogram of crude INFA-H5-1-V5 peptide sequences (corresponding to SEQ ID NOs: 337 to 368).

[0033]FIG. 6 shows an analytical HPLC chromatogram of crude INFA-H5-1-V6 peptide sequences (corresponding to SEQ ID NOs: 369 to 392).

[0034]FIG. 7 shows an analytical HPLC chromatogram of crude INFA-H5-1-V7 peptide sequences (corresponding to SEQ ID NOs: 393 to 424).

[0035]FIG. 8 shows an analytical HPLC chromatogram of crude INFA-H5-1-V8 peptide sequences (corresponding to SEQ ID NOs: 425 to 460).

[0036]FIG. 9 shows a MALDI-TOF spectrum of crude INFA-H5-1-V1 peptide sequences (corresponding to SEQ ID NOs: 249 to 272).

[0037]FIG. 10 shows a MALDI-TOF spectrum of crude INFA-H5-1-V2 peptide sequences (corresponding to SEQ ID NOs: 273 to 288).

[0038]FIG. 11 shows a MALDI-TOF spectrum of crude INFA-H5-1-V3 peptide sequences (corresponding to SEQ ID NOs: 289 to 312).

[0039]FIG. 12 shows a MALDI-TOF spectrum of crude INFA-H5-1-V4 peptide sequences (corresponding to SEQ ID NOs: 313 to 336).

[0040]FIG. 13 shows a MALDI-TOF spectrum of crude INFA-H5-1-V5 peptide sequences (corresponding to SEQ ID NOs: 337 to 368).

[0041]FIG. 14 shows a MALDI-TOF spectrum of crude INFA-H5-1-V6 peptide sequences (corresponding to SEQ ID NOs: 369 to 392).

[0042]FIG. 15 shows a MALDI-TOF spectrum of crude INFA-H5-1-V7 peptide sequences (corresponding to SEQ ID NOs: 393 to 424).

[0043]FIG. 16 shows a MALDI-TOF spectrum of crude INFA-H5-1-V8 peptide sequences (corresponding to SEQ ID NOs: 425 to 460).

[0044]FIG. 17 shows a MALDI-TOF spectrum of crude lipidated INFA-H5-1-V8 peptide sequences (corresponding to SEQ ID NOs: 461 to 496).

[0045]FIG. 18(a)-(h) shows the different variosite peptide sequences of the present invention, with variable residues beneath the consensus sequence. FIG. 18(a) is INFA-H5-1-V1; FIG. 18(b) is INFA-H5-1-V2; FIG. 18(c) is INFA-H5-1-V3; FIG. 18(d) is INFA-H5-1-V4; FIG. 18(e) is INFA-H5-1-V5; FIG. 18(f) is INFA-H5-1-V6; FIG. 18(g) is INFA-H5-1-V7; FIG. 18(h) is INFA-H5-1-V8.

[0046]FIG. 18(i) shows different lipidated variosite peptide sequences based on the consensus sequence in FIG. 18(h).

[0047]FIG. 19 illustrates induction of humoral immunity by a vaccine of the present invention after immunization. Blue bar (top bar)=AviFlu vaccine INFA-02L+alum; Red bar (2^nd bar from top)=AviFlu vaccine INFA-02L without adjuvant; Purple bar (middle bar)=AviFlu vaccine INFA-02P+montanide; Green bar (2^nd bar from bottom)=AviFlu vaccine INFA-02P+alum; Black bar (bottom bar)=control.

[0048]FIG. 20 illustrates a survival plot of vaccinated mice against challenge with H5N1. Legend from top: Black=control; Green=INFA-02P+alum; Purple=INFA-02P+montanide; Red=INFA-02L without adjuvant; Blue=INFA-02L+alum.

[0049]FIG. 21 shows induction of humoral immunity by INFA-01P (INFA-HA-1-(V1-V2)) versus INFA-02P (INFA-HA-1-(V1-V8)) after vaccination in mice as measured by HAI titres. Blue bar (bottom bar)=INFA-01P+montanide; Purple bar (middle bar)=INFA-02P+montanide; Black bar (top bar)=control.

[0050]FIG. 22 shows a survival plot of mice, vaccinated by INFA-01P (INFA-HA-1-(V1-V2)), against challenge with H5N1. Legend from top: Black=control; Blue-INFA-01P+montanide.

DETAILED DESCRIPTION

[0051]Generally, the present invention provides an anti-influenza formulation, and, more specifically, a vaccine for Influenza A, including avian subtypes.

[0052]In a first aspect, the present invention provides a peptide-based anti-influenza formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 1 to 496 and analogues thereof. Particularly, the present invention provides a peptide-based anti-influenza formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 1 to 248 and analogues thereof. In addition, the present invention provides a formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 249 to 496 and analogues thereof. In exemplary embodiments, the present invention provides a formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 1 to 212, a formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 249 to 460, a formulation comprising peptides selected from the group consisting of: a) SEQ ID NOs: 1 to 212, and b) SEQ ID NOs: 249 to 460; a formulation comprising peptides selected from the group consisting of: a) SEQ ID NOs: 213 to 248, and b) SEQ ID NOs: 461 to 496; a formulation comprising peptides selected from the group consisting of: a) SEQ ID NOs: 1 to 248, and b) SEQ ID NOs: 249 to 496; or a formulation comprising peptides selected from the group consisting of: a) SEQ ID NOs: 1 to 40, and b) SEQ ID NOs: 249 to 288.

[0053]In another exemplary embodiment of the present invention, the formulation comprises at least one peptide sequence from at least one of the following groups: a) SEQ ID NOs: 1 to 24; b) SEQ ID NOs: 25 to 40; c) SEQ ID NOs: 41 to 64; d) SEQ ID NOs: 65 to 88; e) SEQ ID NOs: 89 to 120; f) SEQ ID NOs: 121 to 144; g) SEQ ID NOs: 145 to 176, h) SEQ ID NOs: 177 to 212; i) SEQ ID NOs: 249 to 272; j) SEQ ID NOs: 273 to 288; k) SEQ ID NOs: 289 to 312; l) SEQ ID NOs: 313 to 336; m) SEQ ID NOs: 337 to 368; n) SEQ ID NOs: 369 to 392; o) SEQ ID NOs: 393 to 424; or p) SEQ ID NOs: 425 to 460.

[0054]In yet another exemplary embodiment of the present invention, the formulation comprises 2ⁿ peptide sequences from at least one of the following groups: a) SEQ ID NOs: 1 to 24; b) SEQ ID NOs: 25 to 40; c) SEQ ID NOs: 41 to 64; d) SEQ ID NOs: 65 to 88; e) SEQ ID NOs: 89 to 120; f) SEQ ID NOs: 121 to 144; g) SEQ ID NOs: 145 to 176, h) SEQ ID NOs: 177 to 212, i) SEQ ID NOs: 249 to 272; j) SEQ ID NOs: 273 to 288; k) SEQ ID NOs: 289 to 312; l) SEQ ID NOs: 313 to 336; m) SEQ ID NOs: 337 to 368; n) SEQ ID NOs: 369 to 392; o) SEQ ID NOs: 393 to 424; or p) SEQ ID NOs: 425 to 460, wherein n is 1 to 4.

[0055]The formulation can further comprise at least one peptide sequence from SEQ ID NOs: 213 to 248 or SEQ ID NOs: 461 to 496.

[0056]In a further aspect of the present invention there is provided a vaccine comprising the formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 1 to 496 and analogues thereof, together with a pharmaceutically-acceptable diluent or carrier. The vaccine can further comprise an adjuvant. In one example, the adjuvant is alum.

[0057]The anti-viral formulation can be an anti-influenza formulation. More particularly, the anti-influenza formulation can be an avian anti-influenza formulation.

[0058]In a further aspect of the present invention, there is provided a use of the formulation comprising at least one peptide selected from the group consisting of SEQ ID NOs: 1 to 496 and analogues thereof, for the preparation of a vaccine. The vaccine can be used for preventing or treating influenza in an animal in need thereof. In one exemplary embodiment, the influenza is avian influenza. The present invention further relates to a method for inducing an immune response in humans or animals and conferring protection against avian influenza, or novel subtypes of influenza derived from avian influenza, which comprises administering to humans or other animals a peptide-based vaccine as described herein.

[0059]In a further aspect of the present invention, there is provided a method for preparing an anti-viral formulation, such as the anti-viral formulation as described herein. According to one embodiment, there is provided a method for preparing a peptide from SEQ ID NOs: 1 to 212 comprising the steps of determining a linear sequence representative of primary sequences of discontinuous epitopes of an avian influenza viral protein, wherein the epitopes are in proximity to each other when the protein is in a folded conformation; and synthesizing a peptide representative of the linear sequence. In another embodiment, there is provided method for preparing a peptide mixture comprising any two peptide sequences from SEQ ID NOs: 1 to 212 comprising the steps of: determining a linear sequence representative of primary sequences of discontinuous epitopes of an avian influenza viral protein, the epitopes being in proximity to each other when the protein is in a folded conformation; said discontinuous epitopes comprising variable residues, and synthesizing a peptide mixture including at least two different amino acids at a variable residue.

