Isolated replikin antibody and a composition comprising the same

201947/2 [001] The present application is a divisional application derived out of Israel Patent Application No. 158109 filed September 25, 2009 and antedated as of March 26, 2002. IL 158109 relates to an isolated influenza virus peptide, to a therapeutic composition comprising the same, and to an influenza virus vaccine.

FIELD OF THE INVENTION

[002] This invention relates to antibodies which specifically bind to an influenza virus peptide comprising a Replikin, a class of peptides that share structural characteristics. In particular, this invention relates to Replikins which have been identified in influenza viruses and their use in designing influenza virus vaccines.

BACKGROUND OF THE INVENTION

[003] Influenza is an acute respiratory illness of global importance. Despite international attempts to control influenza virus outbreaks through vaccination influenza infections remain an important cause of morbidity and mortality.

Worldwide influenza pandemics have occurred at irregular and previously unpredictable intervals throughout history and it is expected that they will continue to occur in the fixture. The impact of pandemic influenza is substantial in terms of morbidity, mortality and economic cost.

[004] Influenza vaccines remain the most effective defense against influenza virus, but because of the ability of the virus to mutate and the availability of non-human host reservoirs it is expected that influenza will remain an emergent or re-emergent infection. Global influenza surveillance indicates that influenza viruses may vary within a country and between countries and continents during an influenza season. Virologic surveillance is of importance in monitoring antigenic shift and drift.

Disease surveillance is also important in assessing the impact of epidemics. Both types of information have provided the basis of vaccine composition and the correct use of antivirals. However, to date there has been only annual post hoc 201947/2 hematological classification of the increasing number of emerging influenza virus strains, and no specific chemical structure of the viruses has been identified as an indicator of approaching influenza epidemic or pandemic. Currently, the only basis for annual classification of influenza virus as active, inactive or prevalent in a given year is the activities of the virus hemagglutinin and neuraminidase proteins. No influenza viral chemical structure has been identified that can he used for quantitative warning of epidemics or pandemics or to design more effective and safer vaccines.

[005] Because of the annual administration of influenza vaccines and the short period of time when a vaccine can be administered, strategies directed at improving vaccine coverage are of critical importance.

[006] Another disease which has proved difficult to treat and for which there is no effective1 vaccine is malaria. Malaria causes much physical and economic hardship in tropical regions. Malaria is caused by Plasmodium falciparum, which has proved to be extremely resistant to treatment and to date, a vaccine for malaria remains elusive. Thus, there is a need for effective malaria vaccines and methods of treating or preventing the disease.

Other diseases for which an effective vaccine is needed include anthrax and small pox. However, to date, no vaccine has been effective for prevention of disease caused by these pathological organisms. Thus, there is a need for vaccines for these pathogens, as well as a need for effective strategies for formulating vaccines to various pathogens.

SUMMARY OF THE INVENTION

By a first of its aspects the present invention provides an isolated antibody that specifically binds to an influenza virus peptide sequence consisting of 7 to about 50 amino acids with at least one lysine residue on one end of the influenza virus peptide sequence and at least one lysine residue or at least one histidine residue on the other end of the influenza virus peptide sequence, wherein the influenza virus peptide sequence comprises: 2 201947/2 (1) at least one lysine residue located six to ten amino acid residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues.

By a second of its aspects, the present invention provides the isolated antibody of the invention, wherein the influenza virus peptide sequence is present in an emerging strain of influenza virus.

By a third of its aspects, the present invention provides an antibody cocktail comprising a plurality of isolated antibodies of the invention.

By a fourth of its aspects, the present invention provides the antibody cocktail of the invention wherein each of the plurality of isolated antibodies independently and specifically binds to an influenza virus peptide sequence, wherein the influenza virus peptide sequence: (a) is present in an emerging strain of influenza virus; (b) consists of 7 to about 50 amino acids with at least one lysine residue on one end of the influenza virus peptide sequence and at least one lysine residue or at least one histidine residue on the other end of the influenza virus peptide sequence; and (c) comprises: (1) at least one lysine residue located six to ten amino acid residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues

By a fifth of its aspects, the present invention provides a composition comprising the isolated antibody of the invention and a pharmaceutically acceptable carrier or adjuvant.

By a sixth of its aspects, the present invention provides a composition comprising the antibody cocktail of the invention and a pharmaceutically acceptable carrier or adjuvant.

By a seventh of its aspects, the present invention provides a composition comprising a mixture of a plurality of isolated antibodies of the invention and a 3 201947/2 pharmaceutically acceptable carrier or adjuvant wherein at least one isolated antibody of the invention specifically binds to an influenza virus peptide sequence present in an emerging strain of influenza virus.

By an eighth of its aspects, the present invention provides a composition comprising the antibody cocktail of the invention and a pharmaceutically acceptable carrier or adjuvant wherein at least one isolated antibody of the antibody cocktail of the inveniton specifically binds to an influenza virus peptide sequence present in an emerging strain of influenza virus.

By a ninth of its aspects, the present invention provides the isolated antibody of the invention wherein the n-terminus of the influenza virus peptide sequence is a lysine residue and the c-terminus of the influenza virus peptide sequence is a lysine residue.

By a tenth of its aspects, the present invention provides the isolated antibody of the invention wherein the n-terminus of the influenza virus peptide sequence is a histidine residue and the c-terminus of the influenza virus peptide sequence is a lysine residue.

By an eleventh of its aspects, the present invention provides the isolated antibody of the invention wherein the n-terminus of the influenza virus peptide sequence is a lysine residue and the c-terminus of the influenza virus peptide sequence is a histidine residue.

By a twelvth of its aspects, the present invention provides the isolated antibody of the invention wherein the influenza virus peptide sequence comprises no more than two lysine residues.

By a thirteenth of its aspects, the present invention provides the isolated antibody of the invention wherein the influenza virus peptide sequence comprises no more than one histidine residue.

Passages of the description which are outside the scope of the claims do not constitute part of the claimed invention.

EMBODIMENTS OF THE INVENTION

[007] In one aspect of the invention there are provided isolated influenza virus peptides containing a Replikin sequence. The influenza virus peptides comprise 4 201947/2 from 7 to about 50 amino acids including (1) at least one lysine residue located six to ten amino acid residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues.

[008] In another aspect of the invention there is provided a process for stimulating the immune system of a subject to produce antibodies that bind specifically to an influenza virus Replikin sequence, said process comprising administering to the subject an effective amount of a dosage of a composition comprising at least one influenza virus replikin peptide, hi a preferred embodiment the composition comprises at least one peptide that is present in an emerging strain of influenza virus.

[009] The present invention also provides antibodies that bind specifically to an influenza virus Replikin, as defined herein, as well as antibody cocktails containing a plurality of antibodies that specifically bind to influenza virus Replikins. In one embodiment of the invention, there are provided compositions comprising an antibody or antibodies that specifically bind to an influenza Replica and a pharmaceutically acceptable carrier.

[010] The present invention also provides therapeutic compositions comprising one or more of isolated influenza virus peptides having from 7 to about 50 amino acids comprising 1) at least one lysine residue located six to ten residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues, and a pharmaceutically acceptable carrier.

[011] In another aspect of the invention there is provided an antisense nucleic acid molecule complementary to an influenza virus hemagglutinin Replikin mRNA sequence, said Replikin mRNA sequence having from 7 to about 50 amino acids comprising (1) at least one lysine residue located six to ten residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues.

[012] In yet another aspect of the invention, there is provided a method of stimulating the immune system of a subject to produce antibodies to influenza virus comprising administering an effective amount of at least one influenza virus 5 201947/2

Replikin peptide having from 7 to about 50 amino acids comprising (1) at least one lysine residue located six to ten amino acid residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues.

[013] In another aspect, there is provided a method of selecting an influenza virus peptide for inclusion in an influenza virus vaccine comprising (1) obtaining at least one isolate of each strain of a plurality of strains of influenza virus, (2) analyzing the hemagglutinin amino acid sequence of the at least one isolate of each strain of the plurality of strains of influenza virus for the presence and concentration of Replikin sequences, (3) comparing the concentration of Replikin sequences in the hemagglutinin amino acid sequence of the at least one isolate of each strain of the plurality of strains of influenza virus to the concentration of Replikin sequences observed in the hemagglutinin amino acid sequence of each of the strains at least one earlier time period to provide the concentration of Replikins for at least two time periods, said at least one earlier time period being within about six months to about three years prior to step (1), (4) identifying the strain of influenza virus having the highest increase in concentration of Replikin sequences during the at least two time periods, (5) selecting at least one Replikin sequence present in the strain of influenza virus peptide identified in step (4) as a peptide for inclusion in an influenza virus vaccine.

[014] The present invention also provides a method of making an influenza virus vaccine comprising (1) identifying a strain of influenza virus as an emerging strain, (2) selecting at least one Replikin sequence present in the emerging strain as a peptide template for influenza virus vaccine manufacture, (3) synthesizing peptides having the amino acid sequence of the at least one Replikin sequence selected in step (2), and (4) combining a therapeutically effective amount of the peptides of step (4) with a pharmaceutically acceptable carrier and/or adjuvant. 6 201947/1 [015] In another aspect, the invention is directed to a method of identifying an emerging strain of influenza virus for diagnostic or therapeutic purposes comprising (1) obtaining at least one isolate of each strain of a plurality of strains of influenza virus, 5 (2) analyzing the hemagglutinin amino acid sequence of the at least one isolate of each strain of the plurality of strains of influenza virus for the presence and concentration of Replikin sequences, (3) comparing the concentration of Replikin sequences in the hemagglutinin amino acid sequence of the at least one isolate of each strain of the plurality of 10 strains of influenza virus to the concentration of Replikin sequences observed in the hemagglutinin amino acid sequence of each of the strains at at least one earlier time period to provide the concentration of Replikins for at least two time periods, said at least one earlier time period being within about six months to about three years prior to step (1), and 15 (4) identifying the strain of influenza virus having the highest increase in concentration of Replikin sequences during the at least two time periods.

[016] In yet another aspect of the mvention, there is provided an influenza virus vaccine comprising at least one isolated Replikin present in the hemagglutinin protein of an emerging strain of influenza virus and a pharmaceutically acceptable 20 carrier and/or adjuvant.

[017] Also provided by the present invention is a method of preventing or treating influenza virus infection comprising administering to a patient in need thereof a vaccine comprising at least one isolated Replikin present in the hemagglutinin protein of an emerging strain of influenza virus and a pharmaceutically acceptable 25 carrier and/or adjuvant.

[018] In another aspect of the invention, there are provided vaccines and methods for preventing or treating malaria. The malaria vaccines comprise at least one isolated Plasmodium falciparum Replikin. The present invention also provides methods for treating or preventing malaria comprising administering to a patient an 30 effective amount of a vaccine comprising at least one isolated Plasmodium falciparum Replikin. 6a 201947/1 [019] Also provided by the present invention are antibodies, antibody cocktails and compositions that comprise antibodies that specifically bind to a Replikin or Replikins present in a malaria antigen of Plasmodium falciparum.

In another aspect of the invention there are provided isolated Bacillus 5 anthracis (Anthrax) peptides containing a replikin sequence. The Anthrax peptides comprise from 7 to about 50 amino acids including (1) at least one lysine residue located six to ten amino acid residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues. In another embodiment of this aspect of 10 the invention there are provided Small Pox Virus peptides containing a replikin sequence which comprises from 7 to about 50 amino acids including (1) at least one lysine residue located six to ten amino acid residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues.

In another aspect of the invention there is provided a process for stimulating

15 the immune system of a subject to produce antibodies that bind specifically to Anthrax polypeptides containing a replikin sequence, said process comprising administering to the subject an effective amount of a dosage of a composition comprising at least one Anthrax replikin peptide. In a preferred embodiment the composition comprises at least one peptide selected from SEQ ID NO. 91, SEQ ID 20 NO. 92, SEQ ID NO. 93, SEQ ID NO. 94, SEQ ID NO. 95, SEQ ID NO. 96, SEQ ED NO. 79, SEQ ID NO. 98 or a combination thereof.

In another embodiment of this aspect of the invention there is provided a process for stimulating the immune system of a subject to produce antibodies that bind specifically to Small Pox Virus polypeptides containing a replikin sequence, 25 said process comprising administering to the subject an effective amount of a dosage of a composition comprising at least one Small Pox Virus replikin peptide, i a preferred embodiment the composition comprises a peptide selected from SEQ ID NO. 99, SEQ ID NO. 100, SEQ ID NO. 101, SEQ ID NO. 102, SEQ ID NO. 103, or a combination thereof. 30 In another aspect of the invention there are provided antisense nucleic acid molecules complementary to the coding strand of the gene or to the mRNA encoding 6b 201947/1 the Bacillus anthracis Anthrax Lethal Factor Protein pXOl-107 peptide, wherein said antisense nucleic acid molecule is complementary to a nucleotide sequence encoding the peptide of SEQ ID NO. 91, SEQ ID NO. 92, SEQ ID NO. 93, SEQ ED NO. 94, SEQ ID NO. 95, SEQ ID NO. 96, SEQ TD NO. 97, SEQ ID NO. 98. 5 There are also provided antisense nucleic acid molecule complementary to the coding strand of the gene or to the niRNA encoding the Small Pox Virus Surface Antigen S Precursor Protein, wherein said antisense nucleic acid molecule is complementary to a nucleotide sequence encoding the peptide of SEQ ID NO. 99, SEQ ED NO. 100, SEQ ID NO. 101, SEQ ID NO. 102, or SEQ ID NO. 103. 10 The present invention also provides methods for detecting the presence of a contaminating organism in a body sample or environmental sample comprising 1) isolating nucleic acids from the body sample or environmental sample; 2) screening the nucleic acids for the presence of a replikin structure; and 3) correlating the presence of a Replikin structure with the presence of the contaminating organism. 15 In yet another aspect of the invention there is provided a method for increasing the replication rate of an organism comprising transforming a gene encoding an enzyme having a replication function in the organism with at least one Replikin structure.

[020] As used herein, the term "peptide" refers to a compound of two or more 20 amino acids in which the carboxyl group of one is united with an amino group of another, forming a peptide bond. The term peptide is also used to denote the amino acid sequence encoding such a compound. Thus, a peptide sequence may be a subsequence of a larger polypeptide sequence. As used herein, a Replikin peptide is a peptide having 7 to about 50 amino acids comprising (1) at least one lysine residue 25 located six to ten amino acid residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues. Similarly, a replikin sequence is the amino acid sequence encoding such a peptide.

[021] The phrase "emerging strain" as used herein refers to a strain of influenza virus identified as having an increasing concentration of Replikin sequences in its 30 hemagglutinin and/or neuraminidase protein sequence, relative to the concentration of replikins in other strains of influenza virus. The increase in concentration occurs 6c 201947/2 over a period of at least about six months, and preferably over a period of at least about one year, most preferably over a period of at least about three years or more. BRIEF DESCRIPTION OF THE DRAWINGS 5 [022] Figure 1 is a bar graph depicting the frequency of occurrence of replikins in various protein groups. 7 WO 02/085093 PCT/US02/09240 [023] Figure 2 is a graph depicting the percentage of malignin per milligram total membrane protein during anaerobic replication of glioblastoma cells.

