WO2015131053A1

WO2015131053A1 - Polypeptides derived from phl p and methods and uses thereof for immune response modulation

Info

Publication number: WO2015131053A1
Application number: PCT/US2015/018026
Authority: WO
Inventors: Ilka HOOF; Lars Harder CHRISTENSEN; Peters BJOERN; Jason GREENBAUM
Original assignee: Alk-Abelló A/S; La Jolla Institute For Allergy And Immunology
Priority date: 2014-02-28
Filing date: 2015-02-27
Publication date: 2015-09-03

Abstract

The invention relates to polypeptides identified in pollen of several different plant families. The polypeptides comprises sequences of amino acid residues conserved across the different plant families, such as across grass, weed and tree pollen families. The invention further relates to the use of such polypeptides or their conserved amino acid residues as a molecule (e.g. an immunogenic molecule) in modifying an immune response against itself or another unrelated antigen (e.g. major allergen of a pollen source) possible via induction of bystander tolerance.

Description

POLYPEPTIDES DERIVED FROM PHL P AND METHODS AND USES THEREOF FOR IMMUNE RESPONSE MODULATION

Government support

This invention received government support from the National Institutes Health contract NIH-NIAIDHHSN272200700048C. The government has certain rights in the invention.

Field of the invention

The invention relates to pan pollen immunogenic molecules such as polypeptides, proteins and peptides, and methods and uses of such immunogenic molecules for modulating or relieving an immune response in a subject, such as treating a subject for an allergic immune response or inducing or promoting immunological tolerance to the immunogenic molecule or a pollen allergen in a subject. Introduction

Patients with pollen allergies are typically poly-sensitized as evidenced by positive RAST- and/or skin prick tests to multiple pollen allergens, like grass, weed and tree pollen allergens. However, today it is not possible to treat multisensitized patients with one immunotherapeutic product. Although several investigators have suggested that immunotherapy with a single grass species such as Timothy grass (Phleum Pratense (Phi p)) is sufficient to also treat allergies to other grass pollens due to observed cross- reactivity at the IgE level, it has not been suggested to treat multiple pollen allergies with one single immunogenic molecule.

It is firmly established that allergen-specific T-cells play an important role in allergic inflammation and that induction of antigen specific T regulatory cells (Tregs) or elimination of allergen-specific T helper type 2 cells (Th2) might be a prerequisite for the induction of specific tolerance. Yet, cross-reactivity among multiple pollen families at the T-cell level is less explored. Allergen-specific immunotherapy (SIT) is a hyposensitizing immunotherapy introduced in clinical medicine almost a century ago for the treatment of an allergic immune response using the allergens that the subject is sensitized to. An allergic immune response may be mediated by activated allergen-specific Th2 cells, which produce cytokines such as IL-4, IL-5, and IL-13. In healthy individuals, the allergen-specific T-cell response is mediated predominantly by Th1 cells. SIT may reduce the ratio of Th2:Th1 cells and may alter the cytokine profile, reducing the production of IL-4, IL-5, and IL-13 and increasing the production of IFN-gamma in response to major allergens or allergen extracts.

Despite its efficacy, SIT has several limitations, including safety concerns about giving patients allergenic substances. Because most SIT regimens involve the administration of whole, unfractionated, allergen extracts, adverse IgE-mediated events are a considerable risk. Significant efforts have been devoted to developing approaches to modulate allergen-specific T-cell responses without inducing IgE-meditated, immediate-type reactions. These approaches include developing hypoallergens that do not contain IgE- binding epitopes, allergens that are coupled to adjuvants and carriers of bacterial or viral origin or peptides that contain dominant T-cell epitopes and do not react with IgE in allergic individuals.

It was recently shown that a large fraction of Timothy Grass-specific T cells target epitopes contained in novel Timothy Grass antigens (NTGA). NTGA's are unrelated to the known allergens of Timothy grass, which mainly are identified based on their high IgE reactivity. International patent application, WO2013/119863 A1 , relates to novel antigens (NTGA's) derived from Timothy grass pollen.

It has also recently been shown and described in International patent application

WO2012/049310 that an immunogenic molecule derived from an allergenic pollen source is able to reduce an allergic immune response caused by an unrelated allergen of the same pollen source via bystander suppression.

As disclosed herein, it is possible to provide immunogenic molecules with high sequence conservation/homology to polypeptides identified in several different pollen families. Such immunogenic molecules have potential therapeutical utilization against immune responses triggered by pollen allergens of a broad array of pollen families for example via induction of bystander tolerance towards the offending pollen allergens. Summary

Disclosed herein are immunogenic molecules (in short immunogens), also named pan- pollen immunogens, which have been detected in Timothy grass pollen (Phleum pratense (in short Phi p) and in at least one non-grass pollen species, which consist of or contain as part of their sequence an amino acid sequence conserved across the Phi p grass pollen species and at least one of the non-grass pollen species investigated. For example, a molecule (e.g. an immunogenic molecule) of the invention may consist of or contain as part of its sequence a conserved amino acid sequence detected in several different pollen families, e.g. in a grass pollen species (e.g. Phleum Pratense (Phi p) and at least one of the following non-grass pollen species: Ambrosia psilostachya (Amb p), Ambrosia artemisiifolia, (Amb a), Quercus alba (Que a) and Betula verrucosa, (Bet v). Table 1 shows examples of amino acid sequences of "pan pollen" polypeptides detected and identified in Phi p grass pollen and Table 2 shows amino acid sequences of polypeptides homologous to the polypeptides of Table 1 , which is found in pollen of the species Cyn d, Amb a, Amb p, Que a, and Bet v. As those polypeptides can be detected in pollen, they are referred to herein as wild type polypeptides.

Disclosed herein are also conserved regions, i.e. stretches of amino acid residues of the polypeptides of Table 1 and 2 that are conserved across at least one set of homologous polypeptides found in Phi p grass pollen and in at least one weed pollen species (Amb a or Amp) and in at least one tree pollen species (Que a or Bet v). Such stretches are herein named GWT (Grass-Weed-Tree) conserved stretches of amino acid residues (or alternatively GWT conserved regions). Table 3 shows GWT conserved regions identified in the Phi p sequences of Table 1. Table 4 shows the corresponding GWT conserved regions identified in the other pollen species investigated. A conserved region as used herein is defined as the region identified from merging overlapping conserved 15mer peptides in a Phi p sequence, wherein a conserved 15mer peptide is defined as a 15 amino acid peptide containing 0, 1 , or 2 mismatches to a 15mer peptide sequence of a homologous polypeptide in a weed pollen species (Amb a and/or Amb) and in a tree pollen species (Que a and/or Bet v). In addition, there is provided herein conserved amino acid sequences of the polypeptides of Table 1 and 2 that are conserved across at least a set of homologous polypeptides found in Phi p grass pollen and in at least one weed pollen species (Amb a or Amp), but not in a tree pollen species (Que a or Bet v). Such sequences are herein named GW (Grass-Weed) conserved stretches of amino acid residues (or alternatively GW conserved regions). Table 5 shows GW conserved regions identified in the Phi p sequences of Table 1. Table 6 shows the corresponding GW conserved regions identified inthe other pollen species.

Also there is provided herein conserved amino acid sequences of the polypeptides of Table 1 and 2 that are conserved across at least a set of homologous polypeptides found in Phi p grass pollen and in at least one tree pollen species (Que a or Bet v), but not in a weed pollen species (Amb a or Amp). Such sequences are herein named GT (Grass- Tree) conserved stretches of amino acid residues (or alternatively GT conserved regions). Table 7 shows GW conserved regions identified in the Phi p sequences of Table 1. Table 8 shows the corresponding GT conserved regions identifiedin the other pollen species.

Also provided herein are conserved amino acid sequences of the polypeptides of Table 1 and 2 that are conserved across at least a set of homologous polypeptides found in Amb a pollen and in at least one tree pollen species (Que a or Bet v), but not found in Phi p pollen. Such sequences are herein named WT (Weed-Tree) conserved stretches of amino acid residues (or alternatively WT conserved regions). Table 9 shows WT conserved regions identified in polypeptides of Table 2.

The GWT, GW, GT or WT conserved sequences may be an immunogenic molecule in itself, or may give rise to additional immunogens comprising the conserved sequences or subsequences thereof. In certain embodiments, a molecule (e.g. an immunogenic molecule) may contain at least one T cell epitope, as may be determined by the T cell response observed against immunogens disclosed in Tables 1 to 9 when cultured together with PBMC's obtained from grass pollen allergic donors or alternatively from ragweed, oak and/or birch pollen allergic donors. In some embodiments, an immunogenic molecule of the invention which is identified in Phi p pollen may be able to modify a T cell response in a grass allergic donor as well as in donors allergic to a weed pollen species and/or tree pollen species. This is evidenced using Phi p allergens and a selection of recently identified Phi p antigens as model immunogens (Example 8). It was found that a T cell response of grass allergic donors to a first immunogenic molecule derived from Phi p may also be activated in detectable levels by a second immunogenic molecule containing few mismatches to the first immunogenic molecule, e.g. preferably no more than 2 or 3 mismatches.

Therefore, the presently provided conserved sequences shown in Tables 3 to 8 may be able to induce a T cell response in donors not only sensitized to Phi p pollen allergens, but to allergens of any of the pollen species Cyn d, Amb a, Amb p, Que a and Bet v as well as other pollen species containing polypeptides with similar conserved sequences comprising less than 2 or 3 mismatches to the Phi p sequence in question.

Therefore, the invention relates in a first aspect to a molecule, such as an immunogenic molecule comprising, consisting of or consisting essentially of a) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 274, 270-273, 212-269 and 275-293 set out in Table 3; SEQ ID NOS: 617-676, 294-616 and 677-767 set out in Table 4; SEQ ID NOS: 768-808 set out in Table 5; SEQ ID NOS: 809-951 set out in Table 6; SEQ ID NOS: 952-1023 set out in Table 7; SEQ ID NOS: 1024-1231 set out in Table 8 and SEQ ID NOS: 1232-1473 set out in Table 9; or b) a polypeptide comprising an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 274, 270-273, 212-269 and 275-293 set out in Table 3; SEQ ID NOS: 617-676, 294-616 and 677-767 set out in Table 4; SEQ ID NOS: 768-808 set out in Table 5; SEQ ID NOS: 809-951 set out in Table 6; SEQ ID NOS: 952- 1023 set out in Table 7; SEQ ID NOS: 1024-1231 set out in Table 8 and SEQ ID NOS: 1232-1473 set out in Table 9; or c) a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2 mismatches to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 274, 270-273, 212-269 and 275-293 set out in Table 3; SEQ ID NOS: 617-676, 294-616 and 677-767 set out in Table 4; SEQ ID NOS: 768-808 set out in Table 5; SEQ ID NOS: 809-951 set out in Table 6; SEQ ID NOS: 952-1023 set out in Table 7; SEQ ID NOS: 1024-1231 set out in Table 8 and SEQ ID NOS: 1232-1473 set out in Table 9; or d) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 30, 1-29, 31- 37 set out in Table 1 or SEQ ID NOS: 161-172, 38-160 and 173-211 set out in Table 2.

The invention also relates to the use of said molecule (e.g. said immunogenic molecule) as a medicament, in particularly for use in modulating an immune response, e.g. relieving an immune response, triggered by pollen (i.e. a pollen allergen and/or an immunogenic molecule disclosed herein) in a subject. Thus, in further aspects, the invention relates to a method for modulating an immune response, e.g. for relieving an immune response (e.g. triggered by pollen or an immunogen present in pollen), in a subject in need thereof, comprising administering an effective amount of a molecule (e.g. an immunogenic molecule) disclosed herein. In still further aspects, the invention relates to an immunogenic molecule as disclosed herein for use in modulating an immune response, e.g. for relieving an immune response, in a subject in need thereof, comprising administering an effective amount of a molecule (e.g. an immunogenic molecule) disclosed herein.

The invention also relates to the use of a molecule (e.g. an immunogenic molecule) as disclosed herein as a medicament, e.g. use of an immunogenic molecule as disclosed herein for the preparation of a medicament for modulating an immune response, e.g. relieving an immune response, in a subject in need thereof.

The immune response in question may be triggered by pollen, e.g. by pollen of one or more pollen species, pollen genera or pollen families. It follows that the immune response in question may be triggered by one or more pollen allergens from one or more pollen species, pollen genera or pollen families including one or more molecules (e.g.

immunogenic molecules) disclosed herein, for example the immunogenic molecule itself or a subsequence thereof.

Below is provided example embodiments specifically related to each set of pan-pollen immunogens presently identified. For example, in embodiment X, the set of polypeptides identified in Phi p grass pollen and the other pollen species investigated are commonly numbered A0349. In such embodiments, a polypeptide of option d) comprises an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 27-30 set out in Table 1 and SEQ ID NOS: 161-172 set out in Table 2; a polypeptide of option a) comprises an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 270-274 set out in Table 3 and SEQ ID NOS: 617-676 set out in Table 4; a polypeptide of option b) comprises an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 270-274 set out in Table 3 and SEQ ID NOS: 617-676 set out in Table 4, and a polypeptide of option c) includes at least one amino acid sequence with 0, 1 , 2, 3 or 4 mismatches compared to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 270-274 set out in Table 3 and SEQ ID NOS: 617-676 set out in Table 4. Other embodiments (A to AE) may be constructed the same way using the list below:

In some embodiments, the molecule (e.g. immunogenic molecule) may comprise a combination of two or more polypeptides of option a), option b), option c) or option d), so as to construct molecules with desirable properties e.g. immunogenic molecules with high conservation throughout the entire amino acid sequence. For example, a polypeptide of option a) may contain as part of its sequence a combination of two or more amino acid sequences having at least 65% similarity or identity to a sequence selected from any one of SEQ ID NOS: 212-293 set out in Table 3 and SEQ ID NOS: 294-767 set out in Table 4. Likewise, a polypeptide of option b) and c) may comprise as part of its sequence a combination of two or more of said subsequences.

Also provided are cells expressing a molecule (e.g. immunogenic molecule) described herein. In various embodiments, a cell expresses said molecule. In certain aspects, a cell is a eukaryotic or prokaryotic cell and may be a mammalian, insect, fungal or bacterium cell. A molecule (e.g. an immunogenic molecule) of the present invention is suitable as a reagent, for example in immunotherapy against various pollen allergies in a subject.

In other embodiments, there are provided nucleic acid molecules encoding a polypeptide of option a), b), c) or d) or a molecule comprising a polypeptide of option a), b), c) or d).

In additional aspects, there are provided compositions, for example pharmaceutical compositions comprising an immunogenic molecule of the invention. In one embodiment, a pharmaceutical composition is suitable for immunotherapy (e.g. treatment,

desensitization, tolerance induction, bystander suppression (bystander tolerance induction). In certain embodiments, a pharmaceutical composition is a vaccine, e.g.

suitable formulated for the purpose of vaccination.

Brief Description of the Drawings

Figure 1 : Conservation in transcriptome predicts peptide cross-reactivity. For each peptide, Phi p allergic donors were selected that reacted to the peptide after expanding PBMCs in vitro with Phi p extract. PBMCs were stimulated with individual peptides for 14 days and IL-5 responses were measured by ELISPOT to i) the peptide itself, ii) Phi p extract, iii) non-Phi p extracts (e.g. Amb a, Que, Ole e, Bet v, Cyn d), iv) pools of predefined peptide pools that did or did not contain the peptide as relevant and irrelevant controls. T cell cultures that did not induce a robust response (>=200 SFC) to the peptide itself were excluded. Reponses to extracts and peptide pools are expressed as the relative fraction of the response to the peptide itself, and capped at 100%.

Figure 2: Sensitization pattern of an immunogen of the invention (A0349): It is shown that the in vitro T-cell response towards A0349 is much weaker compared to the response to allergen Phi p 5.

Figures 3 Tolerance induction investigated in mice: shows that prophylactic sublingual immunotherapy treatment (SLIT) with A0349 in mice is capable of inducing tolerance towards Phi p extract as shown by the ability of A0349 to reduce the

proliferation of cells of splenocytes from treated mice compared to buffer (sham) treated mice. Thus, an immunogenic molecule that is weaker than Phi p 5, the major allergen in Phi p extract, is able to reduce an immune response triggered by Phi p extract.

Figure 4: Bystander tolerance induction investigated in mice. As shown in Figure 4A, prophylactic SLIT treatment with A0349 could induce tolerance toward the allergen Phi p 5, which amino acid sequence is quite different from A0349. Thus, treatment with A0349 resulted in the suppression of an immune response caused by an unrelated antigen, i.e. Phi p 5, possibly via bystander mechanisms, where the tolerance induction towards one immunogen (e.g. A0349) result in suppression of an immune response caused by another unrelated immunogen (e.g. Phi p 5).

Detailed description

The following terms and phrases shall have the following meaning:

The term "a" or "an" refers to an indefinite number and shall not only be interpreted as "one" but also may be interpreted to mean "some", "several" or one or more. The term "conserved sequence" is in the present context meant to include that a given amino acid sequence of one pollen species contains at least 15 contiguous amino acids within the sequence that has less than 3 mismatches compared to an amino acid sequence of 15 amino acid residues from another pollen species. Longer stretches of conserved sequences may contain several stretches of at least 15 contiguous amino acids having less than 3 mismatches compared to another sequence of 15 amino acids from another pollen species, genera or family. The conserved region is usually determined by multiple sequence alignments of three or more homologous pollen polypeptides. The terms "polypeptide", "protein" and "peptide" may be used interchangeably and mean any peptide-linked chain of amino acids regardless of post-translational modification. While polypeptides can be any length, the use of the term "protein" generally means longer polypeptides of at least 100 amino acid residues, whereas the term "peptide" generally means polypeptides shorter than 30 amino acid residues. In the present context, e.g. for the purpose of detecting a conserved sequence of a polypeptide herein, the term "mismatch" is meant to include any substitution of an amino acid residue within the 15mer peptide. Optionally, a mismatch may be a deletion or an addition of an amino acid residue within the 15mer peptide.

As used herein, the term "homologous polypeptides" refer to a pollen polypeptide derived from a common ancestor and are typically, although not necessarily, polypeptides having one or more similar functions. Typically, homologous pollen polypeptides will have a degree of sequence identity to each other across the entire length of each protein that is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or greater. Typically, homologous pollen polypeptides are found in pollens of different species, genera and families.

The term "sensitized to" is generally meant to encompass that the subject has been exposed to an immunogenic molecule, e.g. an allergen or an antigen, in a manner that the individual's adaptive immune system displays memory to the immunogenic molecule, for example that the immunogenic molecule has induced detectable IgE antibodies against the immunogenic molecule and thus qualifies as an IgE-reactive antigen

(allergen) and/or that T-cells stimulated in vitro are able to proliferate under the presence of the immunogenic molecule or fragments of the immunogenic molecule (e.g. linear peptides derived from the immunogenic molecule).

The term "allergic immune response" is meant to encompass a hypersensitivity immune response, e.g. a type 1 hypersensitivity immune response, such as typically an immune response that is associated with the production of IgE antibodies (i.e. IgE-mediated immune response) and/or production of cytokines usually produced by Th2 cells. An allergic immune response may be associated with an allergic disease, for example atopic dermatitis, urticaria, contact dermatitis, allergic conjunctivitis, allergic rhinitis, allergic asthma, anaphylaxis, food allergy and hay fever. The term "grass pollen" is meant to designate pollen of the plant family Poaceae, for example pollen of the plant genus Anthoxanthum, Cynodon, Dactylis, Festuca, Holcus, Hordeum, Lolium, Oryza, Paspalum, Phalaris, Phleum, Poa, Secale, Sorghum, Triticum or Zea.

As used herein, an "immunogenic molecule" refers to a substance, including but not limited to a molecule comprising as part of its structure or exclusively a protein, a polypeptide or a peptide, which optionally modifies, e.g. elicits, induces, stimulates, promotes enhances or decreases, reduces, inhibits, suppresses, relieves an immune response when administered to a subject, for example laboratory mice or modifies, e.g. elicits, induces, stimulates, promotes enhances or decreases, reduces, inhibits, suppresses or relieves a T cell response in vitro in response to the immunogenic molecule. For example, an immunogenic molecule may induce tolerance to itself in a subject. An immune response elicited by an immunogenic molecule may include, but is not limited to, a B cell or a T cell response. An immune response can include a cellular response with a particular pattern of lymphokine/cytokine production (e.g., Th1 , Th2), a humoral response (e.g., antibody production, like IgE, IgG or IgA), or a combination thereof, to a particular immunogenic molecule.

The term "an antigen" refers to a particular substance to which an immunoglobulin (Ig) isotype may be produced in response to the substance. For example, an "IgG antigen" refers to an antigen that induces an IgG antibody response. Likewise, an "IgE antigen" refers to an antigen that induces an IgE antibody response (and thus qualifies as an allergen); an "IgA antigen" refers to a substance that induces an IgA antibody response, and so forth. In certain embodiments, such an immunoglobulin (Ig) isotype produced in response to an antigen may also elicit production of other isotypes. For example, an IgG antigen may induce an IgG antibody response in combination with one more of an IgE, IgA, IgM or IgD antibody response. In other embodiments, an IgG antigen may induce an IgG antibody response without inducing a response to one more of an IgE, IgA, IgM or IgD antibody response. Accordingly, in certain embodiments, an IgG antigen may induce an IgG antibody response without inducing an IgE, IgA, IgM or IgD antibody response. The term "allergen" refers to a particular type of a substance that can elicit production of IgE antibodies, such as in predisposed subjects. For example, if a subject previously exposed to an allergen (i.e. is sensitized or is hypersensitive) comes into contact with the allergen again, allergic asthma may develop due to a Th2 response characterized by an increased production of type 2 cytokines (e.g., IL-4, IL-5, IL-9, and/or IL-13) secreted by CD4+ T lymphocytes.

The term "immunotherapy" is meant to encompass treatment of a disease by inducing, enhancing, or suppressing an immune response. Typically, the therapeutically active agent is an immunogenic molecule, particularly an antigen, more particularly an allergen. An immunogenic molecule may be a protein or a fragment thereof (e.g. immunogenic peptide including a linear peptide). Immunotherapy in connection with allergy usually encompasses repeated administration of a sufficient dose of the immunogenic molecule/antigen/allergen, usually in microgram quantities, over a prolonged period of time, usually for more than 3 months, 6 months, 1 year, such as 2 or 3 years, during which period the immunogenic molecule may be administered daily or less frequently, such as several times a week, weekly, bi-weekly, or monthly, every second month or quarterly. Immunotherapy can be effected by specific immunotherapy or may be effected by bystander tolerance induction.

The term "specific immunotherapy" in connection with allergy is meant to designate that immunotherapy is conducted with the administration of an immunogenic molecule to which the subject is sensitized to, particularly an immunogenic molecule to which the subject has raised specific IgE antibodies to, e.g. major allergens.

As used herein, the term "immunological tolerance" refers to a) a decreased or reduced level of a specific immunological response (thought to be mediated at least in part by antigen-specific effector T lymphocytes, B lymphocytes, antibodies or a combination thereof); b) a delay in the onset or progression of a specific immunological response; or c) a reduced risk of the onset or progression of a specific immunological response to an immunogenic molecule, such as an antigen or an allergen. "Specific" immunological tolerance occurs when tolerance is preferentially invoked against certain immunogens in comparison with other immunogens. Tolerance is an active immunogenic molecule dependent process and differs from non-specific immunosuppression and immunodeficiency.

The term "bystander tolerance induction" in connection with treatment of allergy is meant to encompass that immunotherapy is conducted with the administration of an

immunogenic molecule that elicits, induces, stimulates, promotes enhances or decreases, reduces, inhibits, suppresses, relieves an immune response against another unrelated immunogenic molecule, for example an allergen, e.g. major allergens of pollen. For example, an immunogenic molecule may induce immunological tolerance to itself, and may be able to reactivate T regulatory cells specific to the immunogenic molecule to down-regulate an immune response caused by another unrelated immunogenic molecule, e.g. an allergen. Thus, an immunogenic molecule may induce immunological tolerance to another unrelated antigen, e.g. an allergen including a pollen allergen described herein. Thus, one immunogenic molecule may provide bystander tolerance induction to another unrelated antigen, e.g. the immunogenic molecule may provide suppression of an immune response triggered by an unrelated antigen (e.g. allergen) via bystander mechanisms.

The term "treatment" refers to any type of treatment that conveys a benefit to a subject afflicted with allergy or at least sensitized to an allergen , including improvement in the condition of the subject (e.g., in one or more symptoms), delay in the onset of symptoms, slowing the progression of symptoms, or induce disease modification etc. Typical symptoms of an allergic reaction are nasal symptoms, such as itchy nose, sneezing, runny nose, blocked nose; conjunctival symptoms, such asitchy eyes, red eyes, watery eyes; and respiratory symptoms, such as decreased lung function. The treatment may also give the benefit that the patient needs less concomitant treatment with

corticosteroids or H1 antihistamines to suppress the clinical symptoms. As used herein, "treatment" is not necessarily meant to imply cure or complete abolition of symptoms, but refers to any type of treatment that imparts a benefit to a patient. Treatment may be initiated before the subject becomes sensitized to a protein. This may be realized by initiating immunotherapy before the subject has raised detectable serum IgE antibodies capable of binding specifically to the sensitizing protein or before any other biochemical marker indicative of an allergic immune response can be detected in biological samples isolated from the individual. Furthermore, treatment may be initiated before the subject has evolved clinical symptoms of the allergic disease, such as symptoms of allergic rhinitis, allergic asthma or atopic dermatitis. The phrase "therapeutically sufficient amount" or "sufficient amount" is meant to designate an amount effective to reduce, suppress, relieve or eliminate an allergic immune response, e.g. an amount sufficient to achieve the desirable reduction in clinical relevant symptoms or manifestations of the allergic immune response. For example, a therapeutically sufficient amount may be the accumulated dose of a polypeptide, a set of polypeptides administered during a course of immunotherapy in order to achieve the intended effect or it may be the maximal dose tolerated within a given period. The total dose or accumulated dose may be divided into single doses administered daily, twice a week or more, weekly, every second or fourth week or monthly depending on the route of administration and the pharmaceutical formulation used. The total dose or accumulated dose may vary. It is expected that a single dose is in the microgram range, such as in the range of 5 to 500 microgram dependent on the nature of the polypeptide.

The term "patient responding to therapy," such as "immunotherapy" is meant to designate that the patient has improvement in the symptoms of the allergic immune response caused by a pollen allergen. Symptoms may be the clinically symptoms of allergic rhinitis, allergic asthma allergic conjunctivitis, atopic dermatitis, food allergy and/or hay fever. Typically, the symptoms are the same as experienced with a flu/cold such as sneezing, itching, congestion, coughing, feeling of fatigue, sleepiness and body aches. For example nasal symptoms may be itchy nose, sneezing, runny nose, blocked nose; conjunctival symptoms may be itchy eyes, red eyes, watery eyes; and respiratory symptoms may be decreased lung function. A responder may also be evaluated by monitoring the patient's reduced need for concomitant treatment with corticosteroids or H1 antihistamines to suppress the clinical symptoms. Symptoms may be subjectively scored or in accordance with official guidelines used in clinical trials of SIT. The term "adjuvant" refers to a substance that enhances the immune response to an immunogenic molecule. Depending on the nature of the adjuvant, it can promote either a cell-mediated immune response, humoral immune response or a mixture of the two.

As used herein an "epitope" refers to a region or part of an immunogenic molecule that elicits an immune response when administered to a subject. In particular embodiments, an epitope is a T cell epitope, i.e., an epitope that elicits, stimulates, induces, promotes, increases or enhances a T cell activity, function or response. An immunogenic molecule can be analyzed to determine whether it include at least one T cell epitope using any number of assays (e.g. T cell proliferation assays, lymphokine secretion assays, T cell non-responsiveness studies, etc.). In the context of the present invention, a T-cell epitope refers to an epitope that are MHC Class II binders (i.e. HLA-II binders), for example an epitope able to connect to/ associate with or bind to a HLA-II molecule shown in Tables 11 b or 11c.

As used herein, the term "immune response" includes T cell (cellular) mediated and/or B cell (humoral) mediated immune responses, or both cellular and humoral responses. Exemplary immune responses include T cell responses, e.g., lymphokine production, cytokine production and cellular cytotoxicity. T-cell responses include Th1 and/or Th2 responses. In addition, the term immune response includes responses that are indirectly affected by T cell activation, e.g., antibody production (humoral responses) and activation of cytokine responsive cells, e.g., eosinophils, macrophages. Immune cells involved in the immune response include lymphocytes, such as T cells (CD4+, CD8+, Th1 and Th2 cells, memory T cells) and B cells; antigen presenting cells (e.g., professional antigen presenting cells such as dendritic cells, macrophages, B lymphocytes, Langerhans cells, and non-professional antigen presenting cells such as keratinocytes, endothelial cells, astrocytes, fibroblasts, oligodendrocytes); natural killer (NK) cells; myeloid cells, such as macrophages, eosinophils, mast cells, basophils, and granulocytes.

The term "subsequence" or "stretch" means a fragment or part of a longer molecule, e.g. of a full length molecule (e.g. the wild type polypeptides shown in Tables 1 and 2) or of a conserved region thereof (e.g. GWT sequences shown in Tables 3 and 4). A

subsequence therefore consists of one or more amino acids less than the wild type polypeptide or a conserved region thereof.

As disclosed herein, a molecule (e.g. an immunogenic molecule) of the invention comprises conserved amino acid sequences detected in a grass pollen species as well as in a weed pollen species and/or a tree pollen species. Thus, such molecules can be used to broadly treat a subject with or at risk of developing an immune response to pollen of a variety of pollen species, genera or families, or to broadly induce or promote tolerance of a subject to pollen of a variety of pollen species, genera or families and may include promoting or inducing tolerance to the immunogenic molecule itself or another immunogenic molecule (e.g. an allergen) unrelated to the immunogenic molecule being administered, for example via induction of bystander tolerance towards an offending allergen.

Thus, by the present invention it is now possible to modify, such as relieving, an immune response in a multisensitized subject, e.g. a subject sensitized to both grass, weed and tree pollen, by administering a molecule (e.g. an immunogenic molecule) described herein. Likewise, it is also now possible to treat subjects with different pollen allergies using the same molecule or set of molecules.

In certain embodiments, the molecule (e.g. the immunogenic molecule) comprises or consists of a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2 mismatches compared to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 212-293 (e.g. SEQ ID NOS: 274, 270-273, 212-269 and 275-293) set out in Table 3 or SEQ ID NOS: 294-767 (e.g. SEQ ID NOS: 665-676, 617-664 and 677-767) set out in Table 4.

The molecule (e.g. the immunogenic molecule) may comprise one or more T cell epitope(s) optionally a Th-2 cell epitope (i.e. the molecule may comprise one or more T cell epitope-containing amino acid sequence(s)). Thus, in some embodiments, the polypeptide of option a), option b), option c) and option d) comprises a T cell epitope, optionally a Th-2 cell epitope. Accordingly, the GWT sequences (SEQ ID NOS:212-293 set out in Table 3 and SEQ ID NOS: 294-767 set out in Table 4), the GW sequences (SEQ ID NOS: 768-808 set out in Table 5 and SEQ ID NOS: 809-951 set out in Table 6), GT sequences (SEQ ID NOS: 952-1023 set out in Table 7 and SEQ ID NOS: 1024-1231 set out in Table 8) and WT sequences (SEQ ID NOS: 1232-1473 set out in Table 9) or subsequences thereof may comprise a T cell epitope, optionally a Th-2 cell epitope.

Thus, a subsequence of a polypeptide of option b) or option c) contains a T cell epitope, optionally a Th-2 cell epitope. It follows that the sequences selected from any of SEQ ID NOS: 1-37 (e.g. SEQ ID NOS: 30, 1-29, 31-37 set out in Table 1 and SEQ ID NOS: 38- 211 (e.g SEQ ID NOS: 161-172, 38-160 and 173-211) set out in Table 2 contains a T cell epitope, optionally a Th-2 cell epitope.

Advantageously, immunogens of the present invention may be used in relieving an immune response against phi p grass pollen, non-phi p grass pollen as well as non-grass pollen to the extent that the pollen species contain polypeptides comprising essentially the same GWT, GW, GT or WT conserved region. For example, an immunogenic molecule of the present invention may at least be used in modulating, e.g. relieving, an immune response triggered by pollen of the grass pollen species Phi p and/or Cyn d as well as pollen of other species closely related to Phi p or Cyn d, e.g. pollen species also belonging to the plant family Poales, such as species of the plant genera selected from any of Anthoxanthum, Cynodon, Dactylis, Lolium, Phleum or Poa. The same

immunogenic molecule may also be used in modulating, e.g. relieving, an immune response triggered by pollen of the weed pollen species Amb a and/or Amb p and pollen of species closely related to Amb a and Amp p, e.g. pollen species also belonging to the plant family Asteraceae, such as species of the plant genera selected from any of Ambrosia, Artemisia, Helianthus. In addition, the same immunogenic molecule may also be used in modulating, e.g. relieving, an immune response triggered by pollen of the tree pollen species Que a and/or Bet v and pollen of species closely related to Que a and/or Bet v, e.g. pollen species also belonging to the plant families Betulaceae, Fagaceae and Oleaceae, such as species of the plant genera selected from any of Alnus, Betula, Carpinus, Castanea, Corylus, Fagus, Quercus, Fraxinus and Ligustrum. As disclosed herein, there can be found several GWT conserved sequences in pollen species of the plant genera Phleum, Cynodon, Ambrosia and Quercus and Betula. Thus, in certain embodiments, a molecule (e.g. an immunogenic molecule) of the present invention may be used in modulating, e.g., relieving, an immune response triggered by pollen of a plant genus selected from any of Phleum, Cynodon Ambrosia, Quercus and Betula.

The following Table lists pollen species of the plant families Asteraceae, Betulaceae, Fagaceae, Oleaceae, Plantaginaceae and Poaceae. Pollen species used for the conservation analysis described herein are highlighted in grey color.

As mentioned, conserved amino acid sequences disclosed herein have been detected in about five different pollen species and may be found in additional pollen species selected from any of the plant families Poaceae, Asteraceae, Fagaceae, Betulaceae, Oleaceae, and Plantaginaceae, e.g. the plant genera Ambrosia, Artemisia, Helianthus, Alnus, Betula, Carpinus, Castanea, Corylus, Ostrya, Ostryopsis, Fagus, Quercus, Fraxinus, Ligustrum, Lilac, Olea or Plantago using the methodology disclosed herein (see exemplary pollen species below):

CateID Common Latin name of Genus Family Order gory Name species

Weed Giant ragweed Ambrosia trifida Ambrosia Asteraceae Asterales Weed Amb a Short Ambrosia Ambrosia Asteraceae Asterales

Ragweed artemisiifolia

Weed Amb p Western Ambrosia Ambrosia Asteraceae Asterales ragweed psilostachya

Weed Mugwort Artemisia Artemisia Asteraceae Asterales vulgaris

Weed Sunflower Helianthus Helianthus Asteraceae Asterales annuus

Tree Common Alnus glutinosa Alnus Betulaceae Fagales

Alder

Tree Bet European Betula Betula Betulaceae Fagales white birch Verrucosa Cate- ID Common Latin name of Genus Family Order gory Name species

Tree Common Carpinus betulus Carpinus Betulaceae Fagales

Hornbeam

Tree European Castanea sativa Castanea Betulaceae Fagales

Chestnuts

Tree Common Corylus avellana Corylus Betulaceae Fagales

Hazel

Tree European Ostrya Ostrya Betulaceae Fagales

Hop- carpinifolia

hornbeam

Tree Hazel- Ostryopsis Ostryopsis Betulaceae Fagales hornbeam

Tree American Fagus Fagus Fagaceae Fagales

Beech grandifolia

Tree European Fagus sylvatica Fagus Fagaceae Fagales beech

Tree Que a White Oak Quercus alba Quercus Fagaceae Fagales Tree Fra e European Ash Fraxinus Fraxinus Oleaceae Lamiales

Excelsior (Oleales)

Tree Common Ligustrum Ligustrum Oleaceae Lamiales

Privet vulgare (Oleales)

Tree Lilac Syringa vulgaris Lilac Oleaceae Lamiales

(Oleales)

Tree Ole e European Olea Europaea Olea Oleaceae Lamiales

Olive (Oleales)

Herb Pla I English Plantago Plantago Plantagina- Lamiales plantain lanceolata ceae (Oleales)

Grass Ant o Sweet vernal Anthoxanthum Anthoxanthum Poaceae Poales grass odoratum

Grass Cyn d Bermuda Cynodon Cynodon Poaceae Poales grass dactylon

Grass Orchard Grass Dactylis Dactylis Poaceae Poales glomerata L.

Grass Meadow Festuca Festuca Poaceae Poales fescue pratensis

Grass Velvet Grass Holcus lanatus Holcus Poaceae Poales Grass Barley Hordeum Hordeum Poaceae Poales vulgare

Grass Lol p Rye grass Lolium Perenne Lolium Poaceae Poales

Grass Rice Oryza sativa Oryza Poaceae Poales

Grass Bahia grass Paspalum Paspalum Poaceae Poales notatum

Grass Canary Grass Phalaris Phalaris Poaceae Poales aquatica CateID Common Latin name of Genus Family Order gory Name species

Grass Phl p Timothy grass Phleum Phleum Poaceae Poales

Pratense

Grass Poa p Kentucky blue Poa pratensis Poa Poaceae Poales grass

Grass Rye Secale Cereale Secale Poaceae Poales

Grass Johnson grass Sorghum Sorghum Poaceae Poales halepense

Grass Wheat Triticum Triticum Poaceae Poales aestivum

Grass Maize Zea mays Zea Poaceae Poales

For example, conserved regions may be found in pollen of other weeds, grasses or tree species, e.g. found in one or more plant species selected from further plant families, like the plant family Chenopidiaceae including the plants Lambs quarters, Russian thistles and Kochias; plant family Amaranthaceae including Pigweeds, plant family Polygonaceae including for example Sheep sorrel, plant family Ulmacea including for example American Elm and Hackberry, plant family Plantanaceae including for example Sycamore, plant family Salicaceae including for example White poplar and Cottonwood, plant family Aceraceae including for example Box elder and Red maple, plant family Cupressaceae including for example Common juniper and Cedar.

Non-limiting examples of species of the genus Ambrosia is Ambrosia artemisiifolia, Ambrosia psilostachya, Ambrosia trifida; a typical species of the genus Artemisia is Artemisia vulgaris; non-limiting examples of species of the genus Betula is Betula verrucosa; non-limiting examples of species of the genus Fagus is Fagus grandifolia or Fagus sylvatica; non-limiting examples of species of the genus Quercus is Quercus alba, non-limiting examples of species of the genus Fraxinus is Fraxinus excelsior; a typical species of the genus Olea is Olea Europaea, a typical species of the genus plantago is Plantago lanceolata, a typical species of the genus plantago is Plantago lanceolata, non- limiting examples of species of the genus Anthoxanthum is Anthoxanthum odoratum, non-limiting examples of species of the genus Conydon is Conydon dactylon, non-limiting examples of species of the genus Lollium is Lollium perenne, non-limiting examples of species of the genus Phleum is Phleum pratense, non-limiting examples of species of the genus Poa is Poa pratensis.

In particular embodiments, a molecule of the invention may modulate an immune response at least triggered by a grass pollen and/or a weed pollen by administering to a subject in need thereof a molecule comprising a GWT conserved sequence set out in Tables 3 or 4 or a subsequence thereof or by administering to a subject in need thereof a molecule comprising a GW conserved sequence set out in Tables 5 or 6 or a

subsequence thereof. In still other particular embodiments the molecule may modulate an immune response triggered by at least a grass pollen and/or a tree pollen by

administering to a subject in need thereof a molecule comprising a GWT conserved sequence set out in Tables 3 or 4 or a subsequence thereof or by administering to a subject in need thereof a molecule comprising a GT conserved sequence set out in Tables 7 or 8 or a subsequence thereof. In more interesting embodiments thereof, the molecule modulate an immune response triggered by at least a grass pollen, a weed pollen and a tree pollen by administering to a subject in need thereof a molecule comprising a GWT conserved sequence set out in Tables 3 or 4 or a subsequence thereof.

As mentioned, a molecule of the invention may modulate, e.g. relieve, an immune response triggered by pollen. Pollen may comprise allergens considered as major and minor allergens according to official guidelines in the art and may in addition comprise additional immunogens, for example a molecule as disclosed herein. A molecule of the invention may be able to relieve an immune response triggered by a major and/or a minor pollen allergen and/or a molecule disclosed herein including the molecule itself.

Molecules (e.g. immunogens) eligible for relieving an immune response triggered by an allergen (e.g. a major allergen or minor allergen) unrelated to the molecule is thought, at least in part, to be mediated via induction of bystander tolerance, which mechanism requires, at least in part, co-existence of the triggering allergen and the unrelated molecule at the target organ for the immune response. The co-existence may inherently be obtained by using molecules present in the same pollen source as the allergen. It is also considered that, in an optimal setting, the triggering allergen and the unrelated molecule may be released from the same pollen source within an overlapping period of time (co-release of triggering allergen and unrelated molecule (e,g. immunogenic molecule)) to ensure co-existence at the target organ. Co-release can be examined in vitro using hydrated pollen as described in Example 4 herein.

Therefore, in some embodiments, the polypeptide of option a), b), c) or d) may be derived, be a part of or comprise a wild type polypeptide that co-releases/co-elutes from the same pollen source with the major or minor allergens the subject is sensitized to and to which allergens the immune response is sought to be relieved. Thus, a molecule with the potential to relieve an immune response triggered by pollen of several different species, genera and families may be identified by investigating the presence of the molecule or a fragment thereof in pollen diffusates of pollen of different species, genera or families including the grass pollen, weed pollen or tree pollen species used for the present investigation within a time period overlapping with the relevant major and/or minor allergen.

In the present context, the term "co-release" or "co-elute" may refer to when a molecule starts to release from pollen, e.g. hydrated pollen, within a period overlapping with a major allergen to which the allergic immune response is sought to be relieved. Major allergens start to release from pollen within few minutes after hydration of pollen and continue to be released within the next 30 or 60 minutes. Thus, the term "co-release" or "co-elute" may refer to when a molecule of the invention starts to release from pollen together with a major allergen, usually within 30 minutes after hydration of the pollen. Co- release/co-elution may be determined by a method comprising extracting pollen in an aqueous solution having pH in the range of 6-8 for a period ranging from 1 to 200 minutes, optionally the aqueous solution comprises at least 60% of water, a buffering agent; a tonicity providing agent. For example, the aqueous solution has an ionic strength corresponding to that of isotonic saline (0.9 g of NaCI in 1 liter of water), e.g. the aqueous solution has an ionic strength in the range of 10 mM to 1000 mM and optionally the aqueous solution has a pH of about 7. Typically, the period of extraction is in the range of 1-180, 1-120 minutes, 5-120 minutes, 5 to 90 minutes, for example 5-60 minutes, for example 5-45 minutes, for example 5-30 minutes. For example some immunogenic molecules may be released from various distinct pollen species, such as from grass pollen species as well as weed and/or tree pollen species.