[0060]In yet another aspect, the present invention relates generally to an anti-influenza vaccine comprising a mixture of peptides containing at least one hemagglutinin (HA) antigen of influenza virus. Hemagglutinin (HA) is a potent immunogen, and viral neutralizing antibodies are directed against the variable regions of HA. The isolated peptide mixture represents variants of multiple variable regions of hemagglutinin. Thus, in accordance with one aspect of the present invention, there is provided an anti-viral formulation comprising a mixture of isolated peptides, said mixture being formulated on the basis of the variable region of the avian influenza virus HA protein and said isolated peptide mixture representing variants of a variable region of the HA or HA1 protein, wherein each of said variable regions comprising a plurality of variable amino acid residues, at least one of which is represented by two or more amino acids.

[0061]In one embodiment, the plurality of variable amino acid residues in the anti-viral formulation comprises three or more residues. One or more of said Avian influenza proteins can be an HA or HA1.

[0062]The vaccine may be formulated with or without representing variation at specific residues for each peptide. When variation is not represented, the peptide formed may be referred to herein as a Discotope® construct. A discotope construct is a linear sequence synthetic construct that approximates the position of primary sequence sections that compose discontinuous epitopes. The individual sections are constructed in sequence to elicit immune responses that recognize the discontinuous epitopes found in the original intact protein.

[0063]Discontinuous epitopes are composed of two or more segments of the primary sequence of a protein that when properly folded come together and are bound by specific antibodies. They are not recognized by antibodies when the secondary structure is lost and therefore have not been represented by a continuous linear peptide.

[0064]When variation is present at particular residues that are known to have different amino acids represented according to different sequences for that particular pathogen, the formulation comprises a number of peptides, which may be collectively referred to herein as a Discosite® construct.

Design of Eptiopes

[0065]Hemagglutinin is the major surface glycoprotein of influenza virus and a potent immunogen against which viral neutralizing antibodies are directed. We have designed eight peptides that mimic discontinuous B- and T-cell epitopes on antigenic sites of HA. The sequences of these peptides are determined based on analysis of the crystal structure of influenza hemagglutinin (HA) protein to determine peptide epitopes. Hemagglutinin is the major surface glycoprotein of influenza virus and a potent immunogen against which viral neutralizing antibodies are directed. The linear peptide epitopes in the cocktail mimic discontinuous epitopes on the HA protein surface. Using bioinformatics software that analyzes the antigenic variation of HA proteins from thousands of human influenza isolates, degenerative peptide cocktails based on these epitopes can be prepared which represent the antigenic variation of HA within these epitopes. Thus, the influenza vaccine formulations of the present invention comprise a cocktail of peptides that represent major epitopes of the HA protein.

[0066]HA is the major envelope glycoprotein of influenza virus, and mediates the penetration of virus into host cells. The native HA is formed by the association of three HA monomers which, as a precondition of virus infectivity, are cleaved enzymatically into the amino-terminal HA1 and carboxy-terminal HA2. Based on the three dimensional structure of HA1, antigenic sites have been mapped by determining the amino acid changes of antigenic variants. The antigenic variations were mostly seen surrounding the receptor binding region of HA. including residues around the antibody inaccessible receptor binding pockets. Monoclonal antibodies to these antigenic sites neutralize influenza virus infectivity when the exact sequences are present. Both T and B cell epitopes are found on these sites.

[0067]All amino acids changes documented in virus escape mutants, selected by MAB or other methods, were analyzed. The proteins were aligned, and position of those amino acids was mapped onto 3-D structure of hemagglutinin H5. The location of the epitope was roughly predicted in hemagglutinin H5 protein as the area surrounds amino acids that undergo the immune pressure. Antigenic sites were then redefined using the three-dimensional structure of A/duck/Singapore/3/97 hemagglutinin (PDB ID code: 1JSM) in a sense that antigenic determinants must be freely accessible for B-cell antibodies, and that different segments of same epitope must be in close proximity to each other (for example, within 20 A).

[0068]The occurrence of amino acids at variable sites within constructed epitopes was assessed by analyzing hemagglutinin HA1 strains of Influenza A (subtype H5) virus, available in the Los Alamos Data Base as of Jun. 28, 2005. Either 460 from all hosts or only 38 human hemagglutinin HA1 strains were used for analysis. A variable residue was defined as a position in which the occurrence of the most frequent amino acid at that position is less than 85% among all viral sequences examined.

[0069]A plurality of variable amino acid residues may comprise three or more residues, with two or more different amino acids at each variable position.

[0070]Part or all of the peptides comprising an influenza vaccine may be lipidated.

[0071]Discontinuous epitopes are composed of two or more segments of the primary sequence of a protein that exist in close proximity when in a native, three-dimensional conformation. They are not recognized by antibodies when the secondary or tertiary structure is lost; thus, linear peptides cannot traditionally be used to represent discontinuous epitopes. Crystallographic data from influenza hemagglutinin was used to design linear sequences that represent at least five conformational epitopes.

[0072]From each variable epitope, the peptide length is selected, and within the peptide, a plurality of variable residues is selected. Each variable residue has at least two optional amino acids, found naturally occurring in sequenced versions of the virus. In this way, a high degree of variability is represented. For example, three or four variable residues may be represented in the mixture of peptides, each having two or more different amino acids represented in the sequenced database records for influenza variants. If two variable residues occur in a variable region, then 2² different peptides would be used in the mixture representing that particular region. If three or four variable residues are indicated in a hypervariable region, the number of peptides in the resulting mixture would be 2³ and 2⁴, respectively. Generally, if variable regions consist of A, B, C, and so on variable sites, with a, b, c, and so on different amino acids at respective site, the total number of peptides would be A^a×B^b×C^c and so on.

[0073]Once the proteins, variable epitopes, peptide lengths, and variable residues are selected, the synthesis of the peptide mixtures occurs, according to any acceptable method of peptide synthesis.

[0074]Peptide mixtures are synthesized with each different peptide sequence represented in roughly equimolar quantities. However, there is no requirement to provide equimolar quantities of the individual peptides.

[0075]Lipidation of peptides may be conducted by any conventional or acceptable route, as would be known to those of skill in the art. Peptides need not be lipidated, but it may be advantageous for certain peptides to be lipidated with any acceptable lipid, such as palmitic acid, so as to allow a peptide to pass through a cell membrane. Peptides incorporating lipid may benefit from placement of a KSS motif at the C-terminal. The peptides incorporating lipid may contain 1 or more lipid moieties, for example, two lipid moieties per peptide. Immunization with lipidated peptides may result in an enhanced cytotoxic T lymphocyte (CTL) response.

[0076]Peptides in accordance with one aspect of the present invention (i.e., corresponding to SEQ ID NOs. 1-212 and SEQ ID NOs. 249-460) form 8 groups derived from H5 antigenic sites on hemagglutinin. These groups are identified as INFA-H5-1-V1, INFA-H5-1-V2, INFA-H5-1-V3, INFA-H5-1-V4, INFA-H5-1-V5, INFA-H5-1-V6, INFA-H5-1-V7 and INFA-H5-1-V8. The groups contain the following sequences:

[0077]Groups INFA-H5-1-V1 (SEQ ID NOs 1-24 and SEQ ID NOs. 249-272), INFA-H5-1-V3 (SEQ ID NOs 41-64 and SEQ ID NOs. 289-312), INFA-H5-1-V4 (SEQ ID NOs 65-88 and SEQ ID NOs. 313-336) and INFA-H5-1-V6 (SEQ ID NOs 121-144 and SEQ ID NOs. 369-392) consist of 24 peptide variants.

[0078]Groups INFA-H5-1-V5 (SEQ ID NOs 89-120 and SEQ ID NOs. 337-368) and INFA-H5-1-V7 (SEQ ID NOs 145-176 and SEQ ID NOs. 393-424) consist of 32 peptide variants.

[0079]Group INFA-H5-1-V2 (SEQ ID NOs 25-40 and SEQ ID NOs. 273-288) consists of 16 peptide variants.

[0080]Group INFA-H5-1-V8 (SEQ ID NOs 177-212 and SEQ ID NOs. 425-460) consists of 36 peptide variants.

[0081]During typical preparation of the peptide sequences, an additional residue (such as a glycine residue) may be added at an end of sequence. Sequences corresponding to peptides having an additional glycine residue are shown in SEQ ID NOs: 249 to 496. The additional glycine residue has no material effect on the function of the peptide, and the presence of the glycine residue is merely a product of peptide synthesis which would be well understood to the person of ordinary skill in the art. In addition, therefore, peptides normally synthesized in this manner would represent typical examples of "analogues" (as described below) of peptides used in the preparation of formulations in accordance with one aspect of the present invention.