[024] Figure 3 is a bar graph showing amount of antimalignin antibody produced in response to exposure to the recognin 16-mer. 5 [025] Figure 4A is a photograph of a blood smear taken with ordinary and fluorescent light. Figure 4B is a photograph of a blood smear taken with ordinary and fluorescent light illustrating the presence of two leukemic cells. Figure 4C is a photograph of a dense layer of glioma cells in the presence of antimalignin antibody. Figure 4D and Figure 4E are photographs of the layer of cells in Figure 4C taken at 10 30 and 45 minutes following addition of antimalignin antibody.

[026] Figure 4F is a bar graph showing the inhibition of growth of small cell lung carcinoma cells in vitro by antimalignin antibody.

[027] Figure 5 is a plot of the amount of antimalignin antibody present in the serum of patients with benign or malignant breast disease pre-and post surgery. 15 [028] Figure 6 is a box diagram depicting an embodiment of the invention wherein a computer is used to cany out the 3-point-recognition method of identifying replikin sequences.

[029] Figure 7 is a graph showing the concentration of Replikins observed in hemagglutinin of influenza B and influenza A strain, H1N1, on a year by year basis 2 0 from 1918 through 2001.

[030] Figure 8 is a graph of the replikin concentration observed in hemagglutinin of influenza A strains, H2N2 and H3N2, as well as an emerging strain defined by its constituent Replikins, designated H3N2(R), on a year by year basis from 1950 to 2001. 25

DETAILED DESCRIPTION OF THE INVENTION

[031] The present invention provides methods for predicting future epidemics or pandemics of influenza virus, and vaccines and methods of designing effective vaccines against influenza virus. Identification of a new family of small peptides 3 0 related to the phenomenon of rapid replication, referred to herein as Replikins, provides new targets for detection of pathogens in a sample and vaccine WO 02/085093 PCT/US02/09240 development, such as for example, influenza virus detection and influenza vaccine development. Identification of this new family of peptides also provides for the detection of malaria and provides new targets for malaria vaccine development. The discovery of this family of peptides also provides for the detection and provides new 5 targets for anthrax and small pox virus, for example. In general, knowledge of and identification of this family of peptides enables development of effective vaccines for any organism that harbors Replikins.

[032] The first Replikin sequence to be identified was the cancer cell Replikin found in a brain cancer protein, malignin, which was demonstrated to be enriched 10 ten-fold during rapid anaerobic replication of glioblastoma multiforme (glioma) cells. (Figure 2) Malignin is a lOKDa portion of the 250 KDa glycoprotein 10B, which was isolated in vivo and in vitro from membranes of glioblastoma multiforme (glioma) cells. Hydrolysis and mass spectroscopy of malignin revealed al6-mer peptide sequence, ykagvaflhkkndide (SEQ Π) NO.:4), which is referred to herein as 15 the glioma Replikin and which includes the shorter peptide, kagvaflhkk (SEQ H> NO.: 1), both of which apparently are absent in the normal human genome.

[033] Table 1 illustrates how the sequence of the glioma Replikin, the 16-mer peptide sequence, ykagvaflhkkndide (SEQ ID NO.: 4) was determined. WO 02/085093 PCT/TJS02/09240

Table 1 16-mer peptide sequence ykagvaflhkkndide obtained from malignin by hydrolysis and mass spectrometry

Seq Fragment MH+ Sequence Method By Which Fragment Obtained ED NO. Identified (mass) Autohydrolysis of malignin free in solution Autohydrolysis of malignin immobilized on bromoacetyl cellulose Microwaved 5 seconds Microwaved 30 seconds 19 1-3 381.21 Oyka(g) + 20 1-5 537.30 Oykagv(a) + 21 2-6 445.28 (y)kagva(f) + 22 2-7 592.35 (Y)kagvaf(l) 4- 23 4-11 899.55 (a)gvaflhkk(n) + 24 5-7 336.19 (g)vaf(l) + 25 6-7 237.12 (v)af(l) + 26 6-10 615.36 (v)aflhk(k) + 27 6-10 615.36 (v)aflhk(k) + 28 6-12 857.50 (v)aflhkkn(d) 4· 29 6-12 857.50 (v)afhkkn(d) + 30 7-8 279.17 (a)fl(h) + 31 10-16 861.43 (h)kkndide0 + 32 11-14 489.27 (k)kndi(d) + 33 12-15 476.2- (k)ndid(e) [034] When the 16-mer glioma Replikin was synthesized and injected as a synthetic vaccine into rabbits, abundant antimalignin antibody was produced. (Bogoch et al., Cancer Detection and Prevention, 26(Supp. 1): 402 (2002). The concentration of antimalignin antibody in serum in vivo has been shown to relate 5 quantitatively to the survival of cancer patients. (Bogoch et al., Protides of

Biological Fluids, 31:739-747 (1984). In vitro antimalignin antibodies have been shown to be cytotoxic to cancer cells at a concentration of pico grams (femtomolar) per cancer cell. (Bogoch et al., Cancer Detection and Prevention, 26(Supp. 1): 402 (2002). 10 WO 02/085093 PCT/US02/09240 [035] Studies carried out by the inventors showed that the glioma Replikin is not represented in the normal healthy human genome. Consequently, a search for the origin and possible homologu.es of the Replikin sequence was undertaken by analysis of published sequences of various organisms. 5 [036] By using the 16-mer glioma Replikin sequence as a template and constructing a recognition proteomic system to visually scan the amino acid sequences of proteins of several different organisms, anew class of peptides, the Replikins, was identified. The present invention provides a method for identifying nucleotide or amino acid sequences that include a Replikin sequence. The method 10 is referred to herein as a 3-point-recognition method. By use of the “3-point recognition” method, described herein below, a new class of peptides was revealed in algae, yeast, fungi, amoebae, bacteria, plant and virus proteins having replication, transformation, or redox functions. Surprisingly, the Replikin peptides were found to be concentrated in larger ‘replicating’ and ‘transforming’ proteins (so designated 15 by their investigators, See Table 2). No sequences were found to be identical to the malignin 16-mer peptide.

[037] Table 2 illustrates several Replikin sequences that were identified by the 3-point recognition method of the invention. 11

Table 2:

Examples Of Replikins ill various organisms - prototype: Glioma Replikin* kagvaflhkk (SEQ ID No.: 1) WO 02/085093 PCT/US02/09240

Algae: SEQ ID NO. 34 35 Caldophera prolifera Isolepisprolifera kaskftldi kaqaetgeikgh Yeast: 36 Schizosaccharomyces pombe ksflcypkldik 37 Oryza sativa kkaygnelhk 2 Sacch. cerevisiae replication binding protein hsikrelgiifdk Fungi: Isocitrate lyase ICI lj’enicillium mameffei kvdivthqk 38 DNA-dependent ENA polymerase 11, Disenla dcstructiva ldeedaayhrkk 39 40 Ophiostoma novo-ulm 1 RNA in Dutch elm disease fungus kvilplrgnikgiffkh Amoeba: 41 Entamoeba invadens, histone H2B Idilkgfflnkh Bacteria: 42 Pribosomal protein replication factor, Helicobacter pylori Replication-associated protein Staph, aureus ksvhaflk 10 Mycoplasma pulmonic, chromosome replication kkektthnk 43 Macrophage infectivity potentiator, L. legionella kvhttqlkk 90 Bacillus anthracis kihlisvkk 91 Bacillus anthracis hvkkekeknk 92 Bacillus anthracis Idiivldevk 93 Bacillus Anthrarig kkkklkdiygkdallh 94 Bacillus anthracis kweldkqh 95 96 Bacillus anthracis Bacillus anthracis kklqipppiepkkddiih hnryasnivesayililnew- knniqsdiikk 97 Bacillus anthracis havddyagylldknqsdlv- tnskk 98 Bacillus anthracis haerikvqknapk Plants: 44 Arabidopsis thaliana, prolifera kdhdfdgdk 45 Arabidopsis thaliana, cytoplasmic ribosomal kmkglkqkkah 46 Arabidopsis thaliana, DNA binding protein kelssttqeksh Viruses: 9 Replication associated protein A [Maize streak virus] kekkpskdeimrdiish 11 Bovine herpes virus 4, DNA replication protein hkinitngqk 12 Meleagrid herpesvirus 1, replication binding protein hkdlyrllmk 47 Feline immunodeficiency hlkdyklvk 3 Foot and Mouth Disease (O) hkqkivapvk 5 HIV Type 1 kcfncgkegh 7 HIV Type 2 kcwncgkegh 99 Small Pox Virus (Variola) khynnitwyk 100 Small Pox Virus (Variola) kysqtgkeliih 101 Small Pox Virus (Variola) hyddvrikndiwsrck 102 Small Pox Virus (Variola) hrfklildski 103 Small Pox Virus (Variola) kerghnyyfek 12 WO 02/085093 PCT/US02/09240

Tumor 48 Rous sarcoma virus tyrosine-protein kinase kldrhek Viruses: 49 v-yes, avian sarcoma kklrhdk 50 c-yes, colon cancer, malignant melanoma Iddrhdk 51 v-srcC, avian sarcoma kldrhek 52 c-src, colon, mammary, panrcreatic cancer kldrhek 53 Neuroblastoma RAS viral (v-ras) oncogene kqahelak 54 VP1 (major capsid protein.) [Polyamavirus sp.] kthrfskh 55 Sindbis ltnlhekik 50 El (Human papilloamavirus type 71] lchrpllqlk 57 v-erbB from AEV and c-erb kspnhvk 58 v-fins (feline sarcoma) knihlekk 59 c-fms (acute and chronic myelomonocytic tumors) knihlekk 60 large t-antigen I (Polyomavirus sp.I kphlaqslek 61 middle t-antigen [Polyomavirus spjl- kqhrelkdk 62 small t-antigen [Polyomavirus spj, kqhrelkdk 63 v-abl, murine acute leukemia kvpvlisptlkh 64 Human T-cell lymphotropic virus typo 2 ksfllevdkdish 65 c-kit, GI tumors, small cell lung carcinoma kagitimvkreyh 18 Hepatitis C hyppkpgdvpak Trans- 66 Transforming protein myb ksgkhlgk forming 67 Transforming protein myc, Burkitt lymphoma krreqlkhk Proteins: 68 Ras-related GTP-binding protein ksfevikvih 69 Transforming protein ras (teratocardnoma) kkkhtvkk 70 TRAF-associated NF'kB activator TANK Icaqkdhlsk 71 RFP transforming protein hlkrvkdlkk 72 Transforming protein U (S.C.) kygspkhrlik 73 Papilloma virus type 11, transforming protein kllchilgkarfik 74 Protein tryosine kinase (EC 2.7.1.il2slk kgdhvkhykirk 75 Transforming protein (axl(-)) keldrdvmvdrhk 76 Transforming protein (N-myc) ldqarqqqllkkieh 77 Fibroblast growth factor 4 (Kaposi sarcoma) kkgnrvsptmkvth Cancer 78 Matrix metaloproteinase 7 (uterine) keiplhfrlc Cell 79 Transcription factor 7-like kkkphikk Proteins: 80 Breast cancer antigen NY-BR-87 ktrhdplak 81 BRCA-l-Associated Ring Domain Protein (breast) khhpkdnlik 82 'Autoantigen from a breast tumor' khkrkkfrqk 83 Glioma Replikin (this study) kagvaflhkk 84 Ovarian cancer antigen khkrkkfrqk 85 EE L leukemia kkksldchkdk 86 Proto-oncogene tyrosine-protein kinase C-ABLE hksekpalprk 87 Adenomatosis polyposis coli kkkkpsdkgdnek 88 Gastric cancer transforming protein ktkkgnrvsptmkvth 89 Transforming protein (K-RAS 2B)Jung khkekmskdgkkkkkksk [038] Identification of an amino acid sequence as a Replikin or as containing a Replikin, z.e., a homologue of the glioma peptide, kagvaflhkk, requires that the three following requirements be met. The peptide sequence must have (1) at least one lysine residue located six to ten residues from another lysine residue; (2) at least one 5 histidine residue; and (3) a composition of at least 6% lysine within an amino acid sequence of 7- to about 50 residues.

[039] Databases were searched using the National Library of Medicine keyword “PubMed” descriptor for protein sequences containing Replikin sequences. Over 4,000 protein sequences were visually examined for homologues. Sequences of all 1 o individual proteins within each group of PubMed-classified proteins were visually 13 WO 02/085093 PCT7US02/09240 scanned for peptides meeting the three above-listed requirements. An infrequent occurrence of homologues was observed in “virus peptides” as a whole (1.5%) (N=953), and in other peptides not designated as associated with malignant transformation or replication such as “brain peptides” and “neuropeptides” (together 5 8.5%) (N=845). However, surprisingly, homologues were significantly more frequently identified in large "replicating proteins," which were identified as having an established function in replication in bacteria, algae, and viruses. Even more surprising was the finding that Replikin homologues occurred in 100% of "tumor viruses" (N=250), in 97% of "cancer proteins" (N=401), and in 85% of 10 "transforming viruses" (N=248). These results suggest that there are shared properties of cancer pathogenesis regardless of cell type and suggest a role of viruses in carcinogenesis, i.e., conversion of cells from a transformed albeit dormant state to a more virulent actively replicating state.

[040] To permit classification of subtypes of Replikins, additional or “auxiliary 15 specifications” to the basic “3-point-recognition” requirements may be added: (a) on a structural basis, such as the common occurrence of adjacent di- and polylysines in cancer cell proteins (e.g., transforming protein P21B(K-RAS 2B), lung, Table 2, SEQ ID NO.: 89), and other adjacent di-amino acids in TOLL-like receptors, or b) on a functional basis, such as exhibiting ATPase, tyrosine kinase or redox activity as 2 0 seen in Table 2.