For example, a polypeptide of option a), option b), option c) or option d), as described herein, may be derived from a wild type polypeptide that co-releases with a major allergen from grass pollen (e.g. pollen of the genera Phleum and or Cynodon) and from a weed pollen (e.g. pollen of the genera Ambrosia) and from tree pollen (e.g. pollen of the genera Quercus or Betula).

For example, it was found that some of the immunogens disclosed herein can be released from grass pollen and weed pollen as well as tree pollen, which polypeptides are herein named "GWT polypeptides", such as the set of polypeptides referred to with polypeptide ID NOs: A0349, A0246, A0209, A0211 , A0325, A0357 and A0203. As shown in Table 11a, these polypeptides have predicted HLA Class II allele binding sites in their conserved part of their sequence, thereby indicating the polypeptides potentially comprises a T cell epitope in their conserved region.

By the present analysis, it was also found that polypeptide A0262 (herein named GT polypeptide) was released from both grass and tree pollen, but not from weed pollen. It was also found that the set of polypeptides having the polypeptide ID NOs A0362,

A0316, A0356, A0376, A0336, A0377 and A0366 could be released from grass as well as weed pollen, but not the tree pollen investigated (herein named GW polypeptides).

Accordingly, in specific embodiments, the molecule (e.g. the immunogenic molecule) comprises a conserved region or a subsequence thereof of the "GWT polypeptide" A0349, such as a molecule comprising, consisting of or consisting essentially of a) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 270-274 set out in Table 3 and SEQ ID NOS: 617-676 set out in Table 4; or b) a polypeptide comprising an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 270-274 set out in Table 3 and SEQ ID NOS: 617-676 set out in Table 4; or c) a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2 mismatches to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 270-274 set out in Table 3 and

SEQ ID NOS: 617-676 set out in Table 4; or d) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 27-30 set out in Table 1 and SEQ ID NOS: 161-172 set out in Table 2. In still specific embodiments, the molecule comprises a conserved region or a

subsequence thereof of the "GWT polypeptide" A0246, such as a molecule comprising, consisting of or consisting essentially of a) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 233 set out in Table 3 and SEQ ID NOS: 414-418 set out in Table 4; or b) a polypeptide comprising an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 233 set out in Table 3 and SEQ ID NOS: 414-418 set out in Table 4; or c) a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2 mismatches to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 233 set out in Table 3 and SEQ ID NOS: 414-418 set out in Table 4; or d) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 12 set out in Table 1 and SEQ ID NOS: 77-81 set out in Table 2.

In still specific embodiments, the molecule comprises a conserved region or a

subsequence thereof of the "GWT polypeptide" A0209, such as a molecule comprising, consisting of or consisting essentially of a) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 217-220 set out in Table 3 and SEQ ID NOS: 321-344 set out in Table 4; or b) a polypeptide comprising an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any of SEQ ID NOS: SEQ ID NOS: 217-220 set out in Table 3 and SEQ ID NOS: 321-344 set out in Table 4; or c) a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2 mismatches to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 217-220 set out in Table 3 and SEQ ID NOS: 321-344 set out in Table 4; or d) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 4,5 set out in Table 1 and SEQ ID NOS: 49-54 set out in Table 2.

In still specific embodiments, the molecule comprises a conserved region or a

subsequence thereof of the "GWT polypeptide" A0211 , such as a molecule comprising, consisting of or consisting essentially of a) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 221-225 set out in Table 3 and SEQ ID NOS: 345-386 set out in Table 4; or b) a polypeptide comprising an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 221-225 set out in Table 3 and SEQ ID NOS: 345-386 set out in Table 4; or c) a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2 mismatches to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 221-225 set out in Table 3 and

SEQ ID NOS: 345-386 set out in Table 4; or d) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS:6-8 set out in Table 1 and SEQ ID NOS: 55-63 set out in Table 2. In still specific embodiments, the molecule comprises a conserved region or a

subsequence thereof of the "GWT polypeptide" A0325, such as a molecule comprising, consisting of or consisting essentially of a) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS:256 set out in Table 3 and SEQ ID NOS: 541-547 set out in Table 4; or b) a polypeptide comprising an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS:256 set out in Table 3 and SEQ ID NOS: 541-547 set out in Table 4; or c) a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2 mismatches to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS:256 set out in Table 3 and SEQ ID NOS: 541-547 set out in Table 4; or d) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 22 set out in Table 1 and SEQ ID NOS: 132-138 set out in Table 2. In still specific embodiments, the molecule comprises a conserved region or a

subsequence thereof of the "GWT polypeptide" A0357, such as a molecule comprising or consisting of a) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 280-281 set out in Table 3 and SEQ ID NOS: 701-709 set out in Table 4; or b) a polypeptide comprising an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 280-281 set out in Table 3 and SEQ ID NOS: 701-709 set out in Table 4; or c) a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2 mismatches to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 280-281 set out in Table 3 and SEQ ID NOS: 701-709 set out in Table 4; or d) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 32 set out in Table 1 and SEQ ID NOS: 179-183 set out in Table 2.

In still specific embodiments, the molecule comprises a conserved region or a

subsequence thereof of the "GWT polypeptide" A0203, such as a molecule comprising, consisting of or consisting essentially of a) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 215, 216 set out in Table 3 and SEQ ID NOS: 309-320 set out in Table 4; or b) a polypeptide comprising an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 215, 216 set out in Table 3 and SEQ ID NOS: 309-320 set out in Table 4; or c) a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2 mismatches to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 215, 216 set out in Table 3 and SEQ ID NOS: 309-320 set out in Table 4; or d) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 2, 3 set out in Table 1 and SEQ ID NOS: 43-48 set out in Table 2.

In some embodiments, a molecule of the present invention is an IgE reactive molecule, e.g. able to bind to IgE antibodies specific for the immunogenic molecule. However, IgE reactivity towards a molecule of the invention may only be conferred by a low fraction of an allergic population. Thus, a molecule of the invention may not fall under the usual definitions of a major allergen, which is an allergen with high prevalence in a population of donors allergic to a pollen species, for example the prevalence may be higher than at least 50%. In some embodiments, the molecule is able to react with, bind to or induce IgG antibodies in a subject, at least in detectable levels. In still other embodiments, the molecule does not react with, bind to or induce IgG antibodies, at least in detectable levels. As demonstrated herein, a molecule of the invention seems to be less

immunogenic than the major allergen Phi p 5 (Figure 2), but still able to induce bystander tolerance (i.e. reducing an immune response) towards an unrelated molecule, such as Phi p 5 allergen (Figure 4).

As disclosed herein, polypeptides containing GWT, GT, GW or WT conserved regions can be detected in various pollen species and families and share high identity and similarity across the various pollen species. Therefore, a polypeptide of option d) comprises an amino acid sequence having at least 70%, such as at least 75%, 80%,

85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% similarity or identity to a sequence selected from any one of SEQ ID NOS: 1-37 (e.g. SEQ ID NOS: 30, 1-29, 31- 37) set out in Table 1 and SEQ ID NOS: 38-211 (eg. SEQ ID NOS: 161-172, 38-160 and 173-211) set out in Table 2. Accordingly, a polypeptide of option a) comprises an amino acid sequence having at least 70% such as at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% similarity or identity to a sequence selected from any one of SEQ ID NOS: 212- 293 (e.g. SEQ ID NOS: 270-274; 212-269; 275-293) set out in Table 3; SEQ ID NOS: 294-767 (e.g. SEQ ID NOS: 617-676, 294-616 and 677-767) set out in Table 4; SEQ ID NOS: 768-808 set out in Table 5; SEQ ID NOS: 809-951 set out in Table 6; SEQ ID NOS: 952-1023 set out in Table 7; SEQ ID NOS: 1024-1231 set out in Table 8 and SEQ ID NOS: 1232-1473 set out in Table 9.

Accordingly, a polypeptide of option b) comprises an amino acid sequence having at least 70%, such as at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 212-293 (e.g. SEQ ID NOS: 270-274; 212-269; 275-293 set out in Table 3; SEQ ID NOS: 294-767 (e.g. SEQ ID NOS: 617-676, 294-616 and 665-676, 617-664, 294-616, 677-767) set out in Table 4; SEQ ID NOS: 768-808 set out in Table 5; SEQ ID NOS: 809-951 set out in Table 6; SEQ ID NOS: 952-1023 set out in Table 7; SEQ ID NOS: 1024-1231 set out in Table 8 and SEQ ID NOS: 1232-1473 set out in Table 9. Optionally, the at least 70%, such as at least 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% similarity or identity is of a subsequence consisting of at least 16 contiguous amino acid residues, for example at least 17, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90, 100 or more contiguous amino acids. A subsequence may comprise any number of amino acids, but typically the subsequence has a length of 15 to 50 amino acid residues, for example 15 to 45, 15 to 40, 15 to 35, 15 to 30; 15 to 25; 15 to 20; 15 to 19; 15 to 18; 15 to 17, or 15 to 16 amino acid residues. As shown herein, there is established evidence that an amino acid sequences having less than 3 mismatches to a T cell epitope containing amino acid sequence may be

recognized by the same T cell population. Therefore, in some embodiments, the number of amino acid mismatches may be 0, 1 , 2, or 3, preferably 0, 1 or 2, more preferably 0 or 1. In some embodiments, the polypeptide of option b) or option c) has a length of 15-800 or more amino acid residues, for example 15-750, 15-700, 15-650 or 15-600 or more amino acid residues, for example 15-20, 20-25, 25-30, 30-35, 35-40, 45-50, 50-60, 60-70, 70-80, 90-100, 100-125, 125-150, 150-175, 175-200, 200-250, 250-300, 300-350, 350-400, 400- 450, 450-500, 500-550, 550-600, 600-650, 650-700, 700-800 or more amino acid residues. The polypeptide of option a) or of option d) has a length of no more than 800 amino acid residues, for example no more than 750, 700, 650, 600, 550, 500, 450, 400, 350 or 300 amino acid residues.

As mentioned, a polypeptide disclosed herein including a subsequence thereof may contain a T cell epitope, such as a Th2 cell epitope. A subsequence or a polypeptide described herein may have HLA Class II binding properties. HLA Class II binding can be predicted using NetMHCIIpan-3.0 tool (Karosiene, Edita, Michael Rasmussen, Thomas Blicher, Ole Lund, S0ren Buus, and Morten Nielsen. "NetMHCIIpan-3.0, a Common Pan- specific MHC Class II Prediction Method Including All Three Human MHC Class II Isotypes, HLA-DR, HLA-DP and HLA-DQ." Immunogenetics) available at the internet site <URL: http://www.cbs. dtu.dk/services/NetMHCIIpan-3.0>. A polypeptide of option b) or c) may have different lengths according to the desirable use, for example of about 15-800 or more amino acid residues in length, for example 15-750, 15-700, 15-650, 15-600, 15-500 or more amino acid residues, for example 15-20, 15-25, 15-30, 20-25, 25-30, 30-35, 35-40, 45-50, 50-60, 60-70, 70-80, 90-100, 100-125, 125- 150, 150-175, 175-200, 200-250, 250-300, 300-350, 350-400, 400-450, 450-500, 500- 550, 550-600, 600-650, 650-700, 700-800 or more amino acid residues. One may consider utilizing short linear peptides, which when administered to a subject need not to be processed by an antigen presenting cells to interact with a relevant T cell receptor, but rather be freely loaded onto a MHC class II molecule to interact with the relevant T cell receptor. Thus, in some embodiments, a polypeptide of option b) or a polypeptide of option c) has a length in the range of 15 to 30 amino acid residues, for example 15 to 25 amino acid residues. In other embodiments, a polypeptide of option a), b), c) or d) is a longer polypeptide which comprises a secondary or tertiary structure, e.g. folded. Thus, in some embodiments, a polypeptide of option a), b), c) or d) has a length in the range of 30 to 500 amino acid residues or more. It is considered that the length of the amino acid sequence of a polypeptide of option a), b), c) or d) is no more than 800 amino acid residues, for example no more than 750, 700, 650, 600, 550, 500 or 450 amino acid residues.

The term "identity" and "identical" and grammatical variations thereof, as used herein, mean that two or more referenced entities are the same (e.g. two or more amino acid sequences). Thus, where two polypeptides are identical, they have the same amino acid sequence. The identity can be over a defined area (region or domain) of the sequence, e.g. over the sequence length of a sequence disclosed in Tables 1 to 9 or over a portion thereof e.g. at least 15 contiguous amino acid residues. Moreover, the identity can be over the length of the sequence overlapping the two polypeptides, when aligned with best fit with gaps permitted.

For example, to determine whether a polypeptide has at least 65% similarity or identity to a sequence set out in Tables 1 to 9, the polypeptide may be aligned with a sequence of Tables 1 to 9 and the percent identity be calculated with reference to said sequence. Identity can be determined by comparing each position in aligned sequences. A degree of identity between amino acid sequences is a function of the number of identical or matching amino acids at positions shared by the sequences, i.e. over a specified region. Optimal alignment of sequences for comparisons of identity may be conducted using a variety of algorithms, as are known in the art, including the Clustal Omega program available at http://www.ebi.ac.uk/Tools/msa/clustalo/, the local homology algorithm of Smith and Waterman, 1981 , Adv. Appl. Math 2: 482, the homology alignment algorithm of Needleman and Wunsch, 1970, J. Mol. Biol. 48:443, the search for similarity method of Pearson and Lipman, 1988, Proc. Natl. Acad. Sci. USA 85: 2444, and the computerized implementations of these algorithms (such as GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, Madison, Wl, U.S.A.). Sequence identity may also be determined using the BLAST algorithm, described in Altschul et al., 1990, J. Mol. Biol. 215:403-10 (using the published default settings).

Software for performing BLAST analysis may be available through the National Center for Biotechnology Information (through the internet at http://www.ncbi.nlm.nih.gov/). Such algorithms that calculate percent sequence identity (homology) generally account for sequence gaps and mismatches over the comparison region or area. For example, a BLAST (e.g., BLAST 2.0) search algorithm (see, e.g., Altschul et al., J. Mol. Biol. 215:403 (1990), publicly available through NCBI) has exemplary search parameters as follows: Mismatch -2; gap open 5; gap extension 2. For polypeptide sequence comparisons, a BLASTP algorithm is typically used in combination with a scoring matrix, such as

PAM100, PAM 250, BLOSUM 62 or BLOSUM 50. FASTA (e.g., FASTA2 and FASTA3) and SSEARCH sequence comparison programs are also used to quantitate the extent of identity (Pearson et al., Proc. Natl. Acad. Sci. USA 85:2444 (1988); Pearson, Methods Mol Biol. 132: 185 (2000); and Smith et al., J. Mol. Biol. 147:195 (1981)). Programs for quantitating protein structural similarity using Delaunay-based topological mapping have also been developed (Bostick et al., Biochem Biophys Res Commun. 304:320 (2003)).

A polypeptide sequence is a "homolog" of, or is "homologous" to, another sequence if the two sequences have substantial identity over a specified region and a functional activity of the sequences is preserved or conserved, at least in part. (As used herein, the term 'homologous' does not infer nor exclude evolutionary relatedness).

Examples of "homologous polypeptides" of the invention include polypeptides with high similarity or identity to Phi P polypeptides and detected in pollen species other than Phi p. For example, a homologous polypeptide to a polypeptide having an amino acid sequence set out in Table 1 or Table 2 may be found in pollen of plant families selected among Asteraceae, Betulaceae, Fagaceae, Oleaceae, or Plantaginaceae, e.g. the plant genera Ambrosia, Artemisia, Helianthus, Alnus, Betula, Carpinus, Castanea, Corylus, Ostrya, Ostryopsis, Fagus, Quercus, Fraxinus, Ligustrum, Lilac, Olea or Plantago.

Two polypeptide sequences are considered to be substantially identical if, when optimally aligned (with gaps permitted), they share at least about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, etc. identify over a specific region), for example, over all or a part of any amino acid sequence in Tables 1 to 9, or if the sequences share defined functional motifs (e.g., epitopes). In particular aspects, the length of the sequence sharing the percent identity is at least 15, 16, 17, 18, 19, 20, etc. contiguous amino acids, e.g. more than 25, 30, 35, 40, 45 or 50 or more contiguous amino acids, including the entire length of a reference sequence of Tables 1 to 9.

An "unrelated" or "non-homologous" sequence is considered to share less than 30% identity. More particularly, it may share less than about 25 % identity, with a polypeptide of the invention over a specified region of homology.

An amino acid sequence set out in any of Tables 1 to 9 may contain one or more modifications, which optionally may result in greater or less activity or function, for example in the ability to elicit, stimulate, induce, reduce, inhibit, suppress an in vitro immune response (e.g. T cell proliferation or T cell cytokine production); in the ability to bind HLA Class II alleles; in the ability to induce or enhance immunological

tolerance(desensitize) to a relevant pollen allergen or a molecule disclosed herein; or in the ability to dissolve in solvents e.g. in an aqueous solution.

A modification includes deletions, including truncations and fragments; insertions and additions, substitutions, for example conservative substitutions, site-directed mutants and allelic variants.

Non-limiting examples of modifications include one or more amino acid substitutions (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20-25, 25-30, 30-50, 50-100 or more residues), additions and insertions (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or more residues) and deletions (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20-25, 25-30, 30-50, 50-100 or more) of a sequence set out in Tables 1 , 2, 3 and 4. The term "similarity" and "similar" and grammatical variations thereof, as used herein, mean that two or more referenced amino acid sequences contains a limited number of conservative amino acid substitutions of the amino acid sequence. A variety of criteria can be used to indicate whether amino acids at a particular position in a polypeptide are similar. In making such changes, substitutions of like amino acid residues can be made on the basis of relative similarity of side-chain substituents, for example, their size, charge, hydrophobicity, hydrophilicity, and the like, and such substitutions may be assayed for their effect on the function of the peptide by routine testing. A "conservative substitution" is the replacement of one amino acid by a biologically, chemically or structurally similar residue. Biologically similar means that the substitution does not destroy a biological activity. Structurally similar means that the amino acids have side chains with similar length, such as alanine, glycine and serine, or a similar size. Chemical similarity means that the residues have the same charge, or are either hydrophilic or hydrophobic. For example, a conservative amino acid substitution is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain, which include amino acids with basic side chains (e.g., lysine, arginine, histidine); acidic side chains (e.g., aspartic acid, glutamic acid); uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, histidine); nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan); beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan). Particular examples include the substitution of one hydrophobic residue, such as isoleucine, valine, leucine or methionine for another or the substitution of one polar residue for another, such as the substitution of arginine for lysine, glutamic for aspartic acids, or glutamine for asparagine, serine for threonine, and the like. Proline, which is considered more difficult to classify, shares properties with amino acids that have aliphatic side chains (e.g., Leu, Val, lie, and Ala). In certain circumstances, substitution of glutamine for glutamic acid or asparagine for aspartic acid may be considered a similar substitution in that glutamine and asparagine are amide derivatives of glutamic acid and aspartic acid, respectively. Conservative changes can also include the substitution of a chemically derivatized moiety for a non- derivatized residue, for example, by reaction of a functional side group of an amino acid. Variants and derivatives of polypeptides include forms having a limited number of one or more substituted residues.

As mentioned, a polypeptide of option a), b), c) and d) may be longer than the reference sequence set out in Tables 1 to 9.

An addition can be one or more additional amino acid residues. For example, a polypeptide of option b) or c) may contain amino acid residues in addition to the subsequence of at least 15 amino acid residues. Optionally, the additional amino acid residues may be identical to those present in the wild type polypeptide from which the subsequence derives from. Thus, in some embodiments, the polypeptide of option b) comprises one or more amino acid residues in addition to the subsequence of at least 15 contiguous amino acids, wherein the additional amino acid residue(s) is/are selected from an amino acid residue or an amino acid sequence within the wild type polypeptide that the subsequence is a part of (e.g. wild type polypeptide sequences of Tables 1 or 2 or a GWT sequence of Tables 3 or 4). For example, the wild type amino acid residue or wild type amino acid sequence to be added may be adjacent to, subtended, comprised within, overlapping with or is a part of the subsequence, when present in its natural biological context within the wild type polypeptide.

Likewise, a polypeptide of option a) may contain additional amino acid residues in addition to the GWT sequence set out in Tables 3 and 4. Thus, a polypeptide of option a) may comprise one or more amino acid residues in addition to the GWT sequence set out in Tables 3 or 4, wherein the additional amino acid residue(s) is/are selected from an amino acid residue or an amino acid sequence within the wild type polypeptide of which the GWT sequence is a part of (e.g. a wild type polypeptide of Tables 1 or 2). An illustrative example is a GWT sequence of A0349 set out in Table 3 that may be extended with amino acid residues from polypeptide A0349 set out in Tables 1 or 2, such as amino acid residues adjacent to the GWT sequence when aligned with the corresponding wild type polypeptide.

The additional amino acid residues may be added to the N- and/or C- terminal end of a sequence set out in Tables 3 to 9, such as additional amino acids selected from amino acids flanking the N- and/or C- terminal ends when sequence is aligned with the source protein it is present in, based upon or derived from. Thus, where a sequence derives from A0349, the additional amino acids may be the amino acids flanking the N- and/or C- terminal ends of the sequence when aligned to polypeptide A0349 of Table 1 or 2.

As mentioned, a polypeptide of option a), b), c) or d) may include a number of

modifications compared to the parent amino acid sequences set out in any of Table 1 to 9, for example to increase or decrease physical or chemical properties of the parent sequence, for example to decrease its ability to resist oxidation, to improve or increase solubility in aqueous solution, to decrease aggregation, to decrease manufacturing problems, e.g. synthesis problems, etc.

Accordingly, in some embodiments of the invention, an amino acid sequence (parent sequence) disclosed in any of the Tables or a subsequence thereof may be modified to comprise: a) one or more (e.g. 1 , 2,3, 4, 5, 6, 7, 8, 9 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) amino acid substitutions in a sequence selected from any of the sequences disclosed in Tables 1 to 9, for example a glutamate residue at the N-terminus of an amino acid sequence disclosed in Tables 1 to 9 may be replaced with pyroglutamate and/or one or more cysteine residues in the an amino acid sequence disclosed in Tables 1 to 9 may be replaced with serine or 2-aminobutyric acid; and/or b) one or more amino acid additions (e.g. 1 , 2,3, 4, 5, 6, 7, 8, 9 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) to an amino acid sequence disclosed in Tables 1 to 9 or a subsequence thereof, for example the addition of one or more (e.g. 1 , 2, 3, or 4) lysine residue(s) and/or arginine residue(s) and/or positively charged residues at the N- and/or C-terminus of amino acid sequence disclosed in Tables 1 to 9 or a subsequence thereof); and/or c) one or more amino acid deletions from the amino acid sequence disclosed in Tables 1 to 9 or a subsequence thereof, for example the deletion of a hydrophobic residue in the up to three amino acids from the N- or C- terminus of said sequence; and/or of any two consecutive amino acids comprising the sequence Asp-Gly up to four amino acids from the N- or C- terminus of said sequence. In one embodiment, a polypeptide of option a), b), c) or d) including a modified

polypeptide is derivatized. Specific non-limiting examples of derivatization are covalent or non-covalent attachment of another molecule. Specific examples include glycosylation, acetylation, phosphorylation, amidation, formylation, ubiquitination, and derivatization by protecting/blocking groups and any of numerous chemical modifications. Typically, a derivative is formed by reacting a functional side group of an amino acid (e.g. amino, sulfhydryl or carboxy-group) with another molecule to form a covalent or non- covalent attachment of any type of molecule (naturally occurring or designed), such as a sugar moiety. Specific examples of derivatives of a peptide include glycosylation, acylation (e.g. acetylation), phosphorylation, amidation, formylation, ubiquitination and derivatization by protecting/blocking groups and any of numerous chemical modifications. Additional specific non-limiting examples are tagged peptides, fusion peptides, chimeric peptides including peptides having one or more non-amino acyl groups (q.v., sugar, lipid, etc.) covalently linked to the peptide. Typically, a derivative comprises one or more modifications, for example selected from any of: (a) N-terminal acylation (e.g. acetylation or formylation); (b) C-terminal amidation (e.g. reaction with ammonia or an amine); (c) one or more hydrogens on the side chain amines of arginine and/or lysine replaced with a methylene group; (d) glycosylation and/or (e) phosphorylation. In particular embodiments, a derivative comprises a fusion (chimeric) sequence of peptides, which optionally may contain an amino acid sequence having one or more molecules not normally present in a reference (wild type) sequence covalently attached to the peptide amino acid sequence. The term "chimeric" and grammatical variations thereof, when used in reference to a sequence, means that the sequence contains one or more portions that are derived from, obtained or isolated from, or based upon other physical or chemical entities.

Another particular example of a derivative is one in which a second heterologous sequence, i.e. a heterologous functional domain, is attached to a peptide disclosed herein, (covalent or non-covalent binding) that may confer a distinct or complementary function to a peptide disclosed herein. Heterologous functional domains are not restricted to amino acid residues. Thus, a heterologous functional domain can consist of any of a variety of different types of small or large functional moieties. Such moieties include nucleic acid, peptide, carbohydrate, lipid or small organic compounds, such as a drug (e.g., an antiviral), a metal (gold, silver), or a radioisotope.

Linkers, such as amino acid or peptidomimetic sequences, may be inserted between the peptide sequence and the addition (e.g., heterologous functional domain) so that the two entities maintain, at least in part, a distinct function or activity. Linkers may have one or more properties that may include a flexible conformation, an inability to form an ordered secondary structure or a hydrophobic or charged character, which could promote or interact with either domain. Amino acids typically found in flexible protein regions include Gly, Asn and Ser. Other near neutral amino acids, such as Thr and Ala, may also be used in the linker sequence.

In a particular aspect of the invention, the polypeptides of option a), b), c) or d) or a combination of such polypeptides are not provided as individual polypeptides, but may be fused together or to a carrier molecule to form an isolated molecule (e.g. immunogenic molecule). For example, the polypeptides may be fused to the N- and C-terminus of a surface polypeptide of a virus, e.g. a virus of the hepadnaviridae family as disclosed in international patent application W012168487 A1. A molecule of the invention, including a polypeptide of option a), b), c) or d), a

subsequence thereof, a modified polypeptide thereof, or a derivatized polypeptide thereof may share the same functionality or activity as the relevant parent polypeptide disclosed in Tables 1 to 9 or may have improved functionality or activity. For example, a molecule of the invention, including a polypeptide of option a), b), c) or d), a subsequence thereof, a modified polypeptide thereof, or a derivatized polypeptide thereof may bind to at least 70% of the group of Class HLA II alleles that the relevant parent polypeptide disclosed in Tables 1 to 9 binds to. Thus, in some embodiments a molecule of the invention, including a polypeptide of option a), b), c) or d), a modified polypeptide thereof, or a derivatized polypeptide binds to the same, substantially the same or at least 75%, 80%, such as at least 82%, 85%, 88%, 90%, 92%, 95%, 98% or more, of the group of HLA Class II alleles that binds to the relevant parent polypeptide disclosed in Tables 1 to 9, optionally wherein this is determined under same test conditions, either using prediction tools or in-vitro binding assay. Moreover, in some embodiments a subsequence disclosed herein, including a modified subsequence thereof, binds to the same, substantially the same or at least 75%, 80%, such as at least 82%, 85%, 88%, 90%, 92%, 95%, 98% or more, of the group of HLA Class II alleles that binds to the relevant subsequent from which the modified sequence derives, optionally wherein this is determined under same test conditions, either using prediction tools or in-vitro binding assay. Optionally, the Class HLA II binding is determined with respect to a particular group of Class HLA II alleles, for example one or more or all of the following alleles: DPA1*02:01-DPB1^*01 :01 ,

DPA1*01 :03-DPB1*02:01 , DPA1*01 :03-DPB1*03:01 , DPA1*01 :03-DPB1*04:01 ,

DPA1*01 :03-DPB1*04:02, DPA1*02:02-DPB1*05:01 , DPA1*02:01-DPB1*14:01 ,

DQA1*05:01-DQB1^*02:01 , DQA1*05:01-DQB1*03:01 , DQA1^*03:01-DQB1*03:02, DQA1*04:01-DQB1*04:02, DQA1*01 :01-DQB1^*05:01 , DQA1*01 :02-DQB1*06:02, DRB1*01 :01 , DRB1^*03:01 , DRB1^*04:01 , DRB1*04:05, DRB1*07:01 , DRB1^*09:01 , DRB1*11 :01 , DRB1^*12:01 , DRB1*13:02, DRB1*15:01 , DRB3^*01 :01 , DRB3^*02:02, DRB4*01 :01 and DRB5*01 :01 , or the alleles disclosed in Tables 11 b or 11 c. Assays for measuring Class HLA II binding in vitro is well known in the art, e.g. as described herein in Example 5.

Furthermore, a polypeptide of option a), b), c) or d), including a modified or derivatized polypeptide thereof may have one or more of the same T cell epitopes or T cell activity (e.g. percent responders) as the amino acid sequence from which it derives (e.g. an amino acid sequence set out in Tables 1 to 9. This may be determined by the ability to induce or stimulate in vitro T cell proliferation using cultured PBMCs (peripheral blood monocytes) in response to the polypeptide of option a), b), c) or d), including a modified or derivatized polypeptide compared to the amino acid sequence set out in Tables 1 to 9, optionally using same test conditions, or by the ability to induce or stimulate production of cytokines, (e.g. cytokines, IL-5, IL-13 and/or IL-10) from T cells (obtained from cultured PBMC's) in response to the polypeptide of option a), b), c) or d), including a modified or derivatized polypeptide compared to the amino acid sequence set out in Tables 1 to 9. Examples of T cell assays are described herein in Example 6.

In particular embodiments, a derivative is a fusion (chimeric) sequence, an amino acid sequence having one or more molecules not normally present in the wild type sequence covalently attached to the sequence. The term "chimeric" and grammatical variations thereof, when used in reference to a sequence, means that the sequence contains one or more portions that are derived from, obtained or isolated from, or based upon other physical or chemical entities. For example, a chimera of two or more different

polypeptides may have one part of a polypeptide, and a second part of the chimera may be from a different sequence, or unrelated protein sequence.

Another particular example of a derivatized polypeptide is one in which a second heterologous sequence, i.e., heterologous functional domain is attached (covalent or non- covalent binding) that confers a distinct or complementary function. Heterologous functional domains are not restricted to amino acid residues. Thus, a heterologous functional domain can consist of any of a variety of different types of small or large functional moieties. Such moieties include nucleic acid, peptide, carbohydrate, lipid or small organic compounds, such as a drug (e.g., an antiviral), a metal (gold, silver), and radioisotope. For example, a tag such as T7 or polyhistidine can be attached in order to facilitate purification or detection of a protein, peptide, etc. For example, a 6-HIS tag may be added to the C- or N-terminal end of a polypeptide of option a), b), c) or d), e.g. the 6- HIS sequence GHHHHHHGSGMLDI, which optionally may remain in the molecule when administered to a subject. Thus, a polypeptide linked to a Tag containing histidines may easily be purified by use of a HIS tag affinity column).

Accordingly, there are provided polypeptides linked to a heterologous domain, wherein the heterologous functional domain confers a distinct function on the polypeptide.

In some embodiments, the polypeptide is derivatized for example to improve solubility, stability, bioavailability or biological activity. For example, tagged polypeptides and fusion proteins; and modifications, including peptides having one or more non-amino acyl groups (q.v., sugar, lipid, etc.) covalently linked to the polypeptide and post-translational modifications.

Linkers, such as amino acid or peptidomimetic sequences may be inserted between the sequence and the addition (e.g., heterologous functional domain) so that the two entities maintain, at least in part, a distinct function or activity. Linkers may have one or more properties that include a flexible conformation, an inability to form an ordered secondary structure or a hydrophobic or charged character, which could promote or interact with either domain. Amino acids typically found in flexible protein regions include Gly, Asn and Ser. Other near neutral amino acids, such as Thr and Ala, may also be used in the linker sequence. The length of the linker sequence may vary without significantly affecting a function or activity of the fusion protein (see, e.g., U.S. Patent No. 6,087,329). Linkers further include chemical moieties and conjugating agents, such as sulfo-succinimidyl derivatives (sulfo-SMCC, sulfo-SMPB), disuccinimidyl suberate (DSS), disuccinimidyl glutarate (DSG) and disuccinimidyl tartrate (DST). Further non-limiting examples of derivatives are detectable labels. Thus, in another embodiment, the invention provides polypeptides that are detectably labeled. Specific examples of detectable labels include fluorophores, chromophores, radioactive isotopes (e.g., S³⁵, P³², I¹²⁵), electron-dense reagents, enzymes, ligands and receptors. Enzymes are typically detected by their activity. For example, horseradish peroxidase is usually detected by its ability to convert a substrate such as 3,3-',5,5-'-tetramethylbenzidine (TMB) to a blue pigment, which can be quantified.

Modified polypeptides also include one or more D-amino acids substituted for L-amino acids (and mixtures thereof), structural and functional analogues, for example, peptidomimetics having synthetic or non-natural amino acids or amino acid analogues and derivatized forms. Modifications include cyclic structures such as an end-to-end amide bond between the amino and carboxy-terminus of the molecule or intra- or inter- molecular disulfide bond.

Polypeptides may be provided in the form of a salt, for example as a pharmaceutically acceptable and/or a physiologically acceptable salt. For example, the salt may be an acid addition salt with an inorganic acid, an acid addition salt with an organic acid, a salt with a basic inorganic acid, a salt with a basic organic acid, a salt with an acidic or basic amino acid or a mixture thereof. In particular embodiments of the invention a salt, such as a pharmaceutically acceptable salt, is an acetate salt.

The invention provides polypeptides and molecules in isolated and/or purified form. The term "isolated," when used as a modifier of a composition, means that the compositions are made by the hand of man or are separated, completely or at least in part, from their naturally occurring in vivo environment. Generally, isolated compositions are substantially free of one or more materials with which they normally associate with in nature, for example, one or more protein, nucleic acid, lipid, carbohydrate, cell membrane. The term "isolated" does not exclude alternative physical forms of the composition, such as fusions/chimeras, multimers/oligomers, modifications (e.g., phosphorylation, glycosylation, lipidation) or derivatized forms, or forms expressed in host cells produced by the hand of man.

An "isolated" composition (e.g. polypeptides or molecules as defined herein) can also be "substantially pure" or "purified" when free of most or all of the materials with which it typically associates with in nature. Thus, an isolated polypeptide that also is substantially pure or purified does not include polypeptides or polynucleotides present among millions of other sequences, such as polypeptide of a peptide library or nucleic acids in a genomic or cDNA library, for example.

A "substantially pure" or "purified" composition can be combined with one or more other molecules. Thus, "substantially pure" or "purified" does not exclude combinations of compositions, such as combinations of polypeptides other antigens, agents, drugs or therapies.

Polypeptides can be prepared recombinant, chemically synthesized, isolated from a biological material or source, and optionally modified, or any combination thereof. A biological material or source would include an organism that produced or possessed any polypeptide or molecule set forth herein. A biological material or source may further refer to a preparation in which the morphological integrity or physical state has been altered, modified or disrupted, for example, by dissection, dissociation, solubilization,

fractionation, homogenization, biochemical or chemical extraction, pulverization, lyophilization, sonication or any other means of manipulating or processing a biological source or material. As mentioned, polypeptides, such as a molecule (e.g. immunogenic molecules) disclosed herein, may be modified by substituting, deleting or adding one or more amino acid residues in the amino acid sequence and screening for biological activity, for example eliciting an immune response. A skilled person will understand how to make such derivatives or variants, using standard molecular biology techniques and methods, described for example in Sambrook et al. (2001) Molecular Cloning: a Laboratory Manual, 3^rd ed., Cold Spring Harbour Laboratory Press).

Molecules and polypeptides disclosed herein, including a modified polypeptide thereof, a derivatized polypeptide thereof, or salts thereof may be manufactured synthetically or recombinantly. Thus, in certain embodiments, the molecule, including a polypeptide of option a), b), c), d) or a subsequence thereof is synthetic. The molecule, including a polypeptide of option a), b), c), d) or a subsequence thereof may be isolated and/or purified, e.g. made by the hand of man, such as by synthesis. Typically, the polypeptides may be combined after synthesis and freeze-dried or dissolved in aqueous solutions, DMSO, glycerol or the like or mixtures thereof.

Molecules (e.g. immunogenic molecules) disclosed herein can be employed in various therapeutic or diagnostic methods and uses. Such methods and uses include, for example, administration in vitro and in vivo of one or more molecules disclosed herein. The methods and uses may include modulating an immune response (e.g. modulating an allergic immune response), including, among others, methods and uses for relieving an immune response (e.g. allergic immune response), protecting and treating subjects against a disorder, disease (e.g. allergic disease); and methods and uses of providing immunotherapy, such as specific immunotherapy against an immune response, e.g. an immune response triggered by an allergen (e.g. a pollen, such as a pollen allergen) and/or a molecule disclosed herein.

In particular embodiments, methods and uses include administration or delivery of a molecule disclosed herein to modulate an immune response in a subject, including, for example, modulating an immune response triggered by an allergen (e.g. triggered by pollen, such as a pollen allergen) and/or a molecule disclosed herein.

As used herein, the term "modulate," means an alteration or effect on the term modified. In certain embodiments, modulating involves decreasing, reducing, inhibiting, suppressing, relieving an immune response in a subject triggered by an allergen (e.g. triggered by pollen, such as a pollen allergen) and/or a molecule disclosed herein. In other embodiments, modulating involves eliciting, stimulating, inducing, promoting, increasing or enhancing an immune response in a subject triggered by an allergen (e.g. triggered by pollen, such as a pollen allergen) and/or a molecule disclosed herein. Thus, where the term "modulate" is used to modify the term "immune response triggered by an allergen (e.g. triggered by pollen, such as a pollen allergen) and/or a molecule disclosed herein in a subject" this means that the immune response in the subject to the allergen, pollen, pollen allergen or molecule is altered or affected (e.g., decreased, reduced, inhibited, suppressed, limited, controlled, prevented, elicited, promoted, stimulated, increased, induced, enhanced, etc. Methods and uses of modulating an immune response triggered by an allergen (e.g. pollen, such as a pollen allergen) and/or a molecule disclosed herein may be used to provide a subject with protection against an immune response or immune reaction to said allergen, pollen, pollen allergen and/or molecule (e.g. immunogenic molecule) disclosed herein, or symptoms or complications caused by or associated with the allergen (e.g. pollen, such as a pollen allergen) and/or a molecule disclosed herein. Accordingly, in other embodiments, methods and uses include administering a molecule (e.g.

immunogenic molecule) of the invention to protect or treat a subject against an immune response, or one or more symptoms caused by, triggered by or associated with exposure to an allergen (e.g. pollen, such as a pollen allergen) or a molecule disclosed herein.

Therefore, in still other aspects, the subject's administration of a therapeutically effective amount of a composition described herein may relieve one or more symptoms of the immune response. For example, the method may comprise relieving one or more symptoms associated with allergic rhinitis, allergic conjunctivitis, allergic asthma and/or allergic eczema (e.g. atopic dermatitis).

In some embodiments, the one or more symptoms may be associated with allergic rhinitis. For example, the method may comprise reducing one or more of the following symptoms: intensity of itchy nose; number of sneezes within a given period (e.g. daily, weekly, monthly); intensity of blocked nose (e.g. congestion); amount of nasal secretions; eosinophilic count in nasal secretions; specific IgE antibody level (titer) in nasal secretions or in serum; and basophil histamine release of blood.

In other embodiments, the one or more symptoms may be associated with allergic conjunctivitis. For example, the method may comprise reducing one or more of the following: intensity of itchy eyes, redness in the white of the eyes and/or watery eyes; eosinophilic count in conjunctival tissue scrapings; specific IgE antibody level (titer) in conjunctival tissue scrapings or in serum; and basophil histamine release in blood.

In some embodiments, the one or more symptoms may be associated with allergic asthma. For example, the method may comprise reducing one or more of the following: number of or frequency of asthma exacerbations (optionally that require hospitalization), intensity and/or number of coughs within a given period (e.g. daily, weekly, monthly); intensity of wheezes; intensity of shortness of breath or congestion (e.g. improvement of being short of breath); reducing Forced Expiratory Volume (FEV1); reducing specific IgE antibody level (titer) in lung fluid or in serum and basophil histamine release in blood; or the method may comprise improving lung function. In some embodiments, the one or more symptoms may be symptoms associated with atopic dermatitis. For example, the method may comprise reducing one or more of the following: itch intensity of the skin; eczema score, and number of (peripheral) blood eosinophils. A therapeutic or beneficial effect also includes reducing or eliminating the need, dosage frequency or amount of a second therapeutic method or therapeutically active drug (e.g. anti-inflammatory, decongestants or anti-allergic agent) used for treating a subject having an immune response or one or more symptoms caused by or associated with an allergen. For example, administration of a peptide combination described herein may reduce the amount of an adjunct therapy administered to a subject, such as reducing the subject's need for concomitant treatment with fast or long-acting p2-agonists, leukotriene modifiers, theophylline corticosteroids or H1 antihistamines (e.g. inhaled or oral) to reduce, relieve, or suppress one or more symptoms of the immune response.

In still other embodiments, methods and uses include administering or delivering a molecule (e.g. an immunogenic molecule) of the invention to elicit, stimulate, induce, promote, increase or enhance immunological tolerance of a subject an allergen (e.g. pollen, such as a pollen allergen) or a molecule disclosed herein.

In various embodiments, there are provided methods and uses of providing a subject with protection against an immune response, or one or more symptoms caused by or associated with exposure to an allergen (e.g. pollen, such as a pollen allergen) or an immunogenic molecule disclosed herein. In various aspects, a method or use includes administering to the subject an amount of an immunogenic molecule of the invention sufficient to provide the subject with protection against an immune response, or symptoms caused by or associated with exposure to an allergen (e.g. pollen, such as a pollen allergen) or a molecule disclosed herein.

Methods and uses of the invention include providing a subject with protection against an allergen (e.g. pollen, such as a pollen allergen) and/or a molecule disclosed herein, or symptoms caused by or associated with the subject's exposure to said allergen (e.g. pollen, such as pollen allergen) and/or a molecule disclosed herein, for example, vaccinating the subject to protect against an immune response to said allergen (e.g.

pollen, such as pollen allergen) and/or a molecule, for example with an immunogenic molecule provided herein. In certain embodiments, methods and uses include protecting the subject against an immune response triggered by pollen, e.g. a pollen allergen or a molecule disclosed herein by inducing tolerance of the subject (desensitizing) to said allergen, pollen, pollen allergen and/or immunogenic molecule.