[0082]FIGS. 1 and 9 are related to peptide group INFA-H5-1-V1. FIG. 1 shows an analytical HPLC chromatogram of crude INFA-H5-1-V1 peptides. FIG. 9 shows a MALDI-TOF spectrum of crude INFA-H5-1-V1 peptides.

[0083]FIGS. 2 and 10 are related to peptide group INFA-H5-1-V2. FIG. 2 shows an analytical HPLC chromatogram of crude INFA-H5-1-V2 peptides. FIG. 10 shows a MALDI-TOF spectrum of crude INFA-H5-1-V2 peptides.

[0084]FIGS. 3 and 11 are related to peptide group INFA-H5-1-V3. FIG. 3 shows an analytical HPLC chromatogram of crude INFA-H5-1-V3 peptides. FIG. 11 shows a MALDI-TOF spectrum of crude INFA-H5-1-V3 peptides.

[0085]FIGS. 4 and 12 are related to peptide group INFA-H5-1-V4. FIG. 4 shows an analytical HPLC chromatogram of crude INFA-H5-1-V4 peptides. FIG. 12 shows a MALDI-TOF spectrum of crude INFA-H5-1-V4 peptides.

[0086]FIGS. 5 and 13 are related to peptide group INFA-H5-1-V5. FIG. 5 shows an analytical HPLC chromatogram of crude INFA-H5-1-V5 peptide. FIG. 13 shows a MALDI-TOF spectrum of crude INFA-H5-1-V5 peptides.

[0087]FIGS. 6 and 14 are related to peptide group INFA-H5-1-V6. FIG. 6 shows an analytical HPLC chromatogram of crude INFA-H5-1-V6 peptides. FIG. 14 shows a MALDI-TOF spectrum of crude INFA-H5-1-V6 peptides.

[0088]FIGS. 7 and 15 are related to peptide group INFA-H5-1-V7. FIG. 7 shows an analytical HPLC chromatogram of crude INFA-H5-1-V7 peptides. FIG. 15 shows a MALDI-TOF spectrum of crude INFA-H5-1-V7 peptides.

[0089]FIGS. 8 and 16 are related to peptide group INFA-H5-1-V8. FIG. 8 shows an analytical HPLC chromatogram of crude INFA-H5-1-V8 peptide. FIG. 16 shows a MALDI-TOF spectrum of crude INFA-H5-1-V8 peptides.

[0090]FIG. 17 shows a MALDI-TOF spectrum of crude lipidated INFA-H5-1-V8 peptide sequences (corresponding to SEQ ID NOs: 213 to 248). SEQ ID NOs 213-248 are lipidated versions of SEQ ID NOs 177-212.

[0091]FIG. 18 shows the variosites of the present invention, including variable amino acid residues. FIG. 18 (a) shows the peptides of group INFA-H5-1-V1. FIG. 18 (b) shows the peptides of INFA-H5-1-V2. FIG. 18 (c) shows the peptides of INFA-H5-1-V3. FIG. 18 (d) shows the peptides of INFA-H5-1-V4. FIG. 18 (e) shows the peptides of INFA-H5-1-V5. FIG. 18 (f) shows the peptides of INFA-H5-1-V6. FIG. 18 (g) shows the peptides of INFA-H5-1-V7. FIG. 18 (h) shows the peptides of INFA-H5-1-V8.

Design of Vaccine Formulations

[0092]In the context of the present invention, a vaccine formulation is a cocktail of peptides that are used in the preparation of an influenza vaccine. The vaccine can comprise the cocktail of peptides and other substituents known in the art that would be found acceptable for inclusion. These substituents can include, but are not limited to, adjuvants, diluents and/or carriers.

[0093]As used in the present application, a peptide "analogue" can include a variant in which one or more residues are added, deleted, inserted or substituted, while having no material effect on the function of the peptide. That is, a peptide analogue in accordance with one aspect of the present invention should be capable of inducing an antibody or T-cell response to HA. A residue (or residues) may be added or deleted from either end of the peptide, deleted from within the peptide, inserted within the peptide, or substituted for one or more of the residues within the peptide. As would be understood by a person of ordinary skill in art, one or more peptide residues may be added, deleted, inserted or substituted while still maintaining the function of the peptide. For example, as many as five or more residues may be added to or removed from either end of a peptide, or inserted into a peptide, and be considered a peptide analogue within the context of the present invention. In a further example, a conservative substitution of one or more residues within a peptide may result in a peptide analogue. As would be well understood to the skilled artisan, a conservative substitution includes a substitution of one amino acid residue with another amino acid residue having one or more similar chemical properties, such as polarity, charge, hydrophobicity, or aromaticity, for example.

[0094]The vaccine formulations of the present invention are particularly suitable for preparing vaccines in the treatment of avian influenza. However, it will be appreciated that any combination of peptide sequences, or formulations comprising these peptide sequences, may be used in other influenza phenotypes.

[0095]A vaccine of the present invention may be formulated from a peptide mixture with or without variation at specific residues within each peptide. When variation is not present, the peptide formed is referred to herein as a consensus epitope. When variation is present at particular residues that are known to have different amino acids represented according to different sequences for that particular viral variant or subtype, the formulation comprises a number of peptides, collectively referred to as a variable epitope or "variosite".

[0096]Peptide vaccines can be prepared with a pool of one or more peptide sequences from SEQ ID NOs: 1 to 212 or SEQ ID NOs: 249 to 460 representing epitopes contained in the three-dimensional structure of HA. The vaccines may further comprise one or more lipidated peptides, including one or more peptides from SEQ ID NOs: 213 to 248 or SEQ ID NOs: 461 to 496. The vaccines may comprise one or more discotope constructs (peptides containing non-variable amino acid residues) or one or more discosite constructs (peptides containing variable amino acid residues). A discosite construct of the present invention is derived from one of these epitopes. Thus, a discosite construct formulation comprises one or more peptide sequences derived from the epitope containing the variable residues.

[0097]Each discosite construct of the present invention represents 2^x possible peptide sequences based on x varied residues. For example, a discosite construct having 3 or 4 variable residues represents 2³=8 or 2⁴=16 sequences, respectively. Therefore, in the context of the present invention, a discosite construct as referred to herein includes the epitope sequence containing the variable residues and the one or more possible sequences derived therefrom. It will be appreciated by the person of ordinary skill in the art that additional sequences may or may not be added as required.

[0098]The vaccine may be prepared by any methodology acceptable to one skilled in the art. For example, oligonucleotides encoding these peptides may be inserted in viral or non-viral vectors for delivery. Peptides may be synthesized individually in and mixed together to accomplish an acceptable formulation. Any variety of different modes by which these peptide antigens may be prepared is acceptable for use with the invention.

[0099]In order to formulate a vaccine that is subtype-specific, the proteins selected may contain variable regions with selected variable amino acids that are characteristic of the variability found within the subtype of interest. This allows the vaccine to be subtype specific, which may have the advantage of better representing the antigenic variation among variants within said subtype. To formulate a vaccine that has less subtype distinctiveness, the final peptide formulation may comprise the different subtype specific formulations. For example, a vaccine formulated against avian flu could target variable residues particular to subtype H5 sequences. A vaccine formulated against human flu could target variable residues characteristic of subtypes 1, 2 and/or 3 sequences.

[0100]In order to formulate a vaccine that is species-specific, the proteins selected may contain variable regions with selected variable amino acids that are characteristic of the variability found within the species of interest. This allows the vaccine to be species specific, which may have the advantage of better representing the antigenic variation among variants within said species. For example, a vaccine formulated against avian flu could target variable residues particular to avian H5 sequences. A vaccine formulated against human flu could target variable residues characteristic of both, human and avian H5 sequences.

[0101]As a specific example, the anti-INF vaccine may include the following isolated peptides: SEQ ID NOs: 1 to 40, SEQ ID NOs: 249 to 288, or peptide analogues thereof, in combination with a pharmaceutically acceptable carrier.

[0102]An exemplary anti-INF formulation may comprise one or more of, or all of SEQ ID NOs: 1 to 212, SEQ ID NOs. 249 to 460 or peptide analogues thereof; in combination with a pharmaceutically acceptable carrier. The formulation may also comprise one or more lipidated peptides of SEQ ID NOs: 1 to 212 or SEQ ID NOs: 249 to 460, such as, for example, one or more of SEQ ID NOs: 213 to 248 or SEQ ID NOs: 461 to 496.