[041] Whether Replikin structures are conserved or are subject to extensive natural mutation was examined by scanning the protein sequences of various isolates of foot and mouth disease virus (FMDV), where mutations in proteins of these viruses have been well documented worldwide for decades. Protein sequences of FMDV isolates 2 5 were visually examined for the presence ofboth the entire Replikin and each of the component Replikin amino acid residues observed in a particular Replikin. For example, in the protein VP1 of FMDV type O, the Replikin (SEQ ID NO.: 3) “hkqkivapvk” was found to he conserved in 78% of the 236 isolates reported in PubMed, and each amino acid was found to be conserved in individual isolates as 3 0 follows: his, 95.6%; lys, 91.8%; gin 92.3%; lys, 84.1%; ile, 90.7%; val, 91.8%; ala, 97.3%; pro, 96.2%; ala, 75.4%; and lys, 88.4%. The high rate of conservation 14 WO 02/085093 PCT/US02/09240 suggests structural and functional stability of the Replikin structure. Similarly, sequence conservation was observed in different isolates of HIV for its Replikins, such as (SEQ ID NO.: 5) “kcfncgkegh” or (SEQ ID NO.: 6) “kvylawvpahk” in HIV Type 1 and (SEQ ID NO.: 7) “kcwncgkegh” in HTV Type 2 (Table 2). Other 5 examples of conservation are seen in the constant presence of malignin in successive generations, over ten years of tissue culture of glioma cells, and by the constancy of affinity of the glioma Replikin for antimalignin antibody isolated by immunoadsoiption from 8,090 human sera from the U.S., U.K., Europe and Asia (e.g., Figure 5 and U.S. Patent 6,242,578 B 1). 10 [042] As seen in Figure 2, during anaerobic respiration when the rate of cell replication is increased, malignin is enriched. That is, malignin is found to increase not simply in proportion to the increase in cell number and total membrane proteins, but is enriched as much as tenfold in concentration, starting with 3% at rest and reaching 30% of total membrane protein. This clear demonstration of a marked 15 increase in Replikin concentration with glioma cell replication points to and is consistent with the presence of Replikins here sought by the 3-point recognition method and found in the proteins of various organisms which were found by mutation studies and other previous studies to be critical to replication. For example, Replikins were identified in such proteins as “Saccharomyces cerevisiae 2 0 replication binding protein” (SEQ ID NO.: 2) (hsikrelgiifdk); the “replication associated protein A of maize streak virus” (SEQ ID NO.: 8) (kyivcareahk) and (SEQ ID NO.: 9) (kekkpskdeimrdush); the “replication-associated protein of Staphylococcus aureus” (SEQ ID NO.: 10) ( kkektthnk); the “DNA replication protein of bovine herpes virus 4" (SEQ ID NO.: 11) (hkiuitngqk); and the 2 5 “Mealigrid herpes virus 1 replication binding protein” (SEQ ID NO.: 12) (hkdlyrllmk). Previous studies of tomato leaf curl gemini virus show that the regulation of virus accumulation appears to involve binding of amino acids 1-160 of the “replicating protein” of that virus to leaf DNA and to other replication protein molecules during virus replication. Analysis of this sequence showed that amino 3 0 acids 1-163 of this “replicating protein” contain five Replikins, namely: (SEQ Π)

NO.: 13) kfrinaknyfltyph, (SEQ ID NO.: 14) knletpvnklfiricrefh, (SEQ ID 15 WO 02/085093 PCT/US02/09240 NO.: 15) hpniqaaksstdvk, (SEQ Π) NO.: 16) ksstdvkaymdkdgdvldh, and (SEQ Π) NO.: 17) kasalnilrekapkdfvlqfh.

[043] Table 2 shows that Replikin-containing proteins also are associated frequently with redox functions, and protein synthesis or elongation, as well as with 5 cell replication. The association with metal-based redox functions, the enrichment of the Replikin-containing glioma malignin concentration during anaerobic replication, and the cytotoxicity of antimalignin at low concentrations (picograms/cell) (Figure 4c-f), all suggest that the Replikins are related to central respiratory functions, which are perhaps less often subjected to the mutations 10 characteristic of proteins of more superficial location or less central survival function.

[044] Of particular interest, it was observed that at least one Replikin per 100 amino acids was found to be present in the hemagglutinin proteins of almost all of the individual strains of influenza viruses examined. The replikin sequences that 15 were observed to occur in the hemagglutinin proteins of isolates of each of the four prevalent strains of influenza virus, influenza Β, H1N1, H2N2, and H3N2, for each year that amino acid sequence data are available (1902-2001) are shown in Tables 3, 4, 5 and 6, below. 16

Table 3

Replikin Sequences present in hemagglutinins of Influenza B viruses in each year for which amino acid sequences were available (1902-2001).

Influenza B Replikins Year Detected in Inflnenza B strain (Peak in Figure 7: EB1 EB2 ) kshfanlk (SEQ ID NO. 104) kshfanlkgtk (SEQ ED NO. 105) kshfanlkgtktrgklcpk (SEQ ID NO. 106) hekygglnk (SEQ ID NO. 107) hekygglnksk (SEQ ID NO. 108) hekygglnkskpyytgehak (SEQ ID NO. 109) hakaigncpiwvk (SEQ ID NO. 110) hakaigncpiwvktplklangtk (SEQ ED NO. Ill) hakaigncpiwvktplklanglkyrppak (SEQ ID NO. 112) hakaigncpiwvktplklangtkyrppakllk (SEQ ID NO. 113) hfanlkgtktrgk (SEQ ID NO. 114) hfanlkgtktrgklcpk (SEQ ID NO. 115) hsdneiqmvklygdsk (SEQ ID NO. 116) hsdneiqdkmvklygdskpqk (SEQ ED NO. 117) hsdneiqmvklygdskpqk (SEQ ED NO. 118) k(a/v)silhevk (SEQ ED NO. 119) 1902,19,24,38,40,43,51,59,75,76,77,89,90,93,97,98,99,00,01 1902,19,24,38,40,43,51,59,75,76,77,89,90,93,97,98,99,00,01 1902,19,24,38,40,43,51,59,75,76,77,89,90,93,97,98,99,00,01 1902,19,24,38,40,43,51,59,75,76,77,89,90,93,97,98,99,00,01 1902,19,24,38,40,43,51,59,75,76,77,89,90,93,97,98,99,00,01 1902,19,24,38,40,43,51,59,75,76,77,89,90,93,97,98,'99,00,01 1902,19,24,38,40,43,51,59,75,76,77,89,90,93,97,98,99,00,01 1902.19.24.38.40.43.51.59.75.76.77.89.90.93.97.98.99.00.01 1902,19,24,38,40,43,51,59,75,76,77,89,90,93,97,98,99,00,01 1902,19,24,38,40,43^1,59,75,76,77,89,90,93,97,98,99,00,01 1919, 76, 89,90, 99,00,01 1919, 76, 90 00,01 1919 1919 1919, 24, 97,98, 00 1919, 40, 59, 90,93 WO 02/085093 PCT/US02/09240 00 kctgtipsakasilh (SEQ ID NO. 120) kctgtipsakasilhevk (SEQ ID NO. 121) kygglnkskpyytgeh (SEQ ID NO. 122) kvwcasgrskvikgslpligeadclh (SEQ ID NO. 123) kpyytgehak (SEQ ID NO. 124) kcmgtipsakasilhevk (SEQ ID NO. 125) hnvinaekapggpyk (SEQ ID NO. 126) hsdnetqmaklygdsk (SEQ ID NO. 127) hgvavaadlkstqeaink (SEQ ID NO. 128) hgvavaadlkstqeainkdtistqeamk (SEQ ID NO. 129) klygdskpqkftssangvtth (SEQ ID NO. 130) hsdnetqmaklygdskpqk (SEQ ID NO. 131) hfanlkgtqtrgk (SEQ ID NO. 132) kprsalkckgfh (SEQ ID NO. 133) kskpyytgehakai(g/a)ncpiwvk (SEQ ID NO. 134) 1919, 1919, 93 1919 1919, 38,40,43, 59,75,76,77,89,90, 98,99,00 1919, 38,40, 59, 89,90,93,97,98, 01' 24, 43, 75,76,77, 93 1938, 93,97, 00 1938, 93,97, 00 1940, 59, 00 1940 1943, 75,76,77, 93,97, 00 1943, 75,76,77, 93 1959 1988 2000 1. Influenza B has not been responsible for any human pandemic (global distribution). 2. Abbreviation for years: eg. “19” = 1919, “01” = 2001. 3. The first year that a given replikin appears is indicated at tbe beginning of the series of years in which that replikin has been found. 4. Overlapping replikin sequences are listed separately. 5. Increase in number of new replikin structures occurs in years of epidemics (underlined): eg. 1951 and 1977 and correlates with increased total replikin concentration (number of replikins per 100 amino acid residues). See Figure 7. WO 02/085093 PCT/US02/09240

Table 4 H1N1 Replikin Sequences present in HINI hemagglutinins of Influenza viruses in each year for which amino acid sequences were available (1918-2000) H1N1 Replikin Year Detected in Influenza H1N1 Strain (Peak in Figure7 : El El El.l, 12,1.3 El .4 ) hp(v/i)tigecpkyv(r/k)(s/t)(t/a)k (SEQ ID NO. 135) 1918.25.28.30.31.35.47.48.51.52. 55,56,57,59,63,77,79,80,81,85 ,87,88,85 »,91,9; 2,95,96,97,98,99,00 hdsnvknly(e/g)kv(k/r)(n/s)ql(k/r)nnak (SEQ ID NO. 136) 1918. 28,30,3b 77.79.80. 88, 91, 95, 98 hdsnvknly(e/g)kv(k/r)(n/s)qlk (SEQ ID NO. 13η 1918. 28,30,31, 77,79.80. 88, 91, 95, 98 hkc(nn/dd)(a/t/e)cmesv(r/k)ngtydypkyseesklnre(e/k)idgvk (SEQ ID NO. 138) 1918, 30, 35, 77, 80, 98 hkc(nn/dd)(a/t/e)cmesv(r/k)ngtydypkyseesk (SEQ ID NO. 139) 1918, 30, 35, 77, 80, 98 hqn(e/g)qgsgyaadqkstqnai(d/n)gitnkvnsviekmntqftavgkefiildek (SEQ ID NO. 1 40)1918. 28,30,31,35, 59, 79, 95 hqn(e/g)qgsgyaadqkstqnai(d/n)gitnkvnsviek (SEQ ID NO. 141) 1918. 28,30,31,35, 59, 79, 95 hqn(e/g)qgsgyaadqkstqnai(d/n)gitnlc (SEQ ID NO. 142) 1918. 28,30.31.35. 59, 79, 95 kfeifpktsswpnh (SEQ ID NO. 143) 1918, 77 kg(n/s/t)sypkl(n/s)ksy(v/t)nnkgkevlvlwgvh (SEQ ID NO. 144) 1918, 35, 77, 96 ksy(v/t)nnkgkevlvlwgvh (SEQ ID NO. 145) 1918. 35, 77, 96 hkcnnecmesvkngtydypkyseesklnrekidgvk (SEQ ID NO. 146) 1928, 31, 95 hkcnnecmesvkngtydypkyseesk (SEQ ID NO. 147) 1928, 31, 95 hkcnnecmesvkngtydypk (SEQ .ID NO. 148) 1928, 31, 95 hkcnnecmesvk (SEQ ID NO. 149) 1928, 31, 95 hngkssfy(k/r)nllwlt(e/g)knglypnlsksyvnnkek (SEQ ID NO. 150) 1928, 95, 00 hngkssfy(k/r)nllwlt(e/g)knglypnlsksyvnnk (SEQ ID NO. 151) 1928, 3b 95, 00 hnglcssfy(k/r)nllwlt(e/g)knglypnlsk (SEQ ID NO. 152) 1928, 3b 95, 00 hngkssfy(k/r)nllwlt(e/g)k (SEQ ID NO. 153) 1928, 3b 95, 00 kssfyknllwlteknglypnlsksyvnnkekevlvlwgvh (SEQ ID NO. 154) 1928, 3b · 95 WO 02/085093 PCT/US02/09240 to ο luillwlteknglypnlsksyvnnkekevlvlwgvh (SEQ ID NO. 155) knglypnlsksyvnnkekevlvlwgvh (SEQ ID NO. 156) ksy(v/a)nnkekev(l/-)(v/-)lwgvh (SEQ ID NO. 157) kesswpnhtvtk (SEQ ID NO. 158) het(t/n)kgvtaacpyagassfymllwlvkkensypklsksyvnnk (SEQ ID NO. 159) het(t/n)kgvtaacpyagassfymllwlvkkensypklsk (SEQ ID NO. 160) Irfeifpktsswpnevlvlwgvh (SEQ ID NO. 161) kerswpkh (SEQ ID NO. 162)