As used herein, the terms "protection," "protect" and grammatical variations thereof, when used in reference to an immune response or symptoms caused by or associated with the exposure to an allergen (e.g. pollen, such as a pollen allergen) and/or an immunogenic molecule disclosed herein, means preventing an immune response or symptoms caused by or associated with the exposure to the allergen, pollen, pollen allergen and/or a molecule disclosed herein, or reducing or decreasing susceptibility to an immune response or one or more symptoms caused by or associated with the exposure to the allergen, pollen, pollen allergen and/or a molecule disclosed herein.

An immune response includes but is not limited to an allergic immune response, such as an allergic reaction, hypersensitivity, an inflammatory response or inflammation. In certain embodiments an immune response may involve one or more of cell infiltration, production of antibodies, production of cytokines, lymphokines, chemokines, interferons and interleukins, cell growth and maturation factors (e.g., differentiation factors), cell proliferation, cell differentiation, cell accumulation or migration (chemotaxis) and cell, tissue or organ damage or remodeling. In particular aspects, an immune response may include an allergic immune response, such as allergic rhinitis; atopic dermatitis; allergic conjunctivitis and asthma. Allergic responses can occur systemically or locally in any region, organ, tissue, or cell. In particular aspects, an allergic immune response occurs in the skin, the upper respiratory tract, the lower respiratory tract, pancreas, thymus, kidney, liver, spleen, muscle, nervous system, skeletal joints, eye, mucosal tissue, gut or bowel.

Methods and uses herein include relieving a subject of, including treating a subject for, an immune response, or one or more symptoms caused by or associated with an allergen (e.g. pollen, such as a pollen allergen) and/or a molecule disclosed herein. Such methods and uses include administering to a subject an amount of an immunogenic molecule sufficient to relieve the subject of, such as treat the subject for, the allergic immune response, or one or more symptoms caused by or associated with the allergen, (e.g. pollen, such as a pollen allergen) and/or a molecule disclosed herein. Methods and uses of the invention include treating or administering to a subject previously exposed to an allergen (e.g. pollen, such as a pollen allergen) and/or an immunogenic molecule disclosed herein. Thus, in certain embodiments, methods and uses are for treating or protecting a subject from an allergic immune response, or one or more symptoms caused by or associated with secondary or subsequent exposure to an allergen, (e.g. pollen, such as a pollen allergen) and/or a molecule disclosed herein.

Immunogens described herein may elicit, stimulate, induce, promote, increase or enhance immunological tolerance to an allergen (e.g. pollen, such as a pollen allergen) and/or a molecule disclosed herein. Methods and uses of the invention therefore further include inducing immunological tolerance of a subject to an allergen (e.g. pollen, such as a pollen allergen) and/or a molecule disclosed herein. Thus, for example, molecules described herein can be effective in relieving, such as treating an immune response, including but not limited to an immune response following a secondary or subsequent exposure of a subject to an allergen (e.g. pollen, such as a pollen allergen) and/or a molecule disclosed herein. In one embodiment, a method or use includes administering to the subject an amount of a molecule disclosed herein sufficient to induce tolerance in the subject to the allergen (e.g. pollen, such as a pollen allergen) or the molecule itself. In particular aspects, the immunological tolerance elicited, stimulated, induced, promoted, increased or enhanced may involve modulation of T cell activity, including but not limited to CD4+ T cells, CD8+ T cells, Th1 cells, Th2 cells and regulatory T cells. For example, immunological tolerance elicited, stimulated, induced, promoted, increased or enhanced from administration of the immunogenic molecule, may involve modulation of the production or activity of pro-inflammatory or anti-inflammatory cytokines produced by T cells.

In additional embodiments, a method or use of inducing immunological tolerance in a subject to an allergen (e.g. pollen, such as a pollen allergen) and/or an immunogenic molecule disclosed herein includes a reduction in occurrence, frequency, severity, progression, or duration of physiological conditions, disorders, illnesses, diseases, symptoms or complications caused by or associated an allergic response to the allergen (e.g. pollen, such as a pollen allergen) and/or immunogenic molecule in the subject. Thus, in certain embodiments, inducing immunological tolerance can protect a subject against or treat a subject for an immune response, or one or more symptoms caused by or associated with an allergen (e.g. pollen, such as a pollen allergen) or a molecule disclosed herein.

Methods and uses of the invention include treating a subject via immunotherapy, including specific immunotherapy. In one embodiment, a method or use includes administering to the subject an amount of a molecule described herein. In one aspect, a molecule administered to a subject during specific immunotherapy to treat the subject is the same immunogenic molecule to which the subject has been sensitized or is hypersensitive (e.g., allergic). In another non-limiting aspect, a molecule is administered to a subject to treat the subject to a different immunogenic molecule, e.g. an allergen, e.g. a pollen allergen, to which the subject has been sensitized or is hypersensitive (e.g., allergic). Thus, the immunotherapeutic mechanism may involve bystander suppression of an immune response caused by an allergen, e.g. a pollen allergen, by administering an unrelated immunogenic molecule, e.g. a molecule disclosed herein.

As described herein, a molecules of the invention may include T cell epitopes, such as Th2 cell epitopes. In methods and uses herein, the subject to be treated has a specific T- cell response to the a molecule before administering the first dose of the a molecule . Accordingly, methods and uses of the invention include administering an amount of an a molecule (e.g., a T cell epitope-containing a molecule ) to a subject sufficient to provide the subject with protection against an immune response disclosed herein, or one or more symptoms disclosed herein. In another embodiment, a method includes administering an amount of an a molecule (e.g., a T cell epitope-containing a molecule ) to a subject sufficient to relieve, e.g. treat, vaccinate or immunize the subject against an immune response disclosed herein, or one or more symptoms caused by or associated with an allergen (e.g. pollen, such as a pollen allergen) and/or an a molecule disclosed herein.

The specific T-cell response may be monitored by determining by way of contacting a sample of PBMCs obtained from the subject with a molecule of the invention and measuring the IL-5 secretion or IL-5 mRNA gene expression in response to the molecule.

In accordance with the invention, methods and uses of modulating anti-allergen activity of T cells, including but not limited to CD8⁺ T cells, CD4⁺ T cells, Th1 cells or Th2 cells, in a subject are provided. In one embodiment, a method or use includes administering to a subject an amount of a polypeptide described herein or derivative thereof including an a molecule described herein, such as a T cell epitope, sufficient to modulate Th2 cell activity in the subject.

In certain embodiments, two or more a molecules may be administered to a subject, e.g. may be administered as a combination composition, or administered separately, such as concurrently or in series or sequentially. For example, methods and uses described herein comprise administration separately or as a combination: at least 2-25 polypeptides defined herein, or separately or as a combination of 3-25, 4-25, 5-25, 6-25, 7-25 polypeptides defined herein, or separately or as a combination of 2-20, 3-20, 4-20, 5-20, 6-20 defined herein, or separately or as a combination of 2-12, 3-12, 4-12, 5-12, 6-12, 7- 12 polypeptides defined herein, or separately or as a combination of 2-10, 3-10, 4-10, 5- 10, 6-10, 7-10 polypeptides defined herein.

Therefore, a further aspect of the invention relates to a composition comprising a polypeptide of option a), b), c) or d) or a combination of two or more polypeptides of option a), b), c) or d).

Methods and uses of the invention therefore include any therapeutic or beneficial effect. In various embodiments, an immune response, or one or more symptoms caused by or associated with a pollen allergen or an a molecule disclosed herein is reduced, decreased, inhibited, limited, delayed or prevented. Methods and uses of the invention moreover include reducing, decreasing, inhibiting, delaying or preventing onset, progression, frequency, duration, severity, probability or susceptibility of one or more adverse symptoms, disorders, illnesses, diseases or complications caused by or associated with an antigen/allergen. In further various particular embodiments, methods and uses include improving, accelerating, facilitating, enhancing, augmenting, or hastening recovery of a subject from an allergic immune response, or one or more physiological conditions, symptoms or complications caused by or associated with a pollen allergen or an a molecule disclosed herein. In yet additional various embodiments, methods and uses include stabilizing an allergic immune response, or one or more physiological conditions, symptoms or complications caused by or associated with a pollen allergen or an a molecule disclosed herein.

A therapeutic or beneficial effect is therefore any objective or subjective measurable or detectable improvement or benefit provided to a particular subject. A therapeutic or beneficial effect can but need not be complete ablation of all or any immune response, or one or more symptoms caused by or associated with a pollen allergen or an a molecule disclosed herein. Thus, a satisfactory clinical endpoint is achieved when there is an incremental improvement or a partial reduction in an allergic immune response, or one or more symptoms caused by or associated with an allergen, or an inhibition, decrease, reduction, suppression, prevention, limit or control of worsening or progression of an immune response, or one or more symptoms caused by or associated with a pollen allergen or an a molecule disclosed herein, over a short or long duration (hours, days, weeks, months, etc.).

A therapeutic or beneficial effect also includes reducing or eliminating the need, dosage frequency or amount of a second therapeutic protocol or active such as another drug or other agent (e.g., anti-inflammatory) used for treating a subject having or at risk of having an allergic immune response, or one or more symptoms caused by or associated with an allergen. For example, reducing an amount of an adjunct therapy, such as a reduction or decrease of a treatment for an allergic immune response, or one or more symptoms caused by or associated with an allergen, or a specific immunotherapy, vaccination or immunization protocol is considered a beneficial effect. In addition, reducing or decreasing an amount of the a molecule used for specific immunotherapy, vaccination or immunization of a subject to provide protection to the subject is considered a beneficial effect.

Methods and uses described herein may relieve one or more symptoms of an allergic immune response or delays the onset of symptoms, slow the progression of symptoms, or induce disease modification. For example, the following symptoms may be decreased or eliminated; nasal symptoms in the form of itchy nose, sneezing, runny nose, blocked nose; conjunctival symptoms in the form of itchy eyes, red eyes, watery eyes; and respiratory symptoms in the form of decreased lung function. Furthermore, the beneficial effect of methods and uses described herein may be observed by the patient's need for less concomitant treatment with corticosteroids or H1 antihistamines to suppress the symptoms.

When an immunogenic molecule is administered to induce tolerance, an amount or dose of the immunogenic molecule to be administered, and the period of time required to achieve a desired outcome or result (e.g., to desensitize or develop tolerance to the allergen or immunogenic molecule) can be determined by one skilled in the art. The immunogenic molecule may be administered to the patient through any route known in the art, including, but not limited to oral, inhalation, sublingual, epicutaneous, intranasal, and/or parenteral routes (intravenous, intramuscular, subcutaneously, intradermal, and intraperitoneal).

Methods and uses of the invention include administration of a molecule (e.g. an immunogenic molecule) to a subject prior to contact by or exposure to a pollen allergen or a molecule (e.g. an immunogenic molecule) disclosed herein; administration prior to, substantially contemporaneously with or after a subject has been contacted by or exposed to an allergen; and administration prior to, substantially contemporaneously with or after an allergic immune response, or one or more symptoms caused by or associated with a pollen allergen or a molecule (e.g. an immunogenic molecule) disclosed herein.

As used herein, a "sufficient amount" or "effective amount" or an "amount sufficient" or an "amount effective" refers to an amount that provides, in single (e.g., primary) or multiple (e.g., booster) doses, a long term or a short term detectable or measurable improvement in a given subject or any objective or subjective benefit to a given subject of any degree or for any time period or duration (e.g., for minutes, hours, days, months, years, or cured).

An amount sufficient or an amount effective need not be therapeutically or

prophylactically effective in each and every subject treated, nor a majority of subjects treated in a given group or population. An amount sufficient or an amount effective means sufficiency or effectiveness in a particular subject, not a group of subjects or the general population. As is typical for such methods, different subjects will exhibit varied responses to a method of the invention, such as immunization, vaccination, specific immunotherapy and therapeutic treatments.

The term "subject" includes but is not limited to a subject at risk of allergen contact or exposure as well as a subject that has been contacted by or exposed to an allergen. A subject also includes those having or at risk of having or developing an immune response to an antigen or an allergen. Such subjects include mammalian animals (mammals), such domestic animal (dogs and cats), a farm animal (poultry such as chickens and ducks, horses, cows, goats, sheep, pigs), experimental animal (mouse, rat, rabbit, guinea pig) and humans.

Target subjects and subjects in need of treatment also include those at risk of allergen exposure or contact or at risk of having exposure or contact to an allergen. Accordingly, subjects include those at increased or elevated (high) risk of an allergic reaction; that have, or have previously had or are at risk of developing hypersensitivity to an allergen; and those that have or have previously had or are at risk of developing asthma.

It should be understood that in some embodiments, the immune response to be treated in a subject in need thereof is against one or more allergens, e.g. one or more pollen, such as one or more pollen allergens. Likewise, immunological tolerance is desirable to be induced or promoted in a subject in need thereof to one or more allergens, e.g. one or more pollen, such as one or more pollen allergens. For example, the subject may be sensitized to one or more of the pollen allergens.

Non-limiting examples of the one or more pollen allergens to which the subject optionally is sensitized or the immune response is triggered by include proteins, polypeptides and peptides including allergens from a plant species selected from any of the plant families /Asferaceae, Betulaceae, Fagaceae, Oleaceae, Poaceae and/or Plantaginaceae, for example plant species selected from any of the plant genera Anthoxanthum, Conydon, Dactylis, Lollium, Phleum, Poa, Ambrosia, Artemisia, Helianthus, AInus, Betula, Carpinus, Castanea, Corylus, Ostrya, Ostryopsis, Fagus, Quercus, Fraxinus, Ligustrum, Lilac, Olea and Plantago; for example plant species selected from any of the plant genera

Anthoxanthum, Conydon, Dactylis, Lollium, Phleum, Poa, Ambrosia, Artemisia, AInus, Betula, Corylus, Fagus, Quercus, Olea and Plantago; for example plant species selected from the plant genera Ambrosia, Artemisia, Helianthus, AInus, Betula, Carpinus,

Castanea, Corylus, Ostrya, Ostryopsis, Fagus, Quercus, Fraxinus, Ligustrum, Lilac, Olea and Plantago; for example plant species selected from the plant genera Ambrosia, Artemisia, AInus, Betula, Corylus, and Quercus; for example plant species selected from the plant genera Ambrosia and Quercus, for example plant species selected from any of the plant genera Anthoxanthum, Conydon, Dactylis, Lollium, Phleum, Poa, Ambrosia, Artemisia, Plantago, Fraxinus, Olea and Quercus; for example a plant species selected from any of the plant genera Phleum, Cynodon, Ambrosia, Artemisia, Betula and

Quercus, such as a plant species selected from any of the plant genera Phleum,

Cynodon, Ambrosia, Betula and Quercus.

Further examples of the one or more pollen allergens to which the subject optionally is sensitized to include proteins, polypeptides and peptides including allergens from species selected from further plant families, like the plant family Chenopidiaceae including the plants Lambs quarters, Russian thistles and Kochias; plant family Amaranthaceae including Pigweeds, plant family Polygonaceae including for example Sheep sorrel, plant family Ulmacea including for example American Elm and Hackberry, plant family

Plantanaceae including for example Sycamore, plant family Salicaceae including for example White poplar and Cottonwood, plant family Aceraceae including for example Box elder and Red maple, plant family Cupressaceae including for example Common juniper and Cedar.

As mentioned, the subject may be sensitized to one or more pollen species from one or more plant families, for example selected from any of the plant families Poaceae,

Asteraceae, Fagaceae, Betulaceae, Oleaceae, and Plantaginaceae, preferably Poaceae, Asteraceae, Fagaceae and Betulaceae. Therefore, in some embodiments, the subject may be sensitized to a pollen species of the plant family Poaceae and a pollen species of a plant family selected from any one of Asteraceae, Fagaceae and Betulaceae, such as a subject that may be sensitized to a pollen species of the plant genus Phleum and a pollen species of a plant genus selected from any one of the genera Conydon, Ambrosia, Betula and Quercus and combinations thereof. The subject may be sensitized to one or more pollen allergens from one or more plant families, for example selected from the any of the plant families Poaceae, Asteraceae, Fagaceae, Betulaceae, Oleaceae, and Plantaginaceae, preferably Poaceae, Asteraceae, Fagaceae and Betulaceae. Therefore, in some embodiments, the subject may be sensitized to a pollen allergen of the plant family Poaceae and a pollen allergen of a plant family selected from any one of Asteraceae, Fagaceae and Betulaceae and combinations thereof, such as a subject that may be sensitized to a pollen allergen of the plant genus Phleum and a pollen allergen of a plant genus selected from the group consisting of Conydon, Ambrosia, Betula and Quercus and combinations thereof. As mentioned, the immune response may be triggered by pollen from one or more plant families, such as from plant families selected from any of Poaceae, Asteraceae,

Fagaceae, Betulaceae, Oleaceae, and Plantaginaceae, e.g. of Poaceae, Asteraceae, Fagaceae, Betulaceae. Therefore, in some embodiments, the immune response is triggered by pollen of the plant family Poaceae and pollen of a plant family selected from any one of Asteraceae, Fagaceae and Betulaceae and combinations thereof, for example the immune response may be triggered by pollen of the plant genus Phleum and pollen of a plant genus selected from the any one of Conydon, Ambrosia, Betula and Quercus or combinations thereof.

As mentioned, the immune response may be triggered by one or more pollen allergens, such as one or more pollen allergens from a plant family selected from any of Poaceae, Asteraceae, Fagaceae, Betulaceae, Oleaceae, and Plantaginaceae, preferably Poaceae, Asteraceae, Fagaceae and Betulaceae. Therefore, in some embodiments, the immune response is triggered by one or more pollen allergens from pollen of the plant family Poaceae and one or more pollen allergens from pollen of a plant family selected from any of Asteraceae, Fagaceae and Betulaceae. For example, the one or more pollen allergens may be from pollen of the plant genus Phleum and from pollen of a plant genus selected from the group consisting of Conydon, Ambrosia, Betula and Quercus including combinations thereof.

In some embodiments the immune responses to be modulated or treated are against pollen allergens of grass species of various plant genera, for example of the genera

Phleum and Cynodon, thus allowing the treatment or modulation of an immune response caused by a broad range of different grass pollen species. Therefore, in some

embodiments, the one or more pollen allergens are from a grass species selected from any of the plant genera Anthoxanthum, Conydon, Dactylis, Lollium, Phleum and/or Poa, for example from grass species selected from any of the genera Conydon and Phleum. In some embodiments, the immune responses to be modulated or treated are against grass pollen allergens as well as weed and/or tree pollen allergens. For example the immune responses to be modulated or treated are against grass pollen allergens of the genera Phleum and against non-grass pollen of the genera Ambrosia and/or Quercus, thus allowing the treatment or modulation of an immune response caused by a broad range of different grass pollen species and non-grass species. Thus, in some

embodiments, the one or more pollen allergens are from a grass species selected from any of the plant genera Anthoxanthum, Conydon, Dactylis, Lollium, Phleum and Poa and from a non-grass species selected from any of the plant families Asteraceae, Betulaceae, Fagaceae, Oleaceae and Plantaginaceae, e.g. wherein the non-grass species are selected from any of the plant genera Ambrosia, Artemisia, Helianthus, Alnus, Betula, Carpinus, Castanea, Corylus, Ostrya, Ostryopsis, Fagus, Quercus, Fraxinus, Ligustrum, Lilac, Olea and Plantago, for example against a non-grass species selected from any of the plant genera Ambrosia, Artemisia, Alnus, Betula, Quercus, Olea and Plantago, such as a non-grass species selected from any of the plant genera Ambrosia, Betula and Quercus.

In some embodiments, the immune responses to be modulated or treated are against non-grass pollen allergens, such as against weed and/or tree pollen allergens. For example the immune responses to be modulated or treated are against non-grass pollen allergens of the genera Ambrosia and against non-grass pollen allergens of the genera Quercus, thus allowing the treatment or modulation of an immune response caused by a broad range of different non-grass pollen species. Thus, in some embodiments, the one or more non-grass pollen allergens are from a plant genus selected from any of

Ambrosia, Artemisia, Helianthus, Alnus, Betula, Carpinus, Castanea, Corylus, Ostrya, Ostryopsis, Fagus, Quercus, Fraxinus, Ligustrum, Lilac, Olea and/or Plantago.

It should be understood that in some embodiments of the invention, the one or more pollen allergens are from same grass species or alternatively from different grass species, optionally wherein the different grass species are from different plant genera selected from any of Anthoxanthum, Conydon, Dactylis, Lollium, Phleum and Poa, for example Conydon and Phleum. Likewise, it should be understood that in some embodiments of the invention the one or more non-grass pollen allergens are from same non-grass species or alternatively from different non-grass species, optionally wherein the different non-grass species are from different plant genera selected from any of

Ambrosia, Artemisia, Helianthus, Alnus, Betula, Carpinus, Castanea, Corylus, Ostrya, Ostryopsis, Fagus, Quercus, Fraxinus, Ligustrum, Lilac, Olea and Plantago. In some embodiments, the immune response to be modulated or treated may be at least against one or more pollen allergens of various grass pollen species, e.g. against one or more pollen allergens of the plant genera Phleum. In some embodiments, the immune response to be modulated or treated may be at least against one or more pollen allergens of various weed pollen species, e.g. against one or more pollen allergens of the plant genera Ambrosia. In some embodiments, the immune response to be modulated or treated may be at least against one or more pollen allergens of various tree pollen species, e.g. against one or more pollen allergens of the plant genera Quercus. In some embodiments, the immune response to be modulated or treated may be at least against one or more pollen allergens of various tree pollen species, e.g. against one or more pollen allergens of the plant genera Betula.

As mentioned, the immune response to be modulated or treated may be against one or more pollen allergens of various grass pollen species and non-grass pollen species, such as two or more, three or more, four or more, five or more pollen allergens of different pollen species, like various grass pollen species and/or non-grass pollen species.

Non-limiting examples of the genus Ambrosia may be Ambrosia artemisiifolia, Ambrosia psilostachya, Ambrosia trifida; a typical species of the genus Artemisia may be Artemisia vulgaris; a typical species of the genus Betula may be Betula verrucosa; a typical species of the genus Fagus may be Fagus grandifolia or Fagus sylvatica; a typical species of the genus Quercus may be Quercus alba, a typical species of the genus Fraxinus may be Fraxinus excelsior; a typical species of the genus Olea may be Olea Europaea, a typical species of the genus plantago may be Plantago lanceolata, a typical species of the genus plantago may be Plantago lanceolata, a typical species of the genus Anthoxanthum may be Anthoxanthum Odoratum, a typical species of the genus Conydon may be Conydon Dactylon, a typical species of the genus Lollium may be Lollium Perenne, a typical species of the genus Phleum may be Phleum Pratense, a typical species of the genus Poa may be Poa Pratensis.

Non-limiting examples of non-grass pollen allergens to which a subject optionally may be sensitized to are Aln g 1 , Aln g 4, Amb a 1 , Amb a 2, Amb a 3, Amb a 4, Amb a 5, Amb a 6, Amb a 7, Amb a 8, Amb a 9, Amb a 10, Amb p 5, Amb t 5, Art v 1 , Art v 2, Art v 3, Art v 4, Art v 5, Art v 6, Bet v 1 , Bet v 2, Bet v 3, Bet v 4, Bet v 6, Bet v 7, Car b 1 , Cas s 1 , Cor a 6, Cor a 10, Fag s 1 , Fra e 1 , Hel a 1 , Hel a, Lig v 1 , Ole e 1 , Ole e 2, Ole e 3, Ole e 4, Oie e 5, Ole e 6, Ole e 7, Ole e 8, Ole e 9, Ole e 10, Ole e 11 , Ost c 1 , Pla I, Que a 1 , Syr v 1 , Syr v 3, and any combination thereof, for example the major allergens Amb a 1 , Que a 1 , Bet v 1 , Bet v 2, Ole e 1 and any combination thereof. Non-limiting examples of grass pollen allergens to which a subject optionally may be sensitized to are Ant o 1 , Cyn d 1 , Cyn d 7, Cyn d 12, Cyn d 15, Cyn d 22w, Cyn d 23, Cyn d 24, Dac g 1 , Dac g 2, Dac g 3, Dac g 4, Dac g 5, Fes p 4, Hoi 1 1 , Hoi I 5, Hor v 1 , Hor v 5, Lol p 1 , Lol p 2, Lol p 3, Lol p 4, Lol p 5, Lol p 11 , Ory s 1 , Pas n 1 , Pha a 1 , Pha a 5, Phi p 1 , Phi p 2, Phi p 4, Phi p 5, Phi p, Phi p 7, Phi p 1 1 , Phi p 12, Phi p 13, Poa p 1 , Poa p 5, Sec c 1 , Sec c 5, Sec c 38 and/or Sor h 1 , and any combination thereof. The group 1 allergens (e.g. Ant o 1 , Cyn d 1 , Dac g 1 , Hoi 1 , Lol p 1 , Pha a 1 , Phi p 1 and Poa p 1 ) or group 5 allergens (Dac g 5, Lol p 5, Pha a 5, Phi p 5, Poa p 5) are considered major allergens of grass pollen

"Prophylaxis" and grammatical variations thereof mean a method or use in which contact, administration or in vivo delivery to a subject is prior to contact with or exposure to a pollen allergen or a molecule (e.g. an immunogenic molecule) disclosed herein. In certain situations it may not be known that a subject has been contacted with or exposed to an allergen, but administration or in vivo delivery to a subject can be performed prior to manifestation of an allergic immune response, or one or more symptoms caused by or associated with an allergen. For example, a subject can be provided protection against an allergic immune response, or one or more symptoms caused by or associated with a pollen allergen or a molecule disclosed herein or provided immunotherapy with a molecule (e.g. an immunogenic molecule) of the present invention. In such case, a method or use can eliminate, prevent, inhibit, suppress, limit, decrease or reduce the probability of or susceptibility towards an allergic immune response, or one or more physiological conditions, symptoms or complications caused by or associated with an a pollen allergen or a molecule disclosed herein.

"Prophylaxis" can also refer to a method or use in which contact, administration or in vivo delivery to a subject is prior to a secondary or subsequent exposure to an allergen (e.g. pollen such as a pollen allergen) and/or a molecule disclosed herein. In such a situation, a subject may have had a prior contact or exposure to a pollen allergen or a molecule (e.g. an immunogenic molecule) disclosed herein. In such subjects, an acute allergic reaction may but need not be resolved. Such a subject typically may have developed anti- allergen antibodies due to the prior exposure. Immunization or vaccination, by

administration or in vivo delivery to such a subject, can be performed prior to a secondary or subsequent allergen exposure. Such a method or use can eliminate, prevent, inhibit, suppress, limit, decrease or reduce the probability of or susceptibility towards a secondary or subsequent allergic immune response, or one or more symptoms caused by or associated with a pollen allergen or a molecule (e.g. an immunogenic molecule) disclosed herein. In certain embodiments, such a method or use includes providing specific immunotherapy to the subject to eliminate, prevent, inhibit, suppress, limit, decrease or reduce the probability of or susceptibility towards a secondary or subsequent allergic immune response, or one or more physiological conditions, symptoms or complications caused by or associated with an a pollen allergen or a molecule disclosed herein.

Treatment of an allergic reaction or response can be at any time during the reaction or response. A molecule (e.g. an immunogenic molecule) can be administered as a single or multiple dose e.g., one or more times hourly, daily, weekly, monthly or annually or between about 1 to 10 weeks, or for as long as appropriate (e.g. 3 months, 6 months or more, for example, to achieve a reduction in the onset, progression, severity, frequency, duration of one or more symptoms or complications associated with or caused by an allergic immune response, or one or more physiological conditions, symptoms or complications caused by or associated with an antigen/allergen.

Accordingly, methods and uses of the invention can be practiced one or more times (e.g., 1-10, 1-5 or 1-3 times) an hour, day, week, month, or year. The skilled artisan will know when it is appropriate to delay or discontinue administration. Doses can be based upon current existing protocols, empirically determined, using animal disease models or optionally in human clinical trials. Initial study doses can be based upon animal studies, e.g. a mouse, and the sufficient amount of immunogenic molecule to be administered for being effective can be determined. Exemplary non-limiting amounts (doses) are in a range of about 0.1 mg/kg to about 100 mg/kg, and any numerical value or range or value within such ranges. Greater or lesser amounts (doses) can be administered, for example, 0.01-500 mg/kg, and any numerical value or range or value within such ranges. The dose can be adjusted according to the mass of a subject, and will generally be in a range from about 1-10 ug/kg, 10-25 ug/kg, 25-50 ug/kg, 50-100 ug/kg, 100-500 ug/kg, 500-1 ,000 ug/kg, 1-5 mg/kg, 5-10 mg/kg, 10-20 mg/kg, 20-50 mg/kg, 50-100 mg/kg, 100-250 mg/kg, 250-500 mg/kg, or more, two, three, four, or more times per hour, day, week, month or annually. A typical range will be from about 0.3 mg/kg to about 50 mg/kg, 0-25 mg/kg, or 1.0-10 mg/kg, or any numerical value or range or value within such ranges. Doses can vary and depend upon whether the treatment is prophylactic or therapeutic, whether a subject has been previously exposed to the antigen/allergen, the onset, progression, severity, frequency, duration, probability of or susceptibility of the symptom, condition, pathology or complication, or vaccination or specific immunotherapy to which treatment is directed, the clinical endpoint desired, previous or simultaneous treatments, the general health, age, gender, race or immunological competency of the subject and other factors that will be appreciated by the skilled artisan. The skilled artisan will appreciate the factors that may influence the dosage and timing required to provide an amount sufficient for providing a therapeutic or prophylactic benefit.

Immunogens of the invention can be provided in compositions, and in turn such compositions can be used in accordance with the invention methods and uses. Such compositions, methods and uses include pharmaceutical compositions and formulations. In certain embodiments, a pharmaceutical composition includes one or more

immunogenic molecules (e.g. polypeptides of option a), b), c) or d). In particular, aspects, such compositions and formulations may be a vaccine, including but not limited to a vaccine to protect against (e.g. modify, relieve or suppress) an immune response disclosed herein, or one or more symptoms caused by or associated with an allergen and/or a molecule (e.g. an immunogenic molecule) disclosed herein.

A pharmaceutical composition comprises a molecule (e.g. an immunogenic molecule) of the invention and a pharmaceutically acceptable ingredient or carrier. As used herein the term "pharmaceutically acceptable" and "physiologically acceptable" mean a biologically acceptable formulation, gaseous, liquid or solid, or mixture thereof, which is suitable for one or more routes of administration, in vivo delivery or contact. Such formulations include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (e.g., oil-in-water or water-in-oil), suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration or in vivo contact or delivery. Aqueous and non-aqueous solvents, solutions and suspensions may include suspending agents and thickening agents. Such pharmaceutically acceptable carriers include tablets (coated or uncoated), capsules (hard or soft), microbeads, powder, granules and crystals. Supplementary active compounds (e.g., preservatives,

antibacterial, antiviral and antifungal agents) can also be incorporated into the

compositions.

A pharmaceutically acceptable or physiologically acceptable excipient, carrier and/or adjuvants are well-known to the person skilled in the art and may include, but are not limited to, solvents, emulsifiers, wetting agents, plasticizers, solubilizers (e.g. solubility enhancing agents) coloring substances, fillers, preservatives, anti-oxidants, anti-microbial agents, viscosity adjusting agents, buffering agents, pH adjusting agents, isotonicity adjusting agents, mucoadhesive substances, and the like. Examples of formulation strategies are well-known to the person skilled in the art. In some embodiments, the pharmaceutical composition may be formulated for parenteral administration, such as formulated for injection, e.g. subcutaneous and/or intradermal injection. Therefore, in some embodiments, the pharmaceutical composition may be a liquid (i.e. formulated as a liquid), including a solution, a suspension, a dispersion, and a gelled liquid. For example, a liquid pharmaceutical composition may be formed by dissolving a powder, granulate or lyophilizate of a molecule (e.g. an immunogenic molecule) combination described herein in a suitable solvent and then administering to a subject. Suitable solvents may be any solvent having physiologically acceptable properties and able to dissolve the immunogenic molecule combination in desired concentrations. A desired concentration may depend on the aliquot to be administered (i.e. to be injected) and the desired single dose. It is emphasized that for the purposes of injection the aliquot is in the range of about 10 to 500 microliters, e.g. 50 to 300 microliters or less and a desired single dose is within range of 1 to 1000 nanomoles. Therefore, a suitable solvent should be able to dissolve any immunogenic molecule of the combination to achieve a final concentration of about 1 to 1000 μΜ for each of the immunogenic molecules. Thus, in one embodiment, a liquid composition comprises each of the immunogenic molecules of the combination in a concentration of 10 to 800 μΜ, for example 20 to 500 μΜ or20 to 300 μΜ. Typically, the concentration of each immunogenic molecule is the same, such as in an equimolar concentration, but each immunogenic molecule of the composition may be present in different concentrations. Typically, the solvent is an aqueous solution, optionally mixed with other solvents. Thus, a solvent may comprise at least 60% w/w of water, e.g. at least 65% w/w, 70% w/w, 75% w/w, 80% w/w , 85% w/w, 90% w/w or 95% w/w , 99% w/w of water, such as distilled water, such as sterile water. In some embodiments, the solvent is sterile distilled water, e.g. water for injection. An aqueous solution may comprise other solvents than water, for example

DMSO (dimethylsulfoxide), glycerol, ethanol, acetonitrile, vegetable or synthetic oils. The pH of the aqueous phase of the solvent may be in a physiological acceptable range, typically in the range of 3 to 9, such as in the range of pH 3 to 8, such as in the range of pH 4 to 8, such as in the range of 5 to 8, such as in the range of 6 to 8. Thus, the liquid formulation may comprise a pH controlling agent or buffering agent (e.g. citrate buffer, phosphate buffer, acetate buffer), optionally the pH may be adjusted with dilutions of strong base (e.g. sodium hydroxide or the like) and/or dilutions of strong acids (e.g.

hydrochloric acid).

Typically, the liquid formulation is isotonic, and optionally sterile. Therefore, in some embodiments, the formulation comprises saline, such as isotonic saline. The liquid may contain additional excipients, such as another solvent, a solubilizing enhancing agent (e.g. polyoxyethylene (20) sorbitan monolaurate (Tween® 20), ionic and non-ionic emulsifiers (e.g. poloxamers (Kolliphor®)), a dispersant, a thickener, a preservative, an anti-microbial agent, and/or an antioxidant. Non-limiting illustrative examples of solvents include water, saline, DMSO, glycerol, ethanol, acetonitrile, vegetable or synthetic oils. Some immunogenic molecules are known to be prone to oxidation or being unstable when exposed to water for a long period. Therefore, to achieve storage stable

compositions, a pharmaceutical composition may be formulated to contain only a limited amount of water or aqueous solution, e.g. containing less than 10% w/w of water or aqueous solution, such as less than 9, 8, 7, 6, 5, 4, 3, 2, 1 , 0.5% w/w of water or aqueous solution. Examples of pharmaceutical compositions with limited levels of water may include granulates, powders, for example lyophilizates, i.e. freeze-dried powders.

Typically, the freeze-dried composition may be dissolved before use, for example dissolved in an aqueous, optionally sterile, solution, for example a solution having a pH in the range of 3-9, such as pH in the range of 3 to 8, such as pH in the range of 4 to 8. A lyophilizate may contain additional ingredients, e.g. bulking agents and lyoprotectants (e.g. sucrose, lactose, trehalose, mannose, mannitol, sorbitol, glucose, raffinose, glycine, histidine or mixtures thereof), buffering agents (e.g. sodium citrate, sodium phosphate, disodium phosphate, sodium hydroxide, Tris base, Tris acetate, Tris HCI or mixtures thereof), antioxidants, antimicrobial agents, solubilizers (e.g. polyoxyethylene (20) sorbitan monolaurate (Tween® 20)).

A freeze-dried composition may also be formulated into a solid dosage form that is administered for example by the oral route such as by oral mucosa. Thus, in some embodiments, the pharmaceutical composition may be formulated for oral administration, for example for sublingual administration. Therefore, the pharmaceutical composition may be a solid dosage form, such as a freeze-dried solid dosage form, typically a tablet, a capsule or sachet, which optionally may be formulated for fast disintegration.

Pharmaceutical formulations and delivery systems appropriate for the compositions, methods and uses of the invention are known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (2003) 20th ed., Mack Publishing Co., Easton, PA; Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing Co., Easton, PA; The Merck Index (1996) 12th ed., Merck Publishing Group, Whitehouse, NJ;

Pharmaceutical Principles of Solid Dosage Forms (1993), Technonic Publishing Co., Inc., Lancaster, Pa.; Ansel ad Soklosa, Pharmaceutical Calculations (2001) 11th ed.,

Lippincott Williams & Wilkins, Baltimore, MD; and Poznansky et al., Drug Delivery Systems (1980), R. L. Juliano, ed., Oxford, N.Y., pp. 253-315). As mentioned, pharmaceutical compositions can be formulated to be compatible with a particular route of administration, such as by intradermal or by sublingual administration. Thus, pharmaceutical compositions may include carriers, diluents, or excipients suitable for administration by various routes. Exemplary routes of administration for contact or in vivo delivery for which a composition can optionally be formulated include inhalation, intranasal, oral, buccal, sublingual, subcutaneous, intradermal, epicutaneous, rectal, transdermal, or intralymphatic.

For oral, buccal or sublingual administration, a composition may take the form of, for example, tablets or capsules, optionally formulated as fast-integrating tablets/capsules or slow-release tablets/capsules. In some embodiments, the tablet is freeze-dried, optionally a fast-disintegrating tablet or capsule suitable for being administered under the tongue.

The pharmaceutical composition may also be formulated into a "unit dosage form", which used herein refers to physically discrete units, wherein each unit contains a

predetermined quantity of a immunogenic molecule or immunogenic molecule

combination, optionally in association with a pharmaceutical carrier (excipient, diluent, vehicle or filling agent) which, when administered in one or more doses, may produce a desired effect. Unit dosage forms also include, for example, ampules and vials, which may include a composition in a freeze-dried or lyophilized state (a lyophilizate) or a sterile liquid carrier, for example that can be added prior to administration or delivery in vivo. Unit dosage forms also include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo. Pharmaceutical formulations can be packaged in single or multiple unit dosage form for ease of administration and uniformity of dosage.

Immunogenic molecules may be prone to degradation when exposed to oxygen, for example when exposed to air or solvents containing air. Therefore, in some

embodiments, the pharmaceutical composition comprises an inert gas, e.g. argon or nitrogen.

Another aspect of the invention relates to a kit comprising a compartment and

instructions, wherein the compartment comprises a pharmaceutical composition as described herein and wherein the instructions are for use in reducing an immune response triggered by pollen, such as a pollen allergen, e.g. of a grass, weed or tree pollen species disclosed herein, such as instructions for use in treating allergy to pollen (e.g. grass, weed and/or tree pollen allergy to a plant family or species disclosed herein. A kit may further comprise packaging material comprising corrugated fiber, glass, plastic, foil, ampules, vials, blister pack, preloaded syringes or tubes, optionally that maintain sterility of the components. A kit may further comprise labels or inserts comprising printed matter or computer readable medium optionally including identifying components, dose amounts, clinical pharmacology and instructions for the clinician or for a subject using one or more of the kit components, prophylactic or therapeutic benefits, adverse side effects or manufacturer information.

In one embodiment, the kit additionally comprises a container comprising a solvent for dissolving the composition before use. Examples of suitable solvents are described supra. Optionally, the kit may also comprise a device for use in parenteral injection, e.g. for injecting the composition (e.g. dissolved composition) to a subcutaneous or intradermal tissue. A device may be any suitable device for that purpose, such as a needle or microneedle adapted for intradermal or subcutaneous delivery of the composition. For example, the device may be a microneedle or a device comprising a plurality of microneedles designed for intradermal delivery of liquids, e.g. as described in international patent applications W014064543 A1 , WO05049107 A2, WO06054280 A2, WO07066341 A3 and W014188429 A1.

A composition may be lyophilized so as to enhance stability and ease of transportation. For the purpose of being used as a vaccine, the composition may be sterile.

Pharmaceutical compositions can be formulated to be compatible with a particular route of administration. Thus, pharmaceutical compositions include carriers, diluents, or excipients suitable for administration by various routes. Exemplary routes of

administration for contact or in vivo delivery for which a composition can optionally be formulated include inhalation, intranasal, oral, buccal, sublingual, subcutaneous, intradermal, epicutaneous, rectal, transdermal, or intralymphatic. In some embodiments, the pharmaceutical composition is aqueous and, in other embodiments, the composition is non-aqueous solutions, suspensions or emulsions of the immunogenic molecule/protein, which compositions are typically sterile and can be isotonic with the biological fluid or organ of the intended recipient. Non-limiting illustrative examples include water, saline, dextrose, fructose, ethanol, vegetable or synthetic oils. For oral, buccal or sublingual administration, a composition can take the form of for example a solid dosage form, e.g. tablets or capsules, optionally formulated as fast- integrating tablets/capsules or slow-release tablets/capsules. In some embodiments, the tablet is a freeze-dried, optionally fast-disintegrating tablet suitable for being administered under the tongue. A solid dosage form optionally is sterile, optionally anhydrous.

To increase an immune response, immunological tolerance or protection against an allergic immune response, or one or more symptoms caused by or associated with an allergen, immunogenic molecules can be mixed with adjuvants.

Adjuvants include, for example: oil (mineral or organic) emulsion adjuvants such as Freund's complete (CFA) and incomplete adjuvant (I FA) (WO 95/17210; WO 98/56414; WO 99/12565; WO 99/11241 ; and U.S. Patent No. 5,422,109); metal and metallic salts, such as aluminum and aluminum salts, such as aluminum phosphate or aluminum hydroxide, alum (hydrated potassium aluminum sulfate); bacterially derived compounds, such as Monophosphoryl lipid A and derivatives thereof (e.g., 3 De-O-acylated monophosphoryl lipid A, aka 3D-MPL or d3-MPL, to indicate that position 3 of the reducing end glucosamine is de-O-acylated, 3D-MPL consisting of the tri and tetra acyl congeners), and enterobacterial lipopolysaccharides (LPS); plant derived saponins and derivatives thereof, for example Quil A (isolated from the Quilaja Saponaria Molina tree, see, e.g., "Saponin adjuvants", Archiv. fur die gesamte Virusforschung, Vol. 44, Springer Verlag, Berlin, p243-254; U.S. Patent No. 5,057,540), and fragments of Quil A which retain adjuvant activity without associated toxicity, for example QS7 and QS21 (also known as QA7 and QA21), as described in W096/33739, for example; surfactants such as, soya lecithin and oleic acid; sorbitan esters such as sorbitan trioleate; and

polyvinylpyrrolidone; oligonucleotides such as CpG (WO 96/02555, and WO 98/16247), polyriboA and polyriboU; block copolymers; and immunostimulatory cytokines such as GM-CSF and IL-1 , and Muramyl tripeptide (MTP). Additional examples of adjuvants are described, for example, in "Vaccine Design-the subunit and adjuvant approach" (Edited by Powell, M. F. and Newman, M. J.; 1995, Pharmaceutical Biotechnology (Plenum Press, New York and London, ISBN 0-306-44867-X) entitled "Compendium of vaccine adjuvants and excipients" by Powell, M. F. and Newman M.