[0103]Although all peptides of SEQ ID NOs: 1 to 212 or SEQ ID NOs: 249 to 460 may be used in combination as the vaccine formulation, sub-groups of these peptides could be used together according to the invention. For example, a formulation may comprise at least one peptide sequence from at least one of the following groups: a) SEQ ID NOs: 1 to 24; b) SEQ ID NOs: 25 to 40; c) SEQ ID NOs: 41 to 64; d) SEQ ID NOs: 65 to 88; e) SEQ ID NOs: 89 to 120; f) SEQ ID NOs: 121 to 144; g) SEQ ID NOs: 145 to 176, h) SEQ ID NOs: 177 to 212, i) SEQ ID NOs: 249 to 272; j) SEQ ID NOs: 273 to 288; k) SEQ ID NOs: 289 to 312; l) SEQ ID NOs: 313 to 336; m) SEQ ID NOs: 337 to 368; n) SEQ ID NOs: 369 to 392; o) SEQ ID NOs: 393 to 424; or p) SEQ ID NOs: 425 to 460. Further, a vaccine of the present invention may comprise a formulation comprising 2ⁿ peptide sequences from at least one of the following groups: a) SEQ ID NOs: 1 to 24; b) SEQ ID NOs: 25 to 40; c) SEQ ID NOs: 41 to 64; d) SEQ ID NOs: 65 to 88; e) SEQ ID NOs: 89 to 120; f) SEQ ID NOs: 121 to 144; g) SEQ ID NOs: 145 to 176, h) SEQ ID NOs: 177 to 212, i) SEQ ID NOs: 249 to 272; j) SEQ ID NOs: 273 to 288; k) SEQ ID NOs: 289 to 312; l) SEQ ID NOs: 313 to 336; m) SEQ ID NOs: 337 to 368; n) SEQ ID NOs: 369 to 392; o) SEQ ID NOs: 393 to 424; or p) SEQ ID NOs: 425 to 460, wherein n is 1 to 4.

EXAMPLES

Peptide Synthesis

[0104]The peptides were synthesized by solid phase peptide synthesis (SPPS) using 9-fluoroenylmethoxycarbonyl (Fmoc) chemistry on Pioneer® automated peptide synthesizer, utilizing pre-loaded Fmoc protected NovaSyn® TGT resin (NovaBiochem) as described. Where variability at a given position is desired, mixture of two amino acids is placed at that position. This is repeated each time during the synthesis wherever the variability is desired. While 1M solution of 2-(1H-Benzotriazole-1-yl)-1, 1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and N-Hydroxybenzotriazole (HOBt) in dimethylformamide (DMF), and 1 M solution of diisopropylethyl amine (DIPEA) in OMF was used for coupling amino acids, 20% piperidine in DMF was used for deblocking amino acids during the synthesis. Coupling was allowed to occur for one hour at room temperature. After the last amino acid was coupled, the resin was taken out from synthesizer and washed on a sintered glass funnel several times with OMF, with 2-propanol and with dichloromethylene (DCM), and dried under high vacuum. The peptide mixtures are cleaved and deprotected by the addition of a solution containing TFA/water/phenol/thioanisole/EDT/TIS [82:5:5:5:2:1]. The resin was incubated at room temperature for 4 hours. Cleavage mixture was then filtered under reduced pressure into a flask containing a 10-fold volume of cold ether. Resin was also rinsed twice with TFA into the same ether solution. Following incubation for 30 minutes in a freezer to further assist precipitation, the sample was centrifuged at 1,000×g for 5 minutes, and the ether removed. This extraction process was repeated three times. Following a final ether extraction, the residual organic solvent was evaporated under nitrogen gas, and the peptide mixture was redissolved in water and purified by using high performance liquid chromatography (HPLC). Excess of the solvent was removed by using a rotor evaporator, and finally lyophilized to dry powder. Mass spectrometry and amino acid analysis were performed on all the Discotopes to ensure that they have the appropriate peptide content.

[0105]Lipidation is performed as follows. Upon completion of the synthesis of a mixed peptide formulation on the synthesiser, the resin is removed from the column and placed into a vial. Dissolve 10 eq. of the Palmitic Acid, 10 eq. of TBTU and 10 eq. HOBT (all relative to the resin) in DMF (10 ml/0.1 mmol resin). Add the solution to the peptidyl resin in the vial. Add 20 eq. (relative to the resin) of the DIPEA. Adjust pH to 8-9 by adding DIPEA drop-wise. Seal the vial with a screw cap and shake the mixture overnight (at least 12 hours).

[0106]Vaccine Efficacy

[0107]Vaccine formulations comprising the peptide sequences of the present invention were tested in mice. The vaccines used are as follows:

[0108]INF-01P consists of two variosites INFA-H5-1-V1 and INFA-H5-1-V2 (SEQ ID NOs: 249-288), also referred as AviFlu-2(Montanide).

[0109]INF-02P consists of 8 variosites INFA-H5-1-V1 to INFA-H5-1-V8 (SEQ ID NOs: 249-460), also referred as AviFlu-8(Montanide), AviFlu(Montanide), AviFlu(Alum).

[0110]INF-02L consist of 9 variosites INFA-H5-1-V1 to INFA-H5-1-V8L (SEQ ID NOs: 249-496), also referred as AviFlu(Lipidated), AviFlu(Lipidated/Alum).

[0111]FIG. 19 illustrates induction of humoral immunity by a vaccine of the present invention after immunization.

[0112]FIG. 20 illustrates a survival plot of mice vaccinated with a vaccine of the present invention against challenge with H5N1.

[0113]FIG. 21 shows induction of humoral immunity by INFA-01P (INFA-HA-1-(V1-V2)) versus INFA-02P (INFA-HA-1-(V1-V8)) after vaccination in mice as measured by HAI titres.

[0114]FIG. 22 shows a survival plot of mice, vaccinated by INFA-01P (INFA-HA-1-(V1-V2)), against challenge with H5N1.

[0115]The above-described embodiments of the present invention are intended to be examples only. Alterations, modifications and variations may be effected to the particular embodiments by those of skill in the art without departing from the scope of the invention, which is defined solely by the claims appended hereto.

REFERENCES

[0116]1. Philpott, M. et al., Journal of virology (1990), 64(6), 2941-2947. [0117]2. Kaverin, N. et al., Journal of General Virology (2002), 83, 2497-2505. [0118]3. Hioe, C. et al., Journal of Virology (1990), 64(12), 6246-6251. [0119]4. Ha, Y. et al., Proceedings of the National Academy of Sciences, USA (2001), 98, 11181-11186. [0120]5. Macken, C. et al., "The value of a database in surveillance and vaccine selection." in Options for the Control of Influenza IV. A. D. M. E. Osterhaus, N. Cox & A. W. Hampson (Eds.) Amsterdam: Elsevier Science, 2001, 103-106.