Idsksyvnnkekevlvlwqvh (SEQ ID NO. 163) knnkekevlvlwqvh (SEQ ID NO. 164) h(k/n)(g/q)kssfy(r/k)nllwltekng(l/s)yp(n/t)lsksyannkek (SEQ ID NO. 165) h(k/n)(g/q)kssfy(r/k)nllwltek (SEQ ID NO. 166) hakkssfyk (SEQ ID NO. 167) hngklcrfkgk (SEQ ID NO. 168) hyklnn(q/g)kk (SEQ ID NO. 169) hdiyrdeainnrfqiqgvkltqgyk (SEQ ID NO. 170) kgngcfeifhk (SEQ ID NO. 171) klnrliektndkyhqiek (SEQ ID NO. 172) klnrliektndkyh (SEQ ID NO. 173) kohtdkgslsttk (SEQ ID NO. 174) kinngdyaklyiwgvh (SEQ ID NO. 175) hngklcrkgiaplqlgk (SEQ ID NO. 176) hetnrqvtaacpyagansffinliwlvkkessypklsk (SEQ ID NO. 177) hetnrqvtaacpyagansffinliwlvkkessypk (SEQ ID NO. 178) hpptstdqqslyqnadayifvgsskynrkfk (SEQ ID NO. 179) hpptstdqqslyqnadayifvgsskynrkfkpeia (SEQ ID NO. 180) hdiyrdeainnrfqiqgvkitqgyk (SEQ ID NO. 181) hqneqgsgyaadqkstqhaidgitnkvnsviekmntqftavgk (SEQ ID NO. 182) 1928, 31, 1928, 31, 1928, 31, 51, 95 95,96, 95,96, 98, 95 00 00 1930, 35 1930, 35 1930 1947, 51,52,55,56, 1947, 51 1947 79, 1948 79, 1948 1951, 57,59 79, 1951.52.55.56.57.59. 79, 89, 96 89, 96 1956, 1956 1956 1956 1956 1956 1956 00 1959, 82 1963, 81 1963, 81 1963. 81 1963. 81 1977,79, WO 02/085093 PCT/US02/09240 1977 hqneqgsgyaadqkstqnaidgitnkvnsviek (SEQ ID NO. 183) hqneqgsgyaadqkstqnaingitnkvnsvietanntqftavgkefnklek (SEQ ID NO. 184) hngklcrlkgiaplqlgk (SEQ ID NO. 185) hkcnnecmesvk (SEQ ID NO. 186) kfeifpkasswpnh (SEQ ID NO. 187) hdsnvknlyekvrsqlmnak (SEQ ID NO. 188) kvnsvikkmntqfaavgkefhh (SEQ ID NO. 189) khngklck (SEQ ID NO. 190) kkgtsypldsksythnkgkevlvlwgvh (SEQ ID NO. 191) kgtsypklsksythnkgkevlvlwgvh (SEQ ID NO. 192) ldsksythnkgkevlvlwgvh (SEQ ID NO. 193) ksytbnkgkevlvlwgvb (SEQ ID NO. 194) kgvtascshk (SEQ ID NO. 195) kgvtascshkgrssfymllwlteknglypnlsk (SEQ ID NO. 196) kgnsypklsksyvnnkekevlvlwgih (SEQ ID NO. 197) W ke&hlek (SEQ ID NO. 198) hpptstdqqslyqnadayvfvgsskynkkfkpeiatrpk (SEQ ID NO. 199). hpptstdqqslyqnadayvfvgsskynkkfk (SEQ ID NO. 200) hegkssfymllwltekegsypklknsyvnk (SEQ ID NO. 201) hegkssfymllwltekegsypk (SEQ ID NO. 202) hkcdnecmesvmgtydypkyseesk (SEQ ID NO. 203) kesswpnhtvtk (SEQ ID NO. 204) knllwlteknglypnlsksyvnnkekeilvlwgvh (SEQ ID NO. 205) hngkssfy(fc/m)(n/-)llwlt(e/g)(-/k)knglypnlsk (SEQ ID NO. 206) hngkssfyknllwltek (SEQ ID NO. 207) htvtkgvtascshngkssfyknllwlteknglypnlsksyvnnkekevlvlwgvh (SEQ ID NO. 208) htvt(k/g)gv(t/s)ascshngkssfy(k/m)(n/-)llwlt(e/g)k(-n/k)glypnlsk (SEQ ID NO. 209) htvtkgvtascshngkssfyknllwltek (SEQ ID NO. 210) 1977 1979. 1979 1979 1981 1981 1981 1981 1981 1981 1981 1981 1985,87 1985,87 1988 1988 1988 1988 91 1991 1991 1991 1991,92 1991,92, 96 1991,92, 96, 1991,92, 96 1995 1995, 1995 00 00 WO 02/085093 PCT/US02/09240 kyvrstldrmvtglmipsiqsrglfgaiagfieggwtgmidgwygyh (SEQ ID NO. 211) hqneqgsgyaadqkstqnaingitnkvnsiiekmntqftavgk (SEQ ID NO. 212) hqneqgsgyaadqkstqnaingitnkvnsiiek (SEQ ID NO. 213) hqneqgsgyaadqkstqnaingitnk (SEQ ID NO. 214) hsgarsfymllwivkkgnsypk (SEQ ID NO. 215) hsgarsfymllwivkkgnsypklnk (SEQ ID NO. 216) hsgarsfymllwivkkgnsypklnksytndk (SEQ ID NO. 217) hsgarsfymllwivkkgnsypklnksytndkgk (SEQ ID NO. 218) htvskgvttscshngk (SEQ ID NO. 219) katswpnhettk (SEQ ID NO. 220) kqvttscshnqk (SEQ ID NO. 221) kgnsypklnksytndkgkevlviwgvh (SEQ ID NO. 222) ldnksytndkglcevlviwgvh (SEQ ID NO. 223) ksytndkgkevlviwgvh (SEQ ID NO. 224) hnqkssfymllwlt(e/q)knglypnlsksy(v/a)annkek (SEQ ID NO. 225) t*·3 hpitigecpkyvrsak (SEQ ID NO. 226) hqneqgsgyaadqkstqnaingitnkvnsviekmntqftavgk (SEQ ID NO. 227) hqneqgsgyaadqkstqnaingitnkvnsviek (SEQ ID NO. 228) hngkssfyrnllwlteknglypnlsksyvnnkek (SEQ ID NO. 229) 1995 1995 1995 1995 1996 1996 1996 1996 ' 1996 1996 1996 1996 1996 1996 1997,98,99 1997 1998 1998 1998 WO 02/085093 1. InfluenzaHINl was responsible for the human pandemic (global distribution) of 1918. 2. Abbreviation for years: eg. “96” = 1996. 3. The first year that a given replikin appears is indicated at the beginning of the series of years in which that replikin has been found in this work. 4. Overlapping replikin sequences are listed separately. 5. Increase in number of new replikin structures occurs in years of epidemics (underlined): eg. 1918 and 1977 and correlates with increased total replikin concentration (number of replikins per 100 amino acid residues). See Figure 7. co o ts)

bJ

U

Table 5

Replikin Sequences present in hemagglutinins of Influenza H2N2 viruses in years 1957-2000 WO 02/085093

Influenza H2N2 Replikins

Year Detected in Influenza H2N2 strain (Peak in Figure 8: P2 E2 ) Ν)

UJ khfekvkilpk (SEQ ID NO. 230) 1957.58.59.60.61.64.65.68. 78,83,84,91 khllssvkhfekvk (SEQ ID NO. 231) 1957.58.59.60.61. 83,84,91 ha(k/q/m)(d/n)ilekthngk (SEQ ID NO. 232) 1957.58.59.60.61.64.65.68. 78,83,84,91, ha(k/q/m)(d/n)ilekthngklc(k/r) (SEQ ID NO. 233) 1957.58.59.60.61.64.65.68. 78,83,84,91, hnvhpltigecpkyvksek (SEQ ID NO. 234) 1957.58.59. 65,68 hpltigecpkyvksek (SEQ ID NO. 235) 1957,58.59. 65,68,64,65,68,78,83,84,91 khllssvkhfekvkilpk (SEQ ID NO. 236) 1957.58.59.60.61.64.65.68. 78 krqssgimktegtlenoetkcqtplgainttlpflinvh (SEQ ID NO. 237) 1957, 59, 83 kgsnyp(v/i)ak(gZr)syimtsgeqmInwq(v/i)h (SEQ ID NO. 238) 1957,58.59. 61, 83, 91, httlgqsracavsgnpsfirnmvwltekgsnypvak (SEQ ID NO. 239) 1957 klifekvk (SEQ ID NO. 240) 1957, 59, 65 kiskrgssgimktegtlencetkcqtplgainttlpfh (SEQ ID NO. 241) 1957, 59, 65, 91 krgssgimktegtlencetkcqtplgaintdpfli (SEQ ID NO. 242) 1957, 59, 65, 91 ktegtlencetkcqtplgainttlpfh (SEQ ID NO. 243) 1957. 59, 65, 91 Wskrgssgimktegtlencetkcqtplgainttlpfh (SEQ ID NO. 244) 1957, 59, 65, 91 ktegtlencetkcqtplgamttlpfbn(v/i)h (SEQ ID NO. 245) 1957. 59, 65, 91 kiskrgssgiraktegtlencetkcqtplgainttlpfh (SEQ ID NO. 246) 1957. 59, 65, 91 k(e/g)snypvakgsynntsgeqni]iiwgvh (SEQ ID NO. 247) 1957, 60, 65 n § (Z3 © hpltigecpkyvksek (SEQ ID NO. 248) 1957, 60, 65 kcqtplgaikttlpfh (SEQ ED NO. 249) 1957, 65 hhsndqgsgyaadkestqka(f/i)dgitnkvnsviek- -mntqfeavgklfin/s)nleklenlnkk (SEQ ID NO. 250) 1961, 65,68, 83,84 hsndqgsgyaadkestqka(f/i)dgitnkvnsviek- -mntqfeavgklf(n/s)nleklenlnkk (SEQ ID NO. 251) 1961, 65,68, 83,84 hsndqgsgyaadkestqka(f/i)dgitnk (SEQ ID NO. 252) 1961, 65,68, 83,84 hdsnvmlydkvrmqlrdnak (SEQ ED NO. 253) 1964, 68,76, 84,91 hkcddecmnsvkngtydypklnmeikgvk (SEQ ID NO. 254) 1964,65,68,76, 83,84,91 hkcddecmnsvkngtydypklnmeik (SEQ ID NO. 255) 1964,65,68,76, 83,84,91 hkcddecmnsvkngtydypk (SEQ ID NO. 256) 1964.65.68.76, 83,84,91 hkcddecmnsvk (SEQ ED NO. 257) 1964,65,68,76, 83,84,91 kgsnypvakgsyimtngeqiliiwgvh (SEQ ID NO. 258) 1976,78 hsndqgsgyaadkestqkavdgitnkvnsviekmntqfeavgk (SEQ ID NO. 259) 1976, 91 krgssgimktegtlencetkcqtplgainttlpfh (SEQ ID NO. 260) 1976,78, 83,84 hpltigecpkyvksek (SEQ ID NO. 261) 1976 hakdileldhngklck (SEQ ID NO. 262) 1976 WO 02/085093 1. Influenza H2N2 was responsible for the human pandemic (global distribution) of 1957. 2. Abbreviation for years: eg. “58” =1958. 3. The first year that a given replikin appears is indicated at the beginning of the series of years in which that replikin has been found.in this work. 4. Overlapping replikin sequences are listed separately. 5. Increase in number of new replikin structures occurs in years of epidemics (underlined): eg. 1957 and 1965 and correlates with increased total replikin concentration (number of replikins per 100 amino acid residues). See Figure 8. cn o v®

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Table 6 H3N2 Replikin Sequences present in H3N2 hemagglutinins of Influenza viruses in each year for which amino acid sequences were available (1968-2000) WO 02/085093 to

Ul (Peak in Figure 8: P3 E3 hdvyrdealnnrfqikgvelksgyk (SEQ ID NO. 263) 1968.72. 75 96,97,98 htidltdsenmklfertrk (SEQ ED NO. 264) 1968 kfhqiek (SEQ ED NO. 265) 1968,72, 75, 77 96,97,98 ktnekfh(g/q)iek (SEQ ID NO. 266) 1968 86 98 klnr(v/l)iektnekfh (SEQ ID NO. 267) 1968,72, 75, 77 97,98 hqiekefsevegriqdlekyvedtk (SEQ ID NO. 268) 1968,72, 98 kicnnphk (SEQ ID NO. 269) 1975 klnrvikktnekfh (SEQ ED NO. 270) 1975 86 E4) 1975.76.77. 1975 1975 hd(I,v)yrdealniirfqik(g/q)ve(r/k)s(q/g)yk (SEQ ID NO. 271) hqiekefsevegriqdlekyvedtk (SEQ ID NO. 272) kyvedtkidlwsynaellvalenqh (SEQ ID NO. 273) kyvkqnslklatgmmvpekqtrglfgaiagfiengwegnridgwygfrh (SEQ ID NO. 274) 1975 kefsevegriqdlekyvedtkidlwsynaellvalenqh (SEQ ED NO. 275) 1975 hqn(s/e)(e/q)g(t/s)g(q/y)aad(l/q)k- -stq(a/n)a(i/l)d(q/g)I(n/t)(g/n)k(l/v)n(r/s)vi(e/c)k (SEQ ID NO. 276) 1975 hcd(g/q)f(q,r)nekwdlf(v,/i)er(s/t)k (SEQ ED NO. 277) 1975.76.77.78.80.81.82.83.84.85.86.88.89.90.91.92.93.94.95.96.97.98 2000 2000 n § cn © fcsi δ k© ts> <fx htidltdsemnkklfertrk (SEQ ID NO. 278) 1977, ksgstypvlkvtmpmidnfdklyiwgvh (SEQ ID NO. 279) 1977 ldnwltksgntypvlnvtmpnndnfdldviwgvh (SEQ ID NO. 280) 1982 htidltdsemnklfektrk (SEQ ID NO. 281) 1986 klnrliektnekfhqtek (SEQ ID NO. 282) 1987 htgkssvmrsdapidfcnsecitpnqsipndkpfqnvnkitygacpk (SEQ ID NO. 283) 1994 htgkssvmrsdapidfcnsecitpnqsipndkpfqnvnk (SEQ ID NO. 284) 1994 hpstdsdqtslyvrasgrvtvstkrsqqtvipk (SEQ ID NO. 285) 1994 kyvedtkidlwsynaellvalenqh (SEQ ID NO. 286) 1997,98 klfertrkqlrenaedmgngcfkiyh (SEQ ID NO. 287) 1998 krrsiksffsrlnwlh (SEQ ID NO. 288) 1998 to

Ch hpvtigecpky(v/r)kstk (SEQ ID NO. 289) kgnsypklsklsksyiinkkkevlviwgih (SEQ ID NO. 290) klsklsks(v/y)iinkkkevlviwgih (SEQ ID NO. 291) klsks(v/y)iinkkkevlviwgih (SEQ ID NO. 292) 1. Influenza H3N2 was responsible for the human pandemic (global distribution) of 1968. 2. Abbreviation for years: eg. “77” =1977. 3. The first year that a given replikin appears is indicated at the beginning of the series of years in which that replikin has been found. 4. Overlapping replikin sequences are listed separately. 5. Increase in number of new replikin structures occurs in years of epidemics (underlined): eg. 1975 and correlates with increased total replikin concentration (number of replikins per 100 amino acid residues). See Figure 8. 2000 2000 2000 2000 WO 02/085093 PCT/US02/09240 WO 02/085093 PCT/US02/09240 [045] Both the concentration and type, i.e., composition of Replildns observed were found to relate to the occurrence of influenza pandemics and epidemics. The concentration of Replikins in influenza viruses was examined by visually scanning the hemagglutinin amino acid sequences published in the National Library of 5 Medicine "PubMed" data base for influenza strains isolated world wide from human and animal reservoirs year by year over the past century, i.e., 1900 to 2001. These Replikin concentrations (number of Replikins per 100 amino acids, mean +/- SD) were then plotted for each strain.

[046] The concentration of Replikins was found to directly relate to the 10 occurrence of influenza pandemics and epidemics. The concentration of Replikins found in influenza B hemagglutinin and influenza A strain, H1N1, is shown in Figure 7, and the concentration of Replikins found in the two other common influenza virus A strains, H2N2 and H3N2 is shown in Figure 8 (H2N2, H3N2). The data in Figure 8 also demonstrate an emerging new strain of influenza virus as 15 defined by its constituent Replikins (H3N2(R)).

[047] Each influenza A strain has been responsible for one pandemic: in 1918, 1957, and 1968, respectively. The data in Figures 7 and 8 show that at least one replikin per 100 amino acids is present in each of the influenza hemagglutinin proteins of all isolates of the four common influenza viruses examined, suggesting a 20 function for Replikins in the maintenance of survival levels of replication. In the 1990s, during the decline of the H3N2 strain there were no Replikins present in many isolates of H3N2, but a high concentration of new replikins appeared in H3N2 isolates, which define the emergence of the H3N2(R) strain.