Cosolvents may be added to the composition. Non-limiting examples of cosolvents contain hydroxyl groups or other polar groups, for example, alcohols, such as isopropyl alcohol; glycols, such as propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Non-limiting examples of cosolvents contain hydroxyl groups or other polar groups, for example, alcohols, such as isopropyl alcohol; glycols, such as propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Supplementary compounds (e.g., preservatives, antioxidants, antimicrobial agents including biocides and biostats such as antibacterial, antiviral and antifungal agents) can also be incorporated into the compositions. Pharmaceutical compositions may therefore include preservatives, anti-oxidants and antimicrobial agents. Preservatives can be used to inhibit microbial growth or increase stability of ingredients thereby prolonging the shelf life of the pharmaceutical formulation. Suitable preservatives are known in the art and include, for example, EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate. Antioxidants include, for example, ascorbic acid, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins. An antimicrobial agent or compound directly or indirectly inhibits, reduces, delays, halts, eliminates, arrests, suppresses or prevents contamination by or growth, infectivity, replication, proliferation, reproduction, of a pathogenic or non- pathogenic microbial organism. Classes of antimicrobials include antibacterial, antiviral, antifungal and antiparasitics. Antimicrobials include agents and compounds that kill or destroy (-cidal) or inhibit (-static) contamination by or growth, infectivity, replication, proliferation, reproduction of the microbial organism.

Pharmaceutical formulations and delivery systems appropriate for the compositions, methods and uses of the invention are known in the art (see, e.g. Remington: The Science and Practice of Pharmacy (David B. Troy, Paul Beringer Lippincott Williams & Wilkins) 2006).

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the invention is not entitled to antedate such publication by virtue of prior invention.

As used in this specification and the appended claims, the use of an indefinite article or the singular forms "a," "an" and "the" include plural reference unless the context clearly dictates otherwise. In addition, it should be understood that the individual peptides, proteins, antigens, allergens (referred to collectively as compositions), or groups of compositions, modeled or derived from the various components or combinations of the compositions, and substituents described herein, are disclosed by the application to the same extent as if each composition or group of compositions was set forth individually. Thus, selection of particular peptides, proteins, antigens, allergens, etc. is clearly within the scope of the invention.

As used in this specification and the appended claims, the terms "comprise",

"comprising", "comprises" and other forms of these terms are intended in the non-limiting inclusive sense, that is, to include particular recited elements or components without excluding any other element or component. Unless defined otherwise all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs. As used herein, "about" means + or - 5%. The use of the wild type (e.g., "or") should be understood to mean one, both, or any combination thereof of the wild types, i.e., "or" can also refer to "and." As used in this specification and the appended claims, any concentration range, percentage range, ratio range or other integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. For example, although numerical values are often presented in a range format throughout this document, a range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the use of a range expressly includes all possible sub ranges, all individual numerical values within that range, and all numerical values or numerical ranges including integers within such ranges and fractions of the values or the integers within ranges unless the context clearly indicates otherwise. This construction applies regardless of the breadth of the range and in all contexts throughout this patent document. Thus, to illustrate, reference to a range of 90-100% includes 91-99%, 92-98%, 93-95%, 91-98%, 91-97%, 91-96%, 91-95%, 91- 94%, 91-93%, and so forth. Reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. Reference to a range of 5-10, 10-20, 20- 30, 30-40, 40-50, 50-75, 75-100, 100-150, and 150-175, includes ranges such as 5-20, 5- 30, 5-40, 5-50, 5-75, 5-100, 5-150, 5-171 , and 10-30, 10-40, 10-50, 10-75, 10-100, 10- 150, 10-175, and 20-40, 20-50, 20-75, 20-100, 20-150, 20-175, and so forth. Further, for example, reference to a series of ranges of 2-72 hours, 2-48 hours, 4-24 hours, 4-18 hours and 6-12 hours, includes ranges of 2-6 hours, 2, 12 hours, 2-18 hours, 2-24 hours, etc., and 4-27 hours, 4-48 hours, 4-6 hours, etc.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. The invention is further exemplified by way of the following non-limited examples.

References

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Greenbaum J, Sidney J, Chung J, Brander C, Peters B, Sette A. Functional classification of class II human leukocyte antigen (HLA) molecules reveals seven different supertypes and a surprising degree of repertoire sharing across supertypes. Immunogenetics, 63, 325-335, 2011.

Karosiene, Edita, Michael Rasmussen, Thomas Blicher, Ole Lund, Soren Buus, and Morten Nielsen. "NetMHCIIpan-3.0, a Common Pan-specific MHC Class II Prediction Method Including All Three Human MHC Class II Isotypes, HLA-DR, H LA-DP and HLA- DQ." Immunogenetics, Vol. 65, No. 10, 2013, p. 711-724.

McKinney DM, Southwood S, Hinz D, Oseroff C, Arlehamn CS, Schulten V, et al. A strategy to determine HLA class II restriction broadly covering the DR, DP, and DQ allelic variants most commonly expressed in the general population. Immunogenetics; 65:357- 70, 2013.

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determinants of T cell epitope recognition to the common Timothy grass allergen. Journal of immunology 2010; 185:943-55. Pearson and Lipman, 1988: Pearson WR, Lipman DJ. Improved tools for biological sequence comparison, Proc. Natl. Acad. Sci. USA 85(8): 2444-2448,1988.

Pearson WR1 , Flexible sequence similarity searching with the FASTA3 program package, Methods Mol Biol. 132, 185-219, 2000. Sidney J, Southwood S, Oseroff C, del Guercio MF, Sette A, Grey HM. Measurement of MHC/peptide interactions by gel filtration. Curr Protoc Immunol. Chapter 18(Unit 18): 13. doi: 10.1002/0471142735.im1803s31 , 2001

Sidney J, Assarsson E, Moore C, Ngo S, Pinilla C, Sette A, Peters B. Quantitative peptide binding motifs for 19 human and mouse MHC class I molecules derived using positional scanning combinatorial peptide libraries. Immunome Res. 4:2, doi: 10.1186/1745-7580-4- 2, 2008

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Examples

Example 1 - Transcriptomic analysis

This example includes a description of transcriptomic analysis of various pollen species.

RNA-sequencing was performed on pollen samples of the following species: Timothy grass (Phleum pratense (Phi p)), Bermuda grass (Cynodon dactylon (Cyn d)), Western ragweed (Ambrosia psilostachya (Amb p)), Short ragweed (Ambrosia artemisiifolia (Amb a)), White oak (Quercus alba (Que a)), and European white birch (Betula verrucosa (Bet v)) (See Table below). RNA-seq was run at UCSD, using an lllumina HiSeq 2000. The table below shows the number of reads assembled for each of the different pollens (top), with over 500 million reads over two replicate runs per allergen. Sequences were assembled into transcripts using Trinity (bottom), resulting in over 50 thousand transcripts per allergen with minimum lengths of 200 nucleotides. The transcripts include related variants, such as isoforms, and homologs.

Transcriptomic analysis may also be performed on RNA sequences of additional species as shown in the Table below showing pollen RNA-seq reads for the pollen species Kentucky blue grass, Sweet vernal grass, Rye grass and Ash tree, Olive tree and English plantain:

Raw read counts (millions)

Additional species

Sweet Ash Rye grass Olive English Kentucky vernal plantain blue grass

Ant O FE Lol P Ole E PL Poa P

1st run 394 410 332 385 303 363

2nd run 360 346 319 350 287 309

Total 754 756 651 735 590 672

Transcripts after Trinity assembly

Count 317,874 81 ,401 122,266 74,333 57,102 128,174 min 201 201 201 201 201 201 median 544 722 631 710 696 635

max 11 ,515 9,838 9,631 8,133 8,090 10,100 Example 2 - Identification of polypeptides in Phi p grass pollen and homologous polypeptides thereof

This example includes a description of the identification of polypeptides in extracts of Phi p grass pollen and homologous polypeptides thereof in other pollen species. In order to identify polypeptides in Phi p grass pollen, the Phi p grass transcriptome was translated into amino acid sequences in all six reading frames, and they were used to search 17 mass spectrometry samples of Phi p grass pollen extract using the Mascot software. This identified 354 polypeptide sequences. Polypeptide sequences shorter than 50 aa were discarded, resulting in 275 sequences. In order to identify the correct coding region of each transcript, there was identified the closest homologous sequence in the rice (Oryza sativa japonica) proteome (via Blast). Rice was chosen since it is a species closely related to Phi p grass with a completely sequenced and annotated genome. Homologous rice sequences were identified for 180 Timothy grass sequences.

Subsequently, homologous sequences were identified (via Blast) in the translated transcriptomes of Cyn d, Amb a, Amb p, Que a, and Bet v of all identified sequences, the one(s) sharing the largest number of conserved peptides with the Phi p sequence was selected as homolog. This resulted in 66 sets of homologous polypeptides. In total, there was found evidence of release of the polypeptides from Phi p grass pollen for 52 of these polypeptides upon extracting pollen in a buffered aqueous solution (see Example 4). Table 1 shows amino acid sequences of the polypeptides detected and identified in Phi p grass pollen and Table 2 shows amino acid sequences of polypeptides homologous to the Phi p sequence of Table 1 found in pollen of the species Cyn d, Amb a, Amb p, Que a, and Bet v.

Table 1. Polypeptides of Timothy Grass Pollen (Phi p)

Table 1 - SEQ ID NO: 1-37

SEQ ID NO: SpeAmino Acid Sequence

ID cies

NO:

1 A0202 Phi p HGIQQRKNSWQDGTPGAMCPIMPGTNFTYKMQFKDQIGTFFYFPSIGMQRAAG

GYGLITIHSRLLIPVPFDPPADDFSVLVGDWYTKD

2 A0203 Phi p KTIPLEVESSATIDNVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQ

3 A0203 Phi p MQIFVKILTGKTITLEVESSDTIDNVKAKIQDKEGIPPDQQRLIFAGKQLEDGR

4 A0209 Phi p ASFGDAPAGNAASGE IFRTKCAQCHTVERGGAHKQGPNLSGLFGRQSGTT

AGYAFSAGN NAAWWGDDTLYDYLLNPKKYIPSTKMVFPGLKKPQERTDLIAY LKESTA

5 A0209 Phi p ASFSEAPPGNAAAGEKIF TKCAQCHTVEKGAGHKQGPNLNGLFGRQSGTTP

GYSYSTANKNMAVIWEEKTLYDYLLNPKKYIPGTKMVFPGLKKPQERADLIAYLK DATA

6 A0211 Phl p MANSASGLAVHDDCKIKFLDLKARRSFRFIVFKIDEKAMEIKVERLGEASHGYEE

FTNSLPADECRYAVYDLDFVTDENCQKSKIFFFSWSPDTARTRSK LYASSKDR

FRREMDGIQCEIQATDPSEMSLDIIKSRAH

7 A0211 Phi p MANSASGMAVSDECKLKFQDLKSKRSFRFITFKINEQTQQVWDKVGQPGDTY

SDFTATMPEGECRYAVFDFDFVTDENCQKSKIFFFSWSPDTARTRSKMLYASS Table 1 - SEQ ID NO: 1-37

SEQ ID NO: SpeAmino Acid Sequence

ID cies

NO:

KDRFRREMDGIQCEIQATDPSEMSLDIIKSRAH

8 A0211 Phi p MSNSASGMAVCDECKLKFQELKAKRSLRFIVFKINEKVQQVWDRLGQPNESY

DDFAACLPADECRYAVFDFDFVTDENCQKSKI

9 A0215 Phi p AITVDDACRQYTKHRSYCAHALSAKAGPSETTLPALAEQAVTLAAESGEEAVAF

VRNLEKMPGGMPLGCLERCVGKFQAAVAELTRSRAAIVEHRDVARVKAWVKAA

RADGETCMDGCHTEGGADPTIIHRIGDLGKLCSIALSLTDA

10 A0219 Phl p LLKVNQIGSVTESIEAVKMS RAGWGV TSHRSGETEDTFIADLAVGLSTGQIKT

GAPCRSERLAKYNQLLRIEEELGAAAVYAGLKFRAP

11 A0233 Phi p M GS LS YVLALAVLAALVTGG AC IT VP PG P N ITTKYDTKWLP AKATWYG KPTG A

GPKDNGGACGIKDVNMAPYLGMTACGNVPIFKDGKGCGSCYQVKCKKPEPCS

DKPITIFITDKNYEPIAPYHFDLSGKAFGL ALPGKDQALRSVGELELQFRRVQC

KYPPGTKITFHVEKGSNPNYLAVLVKFVADDGDIVQVDIQDTQSPAWKPMTESW

GANA/VRWDGVPPLKGPISLRLTSESGKKLTAKDVIPATWKADTVYPSKIQF

12 A0246 Phl p DKEGIPPDQQRLIFAGKQLEDGRTLADYNIQKESTLHLVLRLRGGTMIKVKTLTG

KEIEIDIEPTDTIDRIKERVEEKEGIPPVQQRLIYAGKQLADDKTAKDYNIEGGSVL HLVLALRGGQ

13 A0260 Phi p MAGRGELWSFGE LIDFVPTVAGVSLAEAPAFVKAPGGAPANVAIAVARLGGK

AAFAGKLGDDEFGRMLAAILRDNGVDDSAWFDAGARTALAFVTLRADGDREF

MFYRNPSADMLLTADELNVGLLKRAAVFHYGSISLITEPCRSAHLRAMEIAKEAG

ALLSYDPNLREALWPSLEEARTKILSIWDQADIVKVSEVEVEFLTGVDSVEDDHV

MKLWRPTFKLMLVTLGDQGCKYYARDFRGMVSSYKVQQVDTTGAGDAFVGAL

LRKIVQDPSSLQDQKKLEGIIKFANACGAITTLTKGAIPSLPTETAVLRLMENA

14 A0262 Phi p VEYRCFVGGLAWATDDFNLKQAFSQFGEILDAKIINDRETGRSRGFGFVTFDSA

DAMNAAIEAMNGKDLDGRNITVNKANDRPRRRR

15 A0265 Phi p MGFRSDGSPATGGGISEKGRFSYGFASCTG RASMEDFYETRVDEVDGDTVG

LFGVFDGHGGARAAEYVKKHLFSNLIKHPKFITDTKSAIAETFNHTDSEFLKADS

SQSRDAGSTASTAIIVRGRLWANVGDSRAWSKGGKAIAVSRDHKPDQTDERQ

RIEEAGGFVMWAGTWRVGGVLAVSRAFGDKLLKQYWADPEIKEEWDGSLEF

LILASDGLWDWTNDEAVAMVKPIEDPEQAAKRLLEEASIRGSADNITWIVRFLD

GTTTVG

16 A0270 Phi p PWEAPTPILGEPMDLMTALQLVMKKSSAHDGLVKGLREAAKAIEKHVAQLCVL

AEDCDQPDYVKLVKALCAEHNVHLVTVPSAKTLGEWSGLCKIDSEGKARKWG CSCVWKDYGEESEGLNIVQEYVKSH

17 A0300 Phi p INDAVSRILRVKFTMGLFEDPLPDRRLAEHLGCKSHRELARDAVRKSLVLLKNGK

KNATAVLPLSKNAKKILVAGSHAHDLGLQCGGWTKSWQGQSGNNITGQGTTIL

EAIKSAVNN TVIDYSEHPDKDSISKSEDKYEYAVWVGEQAYAETAGDNQNLTI

PSPGPDVIRDVCELVKCVWLVSGRPLVIEPYLDTMDAFVAAWLPGTEGHGVAD

LLFGDYGFTGKLPRTWFRSVDQLPMNYGDKLYDPLFSFGYGLT

18 A0304 Phi p WFLEINPEGKVPVFNSGDGKWIADSDVITQVIEEKYPTPSLVTPPEYASVGSKIF

STFIAFLKSKDATDGTEKALVDELQALNEHLKAHGPYINGESVSAADLSLGPKLF HLQVALEHFKGWKIPETLTSVHAYT

19 A0311 Phl MSFTGTQDKCKACDKTVHFIDLLTADGVSYHKTCFKCSHCKGTLSMCSYSSMD

GVLYCKTHFEQLFKETGSFSKNFTPGG STDKNDQSKAPNKMSSIFSGTC.DKC AACQKTVYPLEKLSLEGECYHKSCFKCSHGGCILTTSSYAALNGILYCKIHFSQL FKEKGSYNHLIKTAQTKKENEEAAAAAEAEADADAKDNEEEVPPQDAT

20 A0316 Phi p MADAEDIQPLVCDNGTGMVKAGFAGDDAPRAVFPSIVGRPRHTGVMVGMGQK

DAYVGDEAQSKRGILTLKYPIEHGIVSNWDDMEKIWHHTFYNELRVAPEEHPVL

LTEAPLNPKANREKMTQI FETFNTPA YVAIQAVLSLYASGRTTGIVLDSGDGV

SHTVPIYEGYALPHAILRLDLAGRDLTDYLMKILTERGYSh I I I AEREIVRDVKEK

LSYIALDYDQELDTSKTSSSVEKSYELPDGQVITIGSERFRCPEVLFQPSFIGMEA

AGIHETTYNSIMKCDVDIRKDLYGNIVLSGGTTMFPGIADRMSKEITALAPSS KI

KWAPPERKYS\ WIGGSILASLSTFQQ WIAKAEYDESGPSIVHRKCF

21 A0317 Phi p GCITTKELGTV RSLGQNPTEAELQDMINEVDADGNGTIDFPEFLNL ARKMKD

TDSEEELKEAFRVFDKD

22 A0325 Phi p VKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMAKK

RKKKNYTTPKKIKHKRKPVKMAILKYFRVDSDGKIKRLRRECPAETCGPSVF A

QHADRQYCGKCGLTYKFDAE

23 A0326 Phl p TGDELLSDSFPYTELFEGVLWEVNGKWWNGSVDVDIGANPSAEGGCDDEGV

DDQAVKWDIVDTFRLQEQPPFD KQFLGFMKGYIKKLTAKLEGDELDCFKKNIE

GATKFLLGKIKDLQFFVGESMHDDCAWCAYYKEGAIDPTFLYFAHGLNEVKC

24 A0327 Phl p LLAVAVAFSAAAAINVEVAAVCKGTPYAELCSATAGKQASHYATVDALAVLGMQ Table 1 - SEQ ID NO: 1-37

SEQ ID NO: SpeAmino Acid Sequence

ID cies

NO:

VDAFSKRASAASIHATQLIARGKLSPGALIALRKCNEMYVNVEDNLGAARRAISF KDAVTIRAMMS AAQDMKNCDEEFRKNAAVNPMTRFDKSLLDISENCRALSNM

I

25 A0334 Phi p MALRNVAIRVFFLLLWSAAYAGKKEEKKDEKKESGDAASGADGTYDITKLGAK

PDGKTDCTKEVEEAWASACGGTGKNTIVIP GDFLTGPLNFTGPCKGDSVTIKL

DGNLLSSNDLAKYKANWIEIMRIKKLTITGKGTLDGQGKAVWGKNSCAKNYNCKI

LPNTLVLDFCDDALIEGITLLNA FFHMNIYECKGVTVKDVTITAPGDSPNTDGIHI

GDSSNINVTGTTIGTGDDCISIGGGSSRIIVTGVTCGPGQGISVGCLGRYKDEKD

VSDVTVKDCVLRSSTNGVRVKTYEDAVKSITASKLTFENIK DDVANPIIIDQNYC

PEKVCTAKSKSAVTVKDVIFRNITGTSSTPAAVSLLCSDKQPCSGVELIDVNVEY

SGKNNKTIGVCNNAKGTAKDTLQALACL

26 A0336 Phi p MEQTFIMIKPDGVQRGLIGDIISRFEKKGFYLKAMKFMNVERSFAQQHYADLSGK

PFFPKLVDYIISGPWAMVWEGKDWLTGRRIIGATRPWEAAPGTIRGDYAVEVG RNVIHGSDSVENGQKEIALWFPGGLAEWRSNLHPWIYEN

27 A0349 Phi p KELKDLQRDPPTSCSAGPVAEDMFHWQATIMGPAESPYAGGVFLVTIHFPPDY

PFKPPKVAFKTKVFHPNINSNGSICLDILKEQWSPALTVSKVLLSICSLLTDPNPD DPLVPEIAHMYKSDRVKYESTARSWTQKYAMG

28 A0349 Phi p ASKRILKELKDLQKDPPTSCSAGPVGEDMFHWQATIMGPSDSPFTGGLFLVNI

HFPPDYPFKPPKVSFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLT DPNPDDPLVPEIAH YKTDRAKYESTARSWTQKYAMG

29 A0349 Phi p DMFHWQATI GPSDSPYSGGVFLVTIHFPPDYPFKPPKVAFKTKVFHPNVNSN

GSICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYKADRAKYEST ARSWTQ

30 A0349 Phi p MASKRILKELKDLQKDPPTSCSAGPAGEDMFHWQATIMGPPDSPYAGGVFLVNI

HFPPDYPFKPPKVSFKTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLT DPNPDDPLVPEIAHMYKTDRSKYETTARSWTQKYAMG

31 A0356 Phi p MGKEKLHISIWIGHVDSGKSTTTGHLIYKLGGIDKRVIERFEKEAAEMNKRSFKY

AWVLDKLKAERERGITIDIALWKFETTKYSCTVIDAPGHRDFIKNMITGTSQADCA

VLIIDSTTGGFEAGISKDGQTREHALLAFTLGVKQMICCCNKMDATTPKYSKSRF

EEIVKEVSSYLKKVGYNPDKVPFVPISGFEGDN IERSTNLDWYKGPTLLEALDQ

VTEPKRPTDKPLRLPLQDVYKIGGIGTVPVGRVETGLIKPGMLVTFGPTGLTTEV

KSVEMHHESLLEAGPGDNVGFNV NVAVKDIKRGYVASNAKDDPAKESASFVA

QVIIMNHPGQIGNGYAPVLDCHTSHIAVKFAEIQTKVDRRSGKWEEFPKFLKNG

DAGFVKMVPTKPMWETFSQYPPLGRFAVRDMRQTVAVGVIKSVEKKDPTG

32 A0357 Phl p DMERIFKRFDTNGDGKISLSELTDALRTLGSTSADEVQRMMAEIDTDGDGFIDFN

EFISFCNANPGLMKDVAKVF

33 A0358 Phi p MSTPAAQVSEKPALRKPVFLKVDQLKPGTNGHNLIVKWSANPVPGRVRPGAP

ASSSARAPRIAECLVGDETGCIIFTARNDQVDLLKAGATAILRNAKIDMFKSSMRL

AVDKWGRVDSSEPASFTVNEENNLSQVEYELVNVAE

34 A0362 Phi p FSPEEISAMILGKMKETAEAYLGKKINDAWTVPAYFNDAQRQATKDAGVIAGLN

VARIINEPTAAAIAYGLDKKGSEKNILVFDLGGGTFDVSILTIDNGVFEVLATNGDT

HLGGEDFDHRIMDYFIKLIKKKYSKDISKDNRALGKLRREAERA RALSNQHQVR

VEIESLFDGTDFSEPLTRARFEELNNDLFRKTMGPVK AMDDAGLEKSQIHEIVL

VGGSTRIPKVQQLLRDYFDGKEPSKGVNPDEAVAFGAAVQGSILSGEGGDETK

DILLLDVAPLTLGIETVGGVMTKLIPRNTVIPTKKSQVFTTYQDQQTTVSIQVFEG

ERSMTKDCRLLGKFDLNGIPAAPRGTPQIEVTFEVDANGILNVKAEDKGTGKSE

KITITNEKGRLSQEEIDRMVKEAEEFAEEDKKVK

35 A0366 Phi p GTSAVSSLAATVPVEAVLFDIDGTLCDSDPLHHVAFQEMLLAIGYNNGVPIDEEF

FIKNIAGRSDVEAAQNLFPDWPLEKGLKFLEDKETKYRSLAMERLEPVNGLGKV VQWVKDHGYKRAAVTNAPRINAELML LLGLSDFFQAVIVGGECEKPKPAPFPY LKAL ELDVSAAHTFIFEDSASGTRAGVAAGMPWAVLTRNPEKSLEEAGAALIV KDYADPKLWSALEEIDGEEAKLKKGAA

36 A0376 Phi p MAQNFLLGGVGAILWAVWGWATVTHSGNKAGDNFTVPGEATLATSGKSVQ

SLCAPTLYKESCE TLTSASNGTENPKEVFSTMAMSAMESIKSAVERSKTIGEAK

SSDPLTQGAREDCKELLEDSVDDL GMVEMAGGDIKVLLSRSDDIEHWITGVMT

FIDTCADGFADEKLKADMQLILRNATELSSNALAITNSLGAIFKKLDLDVFKKDSR

RRLLSEKDEQGYPAWMKSPERKLLATGAMPAPNAWAKDGSGKFKTIQEAVNA

MPKGHPGRYVIYVKTGLYDEIVMIPKDKVNIFMYGDGPKQSRVTGRKSFKDGITT

MKTATFSIEMGFICKNMGFHNTAGAENHQAVALRVQGDLAAFYNCRFDAFQD

TLYVHARRQFFRNCVISGTIDFIFGNSAAIFQNCLIITRRP DNQQNSVTAHGRTD

PN KSGLVIQNCRLVPDQKLFPDRFKIPSYLGRPWKEYSRLVIMESTIADFIKPE Table 1 - SEQ ID NO: 1-37

SEQ ID NO: SpeAmino Acid Sequence

ID cies

NO:

GYMPWNGDFGIKTLYYAEYANRGPGAGTSKRVNWPGFRVIGRKEAEQFTTGP FVDGATWL FTGMPNYLGFKV

37 A0377 Phi p RLKTGFEKFKTDVYD KPDMFEPLKAGQAPKYMVFACADSRVCPSVTLGLEPG

EAFTVRNIANMVPSYCKNKYAGVGSAIEYAVCALKVEVIWIGHSRCGGIKALLSL KDGADDSFHFVEDWVRIGFPAKKKVQ ECASLSFDDQCGVLEKEAVNVSLENL LTYPFVKEGVSAGTLKLVGGHYDFVSGKFDTWE

Table 2. Polypeptides homologous to Phi p polypeptides shown in Table 1.

Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

38 A0202 Amb a NGMQHRKNSWMDGMPGTQCPILPNTNFTYKWQPKDQIGSF

YYFPSIGMQRAAGGYGGISVYSRLUPVPFDQPPPENDHWLI GDWYTKD

39 A0202 Amb p NGMQQRKNSWQDGLPGTNCPVAPGTNYTFKWQAKDQIGS

FFYFPSLGMQRAAGGYGMISWSRLLIPVPFDPPADDHWLI GDWYTKD

40 A0202 Bet v GIQHRKNSWQDGVLGTMCPIPPGTNYTYHFQVKDQIGSYIY

YPTTATHRAAGAFGGLRVNSRLLIPVPYADPEDDYTVLIGDW

YAK

41 A0202 Que a NGIQHRKNSWQDGLPGTNCPVAPGTNYTFKWQAKDQIGSF

FYFPSLGMQRAAGGYGMISWSRLLIPVPFDPPADDFQVLVG

DWYTKD

42 A0202 Cyn d NGMQHRKNSWMDGLPGTNCPIAPGTNFTYKWQPKDQIGSF

FYFPSIAMQRSAGGYGLISVHSRDLIPVPFDIPADDFAVLAGD WYTKD

43 A0203 Amb a MQIFVKTLTGKTITLEVESSDTIDNVKSKIQDKEGIPPDQQRLI

FAGKQLEDGRTLSDYNIQKESTLH

44 A0203 Amb a MQIFVKTLTGKTITLEVESSDTIDNVKAKIQDKEGIPPDQQRLI

FAGKQLEDGRTLADYNIQKESTLHLVLRLRGGF

45 A0203 Amb p MQIFVKTLTGKTITLEVESSDTIDNVKAKIQDKEGIPPDQQRLI

FAGKQLEDGRTLADYNIQKESTLHLVLRLRGGF

46 A0203 Bet MQIFVKTLTGKTITLEVESSDTIDNVKAKIQDKEGIPPDQQRLI

FAGKQLEDGRTLADYNIQKESTLHLVLRLRGGMQIFVKT

47 A0203 Que a MQIFVKTLTGKTITLEVESSDTIDNVKAKIQDKEGIPPDQQRLI

FAGKQLEDGRTLADYNIQKESTL

48 A0203 Cyn d MQIFVKTLTGKTITLEVESSDTIDNVKAKIQDKEGIPPDQQRLI

FAGKQLEDGRTLADYNIQKESTLHLVLRLRGGL

49 A0209 Amb a MAS FAE AP AG N PTVG E Kl F KTKCAQC HTVE KG AG H KQG P N L

NGLFGRQSGTTAGYSYSAGNKNKAVIWEENTLYDYLLNPKK YIPGTKMVFTGLKKPQERADLISYLKQSTA

50 A0209 Amb a MASFEEAPAGDAKVGEKIFKTKCAQCHTWKGAGHKQGPNL

NGLFGRQSGTTAGYSYSAANKNMAVIWEEKTLYEYLLNPKK

YIPGTKMVFPGLKKPKDRADLIAYLKESTA

51 A0209 Amb p M AS FE E APAG DAKVG E Kl F KTKCAQC HTWKG AG H KQG P N L

NGLFGRQSGTTAGYSYSAANKNMAVIWEEKTLYEYLLNPKK

YIPGTKMVFPGLKKPKDRADLIAYLKESTA Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

52 A0209 Bet v MASFDEAPPGNPKVGEKIFKTKCAQCHTVEKGAGHKQGPNL

NGLFGRQSGTTAGYSYSSANKNMAVNWEEKTLYDYLLNPK

KYIPGTKMVFPGLKKPQDRADLISYLKESTA

53 A0209 Que a SGEKIFKTKCAQCHTVEKGAGHKQGPNLNGLFGRQSGTTA

GYSYSTANKNMAVIWEEKTLYDYLLNPKKYIPGTKMVFPGLK

KPQERADLIAYLKSSTA

54 A0209 Cyn d PPGNPKAGEKIFKTKCAQCHTVDKGAGHKQGPNLNGLFGR

QSGTTPGYSYSAANKNRAVIWEENTLYDYLLNPKKYIPGTKM

VFPGLKKPQERADLIAYLKEATS

55 A0211 Amb a MANAASGMAVDDECKLKFQELKAKRSYRFITFKIEGQQVW

DKFGMPDETYEDFTNSLPADECRYAVFDFDFTTDENCQKSK

IFFIAWSPDTSRVRMKMVYASSKD

56 A0211 Amb p MANAASGMAVHDECKLKFLELKAKRTFRYIIFKIEEKQKEVIV

EKVGEPTQSHGDFAAALPDAECRYAVFDYDFVTEENCQKSR IFFIAWSPDTARVRNKMIYASSKDRFKRELDGIQVELQATDPT EMDLDVFKSRAN

57 A021 1 Amb p LKFQELKAKRSYRFITFKIEGQQVWDKFGMPDETYEDFTNS

LPADECRYAVFDFDFTTDENCQKSKIFFIAWSPDTSRVRMK

MVYASSK

58 A0211 Amb p MANAASGMAVNDECKLKFSELKSKRNYRFIVFKIEQQQVW

EKVGSPDESYEDFTNSLPANECRYAVFDFDFTTDENCQKSKI FFIAWAPDTSKVREKMVYASSKDRFKRELDGIQVEVQATDP SEMSLDIVKARAL

59 A0211 Amb p DECRYAVFDFDFVTDENCQKSKIFFISWAPDIARVRSKMLYA

SSKDRFKRELDGIQVELQATDPSEMSMDIVKARAL

60 A0211 Bet v MANSASGMAVHDECKLKFLELKAKRNHRFIVFKIDEKIQQVIV

EKVGSPDETYDDFNASMPPNECRYAVFDFDFTTDENVQKSK IFFIAWAPDTSRVRSKMLYASSKDRFRRELDGVQVELQATDP SEMSLDIIKGRAL

61 A0211 Bet v MANAASGMAVSDECKLKFLELKTKRNYRFIIFKIENQEVWEK

VGCPDETYEDFTASIPADECRYAVFDFDFITDENCQKSKIFFI AWS P DTS RVRS KMVYAS SKDRFKRELDGI Q VE LQ ATD PS E M SLDIVKGRAL

62 A0211 Que a MANSASGMAVHDDCKLKFLELKAKRNYRFIVFKIEEKIQQVIV

EKLGGPEETYDDFTASMPANECRYAVFDFDFITDENCQKSKI FFISWSPDTSRVRSKMLYASSKDRFRRELDGVQVELQATDP SEMSLDIIKGRAL

63 A0211 Cyn d MSNSASGMAVCDECKLKFQELKAKRSFRFIVFKINEKVQQW

VDRLGQTGESYDDFTACLPADECRYAVFDFDFVTDENCQKS KIFFISWSPDTSRVRSKMLYASSKDRFKRELDGIQVELQATD PSEMSMDIVKARAL

64 A0215 Amb p AITVDEACRQYTKHPSYCKRTLAPKVDPSAPTTLPALAEQAV

LLAAESGVAAVSYVKNLEKIPGGMPLGCLERCVGRFQAAVA ALMQSRVAIVEHRDVARVKAWVKTARVDGENCMAGCHTEG GVDPAVKRRISKLGKICSI

65 A0215 Que a AITVDEACRQYTKHPSYCTHALSAKAGPPETTLPALAVQAVT

LAAESGGSAVLFVKNLEKMPGGMPLGCLERCVGKFQAAVA

ELTLSRVAIVEHRDVARVKAWVKAARADGETCMDGCHTEG Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

GADPTIIHRIGDLGKLCSIALSLTD

66 A0215 Cyn d AITVDEACRKYTKHPSYCTHALSAKAGPPETTLPALAVQAVT

LAAESGGSAVLFVKNLEKMPGGMPLGCLERCVGKFQAAVA ELTLSRVAIVEHR D VAR VKAWVKAARADG ETC DGCHTEG GADPTIIHRIGDLGKLCSIALALTDA

67 A0219 Amb a LLKVNQIGSVTESIEAVKMSKRAGWGVMASHRSGETEDTFIA

DLSVGLATGQIKTGAPCRSERLAKYNQLLRIEEELGAAAVYA

GSKFRAP

68 A0219 Amb p LLKVNQIGSVTESIEAVKMSKRAGWGVMASHRSGETEDTFIA

DLSVGLATGQIKTGAPCRSERLAKYNQLLRIEEELGAAAVYA

GSKFRAP

69 A0219 Bet v LLKVNQIGSVTESIEAVRMSKRAGWGVMASHRSGETEDTFIA

DLSVGLATGQIKTGAPCRSERLAKYNQLLRIEEELGSAAVYA

GSKYRAP

70 A0219 Que a LLKVNQIGSVTESIEAVKMSKHAGWGVMASHRSGETEDTFIA

DLSVGLATGQIKTGAPCRSERLAKYNQLLRIEEELGPAAVYA

GSKFRAP

71 A0219 Cyn d LLKVNQIGSVTESIEAVKMSKHAGWGVMTSHRSGETEDTFIA

DLAVGLATGQIKTGAPCRSERLAKYNQLLRIEEELGAAAVYA

GAKFRAP

72 A0233 Amb a KFPPGPNITTNYNGQWLTARATWYGQPNGAGPDDNGGAC

GIKGVNLPPYNGMTACGNIPIFKDGKGCGSCYEVRCKEKPE CSGQPITVFITDMNYEPIAPYHFDFSGKAFGSLAKPGLNDKL RHCGIMDVEFRRVRCKLPGQKILFHVEKGCNPNYLAVLVKN VADDG

73 A0233 Amb p CITKVPPGPNITTKYDTKWLPAKATWYGKPTGAGPKDNGGA

CGIKDVNLAPYLGMTACGNVPIFKDGKGCGSCYELKCQKPE PCADKP

74 A0233 Que a MGSLSYVLAVAVLAALVTGGVCITKVPPGPNITTKYDTKWLP

AKATWYG KPTGAG PKDNGGACG I KDVN LAPYLG MTACG N V

PIFKDGKGCGSCYELKCQKPAPCADKPITIFITDKNYEPIAPY

HFDLSGKAFGLMALPGQDQKLRSVGELELQFRRVQCKYPA

GTKITFHVEKGSNPNYLAVLVKFVANDGDIVQMEIQDSQSAA

WKPMTESWGAVWRWDGAPPLKGPLSLRLTSESGKKLIAKD

VIPATWKADNVYPSNIQF

75 A0233 Cyn d GSLSYVLAVAVLAALVTGGACITKVPPGPNITTKYDTKWLP

AKATWYGKPTGAGPKDNGGACGIKDVNLAPYLGMTACGNV

PIFKDGKGCGSCYELKCQKPEPCADKPITVFITDKNYEPIAPY

HFDLSGHAFGLMALPGKDQALRSVGELELEFRRVRCKYPPG

TKITFHVEKGSN

76 A0233 Amb p EPCSDKPITVFITDKNYEPIAPYHFDLSGKAFGLMALPGKDQA

LRSVGELELQFRRVQCKYPAGTKITFHVEKGSNPNYLAVLVK FVANDGDIVQ EIQDSQSAAWKPMTESWGAVWRWDGAPP LKGPLSLRLTSESGKKLIAKDVIPATWKADNVYPSNIQF

77 A0246 Amb a DKEGIPPDQQRLIFAGKQLEDGRTLADYNIQKESTLHLVLRLR

GGMQIFVKTLTGKTITLEVESSDTIDNVKAKIQDKEGIPPDQQ

RLIFAGKQLEDGRTLADYNIQKESTLHLVLRLRGG

78 A0246 Amb p NIQKESTLHLVLRLRGGTMIKVKTLTGKEIEIDIEPTDTIDRIKE Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

RVEEKEGIPPVQQRLIYAGKQLADDKTAKDYNIEGGSVLHLV LALRGG

79 A0246 Bet v DKEGIPPDQQRLIFAGKQLEDGRTLADYNIQKESTLHLVLRLR

GGTMIKVKTLTGKEIEIDIEPTDTIDRIKERVEEKEGIPPVQQRL IYAGKQLGDDKTAKDYNIEGGSVLHLVLALRGGS

80 A0246 Que a QQRLIFAGKQLEDGRTLADYNIQKESTLHLVLRLRGGTMIKV

KTLTGKEIEIDIEPTDTIDRIKERVEEKEGIPPVQQRLIYAGKQL

GDDKTAKDYNIEGGSVLHLVLALRGGS

81 A0246 Cyn d DKEGIPPDQQRLIFAGKQLEDGRTLADYNIQKESTLHLVLRLR

GGTMIKVKTLTGKEIEIDIEPTDTIDRIKERVEEKEGIPPVQQRL IYAGKQLADDKTAKDYNIEGGSVLHLVLALRGGQ

82 A0260 Amb a NGSLWCFGEMLIDFVPSVSGVSLAEAPAFHKAPGGAPANV

AVGISRLGGSSAFIGKVGDDEFGRMLADILKENKVDNSGMRF

DQKARTALAFVTLRSDGEREFMFFRNPSADMLLHESELDVN

LIKQASIFHYGSISLIEEPCKSTHLAAMAIAKKSGSILSYDVNLR

LPLWPSEDAARDGIMSIWDQAD

83 A0260 Amb p NGSLWCFGEMLIDFVPSVSGVSLAEAPAFHKAPGGAPANV

AVGISRLGGSSAFIGKVGDDEFGRMLADILKENKVDNSG RF

DQKARTALAFVTLRSDGEREFMFFRNPSADMLLHESELDVN

LIKQASIFHYGSISLIEEPCKSTHLAAMAIAKKSGSILSYDVNLR

LPLWPSEDAARDGIMSIWDQADVIKVSEDEITFLTRGDDPYD

DNWLNKLFHPNLKLLLVSEGPDGCRYYTQNFKGRVPGVKV

KPVDTTGAGDAFVGGILSVLASDTDLYKDEAKLREALLFANA

CGALTVTKKGAIPAMPTRDEVQKILK

84 A0260 Bet v LIVSFGEMLIDFVPTVSGVSLAEAPGFVKAPGGAPANVAIAVS

RMGGKASFVGKLGEDDFGRMLAGILDQNGVDCSGITFDQG

ARTALAFVTLRADGEREFMFYRNPSADMLLRPDELNLELIRS

AKAFHYGSISLIVEPCRSAHLKAMEVARDAGALLSYDPNLRL

PLWPSPEEAREQIMSIWDKADVIKVSDVELEFLTGSDKIDDA

SAFSLLHPNVKLLLVTLGEHGCRYYSKNFHGAVEAFHVTQV

DTTGAGDSFVGALLSKIVDDRSILEDEQRLRRVLTFANACGAI

I I I KKGAIPALPTEAEAVTLLQ

85 A0260 Que a LIVSFGEMLIDFVPTVSGVSLAEAPGFLKAPGGAPANVAIAVS

RLGGKAAFVGKLGDDEFGHMLAGILRENGWDEGINFDKGA

RTALAFVTLRADGEREFMFYRNPSADMLLTPDELNLDLIRSA

KVFHYGSISLIVEPCRTAHLKAMEVAKDAGLLLSYDPNLRLPL

WPSPEEARVQIKSIWDKADLIKVSDVELEFLTGSNKIDDESA

MSLWHPNLKLLLVTLGDLGCRYYTKNFHGEVEAFRVNTV'DT

TGAGDSFVGALLCKIVDDQSILEDEPRLRAVLKFANACGAITT

TKKGAIPALPTESDALSLIK

86 A0260 Cyn d MADRRDLWSFGEMLIDFVPTVAGVSLAEAPAFVKAPGGAP

ANVAIAVSRLGGAAAFVGKLGDDEFGRMLAGILRENGVEDG

GWFDSGARTALAFVTLRADGEREFMFYRNPSADMLLTADE

LNVELITRAAVFHYGSISLIAEPCRSAHLRAMEIAKEAGALLSY

DPNLREALWPSREEARTQILSIWDQADIVKVSEVELEFLTGID

SVEDDWMKLWRPTMKLLLVTLGDQGCKYYARDFRGAVPS

YKVQQVDTTGAGDAFVGALVRKIVQDPSSLQDQKKLEEAIKF

ANACGAITATKKGAIPSLPTETEVLQLIERA

87 A0262 Amb p VEYRCFVGGLAWATSDQSLGDAFSKYGEWDTKIINDRETG Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

RSRGFGFVTFRDEQSLRSAIEGMNGQSLDGRNITVNEAQ

88 A0262 Bet v VEYRCFVGGLAWATDDQALERAFSPYGDILESKIINDRETGR

SRGFGFVTFGNEKA RDAIEGMNGQNLDGRNITVNEA

89 A0262 Que a VEFRCFVGGLAWATDDQALERAFSPYGDILESKIINDRETGR

SRGFGFVTFSNEKSMRDAIEGMNGQNLDGRNITVNEA

90 A0262 Cyn d VEYRCFVGGLAWATSDDSLHAAFSPFGEVLESKIINDRETGR

SRGFGFVTFANEQAMRDAIEQMNGKQLDGRNITVNEA

91 A0262 Amb a KVFVGGLSWATDDKSLREAFSSYGEVTEAKVIRDRETGRSR

GFGFVTFADPDSCPNAIIALDQWELHGRTVSVRWADDRPR

92 A0265 Amb a SPDSGGGVSEDSKFSYGFASTTGKRSSMEDFYEARIDCVDG

EMIGLFGVFDGHGGARAAEYVKHHLFNTLLKHPKFITDTKAAI

SDAYSHTDTEFL SENNQNRDAGSTASTAILVGDRLLVANVG

DSRAVISRGGKAFAVSRDHKPDQSDERQRIEDAGGFVMWA

GTWRVGGVLAVSRAFGDKLLKQYWADPEIQEEKVDNSLEF

LILASDGLWDWTNDEAVAMVKPIESPEDAAKRLVQEASERG

SADNITWWRFLEN

93 A0265 Amb p SPDSGGGVSEDSKFSYGFASTTGKRSSMEDFYEARIDCVDG

EMIGLFGVFDGHGGARAAEYVKHHLFNTLLKHPKFITDTKAAI

SDAYSHTDTEFLKSENNQNRDAGSTASTAILVGDRLLVANVG

DSRAVISRGGKAFAVSRDHKPDQSDERQRIEDAGGFVMWA

GTWRVGGVLAVSRAFGDKLLKQYWADPEIQEEKVDNSLEF

LILASDGLWDWTNDEAVAMVKPIESPEDAAKRLVQEASERG

SADNITWWRFLEN

94 A0265 Bet v HAEDAPVSGGGLSQNGKFSYGYASSPGKRSSMEDFYETRI

DGVEGEIVGLFGVFDGHGGARAAEYVKQNLFSNLIRHPKFIS

DTKSAIADAYNHTDSEFLKSENSQNRDAGSTASTAILVGDRL

LVANVGDSRAVICRGGNAIAVSRDHKPDQTDERQRIEEAGG

FVMWAGTWRVGGVLAVSRAFGDRLLKQYWADPEIQEEKID

SSLEFLILASDGLWDWTNEEAVAMVKPIPEPEEAAKRLMQE

AYQRGSADNITIWVRFL

95 A0265 Cyn d MGFPGERSPTSGGGFSENGKFSFGYASSPGKRSSMEDFYE

TRVDGVDGETVGLFGVFDGHGGARAAEFVKQNLFTNLINHP

KLFSDTKSAIAETYTHTDSELLKGETSHNRDAGSTASTAILVG

DRLWANVGDSRAVICRGGDAIAVSRDHKPDQSDERQRIED

AGGFVMWAGTWRVGGVLAVSRAFGDKLLKQYWADPEIKE

EKVDSSLEFLILASDGLWDWTNEEAVAMVKPIIDSEQAAKKL

LQEASQRGSADNITCWVRFLD

96 A0265 Que a ARAAEFVKQNLFSNLIKHPKFFTDTKSAIAETFTRTDSELLKA

DTTHNRDAGSTASTAILVGDRLWANVGDSRAVICRGGDAIA

VSRDHKPDQTDERQRIEDAGGFVMWAGTWRVGGVLAVSR

AFGDKLLKQYWADPEIKEEWDSSLEFLILASDGLWDWTN

EEAVAMVKPIVDSQEAAKKLLVEATQRGSADNITCWVRFLD

97 A0270 Amb a VEAPAPALGEPMDIMTALQLVLRKSLAHGGLIRGLHEAAKVIE

KHAALLCVLAEDCNQPDYQKLVKALCADHNVSLVTVPSAKTL GEWAGLCKI

98 A0270 Amb p VEAPAPALGEPMDIMTALQLVLRKSLAHGGLIRGLHEAAKVIE

KHAALLCVLAEDCNQPDYQKLVKALCADHNVSLVTVPSAKTL GEWAGLCKIDSEGKARKWGCSCLWKDYGEESEGLHIVQE YVKSH Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID

NO:

99 A0270 Bet v VTETPVAPLGEAMDVMTALQHVLRKSLAHGGLVRGLHEAAK

VIEKHAAQLCVLAEDCNQADYLKLVKALCADHNVKLMTVPSA KTLGEWAGLCKIDSEGKARKWGCSCVWKDFGEQTEGYN VIQEYVKSH

100 A0270 Que a LGEAMDIMTALQWLRKSLAHGGLARGLHEGAKVIEKHAAQL

CVLAEDCNQPDYVKLVKGLCADHNVSLMTVPSAKTLGEWA GLCKIDSEGKARKWGCSCVWKDFGEVHEALHIVQEHVKS

H

101 A0270 Cyn d VEAPTPVLGEPMDLMTALQLVMKKSSAHDGLVKGLREAAKA

I E KH AAQ LCVLAE DC D Q P D YVKLVKALCAE H N VH LVTVPSAK TLGEWAGLCKIDSEGKARKWGCSCVWKDYGEESEGLNIV QEYVKSH

102 A0300 Amb a IDDAVSRILRVKFTMGLFENPLADYSMVNEVGSQAHREIARE

AVRKSLVLLKNGKTAVDPMLPLPKMSSKILVAGSHADNLGYQ

CG

103 A0300 Amb p IDDAVERILRVKFAAGLFEHPMTDRSLLNIVGSKPHRELAREA

VRKSLVLLKNGKDPNKPFLPLNRNVKKVLVAGKHADDLGYQ

CGGWTSTWEGTSGRITIGTTILDAVKETIGDNAEWYEENPS

AETLSEHDFSYAIVWGEAPYVESGGDNSELIIPFKGDELLKL

VAQQIPTLAILISGRPLVLEPSVLETLDALIAAWLPGTEGNGIT

DVIFGDHEFHGRLPVSWFKSVDQLPMDSNKSSYDPLFPLGY

GL

104 A0300 Bet v INDAVKRILRVKFSLGLFENPLADLSLADKLGCKEHRELAREA

VRKSLVLLKNGKSAPAGPLLPLAKKVPKILVAGSHADNLGFQ

CGGWTI EWQGRDG N N LTVGTTI LNG I KATVDTSTQWFN E N

PDPAFVKSSGFSYAIVWGEQPYAETNGDNLNLTLPEPGPST

INNVCGAVKCWIWSGRPLVIEPYLASVDALVAAWLPGSQG

EGVADVLFGDYGFTGKLARTWFKRVDQLPMNVGDAHYDPL

FPFGFGLT

105 A0300 Que a IDDAVKRILRVKFTMGLFENPLADDSQADLLGAQEHRELARE

AVRKSLVLLKNGKSAYAGPVLPLPRKSQRILVAGTHADNLGY

QCGGWTIEWQGLSGNNLTSGTTILKAIKDTVDSSTQWFKEN

PDPAFINSDDFAYAIVWGEQPYAETNGDNLNLTLPAPGPDTI

KNVCSHIKCVWWSGRPLVIEPYLESMDALVAAWLPGTEGQ

GVADVLFG D YG FTG KLARTWFKRVDQLPM N VG DAH YDPLF

PFEFGLT

106 A0300 Cyn d VNDAVSRILRVKFAMGLFEDPLPDPRLAKELGAQNHRAIARE

AVRKSLVLLKNGKKGKAVLPLAKKAKKILVAGSHAHNLGYQC GGWTGTWQGQSG N N FTG VGKTI LEAI KSTVDNSTTVEYS E E PDKETIEKAGDYEYAWAVGELPYAETAGDNQNLTIPAPGAK VIKEVCGLVKCWLIVSGRPLWEPYVDYMDALVAAWLPGTE GQGVTDVLFGDYGFTGKLPRTWFKSVDQLPMNYGDKRYDP LFPFGYGLT

107 A0300 Amb a LGCEEHRDLAREAVRKTLVLLKNGKSSMQPLLLLSKKTSKILV

AGSHADNLGYQCGGWTIEWQGLSGDVTSVEKTVDPNTQVI

YNENPNQDFIKSNNFDFAIVWGERPYAETFGDSSNLTILEPG

PSTIRNVCGSVKCVWLITGRPWMQPFVDTIDALVAAWLPG

TEGQGVTDVLFGDYGFTGKLARTWFKSVNQLPMNVGDPHY

DPLYRFGFGL Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

108 A0300 Amb a GTEGQGVTDLLFGDYGFTGKLARTWFKSVDQLPMNVGDKH

YDPLFPFGFGLT

109 A0304 Amb a WLFEVNPEGKVPLAKFDDNWVSDSDVIVGIIEDKYPHPSLVT

PPELASVGSNIFSKFIAFLKSKDANDGTEQALLDELNALNEHL KSKGPYVNGETITAVDLSLGPKLYHLQVALGHYKKWTVPESL THLHNY

110 A0304 Amb p WFLSISPEGKAPLAKLDDKWISDSDVITQTIEEKFPDPSLVTP

PEKASVGSKIFSTFIAFLKSKDANDGTEQALLNELSAFNDYIK ENG

111 A0304 Bet v WFLKINPDGKVPAIKFDEKWIPDSDVITQALEEKYPVPPLGTP

PEKASVGSKIFSTFIGFLKSKNPSDGTEQALLNELSSFNDYLK ENGPFINGKEVSAVDLSLGPKLHHLEIALGHYKNWSVPDSLP HVKSY

112 A0304 Que a WFLKLNPGGKVPVIKLNEKWISDSDVIAQALEEKYPDPPLGT

PPEKASVGSKIFSTFIGFLKSKDPSDGTEKALISELSSFNNHIK

DNGPYVNGKEVSAVDLSLADR

113 A0304 Cyn d WFLKINPEGKVPVFNSGDGKWIADSDVIVQIVEEKYPTPSLVT

PPEYASVGSKIFSTFVTFLKSKDANDGSEQALLNELQALEEH LKAHGPYINGQNVSAADLSLAPKLYHLHVALEHFKGWKIPES LTNVNAYS

114 A0311 Amb a MSFIGTQQKCKACGKTVYPVELLSADGIDYHKSCFKCSHCK

GTLKLSNYSSMEGVLYCKPHFEQLFKESGNFNKNFTSPA A

ADKLSPMLTKSPSKAAG FSGTQEKCATCGKTAYPLEKVTV

ENQAYHKSCFKCSHGGCSLSPSNYAALEGILYCKHHFSQLF

KEKGSYNHLIKSASIKR

1 15 A0311 Amb a TFSGTQDKCKACDKTVHFIDLLSADGVPYHKTCFKCSHCKG

TLSMSGYSSMEGVLYCKPHFEQLFKETGSFTKKFPSSGAEK REMTRTPSKLSAFFSGTQDKCSTCKKTV

116 A0311 Amb a MGFGGTIDKCNACDKTVHFVDLLTVDSVIYHKRCFKCSHCK

GTLVMSNYSSMDGVLYCMPHFEQLFKETGNFSKNFPSKPN

RDNSTPQLPNKFSFFFSGTQDKCRLCDKTVYFIDKMTMEGE

SYHKQCFRCIHGGCPLTHSSYAALNGVLYCRHHFAQLFLEK

GTLSHVLMAADRKKNTVPPDQETELADDDKLLKQEE

117 A0311 Amb a MSFTGTLDKCKACDKTVYFVDLLSVDGVTYHKACFRCSHCK

GTLAMSNYSSMDGVLYCKPHFEQLFKESGNFSKNFHTSKPD

RESAHSRAPNKLSSLFSGTLDKCRQCNKTVYPLEKVTMEGE

PYHKSCFRCAHGGCPLTHSSYAALDGILYCKHHFAQLFMEK

GNFSHVLEAANRKSNAKAEDIAPEQPP

118 A0311 Amb p MTFTGTQDKCKACDKTVHFIDLLTADSISYHKSCFKCSHCKG

TLSMCNYSSMDGVLYCKTHFEQLFKETGNFNKNFPTCAKAN

NEQSKVPNRLSSVFCGTQDKCAACKKTVYPLEKMTLEEEPY

H TCFKCAHGGCLLTTASYAALNGILYCQHHFWQLFKETGS

YDNLLKPAKKTEEPEATREEVPPEE

119 A0311 Bet MSFTGTQQKCKVCEKTVYPVEQLSADGVIYHKSCFKCSHCK

GTLKLSNYSSMEGVLYCKPHFEQLFKETGSFNKNFQSPAKS AEKLTPEMTRSPSKAASMFSGTQEKCATCGKTAYPLEKVTV ESQAYHKSCFKCSHGGCPITPSNYAALEGILYCKHHFAQLFK E KGS YN H L I KS AS I KRAAAAS VP EAAP A Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

120 A0311 Que a MTFTGTQDKCKACDKTVHFIDLLTADSISYHKSCFKCSHCKG

TLSMCNYSSMDGVLYCKTHFEQLFKETGNFNKNFPTCAKAN

NEQSKVPNRLSSVFCGTQDKCAACKKTVYPLEKMTLEEEPY

HKTCF CAHGGCLLTTASYAALNGILYCQHHFWQLFKETGS

YDNLLKPAKKTEEPEATREEVPPEE

121 A0311 Cyn d MSFTGTQDKCNACDKTVHFIDLLTADGVIYHKTCFKCSHCKG

ILSMCSYSSMDGVLYCKTHFEQLFKETGSFSKKFTPGGKSS

EKGELARAPSKLSSAFSGTQDKCAACQKTVYPLEKLTLEGE

PYHKSCFKCSHGGCILTTSSYAALNGVLFCKIHFSQLFMEKG

SYNHMKKKSESQEALPDWADEQPAASPQDEEV

122 A0316 Amb a MADGEDIQPLVCDNGTGMVKAGFAGDDAPRAVFPSIVGRPR

HTGVMVGMGQKDAYVGDEAQSKRGILTLKYPIEHGIVNNWD

DMEKIWHHTFYNELRVAPEEHPVLLTEAPLNPKANREKMTQI

MFETFNSPAMYVAIQAVLSLYASGRTTGIVLDSGDGVSHTVP

IYEGYALPHAILRLDLAGRDLTDSLMKILTERGYSFTTSAEREI

VRDMKEKLAYIALDFEQELETSKTSSSVEKSFELPDGQVITIG

AERFRCPEVLFQPSMIGMESAGIHETTYNSIMKCDVDIRKDL

YGNIVLSGGTTMFPGIADRMSKEITALAPSSMKIKWAPPERK

YSVWIGGSILASLSTFQQMWIAKAEYDESGPSIVHRKCF

123 A0316 Amb p MADGEDIQPLVCDNGTGMVKAGFAGDDAPRAVFPSIVGRPR

HTGVMVGMGQKDAYVGDEAQSKRGILTLKYPIEHGIVNNWD

DMEKIWHHTFYNELRVAPEEHPVLLTEAPLNPKANREKMTQI

MFETFNSPAMYVAIQAVLSLYASGRTTGIVLDSGDGVSHTVP

lYEGYALPHAILRLDLAGRDLTDSLMKILTERGYSFTTSAEREI

VRDMKEKLAYIALDFEQELETSKTSSSVEKSFELPDGQVITIG

AERFRCPEVLFQPSMIGMESAGIHETTYNSIMKCDVDIRKDL

YGNIVLSGGTTMFPGIADRMSKEITALAPSSMKIKWAPPERK

YSVWIGGSILASLSTFQQMWIAKAEYDESGPSIVHRKCF

124 A0316 Bet v MAEADDIQPLVCDNGTGMVKAGFAGDDAPRAVFPSIVGRPR

HTGVMVGMGQKDAYVGDEAQSKRGILTLKYPIEHGIVSNWD

DMEKIWHHTFYNELRVAPEEHPVLLTEAPLNPKANREKMTQI

M FETFNTPAM YVAI QAVLS LYASG RTTG I VLDSG DG VS HTVP I

YEGYALPHAILRLDLAGRDLTDALMKILTERGYSFTTTAEREI

VRDMKEKLAYIALDYEQELETAKTSSSVEKSYELPDGQVITIG

AERFRCPEVLFQPSMIGMEAAGIHETTYNSIMKCDVDIRKDL

YGNIVLSGGSTMFPGIADRMSKEITALAPNSMKIKWAPPERK

YSVWIGGSILASLSTFQQMWIAKAEYDESGPSIVHRKCF

125 A0316 Que a MAETEDIQPLVCDNGTGMVKAGFAGDDAPRAVFPSIVGRPR

HTGVMVGMGQKDAYVGDEAQSKRGILTLKYPIEHGIVSNWD

DMEKIWHHTFYNELRVAPEEHPVLLTEAPLNPKANREKMTQI

MFETFNTPAMYVAIQAVLSLYASGRTTGIVLDSGDGVSHTVPI

YEGYALPHAILRLDLAGRDLTDHLMKILTERGYSh I I I AEREI

VRDMKEKLAYIALDYEQEIETSKTSSSVEKSYELPDGQVITIG

AERFRCPEVLFQPSMIGMEAAGIHETTYNSIMKCDVDIRKDL

YGNIVLSGGSTMFPGIADRMSKEITALAPSSMKIKWAPPERK

YSVWIGGSILASLSTFQQMWIAKAEYDESGPSIVHRKCF

126 A0316 Cyn d MADAEDIQPLVCDNGTGMVKAGFAGDDAPRAVFPSIVGRPR

HTGVMVGMGQKDAYVGDEAQSKRGILTLKYPIEHGIVSNWD DMEKIWHHTFYNELRVAPEEHPVLLTEAPLNPKANREKMTQI Table 2 - SEQ ID OS:38-21 1

SE ID NO: SpeAmino Acid Sequence

Q cies

ID

NO:

MFETFNTPAMYVAIQAVLSLYASGRTTGIVLDSGDGVSHTVPI

YEGYALPHAILRLDLAGRDLTDYLMKILTERGYSh I I I AEREI

VRDMKEKLAYIALDYDQEMETAKTSSSVEKSYELPDGQVITI

GAERFRCPEVLFQPSFIGMEAAGIHETTYNSIMKCDVDIRKDL

YGNIVLSGGTTMFPGIADRMSKEITALAPSSMKIKWAPPERK

YSVWIGGSILASLSTFQQMWIAKAEYDESGPSIVHRKCF

127 A0317 Amb a GCITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFP

EFLNLMARKMKDTDSEEELKEAFRVFDKD

128 A0317 Amb p GCITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFP

EFLNLMARKMKDTDSEEELKEAFRVFDKD

129 A0317 Bet v GCITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFP

EFLNLMARKMKDTDSEEELKEAFRVFDKD

130 A0317 Que a GCITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFP

EFLNLMARKMKDTDSEEELKEAFRVFDKD

131 A0317 Cyn d GCITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFP

EFLNLMARKMKDTDSEEELKEAFRVFDKD

132 A0325 Amb a AKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLV

LRLRGGAKKRKKKNYSTPKKIKHKKKKIKLAVLKYYKVDENG

KISRLRRECPSEQCGAGVFMAAMEDRHYCGKCSYTLVFN

133 A0325 Amb p VKSKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLH

LVLRLRGGMAKKRKKKVYTTPKKIKHKRKKTKLAVLKYYKVD GDGKIERLRRECPQPECGAGVFMAAMHNRQYCGKCHLTYV FD

134 A0325 Bet v AGKQLEDGRTLADYNIQKESTLHLVLRLRGGAKKRKKKQYTT

PKKIKHKRKKVKMAVLKYYKVDADGALKRLRRECPAPECGA

GTFMAWHENRQYCGKCHLTYLF

135 A0325 Bet v VKSKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLH

LVLRLRGGMAKKRKKKVYTTPKKIK

136 A0325 Bet v FAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG-

AKKRKKKTYTKPKKLKHKKKKVKLSVLQFYKVDDSGKVQRL

RKECPNTECGAGTFMANHFDRHYCGKCGLTYVY

137 A0325 Que a VKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLADYNIQKESTLH

LVLRLRGGAKKRKKKTYTKPKKIKHKHKKVKLAILQFYKVDDS GKVQRLRKECPNSECGAGTFMANHFDRHYCGKCGLTYVY

138 A0325 Cyn d VKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLH

LVLRLRGGMAKKRKKKNYTTPKKIKHKRKPVKMAILKYYRVD SDGKIKRLRRECPSETCGPSVMMAQHADRQYCGKCGLTYK FDAE

139 A0326 Amb a DDEGVDDQAVKWDIVDTFRLQEQPPFDKKQFVAYIKKYIKSI

TPKLDEEKQDFFKKNIEAATKFLLSKLSDLQFFVGESMHDDS TIVFAYYKDGASDPTFLYFGVGLKEVKC

140 A0326 Amb p VWVQGAVDVDIGANPSAEGADEDEGVDDQAVKWDIVDTFR

LQEQPAFNKKQFVAYIKNYIKNVTPKLDEEKQEFFKKNIEAAT

KFLLGKLSDLQFFVGESMHDDS

141 A0326 Bet TGDELLSDSFPYKEIENGMLWEVEGKWWQGAVDVNIGANP

SAEGGDEDEGVDDQHVKWDIVDTFRLQEQPPFEKKQFVTF MKRYIKNLAAKLEPEQQALFKKHIEGAIKYLLPKISDLQFFVGE SMHDDGSLVFAYYKEGATDPTFIYLAYGLKEVKC Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

142 A0326 Que a TGDELLSDSFPYKEIENGMLWEVEGKWWQGAVDVDIGANP

SAEGGGEDEGVDDQAVKWDIVDTFRLQEQPSFDKKQFVTF MKRYIKLLTPKLEGEQQDIFKKNIEGATKFLLSKLSDLQFFVG ESMHDDGGLVFAYYKEGATDPTFLYFAHGLKEIKC

143 A0326 Cyn d TGDELLSDSFPYKEIENGILWEVEGKWWQGPVDVDIGANPS

AEGGDEEGVDDQAVKWDIVDTFRLQEQPAFDKKQFVTFIK RYIKNLTAKLEPEKAEEFKKGIEGATKFLLGKLKDLQFFVGES MHDDGTLVFAYYKDGATNPTFLYFGHGLKEVKC

144 A0327 Amb a LAEICKGTAFPDICTSTVGSDPASHGPLDPMAVLRMQVEQFL

KRTEAARAHVKEAALTASPKARTVLDLCNNLYLDVEDNLGAC RRAIGFHDAVTIRATMGMAAQDMQNCDEQFRQIGEKNPME QFDASLVEMSENCRSLSNMI

145 A0327 Amb p DVAFVCKGTPYAE LC I ATAG KQASH YPTVDALTVLG MQVDA

FSKRAAAARLHAVQISASGKVTPGALAALKTCDELYSNVEDN LGATRRAIGFKDPVTIRAMMSMSAQAMKSCDEEFKKNAAVN PLTRFDQSLLNISENCRALSNMI

146 A0327 Que a DVAFVCKGTPYAELCIATAGKQASHYPTVDALTVLGMQVDA

FSKRAAAARLHAVQISASGKVTPGALAALKTCDELYSNVEDN LGATRRAIGFKDPVTIRAMMS SAQAMKSCDEEFKKNAAVN PLTRFDQSLLNISENCRALSNMI

147 A0327 Cyn d ICKATSFPDVCIKTAGKHVKHYSSVDALSVLHMQVDAFSKRA

AAAR RVASKVRKASPAARNALTMCGKFYLDVEDNLGACRR AMRHRDGVTIRATMSMAAQDMQNCDEQFRQAGENKNPLE RFNKSLGQMAEVCRSLSNMI

148 A0334 Amb a DIAQLGAKGDGKSDSTPMLLKAWKNACDATGVQKIVIPPGN

YLTGGLELKGPCKSSIIIRLDGNLLGTGDLSQYKRNWIEIENV

DNLSINGHGTIDGQGALVWSKNECQKSYNCKILPNSLVLDFV

TNAQIRGITLANSKFFHLNIFSSKNWIDKVTVKAPGNSPNTD

GIHIGDSSNVTITGTTIGVGDDCISIGPGSKTIRIEGVKCGPGH

GISIGSLGRYKDEKDVEDVKVKGCTLVGTSNGLRIKSYEDSK

SSPKCTKFVYEDVTMDNVSYPIIIDQKYCPNNICVKSGASKVA

VTDVIFKNIHGTSNTPEAITLNCANNLPCEGLQLINVDIKYNGS

GNKTMAVCKNAVGKSSGLAKELACL

149 A0334 Amb a LVITGKGTLDGQGKEVWNNNKCAQKYDCKILPNTLVFDFCN

NGTVSGITLLNAKFFHLNVFQCKGMTLKDLTITAPGDSPNTD GIHIGDSSKVTISDTTIGTGDDCISIGPGSTGINITGVTCGPGH GISIGSLGRYADEKDVTDI

150 A0334 Amb p DIAKLGAICDGKTDSTKALQAAWASACGGAGQQTLLIPKGDY

MTGSLRFVGPCQGQVTIQLDGNLLGTSDLSQYKNDKWILIKD

VSNLVITGNGTLDGQGPGVWQKNSCDHKYDCKKLPTSMEL

EFVNSSIITGITFKDAKFFHLKVTDSTDITITGVTVTAPEDSPNT

DGIHIGRSSRVTISGATIGTGDDCVSIGAGTRDINVTGVTCGP

GHGISVGSLGRYKDETDVCNVNIRDCTLRNTANGIRIKTYDD

AACALTASKIDFENIRMEDVNNPIIIDMKYCPNKICPKLAGKKV

TVRDVTFKHISGTSLNPEWKFMCSDKMPCTGMQMIDVNVQ

YAGKRNKTMAICNNAWKAMGCLSALAC

151 A0334 Bet v KSTCQKDKDCDSLPMNIRFDFITNALVRDITSRDSKNFHVNV

LGCKNLTFQHFTVRAPGESVNTDGIHIGRSTGIYIIDSKIGTGD

DCISVGDGTEELHITGVTCGPGHGISVGSLG Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

152 A0334 Que a PPGNYLTGNLELVGPCTSSIIIRLDGNLLGTGDLNAYKKNWIEI

MHVKDFSINGHGTIDGQGPLVWKRNECAKNYNCKILPNSLVL

DYVTNVQIRGITLLNAKFFHMNIYESKNVLVERVNITAPGDSP

NTDGIHIGDSTNVTIAETNIGTGDDCISIGPGSKTIRVRGVRCG

PG HG I SVGS LG RYKDEKDVS DVTVRDCVLRSTTNG VRI KS Y

EDAESVITASRLTFENIRMEDVAKPIIIDQYYCPEKVCPGKKSS

TSHVDVKDWFRNITGTSSTPEAVSLLCSATQPCSGVELIDV

NVEYAGKNNKTMAVCTNAKGVAKGSIEALGCLV

153 A0334 Cyn d APSVPAGPLDITKLGARGDGKSDSTQAIMQAWKHACAATGT

QKIVIPPGNYLTGNLELVGPCTSSIIIRLDGNLLGTGDLNAYKK

NWIEIMHVKDFSINGHGTIDGQGPLVWKRNECAKNYNCKILP

NSLVLDYVTNVQIRGITLLNAKFFHMNIYESKNVLVERVNITAP

GDSPNTDGIHIGDSTNVTIAETNIGTGDDCISIGPGSKTIRVRG

VRCGPGHGISVGSLGRYKDEKDVSDVTVRDCVLKSTTNGVR

IKSYEDAESVITASRLTFENIRMEDVAKPIIIDQYYCPEKVCPG

KKSSTSHVAVKDWFRNITGTSSTPEAVSLLCSETQPCSGVE

LIDVKVEYAGKNNKTMAVCTNAKGVAKGSVEALGCL

154 A0334 Bet v ITGVTCGPGHGISVGSLGKYPNEKPVSGIFVKNCTISDTTNGV

R I KSWP AL YGG VAS NMHFEDIVMN N VQ N P VI I DQVYC PWNQ CSLKAPSKVKISDVSFKSIRGTSATPVWRIACSSGFPCQKVK LANIN

155 A0334 Amb p ASRLTFENIRMEDVAKPIIIDQYYCPEKVCPGKKSSTSHVAVK

DWFRNITGTSSTPEAVSLLCSETQPCS

156 A0336 Amb a MEQTFIMIKPDGVQRGLVGEIIGRFEKKGFTLKGLKLLTVDQA

FAEKHYADLSAKPFFNGLVEYIISGPWAMVWEGKNWTTGR KIIGATNPAESAPGTIRGDFAIDIGRNVIHGSDAVESARKEIGL WFPEGVANWSSSLHPWIYE

157 A0336 Amb p MEQTFIMIKPDGVQRGLVGEIIGRFEKKGFTLKGLKLLTVDQA

FAEKHYADLSSKPFFNGLVEYIISGPWAMVWEGKNWTTGR KIIGATNPAESAPGTIRGDFAIDIGRNVIHGSDAVESARKEIGL WFPEGVANWSSSLHPWIYE

158 A0336 Bet v MEQTFIMIKPDGVQRGLVGEIISRFEKRGFFMKGLKLITVDRS

FAEKHYADLSAKPFFSGLVDYIISGPWATVWEGKNWKTGR KIIGATNPSDSDPGTIRGDFAVEIGRNVIHGSDSVESARKEIAL WFPEAPLSWESSLHSWIYE

159 A0336 Que a MEQTFIMIKPDGVQRGLVGEIISRFEKKGFSLKGLKLITVDRP

FAEKHYADLSAKPFFSGLVDYIISGPWAMIWEGKNVWTGR KIIGATNPSESAPGTIRGDFAVEIGRNVIHGSDSVESARKE!AL WFPDGPVNWESSLHHWVYE

160 A0336 Cyn d MEQTFIMIKPDGVQRGLIGDIISRFEKKGFYLKGMKFMNVEKS

FAQQHYADLSDKPFFAGLVEYIISGPWAMVWEGKDWATG RRMIGATRPWEATPGTIRGDYAVEVGRNVIHGSDSVENGKK EIALWFPEGLAEWRSNLHPWVYES

161 A0349 Amb a MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPP

DSPYSGGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNGSI CLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYK TDRNKYETTARSWTQKYAMG

162 A0349 Amb p MASKRIIKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPS

DSPYSGGVFLVNIHFPPDYPFKPPKVAFRTKVFHPNINSNGSI Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

CLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYK TDKS KYEATARSWTQ KYA

163 A0349 Amb p MASKRILKELKDLQKDPPTSCSAGPVAED FHWQATIMGPS

DSPYSGGVFLVSIHFPPDYPFKPPKVAFRTKVFHPNINSNGSI CLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYK TDKSKYEATARSWTQKYAMG

164 A0349 Amb p MASKRILKEL DLQKDPPTSCSAGPVAEDMFHWQATIMGPP

165 A0349 Bet v EDMFHWQATIMGPADSPYAGGVFLVSIHFPPDYPFKPPKVA

FRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLTD PNPDDPLVPEIAHMYKTDRAKYEATARSWTQKYAMG

166 A0349 Bet v RILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPY

AGGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDIL KEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYKTDRG KYETTARSWTQKYAMG

167 A0349 Bet v MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPP

DSPYAGGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNGSI CLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYK TDRNKYETTARSWTQKYAMG

168 A0349 Que a MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPA

DSPYAGGVFLVSIHFPPDYPFKPPKVAFRTKVFHPN!NSNGSI CLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYK TDRAKYEATARSWTQKYAMG

169 A0349 Que a RILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPTDSPY

AGGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDIL KEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYKTDRA KYETTARSWTQKYAMG

170 A0349 Que a MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPP

DSPYAGGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNGSI CLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYK TDRSKYETTARSWTQKYAMG

171 A0349 Cyn d MASKRILKELKDLQKDPPTSCSAGPVGEDMFHWQATIMGPS

DSPFAGGVFLVNIHFPPDYPFKPPKVSFRTKVFHPNINSNGSI CLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYK TDRAKYESTARSWTQKYAMG

172 A0349 Cyn d MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPS

DSPYAGGVFLVTIHFPPDYPFKPPKVAFKTKVFHPNVNSNGS ICLDILKEQWSPALTVSKVLLSICSLLTDPNPDDPLVPEIAHMY KTDRAKYESTARSWTQKYAMG

173 A0356 Amb a MGKEKIHINIWIGHVDSGKSTTTGHLIYKCGGIDKRTIEKFEK

EAQEMGKGSFKYAWVLDKLKAERERGITIDIALWKFETSKYY VTIIDAPGHRDFIKNMITGTSQADCAVLIVAAGTGEFEAGISKN GQTREHALLAFTLGVKQ

174 A0356 Bet v MGKEKFHINIWIGHVDSGKSTTTGHLIYKLGGIDKRVIERFEK

EAAEMNKRSFKYAWVLDKLKAERERGITIDIALWKFETTKYY

CTVIDAPGHRDFIKNMITGTSQADCAILIIDSTTGGFEAGISKD Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

GQTREHALLAFTLGVRQMICCCNKMDATTPKYSKARYDEIVK

EVSSYLKKVGYNPDKIPFVPISGFEGDNMIERSTNLDWYKGP

TLLEALDLISEPKRPSDKPLRLPLQDVYKIGGIGTVPVGRVET

GVI KPGMWTFG PTG LTTEVKSVEM H H EALQ EALPG DN VG F

NVKNVAVKDLKRGFVASNSKDDPAREAANFTAQVIIMNHPG

QIGNGYAPVLDCHTCHIAVKFAELVTKIDRRSGKEIEKEPKFL

KNGDAGIVKMIPTKPMWETFAEYPPLGRFAVRDMRQTVAV

GVIKGVEKKDPSG

175 A0356 Que a MGKEKVHISIWIGHVDSGKSTTTGHLIYKLGGIDKRVIERFEK

EAAEMNKRSFKYAWVLDKLKAERERGITIDIALWKFETTRYY

CTVIDAPGHRDFIKNMITGTSQADCAVLIIDSTTGGFEAGISKD

GQTREHALLAFTLGVKQMICCCNKMDATTPKYSKARYDEIIK

EVSSYLKKVGYNPDKIPFVPISGFEGDNMIERSTNLDWYKGP

TLLEALDQISEPKRPSDKPLRLPLQDVYKIGGIGTVPVGRVET

GIIKPGMWTFGPTGLTTEVKSVEMHHEALLEALPGDNVGFN

VKNVAVKDLKRGFVASNSKDDPAREAANFTSQVIIMNHPGQI

GNGYAPVLDCHTSHIAVKFAELVTKIDRRSGKEIEKEPKFLKN

GDAGMVKMIPTKPMWETFSEYPPLGRFAVRDMRQTVAVG

VIKSVEKKDPSG

176 A0356 Cyn d MGKEKSHINIWIGHVDSGKSTTTGHLIYKLGGIDKRVIERFEK

EAAEMNKRSFKYAWVLDKLKAERERGITIDIALWKFETTKYY

CTVIDAPGHRDFI NMITGTSQADCAVLIIDSTTGGFEAGISKD

GQTREHALLAFTLGVKQMICCCNKMDATTPKYSKARYDEIVK

EVSSYLKKVGYNPDKIPFVPISGFEGDNMIERSTNLDWYKGP

TLLEALDQINEPKRPSDKPLRLPLQDVYKIGGIGTVPVGRVET

G VLKPG MWTFGPSG LTTEVKSVEM H H EALQEALPG DNVG F

NVKNVAVKDIKRGYVASNSKDDPAKEAASFTSQVIIMNHPGQ

IGNGYAPVLDCHTSHIAVKFAELLTKIDRRSGKELEKEPKFLK

NGDAGMVKMIPTKPMWETFSQYPPLGRFAVRDMRQTVAV

GVI KSVEKKDPTG

177 A0356 Amb a QTREHALLAFTLGVKQMICCCNKMDATTPKYSKARYDEIVKE

VSSYLKKVGYNPDKIPFVPISGFEGDNMIERSTNLDWYKGPT

LLEALDQINEPKRPSDKPLRLPLQDVYKIGGIGTVPVGRVETG

VIKPGMWTFGPSGLTTEVKSVEMHHEALQEALPGDNVGFN

VKNVAVKDLKRGYVASNSKDDPAKGTASFTSQVIIMNHPGQI

GNGYAPVLDCHTSHIAVKFSELLTKIDRRSGKELEKEPKFLKN

GDAGMVKMLPTKPMWETFAEYPPLGRFAVRDMRQTVAVG

VIKSVDKKDPT

178 A0356 Amb p TREHALLAFTLGVKQMICCCNKMDATTPKYSKARYDEIVKEV

SSYLKKVGYNPDKIPFVPISGFEGDNMIERSTNLDWYKGPTL

LEALDQINEPKRPSDKPLRLPLQDVYKIGGIGTVPVGRVETG

VIKPGMWTFGPSGLTTEVKSVEMHHEALQEALPGDNVGFN

VKNVAVKDLKRGYVASNSKDDPAKGAASFTSQVIIMNHPGQI

GNGYAPVLDCHTSHIAVKFSELLTKIDRRSGKELEKEPKFLKN

GDAGMVKMLPTKPMWETFAEYPPLGRFAVRDMRQTVAVG

VIKSVDKKDPTG

179 A0357 Amb a DRERIFKRFDTNGDGKISSTELGDALKTLGSVTSEEIVRMMA

EIDTDGDGFISFEEFTDFAGANRGLIKDVAKIF

180 A0357 Bet v ELERIFKRFDLNGDGQISAAELGDCLKTLGSVTAEEIKRMMA Table 2 - SEQ ID OS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

EIDTDGDGFISFQEFLDFAKANSGLMKDVAKIF

181 A0357 Que a DMERIFKRFDTNGDGKISLAELTDALRTLGSTSADEVQRMMA

EIDTDGDGFIDFNEFISFCNANPGLMKDVAKVF

182 A0357 Cyn d DMERIFKRFDTNGDGKISLAELTDALRTLGSTSADEVQRMMA

EIDTDGDGFIDFDEFISFCNANPGLMKDVAKVF

183 A0357 Amb p TLGSTSADEVQRMMAEIDTDGDGFIDFNEFISFCNANPGLMK

DVAKVF

184 A0358 Amb a RKPVFVKVGDLKPGTNGHTLAVKVLSSTTVLDKKVRNTSSFS

GRPGGSNTRIAECLVGDETGTILFTARNDQVDLM AGSTVIIR NAKIDMFKGSMRLAVDKWGRIEVTDPATFTVKEDNNLSLVEY ELVNVTE

185 A0358 Amb p RKPVFVKVGDLKPGTNGHTLAVKVLSSNTVLDKKVRNTSSF

SGRPGGSNTRIAECLVGDETGTILFTARNDQVDLMKAGGTVI IRNAKIDMFKGSMRLAVDKWGRIEVTDPATFTVKEDNNLSLV EYELVNVTE

186 A0358 Bet v KPGLRKPVFTKVDQLRPGTTGHTLTVKWSTKMVLQKGRAD

GPQVRQMRIAECLVGDETGMIIFTARNDQVDLMKEGGTVILR NAKIDMFKGSMRLAVDKWGRVEVTEPADFTVKEDNNLSLIE YELVNWE

187 A0358 Que a QSNAKPALRKPEFKKVDQLKPGTTGHTLWKWSSNTVLAK

GRSVSQHLRHTRIAECLVGDETATIVFTARNEQVDLMQPGAT VILRNAKIDMFKGSMRLAVDKWGRVEVTEPAKFWKEDNNL SLVEYELVNWE

188 A0358 Cyn d RKPVFVKVDQLKPGTAGHTLIAKVMSSKTVLQKGRPGAAAG

PGARPTRIAECLIGDETGCILFTARNEQVDLMKPDSTVIIRNA KIDMFKGSMRLAVDKWGRIEVTEPAGFNVKEDNNLSLVEYE LVNVSE

189 A0362 Amb a FTN E E I SSM VLVKM KE I AEAYI G ETVKSAVITVPAYFN DAQRQ

ATKDAGVIAGLNVARIINEPTAAAIAYGLDKKGGEKNILVFDLG

GGTFDVSILTIDNGVFEVLATNGDTHLGGEDFDQRIMEYFIKLI

KKKHGKDISKDHRALGKLRREAERAKRALSSQHQVRVEIESL

FDGVDFSEPLTRARFEELNNDLFRKTMGPVKKAMEDAGLEK

RQIDEIVLVGGSTRIPKVQQLLKDYFDGKEPNKGVNPDEAVA

YGAAVQGGILSGEGGDETKDILLLDVAPLTLGIETVGGVMTKL

IPRNTVIPTKKSQVFTTYQDQQTWSIKVYEGERS

190 A0362 Amb p FS P E E I SAM I LTKM KETAE AF LG KKI KD A WTVPAYF N DAQ RQ

ATKDAGVIAGLNVARIINEPTAAAIAYGLDKKGGEKNILVFDLG

GGTFDVSILTIDNGVFEVLATNGDTHLGGEDFDQRIMEYFIKLI

KKKHGKDISKDHRALGKLRREAERAKRALSSQHQVRVEIESL

FDGVDFSEPLTRARFEELNNDLFRKTMGPVKKAMEDAGLEK

RQIDEIVLVGGSTRIPKVQQLLKDYFDGKEPNKGVNPDEAVA

YGAAVQGGILSGEGGDETKDILLLDVAPLTLGIETVGGVMTKL

I PRNTVI PTKKSQVh I I YQDQQTWSIKVYEGERSLTKDCRLL

GTFDLTGIPPAPRGTPQIEVTFEVDANGILNVKAEDKASGKSE

KITITNEKGRLSQEEIERMVREAEEFAEEDKKVK

191 A0362 Bet v FSPEEVSAMILTKMKETAEAFLGKKIKDAWTVPAYFNDAQR

Q ATKD AG 11 AG LN VAR 11 N E PTAAAI AYG LD KKGG EK I LVF D L GGGTFDVSILTIDNGVFEVLATNGDTHLGGEDFDHRIMEYFIK LIKKKHGKDISKDNRALGKLRREAERAKRALSSQHQVRVEIE Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

SLFDGVDFSEPLTRARFEELNNDLFRKTMGPVKKAMDDAGL EKNQIDEIVLVGGSTRIPKVQQLLKDYFDGKEPNKGVNPDEA VAYGAAVQGSILSGEGGEETKDILLLDVAPLTLGIETVGGVMT KLIPRNTVIPTKKSQVh I I YQDQQTTVSIQVYEGERSLTKDCR N LGKFDLSG I PPAPRGTPQI EVTFEVDANG I LNVKAEDKGTG KSEKITITNDKGRLSQEEIDRMVREAEEFAEEDKKVK