Sequence CWU 1

496121PRTInfluenza A virus 1Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Lys Ser Ser Phe Phe 20221PRTInfluenza A virus 2Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Lys Ser Ser Phe Phe 20321PRTInfluenza A virus 3Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Lys Ser Ser Phe Phe 20421PRTInfluenza A virus 4Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Arg Ser Ser Phe Phe 20521PRTInfluenza A virus 5Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Arg Ser Ser Phe Phe 20621PRTInfluenza A virus 6Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Arg Ser Ser Phe Phe 20721PRTInfluenza A virus 7Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Lys Ser Ser Phe Phe 20821PRTInfluenza A virus 8Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Lys Ser Ser Phe Phe 20921PRTInfluenza A virus 9Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Lys Ser Ser Phe Phe 201021PRTInfluenza A virus 10Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Arg Ser Ser Phe Phe 201121PRTInfluenza A virus 11Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Arg Ser Ser Phe Phe 201221PRTInfluenza A virus 12Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Arg Ser Ser Phe Phe 201321PRTInfluenza A virus 13Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Lys Ser Ser Phe Phe 201421PRTInfluenza A virus 14Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Lys Ser Ser Phe Phe 201521PRTInfluenza A virus 15Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Lys Ser Ser Phe Phe 201621PRTInfluenza A virus 16Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Arg Ser Ser Phe Phe 201721PRTInfluenza A virus 17Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Arg Ser Ser Phe Phe 201821PRTInfluenza A virus 18Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Arg Ser Ser Phe Phe 201921PRTInfluenza A virus 19Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Lys Ser Ser Phe Phe 202021PRTInfluenza A virus 20Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Lys Ser Ser Phe Phe 202121PRTInfluenza A virus 21Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Lys Ser Ser Phe Phe 202221PRTInfluenza A virus 22Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Arg Ser Ser Phe Phe 202321PRTInfluenza A virus 23Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Arg Ser Ser Phe Phe 202421PRTInfluenza A virus 24Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Arg Ser Ser Phe Phe 202517PRTInfluenza A virus 25Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln Asn Pro Thr Thr1 5 10 15Tyr2617PRTInfluenza A virus 26Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln Asn Pro Asn Thr1 5 10 15Tyr2717PRTInfluenza A virus 27Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln Asn Ser Thr Thr1 5 10 15Tyr2817PRTInfluenza A virus 28Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln Asn Ser Asn Thr1 5 10 15Tyr2917PRTInfluenza A virus 29Pro Asn Asp Ala Ala Glu Gln Thr Arg Leu Tyr Gln Asn Pro Thr Thr1 5 10 15Tyr3017PRTInfluenza A virus 30Pro Asn Asp Ala Ala Glu Gln Thr Arg Leu Tyr Gln Asn Pro Asn Thr1 5 10 15Tyr3117PRTInfluenza A virus 31Pro Asn Asp Ala Ala Glu Gln Thr Arg Leu Tyr Gln Asn Ser Thr Thr1 5 10 15Tyr3217PRTInfluenza A virus 32Pro Asn Asp Ala Ala Glu Gln Thr Arg Leu Tyr Gln Asn Ser Asn Thr1 5 10 15Tyr3317PRTInfluenza A virus 33Pro Asn Asp Ala Ala Glu Gln Ile Lys Leu Tyr Gln Asn Pro Thr Thr1 5 10 15Tyr3417PRTInfluenza A virus 34Pro Asn Asp Ala Ala Glu Gln Ile Lys Leu Tyr Gln Asn Pro Asn Thr1 5 10 15Tyr3517PRTInfluenza A virus 35Pro Asn Asp Ala Ala Glu Gln Ile Lys Leu Tyr Gln Asn Ser Thr Thr1 5 10 15Tyr3617PRTInfluenza A virus 36Pro Asn Asp Ala Ala Glu Gln Ile Lys Leu Tyr Gln Asn Ser Asn Thr1 5 10 15Tyr3717PRTInfluenza A virus 37Pro Asn Asp Ala Ala Glu Gln Ile Arg Leu Tyr Gln Asn Pro Thr Thr1 5 10 15Tyr3817PRTInfluenza A virus 38Pro Asn Asp Ala Ala Glu Gln Ile Arg Leu Tyr Gln Asn Pro Asn Thr1 5 10 15Tyr3917PRTInfluenza A virus 39Pro Asn Asp Ala Ala Glu Gln Ile Arg Leu Tyr Gln Asn Ser Thr Thr1 5 10 15Tyr4017PRTInfluenza A virus 40Pro Asn Asp Ala Ala Glu Gln Ile Arg Leu Tyr Gln Asn Ser Asn Thr1 5 10 15Tyr4118PRTInfluenza A virus 41Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Ser Ala Tyr1 5 10 15Pro Thr4218PRTInfluenza A virus 42Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Ser Thr Tyr1 5 10 15Pro Thr4318PRTInfluenza A virus 43Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Ser Val Tyr1 5 10 15Pro Thr4418PRTInfluenza A virus 44Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Asn Ala Tyr1 5 10 15Pro Thr4518PRTInfluenza A virus 45Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Asn Thr Tyr1 5 10 15Pro Thr4618PRTInfluenza A virus 46Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Asn Val Tyr1 5 10 15Pro Thr4718PRTInfluenza A virus 47Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Ser Ala Tyr1 5 10 15Pro Thr4818PRTInfluenza A virus 48Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Ser Thr Tyr1 5 10 15Pro Thr4918PRTInfluenza A virus 49Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Ser Val Tyr1 5 10 15Pro Thr5018PRTInfluenza A virus 50Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Asn Ala Tyr1 5 10 15Pro Thr5118PRTInfluenza A virus 51Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Asn Thr Tyr1 5 10 15Pro Thr5218PRTInfluenza A virus 52Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Asn Val Tyr1 5 10 15Pro Thr5318PRTInfluenza A virus 53Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Ser Ala Tyr1 5 10 15Pro Thr5418PRTInfluenza A virus 54Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Ser Thr Tyr1 5 10 15Pro Thr5518PRTInfluenza A virus 55Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Ser Val Tyr1 5 10 15Pro Thr5618PRTInfluenza A virus 56Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Asn Ala Tyr1 5 10 15Pro Thr5718PRTInfluenza A virus 57Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Asn Thr Tyr1 5 10 15Pro Thr5818PRTInfluenza A virus 58Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Asn Val Tyr1 5 10 15Pro Thr5918PRTInfluenza A virus 59Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Ser Ala Tyr1 5 10 15Pro Thr6018PRTInfluenza A virus 60Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Ser Thr Tyr1 5 10 15Pro Thr6118PRTInfluenza A virus 61Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Ser Val Tyr1 5 10 15Pro Thr6218PRTInfluenza A virus 62Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Asn Ala Tyr1 5 10 15Pro Thr6318PRTInfluenza A virus 63Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Asn Thr Tyr1 5 10 15Pro Thr6418PRTInfluenza A virus 64Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Asn Val Tyr1 5 10 15Pro Thr6523PRTInfluenza A virus 65Gly Lys Leu Ser Asp Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys 206623PRTInfluenza A virus 66Gly Lys Leu Ser Asp Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys 206723PRTInfluenza A virus 67Gly Lys Leu Ser Asp Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys 206823PRTInfluenza A virus 68Gly Lys Leu Ser Asp Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys 206923PRTInfluenza A virus 69Gly Lys Leu Ser Asp Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys 207023PRTInfluenza A virus 70Gly Lys Leu Ser Asp Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys 207123PRTInfluenza A virus 71Gly Lys Leu Ser Asp Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys 207223PRTInfluenza A virus 72Gly Lys Leu Ser Asp Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys 207323PRTInfluenza A virus 73Gly Lys Leu Ser Asp Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys 207423PRTInfluenza A virus 74Gly Lys Leu Ser Asp Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys 207523PRTInfluenza A virus 75Gly Lys Leu Ser Asp Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys 207623PRTInfluenza A virus 76Gly Lys Leu Ser Asp Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys 207723PRTInfluenza A virus 77Gly Lys Leu Ser Ser Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys 207823PRTInfluenza A virus 78Gly Lys Leu Ser Ser Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys 207923PRTInfluenza A virus 79Gly Lys Leu Ser Ser Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys 208023PRTInfluenza A virus 80Gly Lys Leu Ser Ser Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys 208123PRTInfluenza A virus 81Gly Lys Leu Ser Ser Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys 208223PRTInfluenza A virus 82Gly Lys Leu Ser Ser Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys 208323PRTInfluenza A virus 83Gly Lys Leu Ser Ser Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys 208423PRTInfluenza A virus 84Gly Lys Leu Ser Ser Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys 208523PRTInfluenza A virus 85Gly Lys Leu Ser Ser Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys 208623PRTInfluenza A virus 86Gly Lys Leu Ser Ser Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys 208723PRTInfluenza A virus 87Gly Lys Leu Ser Ser Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys 208823PRTInfluenza A virus 88Gly Lys Leu Ser Ser Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys 208924PRTInfluenza A virus 89Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn 209024PRTInfluenza A virus 90Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr 209124PRTInfluenza A virus 91Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn 209224PRTInfluenza A virus 92Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr 209324PRTInfluenza A virus 93Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn 209424PRTInfluenza A virus 94Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr 209524PRTInfluenza A virus 95Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn 209624PRTInfluenza A virus 96Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr 209724PRTInfluenza A virus 97Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn 209824PRTInfluenza A virus 98Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr 209924PRTInfluenza A virus 99Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn 2010024PRTInfluenza A virus 100Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr 2010124PRTInfluenza A virus 101Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn 2010224PRTInfluenza A virus 102Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr 2010324PRTInfluenza A virus 103Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn 2010424PRTInfluenza A virus 104Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr

2010524PRTInfluenza A virus 105Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn 2010624PRTInfluenza A virus 106Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr 2010724PRTInfluenza A virus 107Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn 2010824PRTInfluenza A virus 108Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr 2010924PRTInfluenza A virus 109Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn 2011024PRTInfluenza A virus 110Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr 2011124PRTInfluenza A virus 111Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn 2011224PRTInfluenza A virus 112Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr 2011324PRTInfluenza A virus 113Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn 2011424PRTInfluenza A virus 114Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr 2011524PRTInfluenza A virus 115Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn 2011624PRTInfluenza A virus 116Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr 2011724PRTInfluenza A virus 117Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn 2011824PRTInfluenza A virus 118Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr 2011924PRTInfluenza A virus 119Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn 2012024PRTInfluenza A virus 120Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr 2012116PRTInfluenza A virus 121Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Lys Ile1 5 10 1512216PRTInfluenza A virus 122Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Glu Ile1 5 10 1512316PRTInfluenza A virus 123Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Arg Ile1 5 10 1512416PRTInfluenza A virus 124Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Lys Ile1 5 10 1512516PRTInfluenza A virus 125Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Glu Ile1 5 10 1512616PRTInfluenza A virus 126Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Arg Ile1 5 10 1512716PRTInfluenza A virus 127Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Lys Ile1 5 10 1512816PRTInfluenza A virus 128Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Glu Ile1 5 10 1512916PRTInfluenza A virus 129Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Arg Ile1 5 10 1513016PRTInfluenza A virus 130Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Lys Ile1 5 10 1513116PRTInfluenza A virus 131Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Glu Ile1 5 10 1513216PRTInfluenza A virus 132Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Arg Ile1 5 10 1513316PRTInfluenza A virus 133Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Lys Ile1 5 10 1513416PRTInfluenza A virus 134Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Glu Ile1 5 10 1513516PRTInfluenza A virus 135Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Arg Ile1 5 10 1513616PRTInfluenza A virus 136Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Lys Ile1 5 10 1513716PRTInfluenza A virus 137Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Glu Ile1 5 10 1513816PRTInfluenza A virus 138Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Arg Ile1 5 10 1513916PRTInfluenza A virus 139Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Lys Ile1 5 10 1514016PRTInfluenza A virus 140Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Glu Ile1 5 10 1514116PRTInfluenza A virus 141Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Arg Ile1 5 10 1514216PRTInfluenza A virus 142Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Lys Ile1 5 10 1514316PRTInfluenza A virus 143Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Glu Ile1 5 10 1514416PRTInfluenza A virus 144Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Arg Ile1 5 10 1514522PRTInfluenza A virus 145Lys Ala Asn Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2014622PRTInfluenza A virus 146Lys Ala Asn Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2014722PRTInfluenza A virus 147Lys Ala Asn Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2014822PRTInfluenza A virus 148Lys Ala Asn Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2014922PRTInfluenza A virus 149Lys Ala Asn Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2015022PRTInfluenza A virus 150Lys Ala Asn Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2015122PRTInfluenza A virus 151Lys Ala Asn Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2015222PRTInfluenza A virus 152Lys Ala Asn Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2015322PRTInfluenza A virus 153Lys Ala Ser Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2015422PRTInfluenza A virus 154Lys Ala Ser Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2015522PRTInfluenza A virus 155Lys Ala Ser Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2015622PRTInfluenza A virus 156Lys Ala Ser Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2015722PRTInfluenza A virus 157Lys Ala Ser Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2015822PRTInfluenza A virus 158Lys Ala Ser Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2015922PRTInfluenza A virus 159Lys Ala Ser Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2016022PRTInfluenza A virus 160Lys Ala Ser Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2016122PRTInfluenza A virus 161Lys Asp Asn Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2016222PRTInfluenza A virus 162Lys Asp Asn Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2016322PRTInfluenza A virus 163Lys Asp Asn Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2016422PRTInfluenza A virus 164Lys Asp Asn Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2016522PRTInfluenza A virus 165Lys Asp Asn Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2016622PRTInfluenza A virus 166Lys Asp Asn Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2016722PRTInfluenza A virus 167Lys Asp Asn Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2016822PRTInfluenza A virus 168Lys Asp Asn Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2016922PRTInfluenza A virus 169Lys Asp Ser Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2017022PRTInfluenza A virus 170Lys Asp Ser Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2017122PRTInfluenza A virus 171Lys Asp Ser Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2017222PRTInfluenza A virus 172Lys Asp Ser Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2017322PRTInfluenza A virus 173Lys Asp Ser Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2017422PRTInfluenza A virus 174Lys Asp Ser Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2017522PRTInfluenza A virus 175Lys Asp Ser Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp 2017622PRTInfluenza A virus 176Lys Asp Ser Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp 2017722PRTInfluenza A virus 177Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2017822PRTInfluenza A virus 178Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2017922PRTInfluenza A virus 179Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2018022PRTInfluenza A virus 180Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2018122PRTInfluenza A virus 181Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2018222PRTInfluenza A virus 182Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2018322PRTInfluenza A virus 183Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2018422PRTInfluenza A virus 184Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2018522PRTInfluenza A virus 185Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2018622PRTInfluenza A virus 186Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2018722PRTInfluenza A virus 187Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr 2018822PRTInfluenza A virus 188Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2018922PRTInfluenza A virus 189Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2019022PRTInfluenza A virus 190Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr 2019122PRTInfluenza A virus 191Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2019222PRTInfluenza A virus 192Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2019322PRTInfluenza A virus 193Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr 2019422PRTInfluenza A virus 194Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2019522PRTInfluenza A virus 195Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2019622PRTInfluenza A virus 196Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2019722PRTInfluenza A virus 197Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2019822PRTInfluenza A virus 198Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2019922PRTInfluenza A virus 199Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2020022PRTInfluenza A virus 200Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2020122PRTInfluenza A virus 201Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2020222PRTInfluenza A virus 202Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2020322PRTInfluenza A virus 203Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2020422PRTInfluenza A virus 204Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2020522PRTInfluenza A virus 205Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr

2020622PRTInfluenza A virus 206Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2020722PRTInfluenza A virus 207Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2020822PRTInfluenza A virus 208Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr 2020922PRTInfluenza A virus 209Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2021022PRTInfluenza A virus 210Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2021122PRTInfluenza A virus 211Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr 2021222PRTInfluenza A virus 212Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2021322PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 213Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2021422PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 214Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2021522PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 215Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2021622PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 216Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2021722PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 217Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2021822PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 218Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2021922PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 219Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2022022PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 220Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2022122PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 221Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2022222PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 222Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2022322PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 223Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr 2022422PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 224Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2022522PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 225Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2022622PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 226Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr 2022722PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 227Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2022822PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 228Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2022922PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 229Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr 2023022PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 230Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2023122PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 231Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2023222PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 232Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2023322PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 233Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2023422PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 234Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2023522PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 235Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2023622PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 236Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2023722PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 237Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr 2023822PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 238Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr 2023922PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 239Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr 2024022PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 240Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2024122PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 241Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr 2024222PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 242Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2024322PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 243Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2024422PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 244Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr 2024522PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 245Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2024622PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 246Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr 2024722PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 247Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr 2024822PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 248Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr 2024922PRTInfluenza A virus 249Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2025022PRTInfluenza A virus 250Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2025122PRTInfluenza A virus 251Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2025222PRTInfluenza A virus 252Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2025322PRTInfluenza A virus 253Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2025422PRTInfluenza A virus 254Asn His Glu Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2025522PRTInfluenza A virus 255Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2025622PRTInfluenza A virus 256Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2025722PRTInfluenza A virus 257Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2025822PRTInfluenza A virus 258Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2025922PRTInfluenza A virus 259Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2026022PRTInfluenza A virus 260Asn His Glu Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2026122PRTInfluenza A virus 261Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2026222PRTInfluenza A virus 262Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2026322PRTInfluenza A virus 263Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2026422PRTInfluenza A virus 264Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2026522PRTInfluenza A virus 265Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2026622PRTInfluenza A virus 266Asn His Asp Ala Ser Ser Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2026722PRTInfluenza A virus 267Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2026822PRTInfluenza A virus 268Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2026922PRTInfluenza A virus 269Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Lys Ser Ser Phe Phe Gly 2027022PRTInfluenza A virus 270Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Gln Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2027122PRTInfluenza A virus 271Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Asn Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2027222PRTInfluenza A virus 272Asn His Asp Ala Ser Leu Gly Val Ser Ser Ala Ser Pro Tyr Leu Gly1 5 10 15Arg Ser Ser Phe Phe Gly 2027318PRTInfluenza A virus 273Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln Asn Pro Thr Thr1 5 10 15Tyr Gly27418PRTInfluenza A virus 274Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln Asn Pro Asn Thr1 5 10 15Tyr Gly27518PRTInfluenza A virus 275Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln Asn Ser Thr Thr1 5 10 15Tyr Gly27618PRTInfluenza A virus 276Pro Asn Asp Ala Ala Glu Gln Thr Lys Leu Tyr Gln Asn Ser Asn Thr1 5 10 15Tyr Gly27718PRTInfluenza A virus 277Pro Asn Asp Ala Ala Glu Gln Thr Arg Leu Tyr Gln Asn Pro Thr Thr1 5 10 15Tyr Gly27818PRTInfluenza A virus 278Pro Asn Asp Ala Ala Glu Gln Thr Arg Leu Tyr Gln Asn Pro Asn Thr1 5 10 15Tyr Gly27918PRTInfluenza A virus 279Pro Asn Asp Ala Ala Glu Gln Thr Arg Leu Tyr Gln Asn Ser Thr Thr1 5 10 15Tyr Gly28018PRTInfluenza A virus 280Pro Asn Asp Ala Ala Glu Gln Thr Arg Leu Tyr Gln Asn Ser Asn Thr1 5 10 15Tyr Gly28118PRTInfluenza A virus 281Pro Asn Asp Ala Ala Glu Gln Ile Lys Leu Tyr Gln Asn Pro Thr Thr1 5 10 15Tyr Gly28218PRTInfluenza A virus 282Pro Asn Asp Ala Ala Glu Gln Ile Lys Leu Tyr Gln Asn Pro Asn Thr1 5 10 15Tyr Gly28318PRTInfluenza A virus 283Pro Asn Asp Ala Ala Glu Gln Ile Lys Leu Tyr Gln Asn Ser Thr Thr1 5 10 15Tyr Gly28418PRTInfluenza A virus 284Pro Asn Asp Ala Ala Glu Gln Ile Lys Leu Tyr Gln Asn Ser Asn Thr1 5 10 15Tyr Gly28518PRTInfluenza A