[048] Several properties of Replikin concentration are seen in Figure 7 and 25 Figure 8 to be common to all four influenza virus strains: (1) Concentration is cyclic over the years, with a single cycle of rise and fall occurring over a period of two to thirty years. This rise and fall is consistent with the known waxing and waning of individual influenza virus strain predominance by hemagglutinin and neuraminidase classification. (2) Peak Replikin concentrations of each influenza 3 0 virus strain previously shown to be responsible for a pandemic were observed to relate specifically and individually to each of the three years of the pandemics. For 27 WO 02/085093 PCT/US02/09240 example, for the pandemic of 1918, where the influenza virus strain, H1N1, was shown to he responsible, a peak concentration of the Replikins in H1N1 independently occurred (Pl); for the pandemic of 1957, where H2N2 emerged and was shown to be responsible, a peak concentration of the Replikins in H2N2 5 occurred (P2); and for the pandemic of 1968, where H3N2 emerged and was shown to be the cause of the pandemic, a peak concentration of the Replikins in H3N2 occurred (P3). (3) In the years immediately following each of the above three pandemics, the specific Replikin concentration decreased markedly, perhaps reflecting the broadly distributed immunity generated in each case. Thus, this post- 10 pandemic decline is specific for H1N1 immediately following the pandemic (Pl) for which it was responsible, and is not a general property of all strains at the time. An increase of Replikin concentration in influenza B repeatedly occurred simultaneously with the decrease in Replikin concentration in H1N1, e.g., EB1 in 1951 and EB2 in 1976, both associated with influenza B epidemics having the 15 highest mortality. (Stuart-Harris, et al., Edward Arnold Ltd. (1985). (4) A secondary peak concentration, which exceeded the primary peak increase in concentration, occurred 15 years after each of the three pandemics, and this secondary peak was accompanied by an epidemic: 15 years after the 1918 pandemic in an H1N1 ‘epidemic’ year (El); eight years after the 1957 pandemic in anH2N2 2 0 ‘epidemic’ year (E2); and occurred seven years after the 1968 pandemic in an H3N2 ‘epidemic’ year (E3). These secondary peak concentrations of specific Replikins may reflect recovery of the strain. (5) Peaks of each strain’s specific Replikin concentration frequently appear to be associated with declines in Replikin concentration of one or both other strains, suggesting competition between strains 25 for host sites. (6) There is an apparent overall tendency for the Replikin concentration of each strain to decline over a period of 35 years (H2N2) to 60 years (influenza B). This decline cannot be ascribed to the influence of vaccines because it was evident in the case of influenza B from 1901 to 1964, prior to common use of influenza vaccines. In the case of influenza B, Replikin recovery from the decline is 3 0 seen to occur after 1965, but Replikin concentration declined again between 1997 and 2000 (Figure 7), and this correlates with the low occurrence of influenza B in 28 WO 02/085093 PCT/US02/09240 recent case isolates. H1N1 Replikin concentration peaked in 1978-1979 (Figure 7 ) together with the reappearance and prevalence of the H1N1 strain, and then peaked in 1996 coincident with an H1N1 epidemic. (Figure 7). H1N1 Replikin concentration also declined between 1997 and 2000, and the presence of H1N1 5 strains decreased in isolates obtained during these years. For H2N2 Replikins, recovery from a 35 year decline has not occurred (Figure 8), and this correlates with the absence of H2N2 from recent isolates. For H3N2, the Replikin concentration of many isolates fell to zero during the period from 1996 to 2000, but other H3N2 isolates showed a significant, sharp increase in Replikin concentration. This 10 . indicates the emergence of a sub-strain of H3N2, which is designated herein as H3N2(R).

[049] Figures 7 and 8 demonstrate that frequently a one to three year stepwise increase is observed before Replikin concentration reaches a peak. This stepwise increase proceeds the occurrence of an epidemic, which occurs concurrently with the 15 Replikin peak. Thus, the stepwise increase in concentration of a particular strain is a signal that that particular strain is the most likely candidate to cause an epidemic or pandemic.

[050] Currently, Replikin concentration in the H3N2(R) strain of influenza virus is increasing (Figure 8,1997 to 2000). Three similar previous peak increases 20 in H3N2 Replikin concentration are seen to have occurred in the H3N2-based pandemic of 1968 (Figure 8), when the strain first emerged, and in the H3N2-based epidemics of 1972 and 1975 (Figure 8). Each of these pandemic and epidemics was associated with excess mortality. (Ailing, et al., Am J. Epidemiol.,113(1):30-43 (1981). The rapid ascent in concentration of the H3N2(R) subspecies of the H3N2 25 Replikins in 1997-2000, therefore, statistically represents an early warning of an approaching severe epidemic or pandemic. An H3N2 epidemic occurred in Russia in 2000 (Figure 8, E4); and the CDC report of December 2001 states that currently, H3N2 is the most frequently isolated strain of influenza virus world wide. (Morbidity and Mortality Weekly Reports (MMWR), Center for Disease Control; 30 50(48):1084-68 (Dec.7,2001). 29 WO 02/085093 PCT/US02/09240 [051] In each case of influenza virus pandemic or epidemic new Replikins emerge. There has been no observation of two of the same Replikins in a given hemagglutinin in a given isolate. To what degree the emergence of a new Replikin represents mutations versus transfer from another animal or avian pool is unknown. 5 In some cases, each year one or more of the original Replikin structures is conserved, while at the same time, new Replikins emerge. For example, in influenza virus B hemagglutinin, five Replikins were constantly conserved between 1919 and 2001, whereas 26 Replikins came and went during the same period (some recurred after several years absence). The disappearance and re-emergence years later of a 10 particular Replikin structure suggests that the Replikins return from another virus host pool rather than through de novo mutation.

[052] In the case of H1N1 Replikins, the two Replikins present in the Pl peak associated with the 1918 pandemic were not present in the recovery El peak of 1933, which contains 12 new Replikins. Constantly conserved Replikins, therefore, 15 are the best choice for vaccines, either alone or in combination. However, even recently appearing Replikins accompanying one year’s increase in concentration frequently persist and increase further for an additional one or more years, culminating in a concentration peak and an epidemic, thus providing both an early warning and time to vaccinate with synthetic Replikins (see for example, H1N1 in 2 0 the early 1990's, Figure 7).

[053] The data in FIGURES 7 and 8 demonstrate a direct relationship between the presence and concentration of a particular Replikin in influenza protein sequences and the occurrence of pandemics and epidemics of influenza. Thus, analysis of the influenza virus hemagglutinin protein sequence for the presence and 2 5 concentration of Replikins provides a predictor of influenza pandemics and/or epidemics, as well as a target for influenza vaccine formulation.

[054] Composition of Replikins in Strains of Influenza Virus B: Of a total of 26 Replikins identified in this strain (Table 3), the following ten Replikins are 3 0 present in every influenza B isolate examined from 1902-2001. Overlapping 30 WO 02/085093 PCT/US02/09240

Replikin sequences are listed separately. Lysines and histidines are in bold type to demonstrate homology consistent with the "3-point recognition." kshfanlk (SEQ ID NO. 104) kshfanlkgtk (SEQ ID NO. 105) 5 kshfanlkgtktrgklcpk (SEQ ID NO. 106) hekygglnk (SEQ ID NO. 107) hekygglnksk (SEQ ID NO. 108) hekygglnkskpyytgehak (SEQ ID NO. 10) hakaigncpiwvk (SEQ ID NO. 110) 10 hakaigncpiwwkktplklangtk (SEQ ID NO. Ill) hakaigncpiwvktplklangtkyrppak (SEQ ID NO. 112) hakaigncpiwvktplklangtkyrppakllk (SEQ ID NO. 113) [055] Tables 3 and 4 indicate that there appears to be much greater stability of the Replikin structures in influenza B hemagglutinins compared with H1N1 15 Replikins. Influenza B has not been responsible for any pandemic, and it appears not to have an animal or avian reservoirs. (Stuart-Harris et al., Edward Arnold Ltd., London (1985)).

[056] Influenza H1N1 Replikins: Only one replikin 2 0 "hp(v/i)tigecpkyv(r/k)(s/t)(t/a)k" is present in every H1N1 isolate for which sequences are available from 1918, when the strain first appeared and caused the pandemic of that year, through 2000. (Table 4). ("(v/i)" indicates that the amino acid v or i is present in the same position in different years.) Although H1N1 contains only one persistent replikin, H1N1 appears to be more prolific than 2 5 influenza B. There are 95 different replikin structures in 82 years on H1N1 versus only 31 different Replikins in 100 years of influenza B isolates (Table 4). An increase in the number of new Replikin structures occurs in years of epidemics (Tables 3,4,5 and 6) and correlates with increased total Replikin concentration (Figures 7 and 8). 31 WO 02/085093 PCT/US02/09240 [057] Influenza H2N2 Replikins: Influenza H2N2 was responsible for the human pandemic of 1957. Three of the 20 Replikins identified in that strain for 1957 were conserved in each of the H2N2 isolates available for examination on PubMed until 1995 (Table 5). 5 ha(k/q/m)(d/n)ilekthngk (SEQ ID NO. 232) ha(k/q/m)(d/n)ilekthngklc(k/r) (SEQ ID NO. 233) kgsnyp(v/i)ak(g/r)synntsgeqmliiwq(v/i)h (SEQ ID No. 238) [058] However, in contrast to H1N1, only 13 additional Replikins have been found in H2N2 beginning in 1961. This paucity of appearance of new Replikins 10 correlates with the decline in the concentration of the H2N2 Replikins and the appearance of H2N2 in isolates over the years. (Figure 8).

[059] Influenza H3N2 Replikins: Influenza PI3N2 was responsiblefor tiie_ human pandemic of 1968. Five Replikins which appeared in 1968 disappeared after 15 1977, but reappeared in the 1990s (Table 6). The only Replikin structure which persisted for 22 years was hcd(g/q)f(q/r)nekwdlf(v/i)er(s/t)k, which appeared first in 1977 and persisted through 1998. The emergence of twelve new H3N2 replikins in the mid 1990s (Table 6) correlates with the increase in Replikin concentration at the same time (Figure 8), and with the prevalence of the H3N2 strain in recent isolates. 2 0 together with the concurrent disappearance of all Replikins from some of these isolates (Figure. 8), this suggests the emergence of the new substrain H3N2(R).

[060] Figures 1 and 2 show that influenza epidemics and pandemics correlate with the increased concentration of replikins in influenza virus, which is due to the reappearance of at least one replikin from one to 59 years after its 2 5 disappearance. Also, in the A strain only, there is an emergence of new strain- specific Replikin compositions (Tables 4-6). Increase in Replikin concentration by repetition of individual replikins within a single protein appears not to occur in influenza virus, but is seen in other organisms.

[061] It has been believed that changes in the activity of different influenza 3 0 strains are related to sequence changes in influenza hemagglutinins, which in turn are the products of substitutions effected by one of two poorly understood processes: 32 WO 02/085093 PCT/US02/09240 i) antigenic drift, thought to be due to the accumulation of a series of point mutations in the hemagglutinin molecule, or ii) antigenic shift, in which the changes are so great that genetic reassortinent is postulated to occur between the viruses of human and non-human hosts. First, the present data suggests that the change in activity of 5 different influenza strains, rather than being related to non-specific sequence changes, are based upon, or relate to the increased concentration of strain-specific replikins and strain-specific increases in the replication associated with epidemics.

In addition, the data were examined for a possible insight into which sequence changes are due to "drift" or "shift", and which due to conservation, storage in 10 reservoirs, then reappearance. The data show that the epidemic-related increase in replikin concentration is not due to the duplication of existing replikins per hem agglutinin, but is due to the reappearance of at least one replikin composition from 1 to up to 59 years after its disappearance, plus in the A strains only, the emergence of new strain-specific replikin compositions (Tables 3-6). Thus the 15 increase in replikin concentration in the influenza B epidemics of 1951 and 1977 are not associated with the emergence of new replikin compositions in the year of the epidemic but only with the reappearance of replikin compositions which had appeared in previous years then disappeared (Table 3). In contrast, for the A strains, in addition to the reappearance of previously disappeared virus replikins, new 2 0 compositions appear (e.g. in HINI in the year of the epidemic of 1996, in addition to the reappearance of 6 earlier replikins, 10 new compositions emerged). Since the A strains only, not influenza B, have access to non-human animal and avian reservoirs, totally new compositions probably derive from non-human host reservoirs rather than from mutations of existing human replikins which appear to bear no 2 5 resemblance to the new compositions other than the basic requirements of "3-point recognition" (Tables 2-5). The more prolific nature of HINI compared with B, and the fact that pandemics have been produced by the three A strains only, but not by the B strain, both may also be a function of the ability of the human A strains to receive new replikin compositions from non-human viral reservoirs. 3 0 [062] Some replikins have appeared in only one year, disappeared, and not reappeared to date (Tables 3-6). Other replikins disappear for .from one to up to 81 33 WO 02/085093 PCT/US02/09240 years, when the identical replikin sequence reappears. Key replikin 'k' and h' amino acids, and the spaces between them, are conserved during the constant presence of particular replikins over many years, as shown in Tables 23-6for the following strain-specific replikins: ten of influenza B, the single replikin of H1N1, and the 5 single replikin of H2N3, as well as for the reappearance of identical replikins after an absence. Despite the marked replacement or substitution activity of other amino acids both inside the replikin structure and outside it in the rest of the hemagglutinin sequences, influenza replikin histidine (h) appears never to be, and lysine (k) is rarely replaced. Examples of this conservation are seen in the H1N1 10 rephkin"hp(v/i)tigecpkyv(r/k)(s/t)(t/a)k," (SEQ ID NO. 135) constant between 1918 and 2000, in the H3N2 replikin "hcd(g/q)f(q,r)nekwdlf(v/i)er(s/t)k" (SEQ ID NO. 277) constant between 1975 and 1998 and in the H3N2 replikin "hqn(s/e)(e/q)g(t/s)g(q/y)aad(l/q)kstq(a/n)a(i/l)d(q/g)I(n/t)(g/n)k,(l/v)n(r/s)vi(e/c)k” (SEQ ID NO. 276) which first appeared in 1975, disappeared for 25 years, and then 15 reappeared in 2000. While many amino acids were substituted, the basic replikin structure of 2 Lysines, 6 to 10 residues apart, one histidine, a minimum of 6% lysine in not more than approximately 50 amino acids, was conserved.

[063] Totally random substitution would not permit the persistence of these H1N1 and H3N2 replikins, nor from 1902 to 2001 in influenza B the persistence of 20 10 replikin structures, nor the reappearance inl993ofal91918mer replikin after an absence of 74 years. Rather than a random type of substitution, the constancy suggests an orderly controlled process, or in the least, protection of the key replikin residues so that they are fixed or bound in some way: lysines, perhaps bound to nucleic acids, and histidines, perhaps bound to respiratory redox enzymes. The 2 5 mechanisms which control this conservation are at present unknown.

[064] Whether the conservation of replikin structures is unique to influenza or occurs in other virus replikins was examined in foot and mouth disease virus (FMDV) isolates, where extensive mutations in proteins of this virus have been well-documented worldwide over decades. In the protein VP1 of FMDV type 0, the 3 0 replikin "hkqkivapvk" (SEQ ED NO. 3) was found to be conserved in 78% of the 236 isolates reported in PubMed, and each amino acid was found to he conserved in 34 WO 02/085093 PCT/US02/09240

individual isolates as follows: h,95.6%; k,91.8%; q,92.3%; k,84.1%; i,90.7%; v,91.8%; a..97.3%; p,96.2%; a,75.4%; k,88.4%. Similarly, conservation was observed in different isolates of HIV for its replikins such as "kcfncgkegh” (SEQ ID NO. 5) or "kvylawvpahk" (SEQ ID NO. 6) in HIV Type 1 and "kcwncgkegh" (SEQ 5 ID NO. 7) in HIV Type 216. The high rate of conservation observed in FMVD and HIV replikins suggests that conservation observed in influenza replikins is a general property of viral replikins.