192 A0362 Que a FSPEEISA VLTKMKETAEAFLGKKIKDAWTVPAYFNDAQR

QATKDAGVIAGLNVARIINEPTAAAIAYGLDKKGGEKNILVFDL

GGGTFDVSILTIDNGVFEVLATNGDTHLGGEDFDHRVMDYFI

KLIKKKHSKDISKDNRALGKLRREAERAKRALSSQHQVRVEI

ESLFDGVDFSEPLTRARFEELNNDLFRKTMGPVKKAMDDAG

LEKRQIDEIVLVGGSTRIPKVQQLLKDFFDGKEPNKGVNPDE

AVAYGAAVQGGILSGEGGDETKDILLLDVAPLTLGIETVGGV

MTKLIPRNTVIPSKKSQVFTTYQDQQTTVTIQVFEGERSLTKD

CRLLGNFDLTGIAPAPRGTPQIEVTFEVDANGILNVKAEDKAS

GKSEKITITNDKGRLSQEEIDRMVQEAEEFAEEDKKVK

193 A0362 Cyn d FS P E E I SAM I LG KMKDTAEAYLG KKI N DAWTVPAYFN DAQR

QATKDAGVIAGLNVARIINEPTAAAIAYGLDKKGGEKNILVFDL

GGGTFDVSILTIDNGVFEVLATNGDTHLGGEDFDHRIMEYFIK

LIKKKYSKDISKDNRALGKLRREAERAKRALSNQHQVRVEIE

SLFDGTDFSEPLTRARFEELNNDLFRKTMGPVKKAMEDAGL

EKSQIHEIVLVGGSTRIPKVQQLLRDYFDGKEPNKGVNPDEA

VAYGAAVQGSILSGEGGEETKDILLLDVAPLTLGIETVGGVMT

KLIPRNTVIPTKKSQVFTTYQDQQTTVSIQVFEGERSMTKDC

RLLGKFDLSGIPPAPRGTPQIEVTFEVDANGILNVKAEDKGTG

KSEKITITNEKGRLSQEEIDRMVREAEEFAEEDKKVK

194 A0366 Amb a AAFQALAPLEAVLFDVDGTLCDSDPIHHIAFKEMLLEIGFNGG

VPIDEEFFIQNIAGKHNDDIAAVLFPDDIERGLKFCVDKEAYFR

KLVKEKVEPIKGLYKLTKWVEDNGLKRAAVTNAPRPNAELMI

STLGLTDFFHHVIIGDECERAKPAPDPYLKAIELLNVSKDHTFI

CEDSVSGIKAGVAAGMPWGLTTRNPEQMLMTANPTLLIKDY

EDPKLWAVLEEL

195 A0366 Amb p AAFQALAPLEAVLFDVDGTLCDSDPIHHIAFKEMLLEIGFNGG

VPIDEEFFIQNIAGKHNDDIAAVLFPDDIERGLKFCVDKEAYFR

KLVKEKVEPIKGLYKLTKWVEDNGLKRAAVTNAPRPNAELMI

STLGLTDFFHHVIIGDECERAKPAPDPYLKAIELLNVSKDHTFI

CEDSVSGIKAGVAAGMPWGLTTRNPEQLLMTANPTLLIKDY

EDPKLWAVLEEL

196 A0366 Bet v SSLAALAPLQAVLFDVDGTLCDSDPLHYYAFREMLQEIGFNG

GVPITEEFYIENIAGKHNDDVAVLLFPDDVQRGLKFTDDKEA

MFRRLAAEQLEPVNGLYKVTKWVEDRGLKRAAVTNAPRPN

AELMISRLGLSDFFEAVILGSECDHAKPHPEPYLKALEILNVS

KDHTFVFEDSVSGIKAGVAAGLPWGLTTRNPERFLMEAKPT

FLVKDYDDPKLWAALEELD

197 A0366 Que a TTLAELAPLQAVLFDIDGTICDSDPLHHYAFREMLQEIGFNGG

VPITEEFFVDHIAGKHNDDIAKFLFPDDIQRGLKFVDDKEAMF

RRLASEQLKPVNGLYKVKKWIEDRGIKRAAVTNAPKANAELM

ISSLGLSDFFEALIVGSECEHAKPHPDPYLKALEIINVSKDHTF

VFEDSVSGIKAGVAAGMPWGIATRNPEHLLMEAKPVFLIKD Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

YEDPKLWAALEELD

198 A0366 Cyn d TTVSSLASTVPVQAVLFDIDGTLCDSDPLHHVAFQEMLLAIGY

NNGVPIDDEFFIKNIAGRSDVEAAQNLFPDWELEKGLKFLED

KEEKYRSLAKERLVPVKGLEKWQWVKDHGYKRAAVTNAPR

INAELMISLLGLSDFFQAVIVGGECEKPKPAPYPYLKAIKELDV

SAEHTFIFEDSASGIRAGVAAGIPWGVATRNPEKSLLEAGAS

LLIKDYEDPKLWAALEEIDREEAKLKNQGSA

199 A0376 Amb a DIKVIMGRSDDLETWLTGVMTFMDTCIDGFVDEKLKADMHS

VLRNATELSSNALAITNSLGGILKKLDLDMFKKDSRRRLLSEQ

DEKGWPNA/VMKSPERKLLAAGNQPKPNAWAKDGSGQFKTI

QQAVDAVPKGQLGRYVIYVKTGLYDEIVMVPKDKPNIFMYGD

GPKQSRVTGKKSFADGITTMKTATFSIEAAGF!CKNMGFHNT

AGAEKHQAVALRVQGDFAAFYNCRFDAFQDTLYVHARRQF

FRNCVISGTIDFIFG

200 A0376 Bet v HNGSKSAGDSLSPQMKIVKDICSKTDYQEACQNSLSPAADK

GNTDPKEFIKSAIQATINEVAKSANFSDALVQNVSSIPRVKMA

AEDCKDLLSFATDELQASFSTVGDSDMHTINDRSADLKNWL

SAVISYQQTCLDGFDAPEYRTLMEQNLQDASLLTSNALAIVS

ELADILKAFGLEFNIKPSGRRRLLSQDGYPTWFSGSDRKLLA

LVDNGRIRPNAIVAKDGSGQFKTIAAALAAYPKNLRGRYVIYV

KAGIYNEYITVEKTQPNIFMFGDGPRKTIVTGRKSYRDGITTF

KTASFSTMGEGFIAKSMGFQNTAGPEGHQAVALRVQADRS

AFFNCRMDGYQDTLYVQTHRQFFRNCVISGTVDFIFGDAAA

VIQNSLIIVRKPMDNQQNTVTAQGRHDKRETTGLVIHNCRIVP

EQKLFAQRFTIPTYLGRPWKEYARTVIMETTLADFIQPVGYM

PWAGSFALSTCS YFE YAN RG PGARTVRRVRWKGARVI S RS

EALQFTAGPFLQGNLWLKATGFPFLLGLR

201 A0376 Cyn d LGGLSAILWAVWGWATVTRSGNKAGDNFTVPGEATLATS

GKSVKSLCAPTLYKESCEKTLTQASNGTENPKEVFQAVAKT

ALESVKAAYEQSQNIGRKLLDVDDSMTASAREDCKKLLDDSI

DDLRGMIDMAGGDIKVLLSRSDDLETWLTGVMTFLDTCSDG

FTDEKLKADMKLVLRNATELSSNALAITNSLGGIFKKLDLDML

KKDATSRRRLLSDQDEKGWP\AtyMKSPERKLLASGDANRPQ

PNAWAKDGSGQFKTVQDAVNAYPKGLQGRYVIYVKAGWD

EMV ITKEKVNIFMYGDGPKRSRVTGRKSFADGITTMKTATF

SIEASGFICKNMGFHNTAGAERHQAVALRVQGDLAAFFNCR

FDAFQDTLYVHARRQFFRNCVISGTIDFIFGNSAAVFQNCLIIT

RRPMDNQQNSVTAHGRTDPNMKSGLVIQNCRLVPDQKLFP

DRFKIPSYLGRPWKEFSRLVIMESTIADFIKPEGYMPWDRDF

AL KTL Y YAE YN N KG PGAGTS KRVNWPG FRVI G KQ E AAQ FTA

GPFIDGATWLKFTGTPHILGFK

202 A0376 Amb a RYVIYVKAGIYEEIVLIPKDKTNIYMYGDGPKKSRVLGHKSNA

DGLTTQDTATFSVIGQGFICKNMGFSNTAGAIKHQAVALRLQ

SDFAAFYNCRMDGYQDTLYVQARRQFFRNCWSGTIDFIFG

NAAAVFQNCLIIVRRPMDNQQNTVTAHGRTDPKMKSGLVIQ

NCRIVPDQALFPDRFKIPSYLGRPWKEYSRTVIMESTIGDAIR

PEGWMAWNGDFALKTLYYAEYANRGPGANTRSRVRWPGF

HVINRNEAQQFTVGNF!SGNLWLRYTG

203 A0376 Amb a PMDNQQNSVTAHGRTDPNMKSGLVIQNCRLVPDQKLFPDR Table 2 - SEQ ID NOS:38-211

SE ID NO: SpeAmino Acid Sequence

Q cies

ID NO:

FKIPSYLGRPWKEFSRLVIMESTIADFIKPEGYMPWNGDFGI TLFYAEYNNRGPGAGTSKRVKWPGFHVITKKDAEQFTAGPFI DGATWLKFTGTPHILGFK

204 A0376 Amb p KFKSIQEAVNA PKGHPGRYVIYVKTGVYDEIVMVPKDKVNI

FMYGDGPKQTRVTGSKSFHDGITTMKTATFSIEASGFICKNM

GFHNTAGAERHQAVALRVQGDLAAFFNCRFDAFQDTLYVHA

RRQFFRNCVISGTIDFIFGNSAAIFQNCLIITRRPMDNQQNSV

TAHGRTDPNMKSGLVIQNCRLVPDQKLFPDRFKIPSYLGRP

205 A0376 Que a RDSSVTGRKSFADGVTTMKTATFSIEAAGFICKNMGFHNTA

GAERHQAVALRVQGDLAAFYNCRFDAFQDTLYVHARRQFF

RNCVISGTIDFIFGNSAAIFQNCLIITRRPMDNQQNSVTAHGR

TDPNMKSGLVIQNCRLVPDQKLFPDRFKIPSYLGRPWKEFS

RLVIMESTIADFIKPEGYMPWNGDFGLKTLYYAEYANRGPGA

GTSKRVTWPGFRVIGRKEAEQFTAGPFVDGATWLKFTGTPN

YLGFKV

206 A0377 Amb a RIKTGFTHFKTEKYEKNPSLYEELVKEQKPKFMVFACSDSRV

CPSHILDFQPGEAFMVRNIANMVPPYDKTKYSCVGAAIEFAV LTLKVENILVIGHSCCGGIKGLMSIPDDGTTSSDFIEDWVKI

207 A0377 Amb p RIKTGFTHFKTEKYEKNPSLYEELVKEQKPKFMVFACSDSRV

CPSHILDFQPGEAFMVRNIANMVPPYDKTKYSCVGAAIEFAV LNLKVENILVIGHSCCGGIKGLMSIPDDGTTSSDFIEDWVKICS TAKS KVKE E F KE L D FTEQCS KC E VE AVN VS LG N L LTYP FVKS AVMNRTLNIKGGYYNFVNATFDIW

208 A0377 Bet v RIKTGFIHFKKEKYDKNPALYGELAKGQSPKFMVFACSDSRV

CPSHVLDFQPGEAFWRNVANLVPPFDQTKYSGTGAAVEYA

VLHLKVENIWIGHSACGGIKGLLSFPDEGPKSTDFIEDWVKI

GLPA SKVKAEFGNASFPELCGHCEKEAVNVSIGNLLTYPFV

REGLVNKTLALKGGYYDFVKGTFELW

209 A0377 Que a RIKTGFIHFKKEKFEKNPELYGELAKGQKPKFMVFACSDSRV

CPSHILNFQPGEAFMIRNIANMVPPFDKTKYSGGGAAIEYAVL

HLKVEHIWIGHSCCGGIKGLMSIPDDGTTASDFIEHWVQICS

PAKAKVKAEYSGLSFSEQCTNCEKEAVNVSLGNLLTYPFVR

DGLVKKTLALKGAHYDFVKGTFDLWD

210 A0377 Cyn d HLKSGFDKFKADVYDTKPELFEPLKAHQSPKYMVFSCADSR

VCPSVTLGLQPGEAFTVRNIANMVPSYDKTRYASVGSAIEYA

VCALKVEVIWIGHSRCGGIKALLSLKDGAPDTFHFVEDWVRI

GCPAKEKVLAEHAEAPFADQCTILE EAVNLSLENLKSYP-FV

KEGLEKGTIKLVGAHYDFVDGKFETWE

211 A0377 Amb a FIEDWVKICDPARSKIKSVLSCAEFADQCKNCEKEAVNVSLG

NLLTYPFVKEAWNKTLALKGAHYDFVHGAFE

Example 3 - Conservation analysis

This example includes a description of how to identify stretches of amino acid residues (conserved regions) that are conserved across a set of polypeptides found Tables 1 and 2, i.e. which are conserved across a set of polypeptides found in at least two of the pollen species Phi p, Cyn d, Amb a, Amb p, Que a and bet v.

Multiple sequence alignments were generated for each set of homologous sequences using the Phi p sequence of Table 1 as the reference sequence. For each Phi p reference sequence, the degree of conservation of each 15mer contained in this sequence across the other species was determined. For the purpose of this analysis, it was defined that peptides that have a homologous hit with 0, 1 or 2 mismatches are considered as being conserved. Any substitution of an amino acid sequence within the 15mer Phi p peptide is considered to constitute a mismatch. A conserved region was then defined as the region resulting from merging ail conserved 15mer peptides in a Phi p sequence.

A region was defined as conserved across "grass & weed & tree" ("GWT") if the conserved stretches of amino acid residues was detected in the Phi p polypeptide as well as in the homolog polypeptides of at least one weed species (Ambrosia artemisiifolia or Ambrosia psilostachya) and of at least one tree species (Quercus alba or Betula verrucosa). Table 3 shows GWT conserved stretches deriving from Phi p polypeptide sequences shown in Table 1. Table 4 shows GWT conserved stretches deriving from homolog polypeptides shown in Table 2.

Similarly, a region was defined as conserved across "grass & weed" ("GW") if the conserved stretches of amino acid residues was detected in the Phi p polypeptide as well as in the homolog polypeptides of at least one weed species (Ambrosia artemisiifolia or Ambrosia psilostachya) and none of the tree species. Table 5 shows "GW conserved stretches deriving from Phi p polypeptide sequences shown in Table 1. Table 6 shows "GW" conserved stretches deriving from homolog polypeptides shown in Table 2.

Similarly, a region was defined as conserved across "grass & tree" ("GT") if the conserved stretches of amino acid residues was detected in the Phi p polypeptide as well as in the homolog polypeptides of at least one tree species (Quercus alba or Betula verrucosa) and none of the weed species. Table 7 shows "GT" conserved stretches deriving from Phi p polypeptide sequences shown in Table 1. Table 8 shows "GT" conserved stretches deriving from homolog polypeptides shown in Table 2. The conservation analysis was repeated using Amb a as a reference in order to identify amino acid stretches conserved across polypeptides found in in weed pollen (Amb a) and tree pollen (Que a or Bet v), but not in grass pollen (neither Phi p nor Cyn d). Table 9 shows WT conserved stretches of polypeptides shown in Table 1. Table 3. GWT conserved amino acid sequences derived from polypeptides of Table 1

Table 3 - SEQ ID NOS: 212-293

SEQ ID ID NO Spe-cies Amino acid sequences

NO

MDGVLYCKTHFEQLFKETGSFSKNFT

252 A0311 Phi p FSGTQDKCAACQKTVYPLEKL

253 A0311 Phi p ECYHKSCFKCSHGGCILTTSSYAALNGILYCKIHFSQLFKEKGSYNHLIKTAQ

254 A0316 Phi p MADAEDIQPLVCDNGTGMVKAGFAGDDAPRAVFPSIVGRPRHTGVMVGMG

QKDAYVGDEAQSKRGILTLKYPIEHGIVSNWDDMEKIWHHTFYNELRVAPEE HPVLLTEAPLNPKANREKMTQIMFETFNTPAMYVAIQAVLSLYASGRTTGIVL DSGDGVSHTVPIYEGYALPHAILRLDLAGRDLTDYLMKILTERGYSh I I I AER EIVRDVKEKLSYIALD

255 A0317 Phi p GCITTKELGTVMRSLGQNPTEAELQD INEVDADGNGTIDFPEFLNL ARKM

KDTDSEEELKEAFRVFDKD

256 A0325 Phl p VKAKIQD EGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMA

KKRKKKNYTTPKKIKH KRKPVK

257 A0326 Phi p WWNGSVDVDIGANPSAEGGCDDEGVDDQAVKWDIVDTFRLQEQPPFDK

KQFL

258 A0326 Phi p DCFKKNIEGATKFLLGKIKDLQFFVGESMHDDCA

259 A0326 Phl p AYYKEGAIDPTFLYF

260 A0327 Phi p EVAAVCKGTPYAELCSATAGKQASHYATVDALAVLG QVDAFSKRASAAS

261 A0327 Phi p YVNVEDNLGAARRAISFKDAVTIRAMMSMAAQDMKNCDEEFRKNAAVNPMT

RFDKSLLDISENCRALSNMI

262 A0334 Phi p KNYNCKILPNTLVLDF

263 A0334 Phi p DVTITAPGDSPNTDGIHIGDSSNI

264 A0334 Phl p TTIGTGDDCISIGGGSS

265 A0334 Phi p VTG VTC G PGQ G I SVG C LG RYKD EKD VS DVTVK

266 A0334 Phi p DVANPIIIDQNYCPEKVCT

267 A0334 Phi p VTVKDVIFRNITGTSSTPAAVSLLCSD

268 A0336 Phi p EQTFIMIKPDGVQRGLIGDII

269 A0336 Phl p KLVDYIISGPWAMVWEGKDW

270 A0349 Phi p KELKDLQRDPPTSCSAGPVAEDMFHWQATIMGPAESPYAGGVFLVTIHFPP

DYPFKPPKVAFKTKVFHPNINSNGSICLDILKEQWSPALTVSKVLLSICSLLTD PNPDDPLVPEIAHMYKSDRV YESTARSWTQKYAMG

271 A0349 Phi p MASKRILKELKDLQKDPPTSCSAGPVGEDMFHWQATI GPSDSPF

272 A0349 Phi p GGLFLVNIHFPPDYPFKPPKVSFRTKVFHPNINSNGSICLDILKEQWSPALTIS

KVLLSICSLLTDPNPDDPLVPEIAHMYKTDRAKYESTARSWTQKYAMG

273 A0349 Phi p DMFHWQATIMGPSDSPYSGGVFLVTIHFPPDYPFKPPKVAFKTKVFHPNVN

SNGSICLDILKEQWSPALTiSKVLLSICSLLTDPNPDDPLVPEIAHMYKADRAK YE

274 A0349 Phi p MASKRILKELKDLQKDPPTSCSAGPAGEDMFHWQATIMGPPDSPYAGGVFL

VNIHFPPDYPFKPPKVSFKTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSI CSLLTDPNPDDPLVPEIAHMYKTDRSKYETTARSWTQKYAMG

275 A0356 Phi p EKLHISIWIGHVDSG STTTGHLIYKLGGIDKRVIERFEKEA

276 A0356 Phi p EMNKRSFKYAWVLDKLKAERERGITIDIALWKFETTKYSCTVIDAPGHRDFIK

N M ITGTS Q ADC AVLI I D

277 A0356 Phi p TGGFEAGISKDGQTREHALLAFTLGVKQMICCCNKMDATTPKYSKSRFEEIV

KEVSSYLKKVGYNPDKVPFVPISGFEGDNMIERSTNLDWYKGPTLLEALDQV TEPKRPTDKPLRLPLQDVYKIGGIGTVPVGRVETGLIKPGMLVTFGPTGLTTE VKSVEMHHESLLEAGPGDNVGFNVKNVAVKDIKRGYVASN

278 A0356 Phi p ASFVAQVIIMNHPGQIGNGYAPVLDCHTSHIAVKFAEI

279 A0356 Phi p FPKFLKNGDAGFVKMVPTKPMWETFSQYPPLGRFAVRDMRQTVAVGVIKS

VEKKDPTG

280 A0357 Phl p D ERIFKRFDTNGDGKISLSEL

281 A0357 Phl p TLGSTSADEVQRM AEIDTDGDGFIDFNEFISFCNANPGLMKDVAKVF

282 A0358 Phl p PRIAECLVGDETGCIIFTARNDQVDLLKAG

283 A0358 Phi p ILRNAKIDMFKSSMRLAVDKWGRV

284 A0358 Phi p EENNLSQVEYELVNVAE

285 A0362 Phl p FSPEEISA ILGK KETAEAYLGKKINDAWTVPAYFNDAQRQATKDAGVIAG

LNVARIINEPTAAAIAYGLDKKGSEKNILVFDLGGGTFDVSILTIDNGVFEVLAT NGDTHLGGEDFDHRI DYFIKLIKKKYSKDIS DNRALGKLRREAERAKRALS Table 3 - SEQ ID NOS: 212-293

SEQ ID ID NO Spe-cies Amino acid sequences

NO

NQHQVRVEIESLFDGTDFSEPLTRARFEELNNDLFRKTMGPVKKAMDDAGL

EKSQIHEIVLVGGSTRIPKVQQLLRDYFDGKEPSKGVNPDEAVAFGAAVQGS

ILSGEGGDETKDILLLDVAPLTLGIETVGGVMTKLIPRNTVIPTKKSQVFTTYQ

DQQTTVSIQVFEGERSMTKDCRLLGKFDLNGIPAAPRGTPQIEVTFEVDANGI

LNVKAEDKGTGKSE ITITNEKGRLSQEEIDRMVKEAEEFAEEDKKVK

286 A0366 Phi p EAVLFDIDGTLCDSDPLHHVAF

287 A0366 Phi p GYKRAAVTNAPRINAELML

288 A0376 Phi p PNAWAKDGSGKFKTI

289 A0376 Phi p VTGRKSFKDGITTMKTATFSIEAAGFICKN GFHNTAGAENHQAVALRVQGD

I.AAFYNCRFDAFQDTLYVHARRQFFRNCVISGTIDFIFGNSAAIFQNCLIITRR

PMDNQQNSVTAHGRTDPNMKSGLVIQNCRLVPDQKLFPDRFKIPSYLGRPW

KEYSRLVIMESTIADFIKPEGYMPWNGDFGIKTLYYAEYANRGPGAGTSKRV

NWPGFRVI

290 A0376 Phi p AEQ FTTG PF VD G ATWLKFTG M P

291 A0377 Phi p PKYMVFACADSRVCPS

292 A0377 Phi p PGEAFTVR IANMVP

293 A0377 Phi p LEKEAVNVSLENLLTYPFVK

Table 4. GWT conserved amino acid sequences derived from polypeptides of Table

2.

Table 4 (SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

327 A0209 Amb a GHKQGPNLNGLFGRQSGTTAGYSYS

328 A0209 Amb a GHKQGPNLNGLFGRQSGTTAGYSYS

329 A0209 Amb p GHKQGPNLNGLFGRQSGTTAGYSYS

330 A0209 Bet v GHKQGPNLNGLFGRQSGTTAGYSYS

331 A0209 Que a GHKQGPNLNGLFGRQSGTTAGYSYS

332 A0209 Cyn d GHKQGPNLNGLFGRQSGTTPGYSYS

333 A0209 Amb a ENTLYDYLLNPKKYIPGTKMVFTGLKKPQERADLISYLK

334 A0209 Amb a EKTLYEYLLNPKKYIPGTKMVFPGLKKPKDRADLIAYLK

335 A0209 Amb p EKTLYEYLLNPKKYIPGTKMVFPGLKKPKDRADLIAYLK

336 A0209 Bet v EKTLYDYLLNPKKYIPGTK VFPGLKKPQDRADLISYLK

337 A0209 Que a EKTLYDYLLNPKKYIPGTKMVFPGLKKPQERADLIAYLK

338 A0209 Cyn d ENTLYDYLLNPKKYIPGTKMVFPGLKKPQERADLIAYLK

339 A0209 Amb a TVGEKIFKTKCAQCHTVEKGAGHKQGPNLNGLFGRQSGTTAGYSYSAGNKNKA

VIWEENTLYDYLLNPKKYIPGTKMVFTGLKKPQERADLISYLKQ

340 A0209 Amb a KVGEKIFKTKCAQCHTWKGAGHKQGPNLNGLFGRQSGTTAGYSYSAANKNMA

VIWEEKTLYEYLLNPKKYIPGTKMVFPGLKKPKDRADLIAYLKE

341 A0209 Amb p KVGEKIFKTKCAQCHTWKGAGHKQGPNLNGLFGRQSGTTAGYSYSAANKNMA

VIWEEKTLYEYLLNPKKYIPGTKMVFPGLKKPKDRADLIAYLKE

342 A0209 Bet v KVGEKIFKTKCAQCHTVEKGAGHKQGPNLNGLFGRQSGTTAGYSYSSANKN A

VNWEEKTLYDYLLNPKKYIPGTKMVFPGLKKPQDRADLISYLKE

343 A0209 Que a SGEKIFKTKCAQCHTVEKGAGHKQGPNLNGLFGRQSGTTAGYSYSTANKNMAV

IWEEKTLYDYLLNPKKYIPGTKMVFPGLKKPQERADLIAYLKS

344 A0209 Cyn d KAGEKIFKTKCAQCHTVDKGAGHKQGPNLNGLFGRQSGTTPGYSYSAANKNRA

VIWEENTLYDYLLNPKKYIPGTKMVFPGLKKPQERADLIAYLKE

345 A0211 Amb a DFDFTTDENCQKSKIFFIAWSPDTSRVRMKMVYASSKD

346 A0211 Amb p DYDFVTEENCQKSRIFFIAWSPDTARVRNKMIYASSKDRFKRELDGIQVELQATD

PTEMDLDVFKSRA

347 A0211 Amb p DFDFTTDENCQKSKIFFIAWSPDTSRVRMKMVYASSK

348 A0211 Amb p DFDFTTDENCQKSKIFFIAWAPDTSKVREKMVYASSKDRFKRELDGIQVEVQAT

DPSEMSLDIVKARA

349 A0211 Amb p DFDFVTDENCQKSKIFFISWAPDIARVRSKMLYASSKDRFKRELDGIQVELQATD

PSEMSMDIVKARA

350 A0211 Bet v DFDFTTDENVQKSKIFFIAWAPDTSRVRSK LYASSKDRFRRELDGVQVELQAT

DPSEMSLDIIKGRA

351 A0211 Bet v DFDFITDENCQKSKIFFIAWSPDTSRVRSKMVYASSKDRFKRELDGIQVELQATD

PSEMSLDIVKGRA

352 A0211 Que a DFDFITDENCQKSKIFFISWSPDTSRVRSKMLYASSKDRFRRELDGVQVELQAT

DPSEMSLDIIKGRA

353 A0211 Cyn d DFDFVTDENCQKSKIFFISWSPDTSRVRSKMLYASSKDRFKRELDGIQVELQATD

PSEMSMDIVKARA

354 A0211 Amb a MANAASGMAVDDECKLKFQELK

355 A0211 Amb p MANAASGMAVHDECKLKFLELK

356 A0211 Amb p MANAASGMAVNDECKLKFSELK

357 A0211 Bet v MANSASGMAVHDECKLKFLELK

358 A0211 Bet v MANAASGMAVSDECKLKFLELK

359 A0211 Que a MANSASGMAVHDDCKLKFLELK

360 A0211 Cyn d MSNSASGMAVCDECKLKFQELK

361 A0211 Amb a DECRY AVFDFDFTTDENCQKSKIFFIAWSPDTSRVRMKMVYASSKD

362 A0211 Amb p AECRYAVFDYDFVTEENCQKSRIFFIAWSPDTARVRNKMIYASSKDRFKRELDGI

QVELQATDPTEMDLDVFKSRA

363 A0211 Amb p DECRYAVFDFDFTTDENCQKSKIFFIAWSPDTSRVRMKMVYASSK

364 A0211 Amb p NECRYAVFDFDFTTDENCQKSKIFFIAWAPDTSKVREKMVYASSKDRFKRELDGI

QVEVQATDPSEMSLDIVKARA

365 A0211 Amb p DECRYAVFDFDFVTDENCQKSKIFFISWAPDIARVRSKMLYASSKDRFKRELDGI

QVELQATDPSEMSMDIVKARA

366 A0211 Bet v NECRYAVFDFDFTTDENVQKSKIFFIAWAPDTSRVRSKMLYASSKDRFRRELDG

VQVELQATDPSEMSLDIIKGRA

367 A0211 Bet v DECRY AVFDFDFITDENCQKSKIFFIAWSPDTSRVRSKMVYASSKDRFKRELDGI

QVELQATDPSEMSLDIVKGRA

368 A0211 Que a NECRYAVFDFDFITDENCQKSKIFFISWSPDTSRVRSKMLYASSKDRFRRELDG

VQVELQATDPSEMSLDIIKGRA

369 A0211 Cyn d DECRYAVFDFDFVTDENCQKSKIFFISWSPDTSRVRSKMLYASSKDRFKRELDGI Table 4 (SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

QVELQATDPSEMSMDIVKARA

370 A0211 Amb a NAASGMAVDDECKLKFQELKAKRSYRFITFKI

371 A0211 Amb p NAASG AVHDECKLKFLELKAKRTFRYIIFKI

372 A0211 Amb p LKFQELKAKRSYRFITFKI

373 A0211 Amb p NAASGMAVNDECKLKFSELKS RNYRFIVFKI

374 A0211 Bet NSASGMAVHDECKLKFLELKAKRNHRFIVFKI

375 A0211 Bet v NAASGMAVSDECKLKFLELKTKRNYRFIIFKI

376 A0211 Que a NSASGMAVHDDCKLKFLELKAKRNYRFIVF I

377 A0211 Cyn d NSASGMAVCDECKLKFQELKAKRSFRFIVFKI

378 A0211 Amb a NSLPADECRYAVFDFDFTTDENCQKSKI

379 A0211 Amb p AALPDAECRYAVFDYDFVTEENCQKSRI

380 A0211 Amb p NSLPADECRYAVFDFDFTTDENCQKSKI

381 A0211 Amb p NSLPANECRYAVFDFDFTTDENCQKSKI

382 A0211 Amb p DECRY AVFDFDFVTDENCQKSKI

383 A0211 Bet ASMPPNECRYAVFDFDFTTDENVQKSKI

384 A0211 Bet ASIPADECRYAVFDFDFITDENCQKSKI

385 A0211 Que a ASMPANECRYAVFDFDFITDENCQKSKI

386 A0211 Cyn d ACLPADECRYAVFDFDFVTDENCQKSKI

387 A0215 Amb p AITVDEACRQYTKHPSYC

388 A0215 Que a AITVDEACRQYTKHPSYC

389 A0215 Cyn d AITVDEACRKYTKHPSYC

390 A0215 Amb p TTLPALAEQAVLLAAESGV

391 A0215 Que a TTLPALAVQAVTLAAESGG

392 A0215 Cyn d TTLPALAVQAVTLAAESGG

393 A0215 Amb p VKNLEKIPGGMPLGCLERCVGRFQAAVAAL

394 A0215 Que a VKNLEKMPGG PLGCLERCVGKFQAAVAEL

395 A0215 Cyn d VKNLEKMPGG PLGCLERCVGKFQAAVAEL

396 A0215 Amb p QSRVAIVEHRDVARVKAWVKTARVDGE

397 A0215 Que a LSRVAIVEHRDVARVKAVWKAARADGE

398 A0215 Cyn d LSRVAIVEHRDVARVKAWVKAARADGE

399 A0219 Amb a LLKVNQIGSVTESIEAVKMSKRAGWGVMASHRSGETEDTFIADLSVGLATGQIKT

GAPCRSERLAKYNQLLRIEEELGAAAVYAGSKFRAP

400 A0219 Amb p LLKVNQIGSVTESIEAVKMSKRAGWGVMASHRSGETEDTFIADLSVGLATGQIKT

GAPCRSERLAKYNQLLRIEEELGAAAVYAGSKFRAP

401 A0219 Bet v LLKVNQIGSVTESIEAVRMSKRAGWGVMASHRSGETEDTFIADLSVGLATGQIKT

GAPCRSERLAKYNQLLRIEEELGSAAVYAGSKYRAP

402 A0219 Que a LLKVNQIGSVTESIEAVKMSKHAGWGVMASHRSGETEDTFIADLSVGLATGQIKT

GAPCRSERLAKYNQLLRIEEELGPAAVYAGSKFRAP

403 A0219 Cyn d LLKVNQIGSVTESIEAVKMSKHAGWGVMTSHRSGETEDTFIADLAVGLATGQIKT

GAPCRSERLAKYNQLLRIEEELGAAAVYAGAKFRAP

404 A0233 Amb a KFPPGPNITTNYNGQWLTARATWYGQPNGAGPDDNGGACGIKGVNLPPYNG

TACGN!PIFKDGKGCGSCYEVRC

405 A0233 Amb p CITKVPPGPNITTKYDTKWLPAKATWYGKPTGAGPKDNGGACGIKDVNLAPYLG

MTACGNVPIFKDGKGCGSCYELKC

406 A0233 Que a CITKVPPGPNITTKYDTKWLPAKATWYGKPTGAGPKDNGGACGIKDVNLAPYLG

MTACGNVPIFKDGKGCGSCYELKC

407 A0233 Cyn d CITKVPPGPNITTKYDTKWLPAKATWYGKPTGAGPKDNGGACGIKDVNLAPYLG

MTACGNVPIFKDGKGCGSCYELKC

408 A0233 Amb a PECSGQPITVFITDMNYEPIAPYHFDFSGKAFGSLAKPGLNDKLRHCGIMDVEFR

RVRCKLP-GQKILFHVEKGCNPNYLAVLVKNVADDG

409 A0233 Amb p EPCSDKPITVFITDKNYEPIAPYHFDLSGKAFGLMALPGKDQALRSVGELELQFR

RVQCKYPAGTKITFHVEKGSNPNYLAVLVKFVANDGDIVQM

410 A0233 Que a APCADKPITIFITDKNYEPIAPYHFDLSGKAFGLMALPGQDQKLRSVGELELQFRR

VQCKYPAGTKITFHVEKGSNPNYLAVLVKFVANDGDIVQM

411 A0233 Cyn d EPCADKPITVFITDKNYEPIAPYHFDLSGHAFGLMALPGKDQALRSVGELELEFR

RVRCKYPPGTKITFHVEKGSN

412 A0233 Amb p IQDSQSAAWKPMTESWGAVWRWDGAPPLKGPLSLRLTSESGKKLIAKDVIPAT

WKADNVYPSNIQF

413 A0233 Que a IQDSQSAAWKPMTESWGAVWRWDGAPPLKGPLSLRLTSESGKKLIAKDVIPAT

WKADNVYPSNIQF

414 A0246 Amb a DKEGIPPDQQRLIFAGKQLEDGRTLADYNIQKESTLHLVLRLRGGMQIFVKTLTG

KTITLEVESSDTIDNVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLADYNIQKESTL Table 4 (SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

HLVLRLRGG

415 A0246 Amb p NIQKESTLHLVLRLRGGTMIKVKTLTGKEIEIDIEPTDTIDRIKERVEEKEGIPPVQQ

RLIYAGKQLADDKTAKDYNIEGGSVLHLVLALRGG

416 A0246 Bet DKEGIPPDQQRLIFAGKQLEDGRTLADYNIQKESTLHLVLRLRGGTMI VKTLTG

KEIEIDIEPTDTIDRIKERVEEKEGIPPVQQRLIYAGKQLGDDKTAKDYNIEGGSVL HLVLALRGG

417 A0246 Que a QQRLIFAGKQLEDGRTLADYNIQKESTLHLVLRLRGGTMi VKTLTGKEIEIDIEPT

DTIDRIKERVEEKEGIPPVQQRLIYAGKQLGDDKTA DYNIEGGSVLHLVLALRGG

418 A0246 Cyn d DKEGIPPDQQRLIFAGKQLEDGRTLADYNIQKESTLHLVLRLRGGTMIKVKTLTG

KEIEIDIEPTDTIDRIKERVEEKEGIPPVQQRLIYAGKQLADDKTAKDYNIEGGSVL HLVLALRGG

419 A0260 Amb a LWCFGE LIDFVPSVSGVSLAEAPAFHKAPGGAPANVAV

420 A0260 Amb p LWCFGEMLIDFVPSVSGVSLAEAPAFHKAPGGAPANVAV

421 A0260 Bet LIVSFGEMLIDFVPTVSGVSLAEAPGFVKAPGGAPANVAI

422 A0260 Que a LIVSFGEMLIDFVPTVSGVSLAEAPGFLKAPGGAPANVAI

423 A0260 Cyn d LWSFGEMLIDFVPTVAGVSLAEAPAFVKAPGGAPANVAI

424 A0260 Amb a AFIGKVGDDEFGRMLADIL

425 A0260 Amb p AFIGKVGDDEFGR LADIL

426 A0260 Bet SFVGKLGEDDFGRMLAGIL

427 A0260 Que a AFVGKLGDDEFGHMLAGIL

428 A0260 Cyn d AFVGKLGDDEFGR LAGIL

429 A0260 Amb a FDQKARTALAFVTLRSDGEREFMFFRNPSAD LLH

430 A0260 Amb p FDQKARTALAFVTLRSDGEREFMFFRNPSADMLLH

431 A0260 Bet FDQGARTALAFVTLRADGEREF FYRNPSADMLLR

432 A0260 Que a FDKGARTALAFVTLRADGEREFMFYRNPSADMLLT

433 A0260 Cyn d FDSGARTALAFVTLRADGEREFMFYRNPSADMLLT

434 A0260 Amb a FHYGSISLIEEPCKS

435 A0260 Amb p FHYGSISLIEEPCKS

436 A0260 Bet FHYGSISLIVEPCRS

437 A0260 Que a FHYGSISLIVEPCRT

438 A0260 Cyn d FHYGSISLIAEPCRS

439 A0260 Amb p VKPVDTTGAGDAFVGGIL

440 A0260 Bet v VTQVDTTGAG DSFVGALL

441 A0260 Que a VNTVDTTG AG DS F VG ALL

442 A0260 Cyn d VQQVDTTGAGDAFVGALV

443 A0262 Amb p VEYRC F VG G LAW ATS DQ

444 A0262 Bet v VEYRCFVGGLAWATDDQ

445 A0262 Que a VEFRCFVGGLAWATDDQ

446 A0262 Cyn d VEYRCFVGGLAWATSDD

447 A0262 Amb a TEAKVIRDRETGRSRGFGFVTFAD

448 A0262 Amb p VDT IINDRETGRSRGFGFVTFRD

449 A0262 Bet v LESKIINDRETGRSRGFGFVTFGN

450 A0262 Que a LESKIINDRETGRSRGFGFVTFSN

451 A0262 Cyn d LESKIINDRETGRSRGFGFVTFAN

452 A0265 Amb a MIGLFGVFDGHGGARAAEYVKHHLFN

453 A0265 Amb p MIGLFGVFDGHGGARAAEYVKHHLFN

454 A0265 Bet v IVGLFGVFDGHGGARAAEYVKQNLFS

455 A0265 Cyn d TVGLFGVFDGHGGARAAEFVKQNLFT

456 A0265 Amb a LLKHPKFITDTKAAI

457 A0265 Amb p LLKHPKFITDTKAAI

458 , A0265 Bet v LIRHPKFISDTKSAI

459 A0265 Que a LIKHPKFFTDTKSAI

460 A0265 Cyn d LINHPKLFSDT SAI

461 A0265 Amb a QNRDAGSTASTAILV

462 A0265 Amb p QNRDAGSTASTAILV

463 A0265 Bet v QNRDAGSTASTAILV

464 A0265 Que a HNRDAGSTASTAILV

465 A0265 Cyn d HNRDAGSTASTAILV

466 A0265 Amb a RLLVANVGDSRAVISRGGKAFAVSRDHKPDQSDERQRIEDAGGFVMWAGTWR

VGGVLAVSRAFGDKLLKQYWADPEIQEEKVDNSLEFLILASDGLWDWTNDEA VAMVKPIES Table 4 (SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