virus 285Pro Asn Asp Ala Ala Glu Gln Ile Arg Leu Tyr Gln Asn Pro Thr Thr1 5 10 15Tyr Gly28618PRTInfluenza A virus 286Pro Asn Asp Ala Ala Glu Gln Ile Arg Leu Tyr Gln Asn Pro Asn Thr1 5 10 15Tyr Gly28718PRTInfluenza A virus 287Pro Asn Asp Ala Ala Glu Gln Ile Arg Leu Tyr Gln Asn Ser Thr Thr1 5 10 15Tyr Gly28818PRTInfluenza A virus 288Pro Asn Asp Ala Ala Glu Gln Ile Arg Leu Tyr Gln Asn Ser Asn Thr1 5 10 15Tyr Gly28919PRTInfluenza A virus 289Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Ser Ala Tyr1 5 10 15Pro Thr Gly29019PRTInfluenza A virus 290Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Ser Thr Tyr1 5 10 15Pro Thr Gly29119PRTInfluenza A virus 291Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Ser Val Tyr1 5 10 15Pro Thr Gly29219PRTInfluenza A virus 292Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Asn Ala Tyr1 5 10 15Pro Thr Gly29319PRTInfluenza A virus 293Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Asn Thr Tyr1 5 10 15Pro Thr Gly29419PRTInfluenza A virus 294Ser Trp Ser Asn His Glu Ala Ser Leu Ile Lys Lys Asn Asn Val Tyr1 5 10 15Pro Thr Gly29519PRTInfluenza A virus 295Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Ser Ala Tyr1 5 10 15Pro Thr Gly29619PRTInfluenza A virus 296Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Ser Thr Tyr1 5 10 15Pro Thr Gly29719PRTInfluenza A virus 297Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Ser Val Tyr1 5 10 15Pro Thr Gly29819PRTInfluenza A virus 298Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Asn Ala Tyr1 5 10 15Pro Thr Gly29919PRTInfluenza A virus 299Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Asn Thr Tyr1 5 10 15Pro Thr Gly30019PRTInfluenza A virus 300Ser Trp Ser Asn His Asp Ala Ser Leu Ile Lys Lys Asn Asn Val Tyr1 5 10 15Pro Thr Gly30119PRTInfluenza A virus 301Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Ser Ala Tyr1 5 10 15Pro Thr Gly30219PRTInfluenza A virus 302Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Ser Thr Tyr1 5 10 15Pro Thr Gly30319PRTInfluenza A virus 303Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Ser Val Tyr1 5 10 15Pro Thr Gly30419PRTInfluenza A virus 304Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Asn Ala Tyr1 5 10 15Pro Thr Gly30519PRTInfluenza A virus 305Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Asn Thr Tyr1 5 10 15Pro Thr Gly30619PRTInfluenza A virus 306Ser Trp Ser Ser His Glu Ala Ser Leu Ile Lys Lys Asn Asn Val Tyr1 5 10 15Pro Thr Gly30719PRTInfluenza A virus 307Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Ser Ala Tyr1 5 10 15Pro Thr Gly30819PRTInfluenza A virus 308Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Ser Thr Tyr1 5 10 15Pro Thr Gly30919PRTInfluenza A virus 309Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Ser Val Tyr1 5 10 15Pro Thr Gly31019PRTInfluenza A virus 310Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Asn Ala Tyr1 5 10 15Pro Thr Gly31119PRTInfluenza A virus 311Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Asn Thr Tyr1 5 10 15Pro Thr Gly31219PRTInfluenza A virus 312Ser Trp Ser Ser His Asp Ala Ser Leu Ile Lys Lys Asn Asn Val Tyr1 5 10 15Pro Thr Gly31324PRTInfluenza A virus 313Gly Lys Leu Ser Asp Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys Gly 2031424PRTInfluenza A virus 314Gly Lys Leu Ser Asp Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys Gly 2031524PRTInfluenza A virus 315Gly Lys Leu Ser Asp Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys Gly 2031624PRTInfluenza A virus 316Gly Lys Leu Ser Asp Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys Gly 2031724PRTInfluenza A virus 317Gly Lys Leu Ser Asp Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys Gly 2031824PRTInfluenza A virus 318Gly Lys Leu Ser Asp Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys Gly 2031924PRTInfluenza A virus 319Gly Lys Leu Ser Asp Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys Gly 2032024PRTInfluenza A virus 320Gly Lys Leu Ser Asp Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys Gly 2032124PRTInfluenza A virus 321Gly Lys Leu Ser Asp Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys Gly 2032224PRTInfluenza A virus 322Gly Lys Leu Ser Asp Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys Gly 2032324PRTInfluenza A virus 323Gly Lys Leu Ser Asp Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys Gly 2032424PRTInfluenza A virus 324Gly Lys Leu Ser Asp Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys Gly 2032524PRTInfluenza A virus 325Gly Lys Leu Ser Ser Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys Gly 2032624PRTInfluenza A virus 326Gly Lys Leu Ser Ser Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys Gly 2032724PRTInfluenza A virus 327Gly Lys Leu Ser Ser Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Thr Lys Gly 2032824PRTInfluenza A virus 328Gly Lys Leu Ser Ser Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys Gly 2032924PRTInfluenza A virus 329Gly Lys Leu Ser Ser Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys Gly 2033024PRTInfluenza A virus 330Gly Lys Leu Ser Ser Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asn Ala Lys Gly 2033124PRTInfluenza A virus 331Gly Lys Leu Ser Ser Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys Gly 2033224PRTInfluenza A virus 332Gly Lys Leu Ser Ser Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys Gly 2033324PRTInfluenza A virus 333Gly Lys Leu Ser Ser Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Thr Lys Gly 2033424PRTInfluenza A virus 334Gly Lys Leu Ser Ser Leu Asp Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys Gly 2033524PRTInfluenza A virus 335Gly Lys Leu Ser Ser Leu Lys Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys Gly 2033624PRTInfluenza A virus 336Gly Lys Leu Ser Ser Leu Asn Gly Val Lys Pro Leu Ile Leu Leu Glu1 5 10 15Tyr Gly Asn Ser Asp Ala Lys Gly 2033725PRTInfluenza A virus 337Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn Gly 20 2533825PRTInfluenza A virus 338Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr Gly 20 2533925PRTInfluenza A virus 339Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn Gly 20 2534025PRTInfluenza A virus 340Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr Gly 20 2534125PRTInfluenza A virus 341Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn Gly 20 2534225PRTInfluenza A virus 342Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr Gly 20 2534325PRTInfluenza A virus 343Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn Gly 20 2534425PRTInfluenza A virus 344Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr Gly 20 2534525PRTInfluenza A virus 345Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn Gly 20 2534625PRTInfluenza A virus 346Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr Gly 20 2534725PRTInfluenza A virus 347Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn Gly 20 2534825PRTInfluenza A virus 348Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr Gly 20 2534925PRTInfluenza A virus 349Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn Gly 20 2535025PRTInfluenza A virus 350Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr Gly 20 2535125PRTInfluenza A virus 351Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn Gly 20 2535225PRTInfluenza A virus 352Thr Ile Lys Arg Ser Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr Gly 20 2535325PRTInfluenza A virus 353Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn Gly 20 2535425PRTInfluenza A virus 354Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr Gly 20 2535525PRTInfluenza A virus 355Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn Gly 20 2535625PRTInfluenza A virus 356Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr Gly 20 2535725PRTInfluenza A virus 357Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn Gly 20 2535825PRTInfluenza A virus 358Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr Gly 20 2535925PRTInfluenza A virus 359Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn Gly 20 2536025PRTInfluenza A virus 360Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Gln Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr Gly 20 2536125PRTInfluenza A virus 361Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn Gly 20 2536225PRTInfluenza A virus 362Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr Gly 20 2536325PRTInfluenza A virus 363Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn Gly 20 2536425PRTInfluenza A virus 364Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Lys Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr Gly 20 2536525PRTInfluenza A virus 365Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Asn Gly 20 2536625PRTInfluenza A virus 366Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ala Ile Asn Phe Glu Ser Thr Gly 20 2536725PRTInfluenza A virus 367Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Asn Gly 20 2536825PRTInfluenza A virus 368Thr Ile Lys Arg Thr Tyr Asn Asn Thr Asn Val Glu Asp Arg Pro Asn1 5 10 15Asp Ser Ile Asn Phe Glu Ser Thr Gly 20 2536917PRTInfluenza A virus 369Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Lys Ile1 5 10 15Gly37017PRTInfluenza A virus 370Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Glu Ile1 5 10 15Gly37117PRTInfluenza A virus 371Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Arg Ile1 5 10 15Gly37217PRTInfluenza A virus 372Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Lys Ile1 5 10 15Gly37317PRTInfluenza A virus 373Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Glu Ile1 5 10 15Gly37417PRTInfluenza A virus 374Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Arg Ile1 5 10 15Gly37517PRTInfluenza A virus 375Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Lys Ile1 5 10 15Gly37617PRTInfluenza A virus 376Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Glu Ile1 5 10 15Gly37717PRTInfluenza A virus 377Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Arg Ile1 5 10 15Gly37817PRTInfluenza A virus 378Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Lys Ile1 5 10 15Gly37917PRTInfluenza A virus 379Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Glu Ile1 5 10 15Gly38017PRTInfluenza A virus 380Ile Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Arg Ile1 5 10 15Gly38117PRTInfluenza A virus 381Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Lys Ile1 5 10 15Gly38217PRTInfluenza A virus

382Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Glu Ile1 5 10 15Gly38317PRTInfluenza A virus 383Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Val Pro Arg Ile1 5 10 15Gly38417PRTInfluenza A virus 384Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Lys Ile1 5 10 15Gly38517PRTInfluenza A virus 385Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Glu Ile1 5 10 15Gly38617PRTInfluenza A virus 386Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Leu Ile Pro Arg Ile1 5 10 15Gly38717PRTInfluenza A virus 387Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Lys Ile1 5 10 15Gly38817PRTInfluenza A virus 388Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Glu Ile1 5 10 15Gly38917PRTInfluenza A virus 389Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Val Pro Arg Ile1 5 10 15Gly39017PRTInfluenza A virus 390Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Lys Ile1 5 10 15Gly39117PRTInfluenza A virus 391Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Glu Ile1 5 10 15Gly39217PRTInfluenza A virus 392Val Ser Val Gly Thr Ser Thr Leu Asn Gln Arg Ser Ile Pro Arg Ile1 5 10 15Gly39323PRTInfluenza A virus 393Lys Ala Asn Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2039423PRTInfluenza A virus 394Lys Ala Asn Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2039523PRTInfluenza A virus 395Lys Ala Asn Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2039623PRTInfluenza A virus 396Lys Ala Asn Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2039723PRTInfluenza A virus 397Lys Ala Asn Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2039823PRTInfluenza A virus 398Lys Ala Asn Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2039923PRTInfluenza A virus 399Lys Ala Asn Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2040023PRTInfluenza A virus 400Lys Ala Asn Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2040123PRTInfluenza A virus 401Lys Ala Ser Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2040223PRTInfluenza A virus 402Lys Ala Ser Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2040323PRTInfluenza A virus 403Lys Ala Ser Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2040423PRTInfluenza A virus 404Lys Ala Ser Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2040523PRTInfluenza A virus 405Lys Ala Ser Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2040623PRTInfluenza A virus 406Lys Ala Ser Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2040723PRTInfluenza A virus 407Lys Ala Ser Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2040823PRTInfluenza A virus 408Lys Ala Ser Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2040923PRTInfluenza A virus 409Lys Asp Asn Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2041023PRTInfluenza A virus 410Lys Asp Asn Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2041123PRTInfluenza A virus 411Lys Asp Asn Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2041223PRTInfluenza A virus 412Lys Asp Asn Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2041323PRTInfluenza A virus 413Lys Asp Asn Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2041423PRTInfluenza A virus 414Lys Asp Asn Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2041523PRTInfluenza A virus 415Lys Asp Asn Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2041623PRTInfluenza A virus 416Lys Asp Asn Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2041723PRTInfluenza A virus 417Lys Asp Ser Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2041823PRTInfluenza A virus 418Lys Asp Ser Pro Ala Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2041923PRTInfluenza A virus 419Lys Asp Ser Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2042023PRTInfluenza A virus 420Lys Asp Ser Pro Ala Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2042123PRTInfluenza A virus 421Lys Asp Ser Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2042223PRTInfluenza A virus 422Lys Asp Ser Pro Val Asn Asp Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2042323PRTInfluenza A virus 423Lys Asp Ser Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Ile Asn Val Pro Glu Trp Gly 2042423PRTInfluenza A virus 424Lys Asp Ser Pro Val Asn Gly Leu Gly Asn Pro Met Ser Asp Glu Phe1 5 10 15Leu Asn Val Pro Glu Trp Gly 2042523PRTInfluenza A virus 425Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2042623PRTInfluenza A virus 426Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2042723PRTInfluenza A virus 427Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2042823PRTInfluenza A virus 428Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2042923PRTInfluenza A virus 429Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2043023PRTInfluenza A virus 430Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2043123PRTInfluenza A virus 431Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2043223PRTInfluenza A virus 432Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2043323PRTInfluenza A virus 433Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2043423PRTInfluenza A virus 434Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2043523PRTInfluenza A virus 435Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2043623PRTInfluenza A virus 436Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 2043723PRTInfluenza A virus 437Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2043823PRTInfluenza A virus 438Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2043923PRTInfluenza A virus 439Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 2044023PRTInfluenza A virus 440Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2044123PRTInfluenza A virus 441Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2044223PRTInfluenza A virus 442Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 2044323PRTInfluenza A virus 443Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2044423PRTInfluenza A virus 444Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2044523PRTInfluenza A virus 445Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2044623PRTInfluenza A virus 446Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2044723PRTInfluenza A virus 447Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2044823PRTInfluenza A virus 448Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2044923PRTInfluenza A virus 449Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2045023PRTInfluenza A virus 450Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2045123PRTInfluenza A virus 451Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2045223PRTInfluenza A virus 452Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2045323PRTInfluenza A virus 453Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2045423PRTInfluenza A virus 454Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 2045523PRTInfluenza A virus 455Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2045623PRTInfluenza A virus 456Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2045723PRTInfluenza A virus 457Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 2045823PRTInfluenza A virus 458Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2045923PRTInfluenza A virus 459Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2046023PRTInfluenza A virus 460Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 2046123PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 461Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2046223PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 462Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2046323PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 463Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2046423PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 464Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2046523PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 465Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2046623PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 466Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2046723PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 467Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2046823PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 468Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2046923PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 469Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2047023PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 470Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2047123PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 471Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2047223PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 472Pro Tyr Gln Gly Lys Ser Ser Phe Phe Arg Asn

Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 2047323PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 473Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2047423PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 474Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2047523PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 475Pro Tyr Asn Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 2047623PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 476Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2047723PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 477Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2047823PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 478Pro Tyr Leu Gly Lys Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 2047923PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 479Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2048023PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 480Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2048123PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 481Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2048223PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 482Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2048323PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 483Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2048423PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 484Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2048523PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 485Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Ala Tyr Gly 2048623PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 486Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Thr Tyr Gly 2048723PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 487Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Ser Val Tyr Gly 2048823PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 488Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2048923PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 489Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2049023PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 490Pro Tyr Gln Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 2049123PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 491Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2049223PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 492Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2049323PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 493Pro Tyr Asn Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 2049423PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 494Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Ala Tyr Gly 2049523PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 495Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Thr Tyr Gly 2049623PRTInfluenza A virusMISC_FEATURE(1)..(1)residue lipidated, for example with di-palmitoyl-Lys-Ser-Ser- 496Pro Tyr Leu Gly Arg Ser Ser Phe Phe Arg Asn Val Val Trp Leu Ile1 5 10 15Lys Lys Asn Asn Val Tyr Gly 20

Claims

1. A peptide-based immunogenic composition comprising a peptide which is SEQ ID NO: 25.

2. The composition of claim 1 further comprising at least one peptide selected from the group consisting of SEQ ID NOs: 26 to 40.

3. The composition of claim 1 further comprising a pharmaceutically-acceptable diluent or carrier.

4. The composition of claim 3 further comprising an adjuvant.

5. The composition of claim 4 wherein the adjuvant is alum.

6. An immunogenic composition comprising a mixture of isolated peptides selected from the group consisting of SEQ ID NOs: 25 to 40, said peptides representing variants of at least one variable region of an avian influenza virus HA or HA1 protein, wherein each of said variable regions comprises one or more variable amino acid residues, at least one of said variable amino acid residues is represented by two or more amino acids.

7. The immunogenic composition of claim 6, wherein said one or more variable amino acid residues is represented by three or more amino acids.

8. The immunogenic composition of claim 6, further comprising a peptide selected from the group consisting of SEQ ID NOs: 1 to 24 and 41 to 212.

9. The composition of claim 1, further comprising a peptide selected from the group consisting of SEQ ID NOs: 1 to 24 and 41 to 212.

10. The composition of claim 1, comprising peptides of SEQ ID NOs: 25 to 40.

11. The composition of claim 1, comprising peptides of SEQ ID NOs: 1 to 212.

12. A method of preventing or treating influenza in a patient, comprising administering to the patient an immunogenically effective amount of the immunogenic composition according to claim 1.

13. A method of preventing or treating influenza in a patient, comprising administering to the patient an immunogenically effective amount of the composition according to claim 6.

14. A kit for use in the prevention or treatment of influenza in a patient, comprising the immunogenic composition according to claim 1 and instructions for use of the immunogenic composition according to claim 1 in the prevention or treatment of influenza.

15. A kit for use in the prevention or treatment of influenza in a patient, comprising the composition according to claim 6 and instructions for use of the composition according to claim 6 in the prevention or treatment of influenza.

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