[065J Data on anti-Replikin antibodies also support Replikin class unity. An anti-Replildn antibody response has been quantified by immunoadsorption of serum 10 antimalignin antibody to immobilized malignin (see Methods in U.S. Patent #5,866,690). The abundant production of antimalignin antibody by administration to rabbits of the synthetic version of the 16-mer peptide whose sequence was derived from malignin, absent carbohydrate or other groups, has established rigorously that this peptide alone is an epitope, that is, it is a sufficient basis for this immune 15 response (Figure 3). The 16-mer peptide produced both IgM and IgG forms of the antibody. Antimalignin antibody was found to be increased in concentration in serum in 37% of 79 cases in the U.S. and Asia of hepatitis B and C, early, in the first five years of infection, long before the usual observance of liver cancer, which develops about fifteen to twenty-five years after infection. Relevant to both 2 0 infectious hepatitis and HIV infections, transformed cells may be one form of safe haven for the virus: prolonging cell life and avoiding virus eviction, so that the virus remains inaccessible to anti-viral treatment.

[066] Because administration of Replikins stimulates the immune system to produce antibodies having a cytotoxic effect, peptide vaccines based on the 2 5 particular influenza virus Replikin or group of Replikins observed to be most concentrated over a given time period provide protection against the particular strain of influenza most likely to cause an outbreak in a given influenza season., e.g., an emerging strain or re-emerging strain For example, analysis of the influenza virus hemagglutinin amino acid sequence on a yearly or bi-yearly basis, provides data 3 0 which are useful in formulating a specifically targeted influenza vaccine for that year. It is understood that such analysis may be conducted on a region-by-region 35 WO 02/085093 PCT/US02/09240 basis or at any desired time period, so that strains emerging in different areas throughout the world can be detected and specifically targeted vaccines for each region can be formulated.

[067] Currently, vaccine formulations are changed twice yearly at international 5 WHO and CDC meetings. Vaccine formulations are based on serological evidence of the most current preponderance of influenza virus strain in a given region of the world. However, prior to the present invention there has been no correlation of influenza virus strain specific amino acid sequence changes with occurrence of influenza epidemics or pandemics. 10 [068] The observations of specific Replikins and their concentration in influenza virus proteins provides the first specific quantitative early chemical correlates of influenza pandemics and epidemics and provides for production and timely administration of influenza vaccines tailored specifically to treat the prevalent emerging or re-emerging strain of influenza virus in a particular region of the world. 15 By analyzing the protein sequences of isolates of strains of influenza virus, such as the hemagglutinin protein sequence, for the presence, concentration and/or conservation of Replikins, influenza virus pandemics and epidemics can be predicted. Furthermore, the severity of such outbreaks of influenza can be significantly lessened by administering an influenza peptide vaccine based on the 2 0 Replikin sequences found to be most abundant or shown to be on the rise in virus isolates over a given time period, such as about one to about three years.

[069] An influenza peptide vaccine of the invention may include a single Replikin peptide sequence or may include a plurality of Replikin sequences observed in influenza virus strains. Preferably, the peptide vaccine is based on Replikin 2 5 sequence(s) shown to be increasing in concentration over a given time period and · conserved for at least that period of time. However, a vaccine may include a conserved Replikin peptide(s) in combination with a new Rephkin(s) peptide or may be based on new Replikin peptide sequences. The Replikin peptides can be synthesized by any method, including chemical synthesis or recombinant gene 3 0 technology, and may include non-Replikin sequences, although vaccines based on peptides containing only Replikin sequences are preferred. Preferably, vaccine 36 WO 02/085093 PCT/US02/09240 compositions of the invention also contain a pharmaceutically acceptable carrier and/or adjuvant. £070] The influenza vaccines of the present invention can be administered alone or in combination with antiviral drugs, such as gancyclovir; interferon; 5 interleukin; M2 inhibitors, such as, amantadine, rimantadine; neuraminidase inhibitors, such as zanamivir and oseltamivir; and the like, as well as with combinations of antiviral drugs.

[071] Analysis of the primary structure of a Plasmodium farciparum malaria antigen located at the merozoite surface and/or within the parasitophorous vacuole 10 revealed that this organism, like influenza virus, also contains numerous Replikins. However, there are several differences between the observation of Replikins in Plasmodium falciparum and influenza virus isolates. For example, Plasmodium falciparum contains several partial Replikins, referred to herein as “Replikin decoys.” These decoy structures contain an abundance of lysine residues, but lack 15 the histidine required of Replikin structures. It is believed that the decoy structure maximizes the chances that an anti-malarial antibody or other agent will bind to the relatively less important structure containing the lysines, i.e., the Replikin decoys, rather than binding to histidine, which is present in Replikin structure, such as replikins in respiratory enzymes, which could result in destruction of the 2 0 trypanosome.

[072] Another difference seen in Plasmodium falciparum is a frequent repetition of individual Replikin structures within a single protein, which was not observed with influenza virus. Repetition may occur by (a) sharing of lysine residues between Replikins, and (b) by repetition of a portion of a Replikin sequence 2 5 within another Replikin sequence.

[073] A third significant difference between Replikin structures observed in influenza virus isolates and Plasmodium falciparum is a marked overlapping of Replikin structures throughout malarial proteins, e.g., there are nine overlapping replikins in the 39 amino acid sequence of SEQ ID NO. 393 (Replikin concentration

30 = 23.1/100 amino acids); and 15 overlapping replikins in the 41 amino acids of SEQ ID NO. 467 (Replikin concentration = 36.6/100 amino acids). Both of these 37 WO 02/085093 PCT/TJS02/09240 overlapping Replikin. structures occur in blood stage trophozoites and schizonts. In contrast, influenza virus Replikins are more scattered throughout the protein and the maximum Replikin concentration is about 7.5/100 amino acids (Figure 7); and tomato leaf curl gemini virus, which was also observed to have overlapping replikins 5 has only about 3.1/100 amino acids.

[074] This mechanism of lysine multiples is also seen in the Replikins of cancer proteins such as in gastric cancer transforming protein, ktkkgnrvsptmkvth (SEQ ID NO. 88), and in transforming protein P21B (K-RAS 2B) of lung, khkekmskdgkkkkkks (SEQ ID NO. 89). 10 [075] The relationship of higher Replikin concentration to rapid replication is also confirmed by analysis of HIV isolates. It was found that the slow-growing low titer strain of HIV (NSI, "Bru", which is prevalent in early stage HTV infection has a Replikin concentration of 1.1 (+/- 1.6) Replikins per 100 amino acids, whereas the rapidly-growing high titer strain of HIV (SI, "Lai"), which is 15 prevalent in late stage HIV infection has a Replikin concentration of 6.8 (+/- 2.7)

Replikins per 100 amino acid residues.

[076] The high concentration of overlapping Replikins in malaria, influenza virus and cancer cells is consistent with the legendary high and rapid replicating ability of malaria organisms. The multitude of overlapping Replikins in malaria also 2 0 provides an opportunity for the organism to flood and confuse the immune system of its host and thereby maximize the chance that the wrong antibody will he made and perpetuated, leaving key malaria antigens unharmed.

[077] As in the case of influenza virus, for example, peptide vaccines based on the Replikin structure(s) found in the malaria organism can provide an effective 25 means of preventing and/or treating malaria. Vaccination against malaria can be achieved by administering a composition containing one or a mixture of Replikin structures observed in Plasmodium falciparum. Furthermore, antibodies to malaria Replikins can be generated and administered for passive immunity or malaria detection purposes. 30 [078] Table 7 provides a list of several Plasmodium falciparum Replikin sequences. It should be noted that this list is not meant to be complete. Different 38 WO 02/085093 PCTZUS02/09240 isolates of the organism may contain other Replikin structures. 39 WO 02/085093 PCT/US02/09240

Table 7

Malaria replikins a) Primary structure of a Plasmodium falciparum malaria antigen located at the merozoite surface and within the parasitophorous vacuole 5 a) i) DECOYS: (C-Terminal) keeeekekekekekeekekeekekeekekekeekekekeekeeeldc (SEQ ID NO. 293), or keeeekekekekekeekekeekekeekekekeekekekeekeeekkek (SEQ ID NO. 294), or 10 keeeekekekekekeekekeekekekeekekeekekeekeekeeekk (SEQ ID NO. 295), or keeeekekek (SEQ ID NO. 296) ii) REPLIKINS:

Hkklikalkkniesiqnkk (SEQ ID NO. 297) 15 hkklikalkkniesiqnkm (SEQ ID NO. 298) hkklikalkk (SEQ ID NO. 299) hkklikalk (SEQ ID NO. 300) katysfratkkkiislksqghkk (SEQ ED NO. 301) katysfvntkkkiislksqghk (SEQ ID NO. 302) 2 0 katysfratkkkiislksqgh (SEQ ED NO. 303) htyvkgkkapsdpqca dikeeckellkek (SEQ ID NO. 304) kiislksqghk (SEQ ED NO. 305) kkkkfeplkngnvsetiklih (SEQ ID NO. 306) kkkfeplkngnvsetiklih (SEQ ID NO. 307) 2 5 kkfeplkngnvsetiklih (SEQ ID NO. 3 08) kngnvsetiklih (SEQ ID NO. 309) klihlgnkdkk (SEQ ID NO. 310) kvldflgvtlkkfepUmgnvsetddihlgnlcdkldi (SEQ ID NO. 311) hhyknksynpUlscvkkinnmlkenvdyiqnqMfkelinnqkatysf\mtkkkiislk (SEQ ID NO. 312) 3 0 hhyknksynplllscvklanrimllienvdyiqnqrilfkelmnqkatysfvntk (SEQ ID NO. 313) hhyknksynplUscvkkmnmn<envdyiqnqijlfkelmnqk (SEQ ED NO. 314) 40 WO 02/085093 PCT/US02/09240 hhyknlcsynpIUscvkkmnmlkenvdyiqknqnlfk (SEQ ID NO. 315) hhykriksynplEiscvkkmnriilli (SEQ ID NO. 316) ksaniisanngkknnaeeinlinivnflqshkkiilcaikkniesiqnkkh (SEQ ID NO. 317) klamaeernknlvnflqshldklEcaUdaiiesiqnlddi (SEQ ID NO. 318) 5 kidvnflqshkkhkalkkmesiqnkkh (SEQ ID NO. 319) kklikalkkniesiqnkkh (SEQ ED NO. 320) klikalkkniesiqnkkh (SEQ ED NO. 321) kkniesiqnkkh (SEQ ID NO. 322) kniesiqnkkh (SEQ ID NO. 323) 10 knnaeenaknlvnflqsh (SEQ ED NO. 324) kklikaUckniesiqnkkqghkk (SEQ ED NO. 325) ldamaeemknlvnflqshk (SEQ ED NO. 326) knnaeemknlvnflqsh (SEQ ID NO. 327) klikalkkniesiqnkkqghkk (SEQ ID NO. 328) 15 kvkkigvtlkkfeplkngnvsetildih (SEQ ID NO. 329) kngnvsetiklih (SEQ ID NO. 330) klihlgnkdkk (SEQ ID NO. 331) ksannsanngkknnaeeroknlvnflqsh (SEQ ID NO. 332) kknnaeeniknlvnflqsh (SEQ ED NO. 333) 2 0 kklikalkkniesiqnkkh (SEQ ID NO. 334) kalkkniesiqnkkh (SEQ ID NO. 335) kkniesiqnkkh (SEQ ID NO. 336) kelnmqkatysfvntkkkiislksqgh (SEQ ID NO. 337) ksqghkk (SEQ ID NO. 338) 2 5 kkkiislksqgh (SEQ ID NO. 339) kkiislksqgh (SEQ ED NO. 340) kkniesiqnkkh (SEQ ED NO. 341) kniesiqnkkh (SEQ ID NO. 342) htyvkgkkapsdpqcadikeeckellkek (SEQ ED NO. 343) 3 0 htyvkgkkapsdpqcadikeeckellk (SEQ ID NO. 344 ) 41 WO 02/085093 PCT/US02/09240 b)’’liver stage antigen-3" gene=’’LSA-3’’ Replikins henvlsaalentqseeekkevidvieevk (SEQ ID NO. 345) kenwttilekveettaesvttfsnileeiqentitndtieeldeelh (SEQ ID NO. 346) hylqqmkekfskek (SEQ ID NO. 347) 5 hylqqn±ekfskeknnnvievtnkael<kgnvqvtnldekttk (SEQ ID NO. 348) hylqqmliekfskeknnnvievtnkaekkgnvqvtnktekttkvdknnk (SEQ ID NO. 349) hylqqmkekfskeknrmvievtnkaeldignvqvtiddekttkv'dkimkvpkkrrtqk (SEQ ID NO. 350) hylqqii±ekfskeknimvievtnkaekkgnvqvtnktekttkvdknrikvpl<krrtqksk (SEQ ID NO. 351) hvdevndcyvqkidkevdkevskaleskndvtnvlkqnqdffskvknfvkkyk (SEQ ID NO. 352) 10 hvdevmkyvqkidkevdkevskaleskndvtnvlkqnqdffskvknfvkk (SEQ ID NO. 353) hvdevmkyvqkidkevdkevskaleskndvtnvlkqnqdffsk (SEQ ID NO. 354) hvdevmlcyvqlddlcevdkevskaleskndvtnvlk (SEQ ID NO. 355) hvdevmkyvqkidkevdkevskalesk (SEQ ID NO. 356) hvdevmkyvqkidkevdkevsk (SEQ ID NO. 357) 15 hvdevmkyvqkidkevdk (SEQ ID NO. 358) hvdevmkyvqkidk (SEQ ID NO. 359) kdevidlivqkeladekvkakklddekkveegvsgllddi (SEQ ID NO. 360) Icvkakkkldekkveegvsglkkh (SEQ ID NO. 361) kakkkldekkveegvsglkkh (SEQ ID NO. 362) 2 0 kkkklekkveegvsghdkh (SEQ ID NO. 363) kkblekkveegvsglkkh (SEQ ID NO. 364) kklekkveegvsglkkh (SEQ ID NO. 365) klekkveegvsglkkh (SEQ ID NO. 366) kkveegvsglkkh (SEQ ID NO. 367) 2 5 kveegvsglkkh (SEQ ID NO.368) hveqnvyvdvdvpamkdqflgilneagglkemfftiledvfksesdvitveeikdepvqk (SEQ ED NO. 369) hikgleeddleevddlkgsildtnlkgdmelgdmdkesledvttklgerveslk (SEQ ID NO. 370) hikgleeddleevddlkgsildmlkgdmelgdmdkesledvttk (SEQ ID NO. 371) hikgleeddleevddlkgsildmlkgdmelgdmdk (SEQ ID NO. 372) 3 0 hikgleeddleevddlkgsildmlk (SEQ ID NO. 373) hhsgdadvlssalgmdeeqmktrkkaqrpk (SEQ ID NO. 374)· hditttldewelkdveedldek (SEQ ID NO. 375) 42 WO 02/085093 PCT/US02/09240 lddeevhelk (SEQ ID NO. 376) kleevhelk (SEQ ID NO. 377) ktietdileekkkeiekdh (SEQ ID NO. 378) kkeiekdhfek (SEQ ID NO. 379) 5 kdhfek (SEQ ID NO. 380) kfeeeaeeikh (SEQ ID NO. 381) c) 28 KDA ookinete surface antigen precursor Replikins: kdgdtkctlecaqgkkcikhlcsdhnhksdhnhlffidphhkklanmimk (SEQ ID NO. 382) 10 kdgdtkctlecaqgkkcikhksdhnhksdhnhksdpnhkk (SEQ.ID NO. 383) kdgdtiictlecaqgkkcikhlisdhnhksdhrihksdprihk (SEQ ID NO. 384) kdgdtkctlecaqgkkcikhksdhnhksdhnhk (SEQ ID NO. 385) kdgdtkctlecaqgkkcikhksdhiihk (SEQ ID NO. 386) kdgdtkctlecaqgkkcikhk (SEQ ID NO. 387) 15 kdgdtkctlecaqgkk (SEQ ID NO. 388) kdgdtkctlecaqgk (SEQ ID NO. 389) kciqaecnykecgeqkcvwdgih (SEQ ID NO. 390) kecgeqkcvwdgih (SEQ ID NO. 391) hieckcnndyvltnryecepknkctsledtnk (SEQ ED NO. 392) d) Blood stage trophozoites and schizonts Replikins: ksdhnhksdhnhksdhnhksdpnhkkknnnnnk (SEQ ED NO. 394) 2 5 ksdhnhksdpnhkkknnnnnk (SEQ ED NO. 396) kkknnnnnkdnksdpnhk (SEQ ED NO. 397) knnnnnkdnlcsdpnhk (SEQ ID NO. 399) kdnksdpnhk (SEQ ID NO. 400) 3 0 ksdpnhk (SEQ ID NO. 401) hsiyalqqneeyqkvknekdqneikkikqheknk (SEQ ED NO. 402) 43 WO 02/085093 PCT/US02/09240 hslyalqqneeyqkvknekdqneikkik (SEQ ID NO. 403) hslyalqqneeyqkvknekdqneikk (SEQ ID NO. 404) hslyalqqneeyqkvknekdqneik (SEQ ID NO. 405) hklenleemdk (SEQ ID NO. 406) 5 khfddntneqk (SEQ ID NO. 407) kkeddekh (SEQ ID NO. 408) keennkkeddekh (SEQ ID NO. 409) ktssgilnkeennkkeddekh (SEQ ID NO. 410) knihikk (SEQ ID NO. 411) 10 hilckkegidigyk (SEQ ID NO. 412) kkmwtcklwdnkgneitknih (SEQ ID NO. 413 ) kkgiqwnllkkmwtcldwdnkgneitlcnih (SEQ ID NO. 414 ) kekkdsnenrkkkqkedkknpnklkkieytnkithfikakmikqqnnvth (SEQ ID NO. 415) kkdsnenrkkkqkedkknpnklkkieytnkithffkaknnkqqmvth (SEQ ID NO. 416) 15 kdsnemkkkqkedkknpnklkkieytnldthffkaknnkqqnnvth (SEQ ID NO. 417) kkqkedldmpnldkkieytnkithfflcaknnlcqqiinvth (SEQ ID NO. 418) kqkedkknpnklkkieytnkithffkaknnkqqnnvth (SEQ ID NO. 419) kedkknpriklkkieytnldthffkaknnkqqnnvth (SEQ ID NO. 420) knpnklkkieytnkithfQcakimkqqnnvth (SEQ ID NO. 421) 2 0 kkieytnkithffkakimkqqnnvth (SEQ ID NO. 422) kieytnkithfikaknhkqqnnvth (SEQ ED NO. 423) ldthffkaknnkqqnnvth (SEQ ID NO. 424) hknnedikndnskdikndnskdikndnskdikndnnedikndnskdik (SEQ ED NO. 425 ) hknnedikndnskdikndnskdikndnskdikndnnedikndnsk (SEQ ED NO. 426) 2 5 hknnedikndnskdikndnskdikndnskdikndnnedik (SEQ ED NO. 427) hknnedikndnskdikndnskdilcndnskdik (SEQ ID NO. 428) hknnedikndnskdikndnskdikndnsk (SEQ ID NO. 429) hlcnnedikndnskdikndnskdik (SEQ ED NO. 430) hknnedikndnskdikndnsk (SEQ ID NO. 431) 3 0 hknnedikndnskdik (SEQ ED NO. 432) hknnedik (SEQ ED NO. 433) 44 WO 02/085093 PCT/US02/09240 ldiyddlqnkymlnlilknsleekneelkkyh (SEQ ID NO. 434) kyddlqnlcynilnklknsleekneelkkyh (SEQ ID NO. 435) l<ynilnldknsleekneelld<yh (SEQ ID NO. 436) klknsleekneelkkyh (SEQ ID NO. 437) 5 knsleekneelkkyh (SEQ ID NO. 438) kneelkkyh (SEQ ID NO. 439) hmgnnqdinenvynikpqefkeeeeedismvntldc (SEQ ID NO. 440) knsneUomdnffklh (SEQ ID NO. 441) kpclykkckisqclylckcldsqvwwcmpvkdtfhtyemnvlnsldenniekiph (SEQ ID NO. 442) 10 hinneytnknpkncllykneemyndnnikdyinsrnnfkk (SEQ ID NO. 443) hinneytnknpkncllykneemyndnnikdyinsnmfk (SEQ ED NO. 444) hinneyfnknpkncllyk (SEQ ID NO. 445) knktnqskgvkgeyekkketngh (SEQ ID NO. 446) ktnqskgvkgeyekkketngh (SEQ ID NO. 447) 15 kgvkgeyekkketngh (SEQ ID NO. 448) kgeyekkketagh (SEQ ID NO. 449) ksgmytaegnkscecsykkkssssnkvh (SEQ ID NO. 450) kscecsykkkssssnkvh (SEQ ID NO. 451) kkkssssnkvh (SEQ ED NO. 452) 2 0 kkssssnkvh (SEQ ID NO. 453) kssssnkvh (SEQ ID NO. 454) hhnlksgmytaegnkscecsykkkssssnk (SEQ ID NO. 455) himlksgmytnegnkscecsykkk (SEQ ID NO. 456) himlksgmytnegnkscecsykk (SEQ ID NO. 457) 2 5 himlksgmytnegnkscecsyk (SEQ ID NO. 458) kplakkkrektqinktkyergdviidnteiqkiiirdyhetlnvhkldh (SEQ ID NO. 459) krektqihktkyergdviidnteiqkiiirdyhetlnvhkldh (SEQ ED NO. 460) ktqinktkyergdviidnteiqkiiirdyhethivhkldh (SEQ ID NO. 461) kplaklrkrektqinktkyergdviidnteiqkiiirdyhetlnvh (SEQ ED NO. 462) 3 0 kplaklrkrektqinktkyergdviidnteiqkiiirdyh (SEQ ID NO. 463)

Idrkrektqinktkyergdviidnteiqkiiirdyh (SEQ ED NO. 464) 45 WO 02/085093 PCT/US02/09240 krektqinktkyergdviidnteiqkiiirdyh (SEQ ID NO. 465) ktqinktlqyergdviidnteiqldiirdyli (SEQ ID NO. 466) kkdkekklcdsnerirkld<qkedkLmpndN<Uddeytokith (SEQ ID NO. 467) kdlceld±dsnenrklckqkedldaipndnl<lkldeytiildth (SEQ ID NO. 468) 5 kekldidsnertrldd<qkedldmpndnkllddeytnldth (SEQ ID NO. 469) kkkdsnemkkkqkedkknpndnklkkieytakith. (SEQ ED NO. 470) kkdsnerukkkqkedklaipndiildkldeytnkith (SEQ ED NO. 471) kdsnemkkkqkedkkapndnklkkieytnkith (SEQ ID NO. 472) kkkqkedkknpndnklkkieytnkith (SEQ ID NO. 473) 10 kkqkedkknpndnklkkieytakith (SEQ ID NO. 474) kqkedkknpndnkUddeytnkith (SEQ ED NO. 475) kedkknpndnklkkieytnkith (SEQ ED NO. 476) kknpndiikUddeytakith (SEQ ID NO. 477) knpndrklkkieytnkith (SEQ ID NO. 478) 15 kliddeytakith (SEQ ID NO. 479) kkieytakith (SEQ ID NO. 480) kieytnkith (SEQ ID NO. 481) hgqikiedvnneiltaneqmkhkyndeekmdiskskslksdflek (SEQ ED NO. 482) hgqikiedvnneirBmeqnaknkyndeekmdiskskslk (SEQ ID NO. 483) 2 0 hgqikiedvnnenfeneqmknkyndeekmdisksk (SEQ ED NO. 484) hgqikiedvnnenfeneqmknlcyndeelandisk (SEQ ID NO. 485) kkyddlqnkynilx±Umsleekneelkkyh (SEQ ID NO. 486) kyddlqnkymlnklknsleelaieelklcyh (SEQ ED NO. 487) kynilnklknsleekneelkkyh (SEQ ID NO. 488) 2 5 klknsleekneelkkyh (SEQ ED NO. 489) knsleekneelkkyh (SEQ ED NO. 490) kneelkkyh (SEQ ED NO. 491) hmgnnqdinenvyriikpqefkeeeeedisnxvntkkcddiqeriik (SEQ ID NO. 492) khdymynnknddkdtaldnenreglylcdvnaknsnelkrmdnfQdh (SEQ ID NO. 493) 3 0 knsnelkrindnffklh (SEQ ED NO. 494) krindnffklh (SEQ ID NO. 495) 46 WO 02/085093 PCT/US02/09240 hirmeytalmpkncllykneemyndimilidymsmnfkk (SEQ ID NO. 496) Mmeytnknpkncllykneemyndimdcdyinsnmflc (SEQ ID NO. 497) himeytaknpkncllyk (SEQ ID NO. 498) kpclykkckisqvwwcmpvkdtfhtyenrnvlnskieniiieldpli (SEQ ID NO. 499) 5 kdrisqvwwcmpvkdtfiityenmvlnskienniekiph (SEQ ID NO. 500) kienniekiph (SEQ ID NO. 501) knktngskgvkgeyekkketngh (SEQ ID NO. 502) ktngskgvkgeyekkketagh (SEQ ID NO. 503) kgvkgeyekkketagh (SEQ ED NO. 504) 10 kgeyekkketngh (SEQ ED NO. 505) ktiekinkskswffeeldeidkplakkkrektqinktkyergdviidnteiqkiirdyh (SEQ ED NO. 506) kinkskswffeeldeidkplakhkrektqinktkyergdviidnteiqkiirdyh (SEQ ID NO. 507) Iqjlakhkrektqinktkyergdviidnteiqkiirdyh (SEQ ED NO. 508) himlksqmytaegnkscecsykkkssssnkvh (SEQ ID NO. 509) 15 klrkrektqinktkyergdviidnteiqkiirdyh (SEQ ED NO. 510) krektqinktkyergdviidnteiqknrdyh (SEQ ID NO. 511) ktqinktkyergdviidnteiqkiirdyh (SEQ ID NO. 512) kplakbkrektqiliktkyergdviidnteiqkiirdylitirivhkidh (SEQ ED NO. 513) kfrkrektqinktkyergdviidnteiqkiirdyhtlnvhkldh (SEQ ED NO. 514) 2 0 krektqinktkyergdviidnteiqkiirdyhtlnvhlddh(SEQ ID NO. 515) ktqinktkyergdviidnteiqkiirdyhtlnvhlddh (SEQ ID NO. 516) kplakhkrektqinktkyergdviidnteiqkiirdyhtlnvh (SEQ ID NO. 517) klrlaektqinktkyergdviidnteiqldirdyhtlnvh (SEQ ID NO. 518) taektqinktkyergdviidnteiqldirdyhtlnvh (SEQ ED NO. 519) 2 5 ktqinktkyergdviidnteiqkiirdyhtlnvh (SEQ ID NO. 520) himlksqmytaegnkscecsykkkssssnkvh (SEQ ED NO. 521) ksqmytaegnkscecsykkkssssnkvh (SEQ ID NO. 522) kscecsykkkssssnkvh (SEQ ID NO. 523) kkkssssnkvh (SEQ ID NO. 524) 3 0 kkssssnkvh (SEQ ED NO. 525) kssssnkvh (SEQ ID NO. 526) 47 WO 02/085093 PCT/US02/09240 himlksqmytnegnkscecsylckltssssnk (SEQ ID NO. 527) himlksqmytnegnkscecsykkk (SEQ ID NO. 528) himlksqmytnegnkscecsykk (SEQ ID NO. 529) himlksqmytnegnkscecsyk (SEQ ID NO. 530) 5 hnnhniqiykdkrinfixmphkvmyhdnmslaiertek (SEQ ID NO. 531) hnnhniqiykdkrinfinnphkvmyhdnmsk (SEQ ID NO. 532) hnnhniqiykdkrinfinnphk (SEQ ID NO. 533) hkvmyhdnmsknertek (SEQ ID NO. 534) hkvmyhdnmsk (SEQ ID NO. 535) 10 _

Other microorganisms found to contain numerous Replikin structures are Bacillus anthracis, the organism responsible for anthrax infections, in which eight different replikins were identified; and small pox virus, in which five different 15 Replikins were identified. The eight Bacillus anthracis peptides are present in the Anthrax Toxin Lethal Factor Protein pX01-107 and have the amino acid sequence of SEQ TD NO. 91, SEQ ID NO.92, SEQ ID NO. 93, SEQ ID NO. 94, SEQ ID NO. 95, SEQ ID NO. 96, SEQ ID NO. 97 and SEQ ED NO. 98, respectively. The five small pox virus peptides are present in the Small Pox Virus Surface Antigen S Precursor 2 0 Protein, which purportedly enhances Small Pox Virus replication. The five peptides have the amino acid sequence of SEQ ID NO. 99, SEQ ID NO. 100, SEQ ED NO.101, SEQ ED NO. 102 and SEQ ID NO. 103, respectively.