467 A0265 Amb p RLLVANVGDSRAVISRGGKAFAVSRDHKPDQSDERQRIEDAGGFVMWAGTWR

VGGVLAVSRAFGDKLLKQYWADPEIQEEKVDNSLEFLILASDGLWDWTNDEA VA VKPIES

468 A0265 Bet v RLLVANVGDSRAVICRGGNAIAVSRDHKPDQTDERQRIEEAGGFV WAGTWRV

GGVLAVSRAFGDRLLKQYWADPEIQEEKIDSSLEFLILASDGLWDWTNEEAVA

MVKPIPE

469 A0265 Que a RLWANVGDSRAVICRGGDAIAVSRDH PDQTDERQRIEDAGGFVMWAGTWR

VGGVLAVSRAFGDKLL QYWADPEI EEWDSSLEFLILASDGLWDWTNEEAV

AMVKPIVD

470 A0265 Cyn d RLWANVGDSRAVICRGGDAIAVSRDHKPDQSDERQRIEDAGGFVMWAGTWR

VGGVLAVSRAFGD LLKQYWADPEIKEEKVDSSLEFLILASDGLWDWTNEEAV

AMVKPIID

471 A0265 Amb a RGSADNITWWRFLE

472 A0265 Amb p RGSADNITWWRFLE

473 A0265 Bet RGSADNITIVWRFL

474 A0265 Que a RGSADNITCVWRFLD

475 A0265 Cyn d RGSADNITCVWRFLD

476 A0270 Amb a lEKHAALLCVLAEDCNQPDYQKLVKALCADHNVSLVTVPSAKTLGEWAGLCKI

477 A0270 Amb p lEKHAALLCVLAEDCNQPDYQKLVKALCADHNVSLVTVPSA TLGEWAGLCKIDS

EGKARKWGCSCLWKDYGEE

478 A0270 Bet v lEKHAAQLCVLAEDCNQADYLKLVKALCADHNVKLMTVPSAKTLGEWAGLCKID

SEGKARKWGCSCVWKDFGEQ

479 A0270 Que a lEKHAAQLCVLAEDCNQPDYVKLVKGLCADHNVSLMTVPSAKTLGEWAGLCKID

SEGKARKWGCSCVWKDFGEV

480 A0270 Cyn d lEKHAAQLCVLAEDCDQPDYVKLVKALCAEHNVHLVTVPSAKTLGEWAGLCKID

SEGKARKWGCSCVWKDYGEE

481 A0300 Amb a IDDAVSRILRV FTMGLFENPLAD

482 A0300 Amb p IDDAVERILRVKFAAGLFEHP TD

483 A0300 Bet v INDAVKRILRVKFSLGLFENPLAD

484 A0300 Que a IDDAVKRILRVKFTMGLFENPLAD

485 A0300 Cyn d VNDAVSRILRVKFAMGLFEDPLPD

486 A0300 Amb a QAHREIAREAVRKSLVLLKNGKTA

487 A0300 Amb a EEHRDLAREAVRKTLVLLKNGKSS

488 A0300 Amb p KPHRELAREAVRKSLVLLKNGKDP

489 A0300 Bet v KEHRELAREAVRKSLVLLKNGKSA

490 A0300 Que a QEHRELAREAVRKSLVLLKNGKSA

491 A0300 Cyn d QNHRAIAREAVRKSLVLLKNGKKG

492 A0300 Amb a TIDALVAAWLPGTEGQGVTDVLFGDYGFTGKLARTWFK

493 A0300 Amb a GTEGQGVTDLLFGDYGFTGKLARTWFK

494 A0300 Amb p TLDALIAAWLPGTEGNGITDVIFGDHEFHGRLPVSWFK

495 A0300 Bet SVDALVAAWLPGSQGEGVADVLFGDYGFTGKLARTWFK

496 A0300 Que a S DALVAAWLPGTEGQGVADVLFGDYGFTGKLARTWFK

497 A0300 Cyn d YMDALVAAWLPGTEGQGVTDVLFGDYGFTGKLPRTWFK

498 A0304 Amb a LVTPPELASVGSNIFSKFIAFLKSKDANDGTEQAL

499 A0304 Amb p LVTPPEKASVGSKIFSTFIAFLKSKDANDGTEQAL

500 A0304 Bet v LGTPPEKASVGSKIFSTFIGFLKSKNPSDGTEQAL

501 A0304 Que a LGTPPEKASVGS IFSTFIGFLKSKDPSDGTEKAL

502 A0304 Cyn d LVTPPEYASVGSKIFSTFVTFLKSKDANDGSEQAL

503 A0311 Amb a MSFIGTQQKCKACGKTVYPVELLSADGIDYHKSCFKCSHCKGTLKLSNYSSMEG

VLYCKPHFEQLFKESGNFNKNFT

504 A0311 Amb a TFSGTQDKCKACDKTVHFIDLLSADGVPYHKTCFKCSHCKGTLSMSGYSSMEG

VLYCKPHFEQLFKETGSFTKKFP

505 A0311 Amb a GFGGTIDKCNACDKTVHFVDLLTVDSVIYHKRCFKCSHCKGTLVMSNYSSMD

GVLYCMPHFEQLFKETGNFSKNFP

506 A0311 Amb a MSFTGTLDKCKACDKTVYFVDLLSVDGVTYHKACFRCSHCKGTLAMSNYSSMD

GVLYCKPHFEQLFKESGNFSKNFH

507 A0311 Amb p MTFTGTQDKCKACDKTVHFIDLLTADSISYHKSCFKCSHCKGTLSMCNYSSMDG

VLYCKTHFEQLFKETGNFNKNFP

508 A0311 Bet MSFTGTQQKCKVCEKTVYPVEQLSADGVIYHKSCFKCSHCKGTLKLSNYSSME

GVLYCKPHFEQLFKETGSFNKNFQ

509 A0311 Que a MTFTGTQDKCKACDKTVHFIDLLTADSISYHKSCFKCSHCKGTLSMCNYSSMDG

VLYCKTHFEQLFKETGNFNKNFP Table 4 (SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

510 A0311 Cyn d MSFTGTQDKCNACDKTVHFIDLLTADGVIYHKTCFKCSHCKGILSMCSYSSMDG

VLYCKTHFEQLFKETGSFSKKFT

511 A0311 Amb a FSGTQEKCATCGKTAYPLEKV

512 A031 Amb a FSGTQDKCSTCKKTV

513 A0311 Amb a FSGTQDKCRLCDKTVYFIDK

514 A031 Amb a FSGTLDKCRQCNKTVYPLEKV

515 A0311 Amb p FCGTQDKCAACKKTVYPLEK

516 A0311 Bet v FSGTQEKCATCGKTAYPLEKV

517 A0311 Que a FCGTQDKCAACKKTVYPLEKM

518 A0311 Cyn d FSGTQDKCAACQKTVYPLEKL

519 A0311 Amb a QAYHKSCFKCSHGGCSLSPSNYAALEGILYCKHHFSQLFKEKGSYNHLIKSAS

520 A0311 Amb a ESYHKQCFRCIHGGCPLTHSSYAALNGVLYCRHHFAQLFLEKGTLSHVLMAAD

521 A0311 Amb a EPYHKSCFRCAHGGCPLTHSSYAALDGILYCKHHFAQLFMEKGNFSHVLEAAN

522 A0311 Amb p EPYHKTCFKCAHGGCLLTTASYAALNGILYCQHHFWQLFKETGSYDNLLKPAK

523 A0311 Bet v QAYHKSCFKCSHGGCPITPSNYAALEGILYCKHHFAQLFKEKGSYNHLIKSAS

524 A0311 Que a EPYHKTCFKCAHGGCLLTTASYAALNGILYCQHHFWQLFKETGSYDNLLKPAK

525 A0311 Cyn d EPYHKSCFKCSHGGCILTTSSYAALNGVLFCKIHFSQLFMEKGSYNHMKKKSE

526 A0316 Amb a MADGEDIQPLVCDNGTGMVKAGFAGDDAPRAVFPSIVGRPRHTGVMVGMGQK

DAYVGDEAQSKRGILTLKYPIEHGIVNNWDDMEKIWHHTFYNELRVAPEEHPVLL

TEAPLNPKANREKMTQIMFETFNSPAMYVAIQAVLSLYASGRTTGIVLDSGDGVS

HTVPIYEGYALPHAILRLDLAGRDLTDSLMKILTERGYSFTTSAEREIVRDMKEKL

AYIALD

527 A0316 Amb p MADGEDIQPLVCDNGTGMVKAGFAGDDAPRAVFPS!VGRPRHTGVMVGMGQK

DAYVGDEAQSKRGILTLKYPIEHGIVNNWDDMEKIWHHTFYNELRVAPEEHPVLL

TEAPLNPKANREKMTQIMFETFNSPAMYVAIQAVLSLYASGRTTGIVLDSGDGVS

HTVPIYEGYALPHAILRLDLAGRDLTDSLMKILTERGYSFTTSAEREIVRDMKEKL

AYIALD

528 A0316 Bet v MAEADDIQPLVCDNGTGMVKAGFAGDDAPRAVFPS!VGRPRHTGVMVG GQK

DAYVGDEAQSKRGILTLKYPIEHGIVSNWDDMEKIWHHTFYNELRVAPEEHPVLL

TEAPLNPKANREKMTQIMFETFNTPAMYVAIQAVLSLYASGRTTGIVLDSGDGVS

HTVPIYEGYALPHAILRLDLAGRDLTDALMKILTERGYSFTTTAEREIVRDMKEKL

AYIALD

529 A0316 Que a MAETEDIQPLVCDNGTGMVKAGFAGDDAPRAVFPSIVGRPRHTGVMVGMGQK

DAYVGDEAQSKRGILTLKYPIEHGIVSNWDDMEKIWHHTFYNELRVAPEEHPVLL TEAPLNPKANREKMTQIMFETFNTPAMYVAIQAVLSLYASGRTTGIVLDSGDGVS HTVPIYEGYALPHAILRLDLAGRDLTDHLMKILTERGYSh I I I AEREIVRDMKEKL AYIALD

530 A0316 Cyn d MADAEDIQPLVCDNGTGMVKAGFAGDDAPRAVFPS!VGRPRHTGVMVGMGQK

DAYVGDEAQSKRGILTLKYPIEHGIVSNWDDMEKIWHHTFYNELRVAPEEHPVLL

TEAPLNPKANREKMTQIMFETFNTPAMYVAIQAVLSLYASGRTTGIVLDSGDGVS

HTVPIYEGYALPHAILRLDLAGRDLTDYLMKILTERGYSFTTTAEREIVRDMKEKL

AYIALD

531 A0316 Amb a QELETSKTSSSVEKSFELPDGQVITIGAERFRCPEVLFQPSMIGMESAGIHETTY

NSIMKCDVDIRKDLYGNIVLSGGTTMFPGIADRMSKEITALAPSSMKIKWAPPER

KYSVWIGGSILASLSTFQQMWIAKAEYDESGPSIVHRKCF

532 A0316 Amb p QELETSKTSSSVEKSFELPDGQVITIGAERFRCPEVLFQPSMIGMESAGIHETTY

NSIMKCDVDIRKDLYGNIVLSGGTTMFPGIADRMSKEITALAPSSMKIKWAPPER

KYSVWIGGSILASLSTFQQMWIAKAEYDESGPSIVHRKCF

533 A0316 Bet v QELETAKTSSSVEKSYELPDGQVITIGAERFRCPEVLFQPSMIGMEAAGIHETTY

NSIMKCDVDIRKDLYGNIVLSGGSTMFPGIADRMSKEITALAPNSMKIKWAPPER

KYSVWIGGSILASLSTFQQMWIAKAEYDESGPSIVHRKCF

534 A0316 Que a QEIETSKTSSSVEKSYELPDGQVITIGAERFRCPEVLFQPSMIGMEAAGIHETTYN

SIMKCDVDIRKDLYGNIVLSGGSTMFPGIADRMSKEITALAPSSMKIKWAPPERK YSVWIGGSILASLSTFQQMWIAKAEYDESGPSIVHRKCF

535 A0316 Cyn d QEMETAKTSSSVEKSYELPDGQVITIGAERFRCPEVLFQPSFIGMEAAGIHETTY

NSIMKCDVDIRKDLYGNIVLSGGTTMFPGIADRMSKEITALAPSSMKIKWAPPER KYSVWIGGSILASLSTFQQMWIAKAEYDESGPSIVHRKCF

536 A0317 Amb a GCITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLNLMARKMKD

TDSEEELKEAFRVFDKD

537 A0317 Amb p GCITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLNLMARKMKD

TDSEEELKEAFRVFDKD

538 A0317 Bet v GCITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLNLMARKMKD Table 4 (SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

TDSEEELKEAFRVFDKD

539 A0317 Que a GCITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLNLMARKMKD

TDSEEELKEAFRVFDKD

540 A0317 Cyn d GCITTKELG MRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLNLMARKMKD

TDSEEELKEAFRVFDKD

541 A0325 Amb a AKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG- AKKRKKKNYSTPKKIKHKKKKIK

542 A0325 Amb p VKSKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG AKK

RKKKVYTTPKKIKHKRKKTK

543 A0325 Bet v AGKQLEDGRTLADYNIQKESTLHLVLRLRGG-AKKRKKKQYTTPKKIKHKRKKVK

544 A0325 Bet v VKSKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG AKK

RKKKVYTTPKKIK

545 A0325 Bet v FAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG- AKKRKKKTYTKPKKLKHKKKKVK

546 A0325 Que a VKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLADYNIQKESTLHLVLRLRGG- AKKRKKKTYTKPKKIKHKHKKVK

547 A0325 Cyn d VKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMAKK

RKKKNYTTPKKIKHKRKPVK

548 A0326 Amb a DDEGVDDQAVKWDIVDTFRLQEQPPFDKKQFV

549 A0326 Amb p WWQGAVDVDIGANPSAEGADEDEGVDDQAVKWDIVDTFRLQEQPAFNKKQF

V

550 A0326 Bet WWQGAVDVNIGANPSAEGGDEDEGVDDQHVKWDIVDTFRLQEQPPFEKKQF

V

551 A0326 Que a WWQGAVDVDIGANPSAEGGGEDEGVDDQAVKWDIVDTFRLQEQPSFDKKQF

V

552 A0326 Cyn d WVQGPVDVDIGANPSAEGG- DEEGVDDQAVKWDIVDTFRLQEQPAFDKKQFV

553 A0326 Amb a DFFKKNIEAATKFLLSKLSDLQFFVGESMHDDST

554 A0326 Amb p EFFKKNIEAATKFLLGKLSDLQFFVGESMHDDS-

555 A0326 Bet ALFKKHIEGAIKYLLPKISDLQFFVGESMHDDGS

556 A0326 Que a DIFKKNIEGATKFLLSKLSDLQFFVGESMHDDGG

557 A0326 Cyn d EEFKKGIEGATKFLLGKLKDLQFFVGESMHDDGT

558 A0326 Amb a AYYKDGASDPTFLYF

559 A0326 Bet v AYYKEGATDPTFIYL

560 A0326 Que a AYYKEG ATD PTF LYF

561 A0326 Cyn d AYYKDGATNPTFLYF

562 A0327 Amb a LAEICKGTAFPDICTSTVGSDPASHGPLDPMAVLR QVEQFLKRTEAAR

563 A0327 Amb p D VAF VC KGTP YAELC I ATAG KQAS H YPTVD ALTVLG MQ VDAFS KR AAAAR

564 A0327 Que a DVAF VC KGTPYAE LC I ATAG KQASH YPTVD ALTVLG MQ VDAFS KRAAAAR

565 A0327 Cyn d I C KATS FPDVC I KTAG KH VKH YSS VD ALS VLH M Q VDAFS KRAAAAR

566 A0327 Amb a YLDVEDNLGACRRAIGFHDAVTIRAT GMAAQDMQNCDEQFRQIGEKNPMEQF

DASLVEMSENCRSLSNMI

567 A0327 Amb p YSNVEDNLGATRRAIGFKDPVTIRA MSMSAQAMKSCDEEFKKNAAVNPLTRF

DQSLLNISENCRALSNMI

568 A0327 Que a YSNVEDNLGATRRAIGFKDPVTIRAMMSMSAQAMKSCDEEFKKNAAVNPLTRF

DQSLLNISENCRALSNMI

569 A0327 Cyn d YLDVEDNLGACRRAMRHRDGVTIRATMSMAAQDMQNCDEQFRQAGENKNPLE

RFNKSLGQMAEVCRSLSNMI

570 A0334 Amb a KSYNCKILPNSLVLDF

571 A0334 Amb a QKYDCKILPNTLVFDF

572 A0334 Amb p HKYDCKKLPTSMELEF

573 A0334 Bet v KDKDCDSLPMNIRFDF

574 A0334 Que a KNYNCKILPNSLVLDY

575 A0334 Cyn d KNYNCKILPNSLVLDY

576 A0334 Amb a KVTVKAPGNSPNTDGIHIGDSSNV

577 A0334 Amb a DLTITAPGDSPNTDGIHIGDSSKV

578 A0334 Amb p GVTVTAPEDSPNTDGIHIGRSSRV

579 A0334 Bet v HFTVRAPGESVNTDGIHIGRSTGI

580 A0334 Que a RVNITAPGDSPNTDGIHIGDSTNV

581 A0334 JDyn d RVNITAPGDSPNTDGIHIGDSTNV

582 A0334 Amb a TTIGVGDDCISIGPGSK

583 A0334 Amb a TTIGTGDDCISIGPGST Table 4 (SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

584 A0334 Amb p ATIGTGDDCVSIGAGTR

585 A0334 Bet SKIGTGDDCISVGDGTE

586 A0334 Que a TNIGTGDDCISIGPGSK

587 A0334 Cyn d TNIGTGDDCISIGPGSK

588 A0334 Amb a IEGVKCGPGHGISIGSLGRYKDEKDVEDVKVK

589 A0334 Amb a ITGVTCGPGHGISIGSLGRYADEKDVTDI

590 A0334 Amb p VTGVTCG PG HG I SVG S LG RYKD ETD VC N V I R

591 A0334 Bet ITG VTCG PG H GISVGSLGKYPNE KP VSG I F VK

592 A0334 Bet ITGVTCGPGHGISVGSLG

593 A0334 Que a VRGVRCGPGHGISVGSLGRYKDEKDVSDVTVR

594 A0334 Cyn d VRGVRCGPGHGISVGSLGRYKDEKDVSDVTVR

595 A0334 Amb a NVSYPIIIDQKYCPNNICV

596 A0334 Amb p DVNNPIIIDMKYCPNKICP

597 A0334 Amb p DVAKPIIIDQYYCPEKVCP

598 A0334 Bet v NVQNPVIIDQVYCPWNQCS

599 A0334 Que a DVAKPIIIDQYYCPEKVCP

600 A0334 Cyn d DVAKPIIIDQYYCPEKVCP

601 A0334 Amb a VAVTDVIFKNIHGTSNTPEAITLNCAN

602 A0334 Amb p VTVRDVTFKHISGTSLNPEWKF CSD

603 A0334 Amb p VAVKDWFRNITGTSSTPEAVSLLCSE

604 A0334 Bet VKISDVSFKSIRGTSATPVWRIACSS

605 A0334 Que a VDVKDWFRNITGTSSTPEAVSLLCSA

606 A0334 Cyn d VAVKDWFRNITGTSSTPEAVSLLCSE

607 A0336 Amb a MEQTFI IKPDGVQRGLVGEII

608 A0336 Amb p MEQTFIMIKPDGVQRGLVGEII

609 A0336 Bet v MEQTFIMIKPDGVQRGLVGEII

610 A0336 Que a MEQTFIMIKPDGVQRGLVGEII

611 A0336 Cyn d MEQTFIMIKPDGVQRGLIGDII

612 A0336 Amb a GLVEYIISGPWAMVWEGKNW

613 A0336 Amb p GLVEYIISGPWAMVWEGKNW

614 A0336 Bet v GLVDYIISGPWATVWEGKNW

615 A0336 Que a GLVDYIISGPWAMIWEGKNW

616 A0336 Cyn d GLVEYIISGPWAMVWEGKDW

617 A0349 Amb a KELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPYSGGVFLVTIHFPPDYP

FKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLTDPNPDDP LVPEIAHMYKTDRNKYETTARSWTQKYAMG

618 A0349 Amb p KELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPSDSPYSGGVFLVNIHFPPDY

PFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLTDPNPDD

PLVPEIAHMYKTDKSKYEATARSWTQKYA

619 A0349 Amb p KELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPSDSPYSGGVFLVSIHFPPDYP

FKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLTDPNPDDP LVPEIAHMYKTDKSKYEATARSWTQKYAMG

620 A0349 Amb p KELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPYSGGVFLVTIHFPPDYP

621 A0349 Bet v EDMFHWQATIMGPADSPYAGGVFLVSIHFPPDYPFKPPKVAFRTKVFHPNINSN

GSICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYKTDRAKYEATA

RSWTQKYAMG

622 A0349 Bet v KELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPYAGGVFLVTIHFPPDYP

FKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLTDPNPDDP LVPE I AH M YKTD RG KYETTARSWTQKYAMG

623 A0349 Bet v KELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPYAGGVFLVTIHFPPDYP

624 A0349 Que a KELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPADSPYAGGVFLVSIHFPPDYP

FKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLTDPNPDDP LVPEIAHMYKTD R AKYEATARSWTQ KYAMG

625 A0349 Que a KELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPTDSPYAGGVFLVTIHFPPDYP

FKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLTDPNPDDP LVPE I AH M YKTD R AKYETTARS WTQKYAMG

626 A0349 Que a KELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPYAGGVFLVTIHFPPDYP

FKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLTDPNPDDP Table 4 (SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

LVPEIAHMYKTDRSKYETTARSWTQKYAMG

627 A0349 Cyn d KELKDLQKDPPTSCSAGPVGEDMFHWQATIMGPSDSPFAGGVFLVNIHFPPDY

PFKPPKVSFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLTDPNPDD

PLVPEIAHMYKTDRAKYESTARSWTQKYAMG

628 A0349 Cyn d KELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPSDSPYAGGVFLVTIHFPPDYP

FKPPKVAFKTKVFHPNVNSNGSICLDILKEQWSPALTVSKVLLSICSLLTDPNPDD PLVPEIAHMYKTDRAKYESTARSWTQKYAMG

629 A0349 Amb a MASKRILKELKDLQ DPPTSCSAGPVAEDMFHWQATI GPPDSPY

630 A0349 Amb p MASKRIIKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPSDSPY

631 A0349 Amb p MASKRILKELKDLQ DPPTSCSAGPVAEDMFHWQATIMGPSDSPY

632 A0349 Amb p MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPY

633 A0349 Bet v ED FHWQATIMGPADSPY

634 A0349 Bet v RILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPY

635 A0349 Bet v MASKRIL ELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPY

636 A0349 Que a MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPADSPY

637 A0349 Que a RILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPTDSPY

638 A0349 Que a MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATI GPPDSPY

639 A0349 Cyn d MASKRILKELKDLQKDPPTSCSAGPVGEDMFHWQATIMGPSDSPF

640 A0349 Cyn d MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATI GPSDSPY

641 A0349 Amb a GGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVL

LSICSLLTDPNPDDPLVPEIAH YKTDRNKYETTARSWTQKYAMG

642 A0349 Amb p GGVFLVNIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKV

LLSICSLLTDPNPDDPLVPEIAHMYKTDKSKYEATARSWTQKYA

643 A0349 Amb p GGVFLVSIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVL

LSICSLLTDPNPDDPLVPEIAHMYKTDKSKYEATARSWTQKYA G

644 A0349 Amb p GGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDIL EQWSPALTISKVL

LSICSLLTDPNPDDPLVPEIAHMYKTDRNKYETTARSWTQKYAMG

645 A0349 Bet v GGVFLVSIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVL

LSICSLLTDPNPDDPLVPEIAHMYKTDRAKYEATARSWTQKYAMG

646 A0349 Bet v GGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVL

LSICSLLTDPNPDDPLVPEIAHMYKTDRGKYETTARSWTQKYAMG

647 A0349 Bet v GGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVL

LSICSLLTDPNPDDPLVPEIAHMYKTDRNKYETTARSWTQKYAMG

648 A0349 Que a GGVFLVSIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVL

LSICSLLTDPNPDDPLVPEIAHMYKTDRAKYEATARSWTQKYAMG

649 A0349 Que a GGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVL

LS I CSLLTD P N P D D P LVP E I AH YKTD R AKYETTARS WTQ KYAM G

650 A0349 Que a GGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVL

LSICSLLTDPNPDDPLVPEIAHMYKTDRSKYETTARSWTQKYAMG

651 A0349 Cyn d GGVFLVNIHFPPDYPFKPPKVSFRTKVFHPNINSNGSICLDILKEQWSPALTISKV

LLSICSLLTDPNPDDPLVPEIAHMYKTDRAKYESTARSWTQKYAMG

652 A0349 Cyn d GGVFLVTIHFPPDYPFKPPKVAFKTKVFHPNVNSNGSICLDILKEQWSPALTVSK

VLLSICSLLTDPNPDDPLVPEIAHMYKTDRAKYESTARSWTQKYA G

653 A0349 Amb a DMFHWQATIMGPPDSPYSGGVFLVTIHFPPDYPFKPPKVAFRTKVFHPN!NSNG

SICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYKTDRNKYE

654 A0349 Amb p DMFHWQATIMGPSDSPYSGGVFLVNIHFPPDYPFKPPKVAFRTKVFHPNINSNG

SICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAH YKTDKS YE

655 A0349 Amb p DMFHWQATI GPSDSPYSGGVFLVSIHFPPDYPFKPPKVAFRTKVFHPNINSNG

SICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYKTDKSKYE

656 A0349 Amb p DMFHWQATIMGPPDSPYSGGVFLVTIHFPPDYPFKPPKVAFRTKVFHPN!NSNG

S I C LD I LKEQ WS PALTI S VLLS ICSLLTDPNPDDP LVP EIAHMYKTDRNKYE

657 A0349 Bet DMFHWQATIMGPADSPYAGGVFLVSIHFPPDYPFKPPKVAFRT VFHPNINSNG

SICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYKTDRAKYE

658 A0349 Bet v DMFHWQATI GPPDSPYAGGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNG

SICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYKTDRGKYE

659 A0349 Bet v D FHWQATI GPPDSPYAGGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNG

SICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYKTDRNKYE

660 A0349 Que a DMFHWQATIMGPADSPYAGGVFLVSIHFPPDYPFKPPKVAFRTKVFHPNINSNG

SICLDILKEQWSPALTIS VLLSICSLLTDPNPDDPLVPEIAHMYKTDRAKYE

661 A0349 Que a DMFHWQATI GPTDSPYAGGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNG

SICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYKTDRAKYE

662 A0349 Que a DMFHWQATIMGPPDSPYAGGVFLVTIHFPPDYPFKPPKVAFRTKVFHPNINSNG Table 4 (SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

SICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAHMYKTDRSKYE

663 A0349 Cyn d DMFHWQATIMGPSDSPFAGGVFLVNIHFPPDYPFKPPKVSFRTKVFHPNINSNG

SICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPE!AHMY TDRAKYE

664 A0349 Cyn d D FHWQATI GPSDSPYAGGVFLVTIHFPPDYPFKPPKVAFKTKVFHPNVNSNG

SICLDILKEQWSPALTVSKVLLSICSLLTDPNPDDPLVPEIAHMYKTDRAKYE

665 A0349 Amb a ASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPYSGGVFLVTI

HFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLT DPNPDDPLVPEIAH YKTDRNKYETTARSWTQKYAMG

666 A0349 Amb p MASKRIIKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPSDSPYSGGVFLVNI

HFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLT DPNPDDPLVPEIAHMYKTDKSKYEATARSWTQKYA

667 A0349 Amb p ASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPSDSPYSGGVFLVSI

HFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLT DPNPDDPLVPEIAHMYKTDKSKYEATARSWTQKYAMG

668 A0349 Amb p MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPYSGGVFLVTI

HFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLT DPNPDDPLVPEIAHMYKTDRNKYETTARSWTQKYAMG

669 A0349 Bet v ED FHWQATIMGPADSPYAGGVFLVSIHFPPDYPFKPPKVAFRTKVFHPNINSN

GSICLDILKEQWSPALTISKVLLSICSLLTDPNPDDPLVPEIAH YKTDRAKYEATA

RSWTQKYAMG

670 A0349 Bet RILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPYAGGVFLVTIHFPP

DYPFKPPKVAFRTKVFHPNINSNGS!CLDILKEQWSPALTISKVLLSICSLLTDPNP DDPLVPEIAHMYKTDRGKYETTARSWTQKYAMG

671 A0349 Bet v MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPYAGGVFLVTI

HFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLT DPNPDDPLVPEIAHMY TDRNKYETTARSWTQKYAMG

672 A0349 Que a MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPADSPYAGGVFLVSI

HFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLT DPNPDDPLVPEIAHMYKTDRA YEATARSWTQKYAMG

673 A0349 Que a RILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPTDSPYAGGVFLVTIHFPP

DYPFKPPKVAFRTKVFHPNINSNGSICLD!LKEQWSPALTISKVLLSICSLLTDPNP

DDPLVPEIAHMYKTDRAKYETTARSWTQ YAMG

674 A0349 Que a MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATIMGPPDSPYAGGVFLVTI

HFPPDYPFKPPKVAFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLT DPNPDDPLVPEIAH YKTDRSKYETTARSWTQKYA G

675 A0349 Cyn d MASKRILKELKDLQKDPPTSCSAGPVGEDMFHWQATIMGPSDSPFAGGVFLVNI

HFPPDYPFKPPKVSFRTKVFHPNINSNGSICLDILKEQWSPALTISKVLLSICSLLT DPNPDDPLVPEIAHMYKTDRAKYESTARSWTQKYAMG

676 A0349 Cyn d MASKRILKELKDLQKDPPTSCSAGPVAEDMFHWQATi GPSDSPYAGGVFLVTI

HFPPDYPFKPPKVAFKTKVFHPNVNSNGSICLDILKEQWSPALTVSKVLLSICSLL TDPNPDDPLVPEIAHMYKTDRAKYESTARSWTQKYAMG

677 A0356 Amb a EKIHINIWIGHVDSGKSTTTGHLIYKCGGIDKRTIEKFEKEA

678 A0356 Bet EKFHINIWIGHVDSGKSTTTGHLIYKLGGIDKRVIERFE EA

679 A0356 Que a EKVHISIWIGHVDSGKSTTTGHLIY LGGIDKRVIERFEKEA

680 A0356 Cyn d EKSHINIWIGHVDSGKSTTTGHLIYKLGGIDKRVIERFEKEA

681 A0356 Amb a E GKGSFKYAWVLDKLKAERERGITIDIALWKFETSKYYVTIIDAPGHRDFIKNMI

TGTSQADCAVLIVA

682 A0356 Bet E NKRSFKYAVvVLDKLKAERERGITIDIALWKFETTKYYCTVIDAPGHRDFIKNMI

TGTSQADCAILIID

683 A0356 Que a EMNKRSFKYAvWLDKLKAERERGITIDIALWKFETTRYYCTVIDAPGHRDFIKNMI

TGTSQADCAVLI I D

684 A0356 Cyn d EMNKRSFKYAWVLDKLKAERERGITID!ALWKFETTKYYCTVIDAPGHRDFIKNMi

TGTSQADCAVLI ID

685 A0356 Amb a QTREHALLAFTLGVKQMICCCNKMDATTPKYSKARYDEIVKEVSSYLKKVGYNP

DKIPFVPISGFEGDNMIERSTNLDWYKGPTLLEALDQINEPKRPSDKPLRLPLQD VYKIGGIGTVPVGRVETGVI PGMWTFGPSGLTTEVKSVEMHHEALQEALPGD NVGFNVKNVAVKDLKRGYVASN

686 A0356 Amb a TGEFEAGISKNGQTREHALLAFTLGVKQ

687 A0356 Amb p TREHALLAFTLGVKQ ICCCNKMDATTPKYSKARYDEIVKEVSSYLK VGYNPD

KIPFVPISGFEGDNMIERSTNLDWYKGPTLLEALDQINEPKRPSDKPLRLPLQDV YKIGGIGTVPVGRVETGVIKPGMWTFGPSGLTTEVKSVEMHHEALQEALPGDN VGFNVKNVAVKDLKRGYVASN Table 4 (SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

688 A0356 Bet TGGFEAGISKDGQTREHALLAFTLGVRQMICCCNKMDATTPKYSKARYDEIVKE

VSSYLKKVGYNPDKIPFVPISGFEGDNMIERSTNLDWYKGPTLLEALDLISEPKRP SDKPLRLPLQDVYKIGGIGTVPVGRVETGVIKPGMNA/TFGPTGLTTEVKSVEMHH EALQEALPGDNVGFNVKNVAVKDLKRGFVASN

689 A0356 Que a TGGFEAGISKDGQTREHALLAFTLGVKQMICCCNKMDATTPKYSKARYDEIIKEV

SSYLKKVGYNPDKIPFVPISGFEGDNMIERSTNLDWYKGPTLLEALDQISEPKRP SDKPLRLPLQDVYKIGGIGTVPVGRVETGIIKPGMWTFGPTGLTTEVKSVEMHH EALLEALPGDNVGFNVKNVAVKDLKRGFVASN

690 A0356 Cyn d TGGFEAGISKDGQTREHALLAFTLGVKQMICCCNKMDATTPKYSKARYDEIVKE

VSSYLKKVGYNPDKIPFVPISGFEGDNMIERSTNLDWYKGPTLLEALDQINEPKR PSDKPLRLPLQDVYKIGGIGTVPVGRVETGVLKPGMWTFGPSGLTTEVKSVEM HHEALQEALPGDNVGFNVKNVAVKDIKRGYVASN

691 A0356 Amb a ASFTSQVIIMNHPGQIGNGYAPVLDCHTSHIAVKFSEL

692 A0356 Amb p ASFTSQVIIMNHPGQIGNGYAPVLDCHTSHIAVKFSEL

693 A0356 Bet ANFTAQVIIMNHPGQIGNGYAPVLDCHTCHIAVKFAEL

694 A0356 Que a ANFTSQVIIMNHPGQIGNGYAPVLDCHTSHIAVKFAEL

695 A0356 Cyn d ASFTSQVIIMNHPGQIGNGYAPVLDCHTSHIAVKFAEL

696 A0356 Amb a EPKFLKNGDAGMVK LPTKPMWETFAEYPPLGRFAVRDMRQTVAVGVIKSVD

K DPT

697 A0356 Amb p EPKFLKNGDAGMVKMLPTKPMWETFAEYPPLGRFAVRDMRQTVAVGVIKSVD

KKDPTG

698 A0356 Bet EPKFLKNGDAGIVKMIPTKPMWETFAEYPPLGRFAVRDMRQTVAVGVIKGVEK

KDPSG

699 A0356 Que a EPKFLKNGDAGMVKMIPTKPMWETFSEYPPLGRFAVRDMRQTVAVGVIKSVEK

KDPSG

700 A0356 Cyn d EPKFLKNGDAGMVKMIPTKPMWETFSQYPPLGRFAVRDMRQTVAVGVIKSVEK

KDPTG

701 A0357 Amb a DRERIFKRFDTNGDGKISSTEL

702 A0357 Bet v ELERIFKRFDLNGDGQISAAEL

703 A0357 Que a DMERIFKRFDTNGDGKISLAEL

704 A0357 Cyn d DMERIFKRFDTNGDGKISLAEL

705 A0357 Amb a TLGSVTSEEIVRMMAEIDTDGDGFISFEEFTDFAGANRGLIKDVAKIF

706 A0357 Amb p TLGSTSADEVQRM AEIDTDGDGFIDFNEFISFCNANPGLMKDVAKVF

707 A0357 Bet v TLGSVTAEEIKRMMAEIDTDGDGF!SFQEFLDFAKANSGLMKDVAKIF

708 A0357 Que a TLGSTSADEVQRMMAEIDTDGDGFIDFNEFISFCNANPGLMKDVAKVF

709 A0357 Cyn d TLGSTSADEVQRMMAEIDTDGDGFIDFDEFISFCNANPGLMKDVAKVF

710 A0358 Amb a TRIAECLVGDETGTILFTARNDQVDLMKAG

711 A0358 Amb p TRIAECLVGDETGTILFTARNDQVDLMKAG

712 A0358 Bet MRIAECLVGDETGMIIFTARNDQVDLMKEG

713 A0358 Que a TRIAECLVGDETATIVFTARNEQVDLMQPG

714 A0358 Cyn d TRIAECLIGDETGCILFTARNEQVDLMKPD

715 A0358 Amb a IIRNAKIDMFKGSMRLAVDKWGRI

716 A0358 Amb p IIRNAKID FKGSMRLAVDKWGRI

717 A0358 Bet ILRNAKIDMFKGSMRLAVDKWGRV

718 A0358 Que a ILRNAKIDMFKGSMRLAVDKWGRV

719 A0358 Cyn d IIRNAKIDMFKGSMRLAVDKWGRI

720 A0358 Amb a EDN N LSLVEYELVN VTE

721 A0358 Amb p ED N N LS LVEYE LVN VTE

722 A0358 Bet EDNNLSLIEYELVNWE

723 A0358 Que a E D N N LS LVEYELVN WE

724 A0358 Cyn d EDNNLSLVEYELVNVSE

725 A0362 Amb p FSPEEISAMILTKMKETAEAFLGKKIKDAWTVPAYFNDAQRQATKDAGVIAGLNV

ARIINEPTAAAIAYGLDKKGGEKNILVFDLGGGTFDVSILTIDNGVFEVLATNGDTH

LGGEDFDQRIMEYFIKLIKKKHGKDISKDHRALGKLRREAERAKRALSSQHQVRV

EIESLFDGVDFSEPLTRARFEELNNDLFRKTMGPVKKAMEDAGLEKRQIDEIVLV

GGSTRIPKVQQLLKDYFDGKEPNKGVNPDEAVAYGAAVQGGILSGEGGDETKDI

LLLDVAPLTLG I ETVGGVMTKLI PRNTVI PTKKSQVFTTYQDQQTWSI KVYEGER

SLTKDCRLLGTFDLTGIPPAPRGTPQIEVTFEVDANGILNVKAEDKASGKSEKITIT

NEKGRLSQEEIERMVREAEEFAEEDKKVK

726 A0362 Bet v FSPEEVSAMILTKMKETAEAFLGKKIKDAWTVPAYFNDAQRQATKDAGIIAGLNV

ARIINEPTAAAIAYGLDKKGGEKNILVFDLGGGTFDVSILTIDNGVFEVLATNGDTH LGGEDFDHRIMEYFIKLIKKKHGKDISKDNRALGKLRREAERAKRALSSQHQVRV Table 4 (SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

EIESLFDGVDFSEPLTRARFEELNNDLFRKTMGPVKKAMDDAGLEKNQIDEIVLV GGSTRIPKVQQLLKDYFDGKEPNKGVNPDEAVAYGAAVQGSILSGEGGEETKDI LLLDVAPLTLGIETVGGVMTKLIPRNTVIPTKKSQVFTTYQDQQTTVSIQVYEGER SLTKDCRNLGKFDLSGIPPAPRGTPQIEVTFEVDANGILNVKAEDKGTGKSEKITI TNDKGRLSQEEIDRMVREAEEFAEEDKKVK

727 A0362 Que a FSPEEISAMVLTKMKETAEAFLGKKIKDAWTVPAYFNDAQRQATKDAGVIAGLN

VARIINEPTAAAIAYGLDK GGEKNILVFDLGGGTFDVSILTIDNGVFEVLATNGDT

HLGGEDFDHRVMDYFIKLIKKKHSKDISKDNRALG LRREAERAKRALSSQHQV

RVEIESLFDGVDFSEPLTRARFEELNNDLFRKTMGPVKKAMDDAGLEKRQIDEIV

LVGGSTRIPKVQQLLKDFFDGKEPNKGVNPDEAVAYGAAVQGGILSGEGGDET

KDILLLDVAPLTLGIETVGGVMT LIPRNTVIPSKKSQVFTTYQDQQTTVTIQVFEG

ERSLTKDCRLLGNFDLTGIAPAPRGTPQIEVTFEVDANGILNVKAEDKASGKSEKI

TITNDKGRLSQEEIDRMVQEAEEFAEEDKKVK

728 A0362 Cyn d FSPEEISAMILG MKDTAEAYLGKKINDAWTVPAYFNDAQRQATKDAGVIAGLN

VARIINEPTAAAIAYGLDKKGGEKNILVFDLGGGTFDVSILTIDNGVFEVLATNGDT

HLGGEDFDHRIMEYFIKLIKKKYSKDISKDNRALGKLRREAERAKRALSNQHQVR

VEIESLFDGTDFSEPLTRARFEELNNDLFRKTMGPVK AMEDAGLEKSQIHEIVL

VGGSTRIPKVQQLLRDYFDGKEPNKGVNPDEAVAYGAAVQGSILSGEGGEETK

DILLLDVAPLTLGIETVGGVMTKLIPRNTVIPTKKSQVFTTYQDQQTTVSIQVFEGE

RSMTKDCRLLGKFDLSGIPPAPRGTPQIEVTFEVDANGILNVKAEDKGTGKSEKI

TITNEKGRLSQEEIDRMVREAEEFAEEDKKVK

729 A0362 Amb a VDWSKWHMFWVDERWPKDHPDSNYLLA

730 A0362 Amb p VDWSKWHMFWVDERWPKDHPDSNYLLA

731 A0362 Bet v VEWSKWHVFWVDERWPKDHEDSNYKLA

732 A0362 Que a IEWSRWHIFWADERWPKDHEDSNYKLA

733 A0362 Cyn d VDWSKWHVFWVDERWPKDHEDSNYKLA

734 A0366 Que a QAVLFDIDGTICDSDPLHHYAF

735 A0366 Cyn d QAVLFDIDGTLCDSDPLHHVAF

736 A0366 Amb a GL RAAVTNAPRPNAELMI

737 A0366 Amb p GLKRAAVTNAPRPNAELMI

738 A0366 Bet v GLKRAAVTNAPRPNAELMI

739 A0366 Que a GIKRAAVTNAPKANAELMI

740 A0366 Cyn d GYKRAAVTNAPRINAELMI

741 A0376 Amb a VLGHKSNADGLTTQDTATFSVIGQGFICKNMGFSNTAGAIKHQAVALRLQSDFA

AFYNCRMDGYQDTLYVQARRQFFRNCWSGTIDFIFGNAAAVFQNCLIIVRRPM

DNQQNTVTAHGRTDPKMKSGLVIQNCRIVPDQALFPDRFKIPSYLGRPWKEYSR

TVIMESTIGDAIRPEGWMAWNGDFALKTLYYAEYANRGPGANTRSRVRWPGFH

VI

742 A0376 Amb a VTGKKSFADGITTMKTATFSIEAAGFICKNMGFHNTAGAEKHQAVALRVQGDFA

AFYNCRFDAFQDTLYVHARRQFFRNCVISGTIDFIFG

743 A0376 Amb a PMDNQQNSVTAHGRTDPNMKSGLVIQNCRLVPDQKLFPDRFKIPSYLGRPWKE

FSRLVIMESTIADFIKPEGYMPWNGDFGIKTLFYAEYNNRGPGAGTSKRVKWPG FHVI

744 A0376 Amb p VTGSKSFHDG!TTMKTATFSIEASGFICKNMGFHNTAGAERHQAVALRVQGDLA

AFFNCRFDAFQDTLYVHARRQFFRNCVISGTIDFIFGNSAAIFQNCLIITRRPMDN QQNSVTAHGRTDPNMKSGLVIQNCRLVPDQKLFPDRFKIPSYLGRP

745 A0376 Bet VTGRKSYRDGITTFKTASFSTMGEGFIAKSMGFQNTAGPEGHQAVALRVQADR

SAFFNCRMDGYQDTLYVQTHRQFFRNCVISGTVDFIFGDAAAVIQNSLIIVRKPM DNQQNTVTAQGRHDKRETTGLVIHNCRIVPEQKLFAQRFTIPTYLGRPWKEYAR TVIMETTLADFIQPVGYMPWAGSFALSTCSYFEYANRGPGARTVRRVRWKGAR VI

746 A0376 Que a VTGRKSFADGVTTMKTATFSIEAAGFICKNMGFHNTAGAERHQAVALRVQGDLA

AFYNCRFDAFQDTLYVHARRQFFRNCVISGTIDFIFGNSAAIFQNCLIITRRPMDN QQNSVTAHGRTDPNMKSGLVIQNCRLVPDQKLFPDRFKIPSYLGRPWKEFSRLV IMESTIADFIKPEGYMPWNGDFGLKTLYYAEYANRGPGAGTSKRVTWPGFRVI

747 A0376 Cyn d VTGRKSFADGITTMKTATFSIEASGFICKNMGFHNTAGAERHQAVALRVQGDLA

AFFNCRFDAFQDTLYVHARRQFFRNCVISGTIDFIFGNSAAVFQNCLIITRRPMDN QQNSVTAHGRTDPNMKSGLVIQNCRLVPDQKLFPDRFKIPSYLGRPWKEFSRLV IMESTIADFIKPEGYMPWDRDFALKTLYYAEYNNKGPGAGTSKRVNWPGFRVI

748 A0376 Amb a AQQFTVGNFISGNLWLRYTG

749 A0376 Amb a AEQFTAGPFIDGATWLKFTGTP

750 A0376 Bet ALQFTAGPFLQGNLWLKATGFP

751 A0376 Que a AEQFTAGPFVDGATWLKFTGTP Table 4 {SEQ ID NOS: 294-767)

SEQ ID NO SpeAmino acid sequence

ID NO cies

752 A0376 Cyn d AAQ FTAG P F I DG ATWLKFTGTP

753 A0377 Amb a PKFMVFACSDSRVCPS

754 A0377 Amb p PKFMVFACSDSRVCPS

755 A0377 Bet v PKFMVFACSDSRVCPS

756 A0377 Que a PKFMVFACSDSRVCPS

757 A0377 Cyn d PKYMVFSCADSRVCPS

758 A0377 Amb a PGEAFMVRNIANMVP

759 A0377 Amb p PGEAFMVRNIANMVP

760 A0377 Bet v PGEAFWRNVANLVP

761 A0377 Que a PGEAFMIRNIANMVP

762 A0377 Cyn d PGEAFTVRNIANMVP

763 A0377 Amb a CEKEAVNVSLGNLLTYPFVK

764 A0377 Amb p C E VE AVN VS LG N LLTYPFVK

765 A0377 Bet v CEKEAVNVSIGNLLTYPFVR

766 A0377 Que a CEKEAVNVSLGNLLTYPFVR

767 A0377 Cyn d LEKEAVNLSLENLKSYPFVK

Table 5. GW conserved amino acid sequences derived from polypeptides derived from polypeptides of Table 1

Table 5 - SEQ ID NOS: 768-808

Table 5 - SEQ ID NOS: 768-808

Table 6. GW conserved amino acid sequences derived from polypeptides of Table 2

Table 6 - SEQ ID NOS: 809-951

Table 6 - SEQ ID NOS: 809-951

SEQ ID NO Spe-cies Amino acid sequence

ID

NO

853 A0265 Amb p QEASERGSADNITWWRF

854 A0265 Cyn d QEASQRGSADNITCVWRF

855 A0270 Amb a PALGEPMDIMTALQLVL

856 A0270 Amb p PALGEPMDI TALQLVL

857 A0270 Cyn d PVLGEPMDLMTALQLVM

858 A0270 Amb a KLVKALCADHNVSLVTVPSAKTLGEWA

859 A0270 Amb p KLVKALCADHNVSLVTVPSAKTLGEWA

860 A0270 Cyn d KLVKALCAEHNVHLVTVPSAKTLGEWA

861 A0270 Amb p VGCSCLWKDYGEESEGLHIVQEYVKSH

862 A0270 Cyn d VGCSCVWKDYGEESEGLNIVQEYVKSH

863 A0300 Amb a DTI DALVAAWLPGTE

864 A0300 Amb p ETLDALIAAWLPGTE

865 A0300 Cyn d DYMDALVAAWLPGTE

866 A0300 Amb a DYG FTG KLARTWFKS VN QLPM VGDPHYDPLY

867 A0300 Amb a DYGFTGKLARTWFKSVDQLPMNVGDKHYDPLF

868 A0300 Amb p DHEFHGRLPVSWFKSVDQLPMDSNKSSYDPLF

869 A0300 Cyn d DYGFTGKLPRTWFKSVDQLPMNYGD RYDPLF

870 A0304 Amb a NWVSDSDVIVGIIEDKYPHPSLVTPPELASVGSNIFSKFIAFLKSKDANDGTEQA

871 A0304 Amb p KWISDSDVITQTIEEKFPDPSLVTPPEKASVGSKIFSTFIAFLKSKDANDGTEQA

872 A0304 Cyn d KWIADSDVIVQIVEEKYPTPSLVTPPEYASVGSKIFSTFVTFLKSKDANDGSEQA

873 A0304 Amb a AVDLSLGPKLYHLQVALGH

874 A0304 Cyn d AADLSLAPKLYHLHVALEH

875 A0311 Amb a PVELLSADGIDYHKSCFKCS

876 A0311 Amb a FIDLLSADGVPYHKTCFKCS

877 A0311 Amb a FVDLLTVDSVIYHKRCFKCS

878 A0311 Amb a FVDLLSVDGVTYHKACFRCS

879 A0311 Amb p FIDLLTADSISYHKSCFKCS

880 A0311 Cyn d FIDLLTADGVIYHKTCFKCS

881 A0311 Amb a SNYAALEGILYCKHHFSQLFK

882 A0311 Amb a SSYAALNGVLYCRHHFAQLFL

883 A0311 Amb a SSYAALDGILYCKHHFAQLFM

884 A0311 Amb p ASYAALNGILYCQHHFWQLFK

885 A0311 Cyn d SSYAALNGVLFCKI HFSQLF

886 A0316 Amb a EQELETSKTSSSVEK

887 A0316 Amb p EQELETSKTSSSVEK

888 A0316 Cyn d DQEMETAKTSSSVEK

889 A0325 Amb a VDENGKISRLRRECP

890 A0325 Amb p VDGDGKIERLRRECP

891 A0325 Cyn d VDSDGKIKRLRRECP

892 A0326 Amb a RLQEQPPFDKKQFVA

893 A0326 Amb p RLQEQPAFNKKQFVA

894 A0326 Cyn d RLQEQPAFDKKQFVT

895 A0326 Amb a ATKFLLSKLSDLQFFVGE

896 A0326 Amb p ATKFLLGKLSDLQFFVGE

897 A0326 Cyn d ATKFLLGKLKDLQFFVGE

898 A0327 Amb a DAVTIRATMGMAAQDM

899 A0327 Amb p DPVTIRAM SMSAQAM

900 A0327 Cyn d DGVTIRATMSMAAQDM

901 A0334 Amb a LSINGHGTIDGQGALVWS

902 A0334 Amb a LVITGKGTLDGQGKEVWN

903 A0334 Amb p LVITGNGTLDGQGPGVWQ

904 A0334 Cyn d FSINGHGTIDGQGPLVWK

905 A0334 Amb a YNCKILPNSLVLDFV

906 A0334 Amb a YDCKILPNTLVFDFC

907 A0334 Amb p YDCKKLPTSMELEFV

908 A0334 Cyn d YNCKILPNSLVLDYV

909 A0334 Amb a VIDKVTVKAPGNSPNTDGIHIGDSSNVTITGTTIGVGDDCISIGP

910 A0334 Amb a TLKDLTITAPGDSPNTDGIHIGDSSKVTISDTTIGTGDDCISIGP

911 A0334 Amb p TITGVTVTAPEDSPNTDGIHIGRSSRVTISGATIGTGDDCVSIGA

912 A0334 Cyn d LVERVNITAPGDSPNTDGIHIGDSTNVTIAETNIGTGDDCISIGP Table 6 - SEQ ID NOS: 809-951

Table 7. GT conserved amino acid sequences derived from polypeptides derived from polypeptides of Table 1

Table 7 - SEQ ID NOS: 952-1023

Table 8. GT conserved amino acid sequences derived from polypeptides derived from polypeptides of Table 2.

Table 8 - SEQ ID NOS: 1024-1231

Table 9. WT conserved amino acid sequences derived from polypeptides of Table 2.

Table 9 - (SEQ ID NOS: 1232-1473)

Example 4 - Release from pollen

This example includes a description of how to examine release patterns of immunogenic molecules from pollen, e.g. the release kinetics of polypeptides of Tables 1 and 2 from pollen and detection of polypeptides in pollen diffusates by Mass Spectrometry.

Materials for Extraction:

Raw pollen or defatted pollen of various pollen sources, Glass bottles (100 ml) for extraction, PD-10 columns with PE bed support combined with 10 ml syringe with silicone tubing, PBS buffer, pH 7.2 containing the following salts: Salt Mw (g/mole) Cone. g/L Cone. mM

Sodium chloride NaCI 58.44 8.0 137

Potassium chloride KCI 74.55 0.2 2.7

Na-phosphate Na2HP04, 175.98 1.44 8.2

2H20

K-phosphate KH2P04 136.09 0.2 1.5

Phosphate cone: 8.2 + 1.5 = 9.7 mM phosphate

NaCI: μ = ¹/₂ * (137 * 12 + 137 * 12) = 137 mM

KCI: μ = ½ * (2.7 * 12 + 2.7 * 12) = 2.7 mM

Na2HP04: μ = ¹/₂ * ((8.2 * 2 * 12) + (8.2 * 22)) = 24.6 mM

KH2P04: i = ½ * ((1.5 * 12) + (1.5 * 12)) = 1.5 mM

Total ionic strength: μ = 165.8 mM « 0.17 M

Extraction Procedure (at room temperature, 21-24 °C):

5.0 g of pollen are weighed into a glass bottle and 50 ml of PBS is added and the bottle is immediately rotated, first 5 minutes by hand and thereafter rotated in a sample rotator during the entire extraction.

5 ml of slurry is taken out after 20 sec, transferred to a column with a bed filter and dragged through the filter with a syringe. The syringe is immediately transferred to a filter unit and the extract is pushed through the combined filters into a labelled test tube. The tube is stored in an ice bath until the sample is pipetted in aliquots for further analysis and frozen. About 5 ml of the suspension is taken out at various time points.

Samples are analyzed for presence of a polypeptide of Tables 1 and 2 and, optionally major allergens by MS (Mass Spectrometry).

Mass Spectrometry Buffers/solutions for reduction, alkylation and digestion of the sample:

Sample buffer: 8 M urea in 0.4 M NH4HC03

DTT (45 mM): Make it fresh from the frozen stock 1.0 M: 45 μ1 1 M DTT + 955 μΙ water lodoacetamide (IAA): Make fresh solution, lodoacetamid 100 mM,

Trypsin: Sigma T6567, Dissolve one vial in 20 μΙ of 1 mM HCI. This results in a solution containing 1 Mg/μΙ trypsin. After reconstitution in 1 mM HCI frozen aliquots can be stored for up to 4 weeks.

Enzymatic digestion with trypsin in solution for mass spectrometry: Dilute the dried sample in 5 μΙ of water, add 15 μΙ of sample buffer (8 M Urea in 0.4 M NH4HC03), add 5 μΙ 45 mM DTT, incubate at 56°C for 15 min, cool it to room temperature, add 5 μΙ of 100 mM lodoacetamide, incubate in the dark in room temperature for 15 min, add 90 μΙ of water to lower the concentration of urea <1-2 M, add 1 μg trypsin, incubate at 37°C over night.

Chromatography:

Reverse phase chromatography (Ultimate 3000 HPLC, Dionex) was performed using a C18 pre- and analytical column. The eluting peptides were sprayed directly into an ESI- QTOF mass spectrometer (MaXis, Bruker). After washing the trap column with 0.05% v/v formic acid for 5 min with a flow rate of 30 μΙ/min, the peptides were eluted with an acetonitrile gradient at a flow rate of 2 μΙ/min using solvent A: 0.05% v/v formic acid and solvent B: 80% v/v acetonitrile/0.04% v/v formic acid and the gradient: 4-50% B in 200 minutes; 50-80% B in10 minutes; 100% B in 10 min, 4% B in 5 min. Spectra were acquired in the mass range 50-2599 m/z and a spectra rate of 1.5 Hz. The instrument was tuned and calibrated using ESI-L Low concentration Tunning Mix from Agilent Technology.

Data acquisition and instrument control were carried out with Bruker Compass HyStar 3.2. Data processing was performed using DataAnalysis 4.0 (Bruker). Protein identification was performed using the program Biotools3.2 (Bruker) and two different databases, i.e. Swiss prot and NCBInr. The MS/MS data sets for the tryptic digest were analyzed using the following parameters; peptide tolerance 10 ppm and fragment tolerance 0.05 Da.

Procedure: The extraction samples were all evaporated (50 μΙ) and re-suspended in 5 μΙ of water. The sample is then reduced, alkylated and digested with trypsin. Resulting peptides are separated and identified by reversed phase chromatography followed by MS/MS.

Results: The release of major allergens from the various pollen species investigated is initiated almost instantly after hydration of pollen with buffer and the release continues with high rate within a time range of at least 30 to 60 minutes (data not shown). Table 10 shows polypeptides that starts release from grass pollen (Phi p or Cyn d), weed pollen (Amb a) and/or tree pollen (Que a and/or Bet v) within a period overlapping with the release of major allergens, respectively. In table 10 it is indicated which of the

polypeptides detected in Phi p pollen that can be released from hydrated pollen (pollen extracts) and which of the corresponding homolog polypeptides detected in Cyn d, Amb a, Que a and Bet v pollen that can be released from hydrated pollen of the species Cyn d, Amb a, Que a and Bet v, respectively, within a time period of 10 minutes to 120 minutes. The label "x" means that polypeptides or its homolog is detected in the extracts within the specified time period. No label means no detectable release of the polypeptide within the time period indicated. "GW" means that a given polypeptide is releasable from grass pollen (Phi p and/or Cyn d) and that its corresponding homolog found in Amb a pollen is releasable from weed pollen (Amb a). "GT" means that a given polypeptide is releasable from grass pollen (Phi p and/or Cyn d) and that its corresponding homolog found in Que a or Bet v pollen is releasable from tree pollen (Que a and/or Bet v). "GWT" means that a given polypeptide of Table 1 is releasable from grass pollen (Phi p and/or Cyn d),) that its corresponding homolog found in Amb a pollen is releasable from weed pollen (Amb a) and that its corresponding homolog found in tree pollen is releasable from tree pollen (Que a and/or Bet v).

It was found that the set of polypeptides having the polypeptide ID NOs A0349, A0246, A0209, A0211 , A0325, A0357, A0203 could be released from the grass, weed as well as the tree pollen investigated (herein named GWT polypeptides).

Polypeptide A0262 (herein named GT polypeptide) was released from both grass and tree pollen, but not from weed pollen.

The set of polypeptides having the polypeptide ID NOs A0362, A0316, A0356, A0376, A0336, A0377 and A0366 could be released from grass as well as weed pollen, but not the tree pollen investigated (herein named GW polypeptides).

Table 10. Release of polypeptides from grass, weed and/or tree pollen

Release of polypeptides from pollen species Release from multiple % Identity to pollen species: Human

ID No Phi p Cyn d Amb a Que a Bet v GW GT GWT Homolog

A0233 X X NA

A0246 X X X X X X X X 75.2

A0260 X NA

A0262 X X X X X 51.2

A0265 X NA

A0270 X X NA

A0300 X NA

A0304 X X NA

A0311 X NA

A0316 X X X X NA

A0317 X X X NA

A0325 X X X X X X X X 82.6

A0326 X X X NA

A0327 X NA

A0334 X X NA

A0336 X X X X NA

A0349 X X X X X X X X 75.6-82.6

A0356 X X X X 75.9

A0357 X X X X X X X X 47.2

A0358 X NA

A0362 X X X NA

A0366 X X X X NA

A0376 X X X X NA

A0377 X X X X NA

Example 5 - In silico prediction in vitro and determination of HLA Class II allele binding

To investigate the immunogenic potential of polypeptides of the invention, the binding affinity to a panel of HLA class II molecules may be predicted in silico or determined in vitro, for example as described in PCT application WO 2013/119863 to a set of 15mer or 20-mer overlapping peptides that are subsequences to the polypeptides and conserved sequences set out in Tables 1 to 9.

HLA binding affinity of peptides may be predicted using NetMHC 3.2, for example HLA affinity to the number of commonly found alleles DPA1*01-DPB1*0401 , DPA1^*0103-

DPB1*0201 , DPA1*0201-DPB1^*0101 , DPA1*0201 , PB1^*0501 , DPA1^*0301-DPB1^*0402, DQA1*0101-DQB1^*0501 , DQA1*0102-DQB1^*0602, DQA1*0301-DQB1*0302,

DQA1*0401-DQB1*0402, DQA1*0501-DQB1*0201 , DQA1^*0501-DQB1^*0301 , DRB1^*0101 , DRB1*0301 , DRB1^*0401 , DRB1*0404, DRB1*0405, DRB1*0701 ,

DRB1^*0802, DRB1^*0901. Subsequences with predicted binding scores in the top 20% for a given allele may be considered potential binders. Subsequences predicted to bind 13 or more HLA molecules at this threshold may be considered promiscuous binders. Also, the HLA binding of polypeptides or subsequences thereof may be predicted in silico for an estimated worldwide allele distribution. Average haplotype and phenotype frequencies for 63 individual HLA-DRB1 alleles are based on MHC data available at the Allele Frequency Net Database (AFND, http://www.allelefrequencies.net). Frequencies from the four major ethnical groups, Hispanics, Caucasians, African Americans, and Asians, are used as an estimated worldwide allele distribution. The frequencies are calculated as the mean of the frequencies from population IDs, 1514, 1513, 2419, and 2420, respectively. Each ethnical group consists of data from more than 1000 individuals. A set of 15mers peptides, overlapping each other with 14 amino acids, were constructed from each of the wild type sequences of Table 1 as well as the GWT conserved regions of Table 3. The numbers of 15mers peptides that can be derived from these sequences in total are summarized in Table 11a (column 4). For each peptide, the binding was predicted with NetMHCIIpan-3.0 for each of the 63 HLA alleles derived from AFND. Per peptide-allele combination, a binding threshold of 300 nM as well as a percentile rank score, as reported by the algorithm, of at least 30 is applied. Some HLAs bind to the same peptide, and given the estimated worldwide allele distribution, we can estimate the binding capability for each peptide. For each sequence (derived from Table 1 and 3), the number of 15mer peptides predicted to bind to at least half of the estimated worldwide allele distribution are shown in Table 11a, column 5. For example, a total number of 74 15mer peptides could be derived from the sequence representing wild type polypeptide A202, and 13 of those were predicted to be binders in at least half of the worldwide population, as estimated for the four major ethnic groups. This amount to that 18% of the 15mers was predicted to bind DRB1 alleles. Finally, the sum of 15mers with DRB1 allele binding that could be derived from GWT conserved sequences were calculated and summarized in the last column of Table 11a. According to this analysis, the wild type polypeptides may be ranked according to their potential possess several HLA Class II binding sites in the part of the sequence that is conserved across pollen species. For example, some wild type polypeptides have considerable more potential to bind HLA Class alleles in their conserved regions than others, e.g. polypeptides with ID NO: 246, 270, 311 , 316, 325, 356 or 376 versus polypeptides with ID NO: 203, 233, 366 or 377. Table 11a. Number of 15mers peptides with DRB1 HLA allele binding derivable from polypeptides of Table 1 and their GWT sequences of Table 3.

The wording "FL" and "GWT in Table 11 a refer to the wild type sequence of Table 1 and the GWT conserved sequences of Table 3, respectively.

Table 11b. DRB1 alleles for use in prediction of HLA Class II allele binding

Allele Average Allele Average Allele Average frequency frequency frequency

DRB1 0101 0.04275 DRB1 0804 0.0.1625 DRB1 1312 0.001 DRB1_0102 0.02325 DRB1 0806 0.0015 DRB1 1323 0.00025 Allele Average Allele Average Allele Average frequency frequency frequency

DRB1 0103 0.00475 DRB1 0809 0.0005 DRB1 1331 0.00025

DRB1 0301 0.07725 DRB1 0811 0.0005 DRB1 1401 0.02275

DRB1 0302 0.0175 DRB1 0901 0.0395 DRB1 1402 0.00925

DRB1 0307 0.00025 DRB1 1001 0.017 DRB1 1403 0.00125

DRB1 0401 0.03375 DRB1 1101 0.057 DRB1 1404 0.00525

DRB1 0402 0.00775 DRB1 1102 0.01325 DRB1 1405 0.0045

DRB1 0403 0.01575 DRB1 1103 0.00275 DRB1 1406 0.01

DRB1 0404 0.0275 DRB1 1104 0.0185 DRB1 1407 0.001

DRB1 0405 0.02325 DRB1 1106 0.00075 DRB1 1418 0.00025

DRB1 0406 0.00625 DRB1 1110 0.00075 DRB1 1419 0.00025

DRB1 0407 0.0245 DRB1 1111 0.00025 DRB1 1424 0.00025

DRB1 0408 0.0025 DRB1 1201 0.02325 DRB1 1501 0.074

DRB1 0410 0.0025 DRB1 1202 0.0195 DRB1 1502 0.02575

DRB1 0411 0.0035 DRB1 1301 0.04575 DRB1 1503 0.03125

DRB1 0417 0.00025 DRB1 1302 0.0445 DRB1 1504 0.00025

DRB1 0701 0.1015 DRB1 1303 0.01525 DRB1 1506 0.001

DRB1 0801 0.01125 DRB1 1304 0.004 DRB1 1601 0.00425

DRB1 0802 0.02725 DRB1 1305 0.002 DRB1 1602 0.01725

DRB1 0803 0.014 DRB1 1311 0.00025 DRB1 1607 0.00025

This example also describes how to determine the HLA class II binding in vitro of polypeptides of the invention including subsequences thereof. The assay employed is a competitive MHC class II binding assay, wherein each polypeptide or 15mer or 20mer peptide is analyzed for its ability to displace a known control binder from each of the human MHC class II allotypes shown in Table 11c. Due to the nature of the competitive assay, the data for each polypeptide or subsequence is determined as a ratio of its own IC50 to that of the control peptide. Thus, a polypeptide or subsequence that has an IC50 value that is parity to the control peptide has an identical binding affinity, while

polypeptides or subsequences with a ratio less than one have a higher affinity and those with a ratio greater than one have a lower affinity. The ratio of IC50 may be determined at different cutoff concentrations, for example at 300 or 1000 nM.

Assays to quantitatively measure binding to purified class II MHC molecules are based on the inhibition of binding of a high affinity radiolabeled peptide to purified MHC molecules, and were performed essentially as detailed elsewhere (Sidney et al. 2008; Sidney et al. 2010b, a; Greenbaum et al. 2011 ; Sidney et al. 2001 , Sidney et al 2013, McKinney et al 2013). Briefly, 0.1-1 nM of radiolabeled polypeptide or subsequences may be co- incubated at room temperature or 37°C with purified MHC in the presence of a cocktail of protease inhibitors. Following a two- to four-day incubation, MHC bound radioactivity may be determined by capturing MHC/peptide complexes on monoclonal Ab coated Lumitrac 600 plates (Greiner Bio-one, Frickenhausen, Germany), and may be measuring bound cpm using the TopCount (Packard Instrument Co., Meriden, CT) microscintillation counter. In the case of competitive assays, the concentration of polypeptide or subsequence yielding 50% inhibition of the binding of the radiolabeled peptide may be calculated. Under the conditions utilized, where [label] < [MHC] and IC50 > [MHC], the measured IC50 values are reasonable approximations of the true Kd values (Cheng and Prusoff 1973; Gulukota et al. 1997). Each polypeptide or subsequence may be tested at six different concentrations covering a 100,000-fold dose range in three or more independent experiments. As a positive control, the unlabeled version of the radiolabeled probe may also be tested in each experiment.

Table 11c. HLA alleles used for HLA prediction

Table 11c shows a panel of 25 MHC II molecules (alleles) for which peptide binding affinities may be predicted or determined in vitro.

Example 6 - T cell activity

To investigate the immunogenic potential of a polypeptide of the invention, the

polypeptide may be tested for T cell immune reactivity, which may be determined by the production of IL-5 or IFN-gamma from PBMCs f allergic donors, wherein the PBMC's are cultured under the presence of the polypeptide. The cytokines IL-5 and IFNg may be measured by known methods in the art, for example as described in PCT application WO 2013/119863.

Briefly, specific T cells may be obtained in the following manner; PBMCs may be thawed and cultured with 5% human AB serum at a density of aboutn 2 x 10⁶ cells/ml in 24-well plates and stimulated with the polypeptide or a pollen extract comprising the polypeptide or a subsequence thereof (concentration may be about i g/ml). Cells may be kept at 37°C, 5% C0₂ and IL-2 may be added every 3 days after the initial stimulation with the polypeptide. On day 14, cells may be harvested and screened for reactivity to the polypeptide or a subsequence thereof. The production of IL-5 and IFN-γ from the cultured PBMCs described above may be measured in response to stimulation with the to the polypeptide or a subsequence thereof using ELISpot as described in Oseroff C et al, 2010. The criteria for positive response may be 20 SFCs/10 PBMCs, p< 0.05 of stimulated cells compared to background, and a stimulation index (SI) > 2.

Alternative to the ELISpot assay, the cytokine production of T cells can be measured in cell culture supernatants harvested at day 1 of the above procedure by MesoScale or MagPix analysis. The design of both assays resemble ELISA assays with the capture antibodies of several different specificities spotted in each well of a 96 well plate

(Mesoscale, #144259) or the individual catching antibodies attached to beads that can be mixed to the final assay reagent (MagPix #230608) and both assays are developed to analyze various different cytokines or cellular mediators in a single sample. The cytokines IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, and IFN-g may be measured by Mesoscale, whereas IL-4, IL-5, IL-9, IL-10, IL-12, IL-13, IL-17, IL-22, IL-31 may bemeasured by MagPix.

The T cell reactivity may also be tested by Ex-Vivo FluoroSpot or EliSpot analysis of cytokines induced in response to polypeptides added to PBMCs that have not previously been stimulated with the polypeptides or pollen extract.

Example 7 - In vivo activity

This example describes how to determine the ability of a polypeptide of the invention to relieve, e.g. treat, an immune response in mice.

Initially, the sensitization pattern of a molecule (e.g. an immunogenic molecule) of the invention (A0349) was investigated in BALB/c mice sensitized to Phi p extract (Figure 2). For the purposes of these studies, the immunogenic molecule were expressed in E. coli using standard expression protocols.

Mice were sensitized by one intraperitoneal injection with Phi p extract adsorbed to aluminium hydroxide. Eleven days later the mice were euthanized and splenocytes were stimulated in vitro with Phi p pollen extract, the allergen Phi p 5 or A0349. The cells were incubated for 6 days at 37°C under 5% C02 and incorporated 3H-thymidine was counted and used as a measure for T cell proliferation.

The results show that the in vitro T-cell response towards A0349 is much weaker compared to the response to Phi p 5 (Figure 2). This correlates well with the human situation, where Phi p 5 is considered to be a major T-cell allergen. In line with this, the results also show that the response towards A0349 is much weaker compared to the response towards the Phi p extract that was used for intraperitoneal sensitization. Then the tolerance inducing potential of A0349 was investigated in a prophylactic mouse model using sublingual administration.

The ability of A0349 to induce prophylactic tolerance was investigated by SLIT treatment of naive BALB/c mice with A0349for two weeks (Monday-Friday) followed by one intraperitoneal Phi p extract sensitization. Eleven days after the sensitization, splenocytes were harvested and stimulated in vitro with Phi p extract or the allergen Phi p 5.

Figure 3 shows that prophylactic SLIT treatment with A0349 is capable of inducing tolerance towards the Phi p extract as shown by the reduced Phi p extract specific proliferation in splenocytes from the A0349-treated mice compared to buffer (sham) treated mice. In addition, it was shown that A0349 was capable of inducing tolerance toward the allergen Phi p 5 (Figure 4), which amino acid sequence is different from A0349. Thus, the treatment with A0349 resulted in the suppression of an immune response caused by an unrelated antigen, i.e. Phi p 5, possibly via bystander tolerance induction. Further polypeptides identified in the same manner and reported in patent application PCT/US2014/066577 also shows low immunogenicity of the polypeptide compared to major allergens, but nevertheless they were able to reduce an immune response caused by an allergen unrelated to the polypeptide itself (In vivo data of the polypeptides NTGA 86/51 and NTGA 6 shown in Example 5 of PCT/US2014/066577). Whether a molecule (e.g. an immunogenic molecule) of the invention can relieve, e.g. treat, an immune response triggered by a pollen allergen in mice that are sensitized to the pollen allergen when starting SLIT treatment can be investigated in a therapeutic mouse model. For example, BALB/cJ mice or HLA-transgenic mice may be IP sensitized with model allergen adsorbed to aluminium hydroxide (e.g. an extract of a grass pollen species, e.g. Cyn d, Poa p, Phi p or a model allergen like OVA). Subsequently, the mice might be treated by sublingual immunotherapy (SLIT) with a molecule (e.g. an immunogenic molecule) of the invention for a period of about 4-8 weeks, followed by about 2-3 weeks of intranasal challenge with model allergen together with the

immunogenic molecule or model allergen alone to induce an allergic immune response in the airways. Mice are then sacrificed one day after the last challenge and blood, Broncho alveolar fluid (BAL), spleen and cervical lymph nodes may be collected for analysis. Clinically relevant readouts, such as sneezes, airway hyper-reactivity and presence of eosinophils, might be obtained on the last day of intranasal challenge. For example, sneezes may be observed in an 8 min-period after intranasal administration of model allergen and the numbers of sneezes be counted during this period. Airway hyperreactivity may be determined using a whole body pletysmograph; airflow obstruction might be induced by increasing concentrations of aerosolized metacholine. Pulmonary airflow obstruction may be measured by enhanced pause (penh) in a period of 6 minutes after administration of metacholine. Differential counting of bronchial fluid (BAL) is performed after centrifugation of BAL fluid and removal of supernatant. The pellet was re- suspended in PBS and the fraction of eosinophils might be determined by an automated cell counter (Sysmex).

The results may show that a molecule (e.g. an immunogenic molecule) of the invention is able to reduce the number of sneezes, number of eosinophils, airway obstruction, T cell proliferation of spleen cells or cervical lymph nodes and may be shown to depend on the co-exposure of model allergen and immunogenic molecule at the target organ

(e.g. airways).

Whether SLIT treatment with pan pollen immunogenic molecules is capable of inducing tolerance that can be re-activated by a non-identical, but highly conserved immunogenic molecule from a different pollen source can be addressed in several different in vivo models, as outlined below.

Experiment 1 :

1. SLIT treatment with immunogenic molecule A 2. IP Sensitization with immunogenic molecule B (contains conserved regions

overlapping with A)

3. in vitro stimulation with immunogenic molecule B

Where results verify that the specific in vitro proliferation to immunogenic molecule B is down-regulated in mice SLIT-treated with immunogenic molecule A, then cross-species tolerance induction has been demonstrated for this immunogenic molecule, since the two immunogenic molecules are sufficiently similar in order for cross-species tolerance induction to occur.

Experiment 2:

1. SLIT treatment with immunogenic molecule A 2. IP Sensitization with extract of pollen source containing immunogenic molecule B (pollen extract containing the homologous immunogenic molecule B)

3. In vitro stimulation with extract of pollen source containing immunogenic molecule B and immunogenic molecule B Where results verify that the specific in vitro proliferation to immunogenic molecule B extract is down-regulated in mice SLIT-treated with immunogenic molecule A, then cross- species tolerance induction has been demonstrated for this immunogenic molecule.

Furthermore, it has been demonstrated that pollen source B contains sufficient amounts of immunogenic molecule B to re-activate the tolerance induced by SLIT treatment with immunogenic molecule A.

In the above-mentioned mouse model, Balb/cJ mice have been suggested. However, in vivo studies may instead be carried out in humanized mice models using transgenic mice, e.g. "HLA-DRB1^*0401 transgenic mice" that may be obtained from Taconic. Also, in the above-mentioned mouse models, the immune response against an allergen of a grass pollen (Phi p grass extract) have been investigated, but other models may investigate the immune response against non-grass pollen allergens, e.g. allergens of weed or tree pollen, or there may be used model allergens like OVA protein.

Furthermore, the T cell responses in mice or humans may be evaluated by in-vitro T cell proliferation assays or ELISPOT assays. The production of IL-5 and IFN-γ from cultured PBMCs (Peripheral blood monocytes) obtained from humans or splenocytes obtained from mice in response to stimulation with a molecule (e.g. an immunogenic molecule) disclosed herein. Such assays are well known in the art. The assays may be able to analyze various different cytokines or cellular mediators associated with the immune response, e.g. the cytokines IL-2, IL-4, IL-5, IL-9, IL-10, IL-12, IL-13, IL-17, IL-22, IL-31 and IFN-gamma.

Example 8 - Analysis of cross reactivity

This example describes how to determine that T cells responding to a particular polypeptide containing a conserved sequence, e.g. GWT, GT, GW sequence derived from Phi p polypeptides (Tables 3, 5 and 7) also recognizes the corresponding

polypeptide identified in another pollen species.

In the present set-up, the cross reactivity was investigated using model polypeptides derived from Phi p pollen, for example the known allergens (Phi p 1 and Phi p 5) or polypeptides described in international patent application WO2013/119863: PBMCs from Phi p reactive donors were expanded with conserved peptides derived from the model polypeptidesfor 14 days (the specific peptides used for the analysis is shown in Table 12). For each peptide, the mismatch to a corresponding sequence in a non-grass pollen species or a pollen species other than Phi p were determined. Cytokine IL-5 responses were measured in response to the peptide itself, Phi p extract and extracts of the other pollen species. Reponses to extracts and peptide pools were expressed as the relative fraction of the response to the peptide itself and plotted as a function of conservation of the peptide in the different extracts (Fig 1). The data points for each peptide are contained in Table 12. A clear hierarchy of responses was observed, with non-Phi p extracts in which the peptide is completely conserved (zero mismatches) showing the highest response, followed by non-Phi p extracts with 1-2 mismatches, and lowest responses with non-Phi p extracts with 3 or more mismatches. The exact same hierarchy was observed when analyzing peptides from the major allergens and the NTGA-derived peptides separately. Thus, Phi p epitopes conserved in other pollen species, including pollen of Amb a and Que a and other non-grass pollen, were indeed able to induce cross- reactive T cell immune responses.

Table 12. Cross reactivity data

Table 12 shows individual peptide data for the cross reactivity experiments and the peptide used. Each peptide was used to stimulate cells and cross reactivity was tested for extracts from each pollen species. The number of mismatches (# of mm) for each peptide compared to the pollen species and the reactivity of the extracts as a percentage of the reactivity compared to the peptide are shown.

CD

O

Claims

1. A molecule comprising or consisting of a) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 274, 270-273, 212-269 and 275-293; SEQ ID NOS: 617-676, 294-616 and 677-767; SEQ ID NOS: 768- 808; SEQ ID NOS: 809-951 , SEQ ID NOS: 952-1023, SEQ ID NOS: 1024-1231 ; and SEQ ID NOS: 1232-1473; or b) a polypeptide comprising an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 274, 270-273, 212-269 and 275-293; SEQ ID NOS: 617-676, 294-616 and 677-767; SEQ ID NOS: 768-808; SEQ ID NOS: 809-951 ; SEQ ID NOS: 952-1023; SEQ ID NOS: 1024-1231 and SEQ ID NOS: 1232-1473; or c) a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2

mismatches to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 274, 270-273, 212-269 and 275-293; SEQ ID NOS: 617-676, 294-616 and 677-767; SEQ ID NOS: 768-808; SEQ ID NOS: 809-951 ; SEQ ID NOS: 952-1023; SEQ ID NOS: 1024-1231and SEQ ID NOS: 1232-1473; or d) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 30, 1-29, 31-37 set out in Table 1 and SEQ ID NOS: 161-172, 38-160 and 173-211.

2. The molecule according to claim 1 , wherein the polypeptide of option d) comprises an amino acid sequence having at least 75% similarity or identity to a sequence selected from any one of SEQ ID NOS: 30, 1-29, 31-37 and SEQ ID NOS: 161-172, 38-160 and 173-211.

3. The molecule according to claim 1 , wherein the polypeptide of option a) comprises an amino acid sequence having at least 75% similarity or identity to a sequence selected from any one of SEQ ID NOS: 270-274; 212-269; 275-293; SEQ ID NOS: 617- 676, 294-616 and 677-767; SEQ ID NOS: 768-808; SEQ ID NOS: 809-951 ; SEQ ID NOS: 952-1023; SEQ ID NOS: 1024-1231and SEQ ID NOS: 1232-1473.

4. The molecule according to claim 1 , wherein the polypeptide of option b) comprises an amino acid sequence having at least 75% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 270-274; 212-269; 275-293;SEQ ID NOS: 617-676, 294-616 and 677-767; SEQ ID NOS: 768-808; SEQ ID NOS: 809-951 ; SEQ ID NOS: 952-1023; SEQ ID NOS: 1024-1231 and SEQ ID NOS: 1232-1473.

5. The molecule according to claim 1 , wherein the immunogenic molecule comprises or consists of a) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 270-274 and SEQ ID NOS: 617-676; or b) a polypeptide comprising an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 270-274 and SEQ ID NOS: 617-676; or c) a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2 mismatches to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 270-274 and SEQ ID NOS: 617-676; or d) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 27-30 or SEQ ID NOS: 161-172.

6. The molecule according to claim 1 , wherein the immunogenic molecule comprises or consists of a) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 217-220 and SEQ ID NOS: 321-344; or b) a polypeptide comprising an amino acid sequence having at least 65% similarity or identity to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 217-220 and SEQ ID NOS: 321-344; or c) a polypeptide, which includes at least one amino acid sequence with 0, 1 or 2 mismatches to a subsequence of at least 15 contiguous amino acid residues of a sequence selected from any one of SEQ ID NOS: 217-220 and SEQ ID NOS: 321-344; or d) a polypeptide comprising an amino acid sequence having at least 65% sequence similarity or identity to a sequence selected from any one of SEQ ID NOS: 4 and 5 and SEQ ID NOS: 49-54.

7. The molecule according to any one of claims 1 to 3, 5 and 6 wherein the polypeptide of option a) or of option d) has a length of no more than 800 amino acid residues.

8. The molecule according to any one of claims 1 and 4 to 6, wherein the polypeptide of option b) or option c) has a length of 15-800 amino acid residues.

9. The molecule according to any one of the preceding claims, comprising one or more T cell epitope-containing amino acid sequence(s).

10. The molecule according to any one of claims 1 , 5 and 6 wherein the subsequence comprises a T cell epitope.

11. The molecule according to any one of the preceding claims, wherein the polypeptide of option a), b), c) or d) modifies a cytokine response by a cell from an allergic subject.

12. The molecule according to claim 11 , wherein the cytokine response comprises one or more of IL-5, IFN gamma, IL-4, IL-10, IL-13 and IL-17.

13. A composition comprising one or more molecules according to any one of claims 1 to 12.

14. The composition according to claim 13 that is lyophilized and optionally sterile.

15. A pharmaceutical composition comprising one or more molecules according to any one of claims 1 to 12 or a composition according to any one of claims 13 or 14 and a pharmaceutically acceptable carrier, excipient and/or adjuvant.

16. A method for relieving an immune response in a subject in need thereof, comprising administering a therapeutically effective amount of a molecule according to any one of claims 1 to 12 or a composition according to any one of claims 13 to 15.

17. A method for relieving one or more symptoms of an immune response in a subject in need thereof, comprising administering a therapeutically effective amount of a molecule according to any one of claims 1 to 12 or a composition according to any one of claims 13 to 15.

18. A method for bystander suppression of an immune response in a subject in need thereof, comprising administering a therapeutically effective amount of a molecule according to any one of claims 1 to 12 or a composition according to any one of claims 13 to 15.

19. The method according to any one of claims 16 to 18, wherein the immune response is triggered by pollen from one or more plant families.

20. The method according to claim 19, wherein the one or more plant families are selected from the group consisting of Poaceae, Asteraceae, Fagaceae, Betulaceae,

Oleaceae, and Plantaginaceae.

21. The method according to claim 20, wherein the immune response is triggered by pollen of the plant family Poaceae and pollen of a plant family selected from the group consisting of Asteraceae, Fagaceae and Betulaceae.

22. The method according to claim 20, wherein the immune response is triggered by pollen of the plant genus Phleum and pollen from one or more of a plant genus selected from the group consisting of Conydon, Ambrosia, Betula and Quercus or combinations thereof.

23. The method according to any one of claims 16 to 22, wherein the immune response is triggered by one or more pollen allergens.

24. The method according to claim 23, wherein the one or more pollen allergens are from a plant family selected from the group consisting of Poaceae, Asteraceae, Fagaceae, Betulaceae, Oleaceae, and Plantaginaceae.

25. The method according to claim 24, wherein the one or more pollen allergens are from pollen of the plant family Poaceae and from pollen of a plant family selected from the group consisting of Asteraceae, Fagaceae and Betulaceae.

26. The method according to claim 25, wherein the one or more pollen allergens are from pollen of the plant genus Phleum and from pollen of a plant genus selected from the group consisting of Conydon, Ambrosia, Betula and Quercus and combinations thereof.

27. The method according to any one of the preceding claims, wherein the subject is sensitized to one or more pollen species from one or more plant families.

28. The method according to claim 27, wherein the one or more plant families are selected from the group consisting of Poaceae, Asteraceae, Fagaceae, Betulaceae, Oleaceae, and Plantaginaceae.

29. The method according to any one of the claims 16 to 28, wherein the subject is sensitized to a pollen species of the plant family Poaceae and a pollen species of a plant family selected from the group consisting of Asteraceae, Fagaceae and Betulaceae.

30. The method according to any one of the claims 16 to 29, wherein the subject is sensitized to a pollen species of the plant genus Phleum and a pollen species from one ore more plant genera selected from the group consisting of Conydon, Ambrosia, Betula and Quercus and combinations thereof.

31. The method according to any one of claims 16 to 30, wherein the subject is sensitized to one or more pollen allergens from one or more plant families.

32. The method according to claim 31 , wherein the one or more plant families are selected from the group consisting of Poaceae, Asteraceae, Fagaceae, Betulaceae, Oleaceae, and Plantaginaceae.

33. The method according to any one of claims 16 to 32, wherein the subject is sensitized to a pollen allergen of the plant family Poaceae and a pollen allergen from one or more of plant families selected from the group consisting of Asteraceae, Fagaceae and Betulaceae and combinations thereof.

34. The method according to any one of claims 16 to 33, wherein the subject is sensitized to a pollen allergen of the plant genus Phleum and a pollen allergen from one or more plant genera selected from the group consisting of Conydon, Ambrosia, Betula and Quercus and combinations thereof.

35. The method according to any one of claims 16 to 34, wherein the immune response is a specific T-cell response to the immunogenic molecule being administered to the subject.

36. The method according to claim 35, wherein the specific T-cell response is determined by way of contacting a sample of PBMCs obtained from the subject with said immunogenic molecule polypeptides and measuring the IL-5 secretion or IL-5 mRNA gene expression.

37. A molecule according to any one of claims 1-12 or a composition according to any one of claims 13-15 for use in a method according to any one of claims 16 to 36.

38. Use of a molecule according to any one of claims 1-12 or a composition according to any one of claims 13-15 for the preparation of a medicament for use in a method according to any one of claims 16 to 36.