[079] Synthetic Replikin vaccines, based on Replikins such as the glioma Replikin (SEQ ID NO.: 1) “kagvaflhkk” or the hepatitis C Replikin (SEQ ID 2 5 NO.: 18) “hyppkpgcivpak”, or HIV Replikins such as (SEQ ID NO.: 5) “kcfncgkegh” or (SEQ Π> NO.: 6) “kvylawvpahk” or preferably, an influenza vaccine based on conserved and/or emerging or re-emerging Replikin(s) over a given time period may be used to augment antibody concentration in order to lyse the respective virus infected cells and release virus extracellularly where chemical 3 0 treatment can then be effective. Similarly, a malaria vaccine, based on Replikins observed in Plasmodium falciparum malaria antigens on the merozoite surface or 48 WO 02/085093 PCT/US02/09240 within the parasitophorous vacuole, for example, can be used to generate cytotoxic antibodies to malaria. Vaccines based on the Replikin structures identified in small pox virus, or Bacillus anthracis, or any pathological organism in which Replikins are identified, can be generated and administered to prevent the respective disease. 5 Recognin and/or Replikin peptides may be administered to a subject to induce the immune system of the subject to produce anti-Replikin antibodies. Generally, a 0.5 to about 2 mg dosage, preferably a 1 mg dosage of each peptide is administered to the subject to induce an immune response. Subsequent dosages may be administered if desired. 10 [080] In another embodiment of the invention, isolated Replikin peptides may be used to generate antibodies, which may be used, for example to provide passive immunity in an individual. Passive immunity to the strain of influenza identified by the method of the invention to be the most likely cause of future influenza infections maybe obtained by administering antibodies to Replikin sequences of the identified 15 strain of influenza virus to patients in need. Similarly, passive immunity to malaria maybe obtained by administering antibodies to Plasmodium falciparum Replikin(s); immunity to Small pox is achieved by administering antibodies to small pox virus Replin(s); immunity to anthrax is achieved by administering antibodies to Bacillus anthracis Replikin(s); and the like. 20 [081] Various procedures known in the art may be used for the production of antibodies to Replikin sequences. Such antibodies include but are not limited to polyclonal, monoclonal, chimeric, humanized, single chain, Fab fragments and fragments produced by an Fab expression library. Antibodies that are linked to a cytotoxic agent may also be generated. Antibodies may also be administered in 2 5 combination with an antiviral agent. Furthermore, combinations of antibodies to different Replikins maybe administered as an antibody cocktail.

[082] For the production of antibodies various host animals may be immunized by injection with a Replikin peptide or a combination of Replikin peptides, including but not limited to rabbits, mice, rats, and larger mammals. Various adjuvants may 30 be used to enhance the immunological response, depending on the host species, including but not limited to Freund’s (complete and incomplete), mineral gels, such 49 WO 02/085093 PCT/US02/09240 as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, key limpet hemocyanin, dintrophenol, and potentially useful human adjuvants such as BCG and Corynebacterium parvum. [083] Monoclonal antibodies to Replildns may be prepared by using any 5 technique that provides for the production of antibody molecules. These include but are not limited to the hybridoma technique originally described by Kohler and Milstein, (Nature, 1975, 256:495-497), the human B-cell hybridoma technique (Kosbor et al., 1983, Immunology Today, 4:72), and the EBV hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77- 10 96). In addition, techniques developed for the production of chimeric antibodies (Morrison et al., 1984, Proc. Nat. Acad. Sci USA, 81:6851-6855) or other techniques may be used. Alternatively, techniques described for the production of single chain antibodies (US 4,946,778) can be adapted to produce Replikin-specific single chain antibodies. 15 [084] Particularly useful antibodies of the invention are those that specifically bind to Replikin sequences contained in peptides and/or polypeptides of influenza virus. For example, antibodies to any of peptides observed to be present in an emerging or re-emerging strain· of influenza virus and combinations of such antibodies are useful in the treatment and/or prevention of influenza. Similarly, 2 0 antibodies to any replikins present on malaria antigens and combinations of such antibodies are useful in the prevention and treatment of malaria.

[085] Antibody fragments which contain binding sites for a Replikin may be generated by known techniques. For example, such fragments include but are not limited to F(ab’)2 fragments which can be produced by pepsin digestion of the 2 5 antibody molecules and the Fab fragments that can be generated by reducing the disulfide bridges of the F(ab’)2 fragments. Alternatively, Fab expression libraries can be generated (Huse et al., 1989, Science, 246:1275-1281) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity.

[086] The fact that antimalignin antibody is increased in concentration in 3 0 human malignancy regardless of cancer cell type (Figure 5), and that this antibody binds to malignant cells regardless of cell type now may be explained by the 50 WO 02/085093 PCT/US02/09240 presence of the Replikin structures herein found to he present in most malignancies (Figure 1 and Table 2). Population studies have shown that antimalignin antibody increases in concentration in healthy adults with age, and more so in high-risk families, as the frequency of cancer increases. An additional two-fold or greater 5 antibody increase which occurs in early malignancy has been independently confirmed with a sensitivity of 97% in breast cancers 1-10 mm in size. Shown to localize preferentially in malignant cells in vivo, histochemically the antibody does not bind to normal cells but selectively binds to (Figure 4a,b) and is highly cytotoxic to transformed cells in vitro (Figure 4c-f). Since in these examples the 10 same antibody is bound by several cell types, that is, brain glioma,· hematopoietic cells (leukemia), and small cell carcinoma of lung, malignant Replikin class unity is again demonstrated.

[087] Antimalignin does not increase with benign proliferation, but specifically increases only with malignant transformation and replication in breast in vivo and 15 returns from elevated to normal values upon elimination of malignant cells (Figure 5). Antimalignin antibody concentration has been shown to relate quantitatively to the survival of cancer patients, that is, the more antibody, the longer the survival. Taken together, these results suggest that anti-Replikin antibodies maybe a part of a mechanism of control of cell transformation and replication. Augmentation of this 2 0 immune response may be useful in the control of replication, either actively with synthetic Replikins as vaccines, or passively by the administration of anti-Replikin antibodies, or by the introduction of non-immune based organic agents, such as for example, carbohydrates, lipids and the like, which are similarly designed to target the Replikin specifically. For organisms such as diatom plankton, foot and mouth 2 5 disease virus, tomato leaf curl gemini virus, hepatitis B and C, HIV, influenza virus and malignant cells, identified constituent Replikins are useful as vaccines, and also may be usefully targeted for diagnostic purposes. Blood collected for transfusions, for example, may be screened for contamination of organisms, such as HIV, by screening for the presence of Replikins shown to be specific for the contamination 3 0 organism. Also, screening for Replikin structures specific for a particular 51 WO 02/085093 PCT/US02/09240 pathological organism, e.g., anthrax., leads to diagnostic detection of the organism in body tissue or in the environment.

[088] The Replikin sequence structure is associated with the function of replication. Thus, whether the Replikins of this invention are used for targeting 5 sequences that contain Replikins for the purpose of diagnostic identification, promoting replication, or inhibiting or attacking replication, for example, the structure-function relationship of the Replikin is fundamental. Thus, while the structure of the Replikin may be a part of a larger protein sequence, which may have been previously identified, it is preferable to utilize only the specific Replikin 10 structure when seeking to induce antibodies that will recognize and attach to the Replikin fragment and the^’y cause destruction of the cell. Even though the larger protein sequence may be known in the art as having a "replication associated function," vaccines using the larger protein often have failed or proven ineffective, even though they contain one or more Replikin sequences. 15 [089] Although the present inventors do not wish to be held to a single theory, the studies herein suggest that the prior art vaccines are ineffective because they are based on the use of the larger protein sequence. The larger protein sequence invariably has one or more epitopes (independent antigenic sequences that can induce specific antibody formation); Replikin structures usually comprise one of 2 0 these potential epitopes. The presence of other epitopes within the larger protein may interfere with adequate formation of antibodies to the Replikin, by "flooding" the immune system with irrelevant antigenic stimuli which may preempt the Replikin antigens, See, e.g., Webster, R.G., J. Immunol., 97(2):177-183 (1966); and Webster et al., J. Infect. Dis., 134:48-58,1976; Klenennan et al, Nature 394:421-422 2 5 (1998) for a discussion of the well-known phenomenon "original antigenic sin").

The formation of an antibody to a non-Replikin epitope may allow binding to the cell, but not necessarily lead to cell destruction. The presence of structural "decoys" on the C-termini of malaria proteins is another aspect of this ability of other epitopes to interfere with binding of effective anti-Replikin antibodies, since the decoy 3 0 epitopes have many lysine residues, but no histidine residues. Thus, decoy epitopes 52 WO 02/085093 PCT/US02/09240 may bind anti-Replikin antibodies, but keep the antibodies away from histidine -hound respiratory enzymes.

[090] It is well known in the art that in the course of antibody production against a "foreign" protein, the protein is first hydrolyzed into smaller fragments. 5 Usually fragments containing from about six to ten amino acids are selected for antibody formation. Thus, if hydrolysis of a protein does not result in Replikin-containing fragments, anti-Replikin antibodies will not be produced. In this regard, it is interesting that Replikins contain lysine residues located six to ten amino acids apart, since lysine residues are known to bind to membranes. 10 [091] Furthermore, Replikin sequences contain at least one histidine residue.

Histidine is frequently involved in binding to redox centers. Thus, an antibody that specifically recognizes a Replikin sequence has a better chance of inactivating or destroying the cell in which the Replikin is located, as seen with anti-malignin antibody, which is perhaps the most cytotoxic antibody yet described, being active at 15 picograms per cell.

[092] One of the reasons that vaccines directed towards a particular protein antigen of a disease causing agent have not been fully effective in providing protection against the disease (such as foot and mouth vaccine which has been developed against the VP 1 protein or large segments of the VP1 protein) is that 2 0 antibody to the Replikins have not been produced. That is, either epitopes other than

Replikins present in the larger protein fragments may interfere according to the phenomenon of "original antigenic sin", and/or because the hydrolysis of larger protein sequences into smaller sequences for processing to produce antibodies results in loss of integrity of any Replikin structure that is present, e.g., the Replikin 25 is cut in two and/or the histidine residue is lost in the hydrolytic processing. The present studies suggest that for an effective vaccine to he produced, the Replikin sequences, and no other epitope, should be used as the vaccine. For example, a vaccine of the invention can be generated using any one of the Replikin peptides identified by the three point recognition system. Particularly preferred peptides for 3 0 an influenza vaccine include peptides that have been demonstrated to be conserved over a period of one or more years, preferably about three years or more, and/or 53 WO 02/085093 PCT/US02/09240 which are present in a strain of influenza virus shown to have the highest increase in concentration of Replikins relative to Replikin concentration in other influenza virus strains, e.g., an emerging strain. The increase in Replikin concentration preferably occurs over a period of at least about six months to one year, preferably at least 5 about two years or more, and most preferably about three years or more. Among the preferred Replikin peptides for use in an influenza virus vaccine are those replikins observed to "re-emerge" after an absence from the hemagglutinin amino acid sequence for one or more years.

[093] The Replikin peptides of the invention, alone or in various combinations 10 are administered to a subject, preferably by i.v. or intramuscular injection, in order to stimulate the immune system of the subject to produce antibodies to the peptide. Generally the dosage of peptides is in the range of from about 0.1 pg to about 10 mg, preferably about 10 pg to about 1 mg, and most preferably about 50 pg to about 500 ug. The skilled practitioner can readily determine the dosage and number of 15 dosages needed to produce an effective immune response.

[094] Replikin DNA or RNA may have a number of uses for the diagnosis of diseases resulting from infection with a virus, bacterium or other Replikin encoding agent. For example, Replikin nucleotide sequences may he used in hybridization assays of biopsied tissue or blood, e.g., Southern or Northern analysis, including in 2 0 situ hybridization assays, to diagnose the presence of a particular organism in a tissue sample or an environmental sample, for example. The present invention also contemplates kits containing antibodies specific for particular Replikins that are present in a particular pathogen of interest, or containing nucleic acid molecules (sense or antisense) that hybridize specifically to a particular Replikin, and 2 5 optionally, various buffers and/or reagents needed for diagnosis.

[095] Also within the scope of the invention are oligoribonucleotide sequences, that include antisense RNA and DNA molecules and ribozymes that function to inhibit the translation of Replikin- or recognin-containing mRNA. Both antisense RNA and DNA molecules and ribozymes may be prepared by any method known in 30 the art. The antisense molecules can be incorporated into a wide variety of vectors for delivery to a subject. The skilled practitioner can readily determine the best 54 WO 02/085093 PCT/US02/09240 route of delivery, although generally i.v. or i.m. delivery is routine. The dosage amount is also readily ascertainable.

[096] Particularly preferred antisense nucleic acid molecules are those that are complementary to a Replikin sequence contained in a mRNA encoding an influenza 5 virus polypeptide, wherein the Replikin sequence comprises from 7 to about 50 amino acids including (1) at least one lysine residue located six to ten residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues. More preferred are antisense nucleic acid molecules that are complementary to a Replikin present in the coding strand of the gene or to the 10 mRNA encoding the influenza virus hemagglutinin protein, wherein the antisense nucleic acid molecule is complementary to a nucleotide sequence encoding a Replikin that has been demonstrated to be conserved over a period of six months to one or more years and/or which are present in a strain of influenza virus shown to have an increase in concentration of Replikins relative to Replikin concentration in 15 other influenza virus strains. The increase in Replikin concentration preferably occurs over a period of at least six months, preferably about one year, most preferably about two or three years or more.

Similarly, antisense nucleic acid molecules that are complementary to mRNA those that are complementary to a mRNA encoding a Bacillus anthracis polypeptide 2 0 comprising a replikin sequence comprising from 7 to about 50 amino acids including (1) at least one lysine residue located six to ten residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues. More preferred are antisense nucleic acid molecules that are complementary to the coding strand of the gene or to the mRNA encoding the Bacillus anthracis Anthrax Lethal 2 5 Factor Protein pXO 1-107 peptide, wherein the antisense nucleic acid molecule is complementary to a nucleotide sequence encoding the peptide of SEQ ID NO. 91, SEQ ID NO. 92, SEQ ID NO. 93, SEQ ID NO. 94, SEQ ID NO. 95, SEQ ID NO. 96, SEQ ID NO. 97, or SEQ ID NO. 98.

[049] Another preferred set of antisense nucleic acid molecules includes those 3 0 that are complementary to a mRNA encoding a Small Pox Virus polypeptide comprising a replikin sequence comprising from 7 to about 50 amino acids including 55 WO 02/085093 PCT/US02/09240

(1) at least one lysine residue located six to ten residues from a second lysine residue; (2) at least one histidine residue; and (3) at least 6% lysine residues. More preferred are antisense nucleic acid molecules that are complementary to the coding strand of the gene or to the mRNA encoding the Small Pox Virus Surface Antigen S 5 Precursor Protein, wherein the antisense nucleic acid molecule is complementary to a nucleotide sequence encoding the peptide of SEQ ID NO. 99, SEQ ID NO. 100, SEQ ID NO. 101, SEQ ID NO. 102, or SEQ ID NO. 103.

[097] In another embodiment of the invention, immune serum containing antibodies to one or more Replikins obtained from an individual exposed to one or 10 more Replikins may be used to induce passive immunity in another individual or animal· Immune serum may be administered via i.v. to a subject in need of treatment. Passive immunity also can be achieved by injecting a recipient with preformed antibodies to one or more Replikins. Passive immunization may be used to provide immediate protection to individuals who have been exposed to an 15 infectious organism. Administration of immune serum or preformed antibodies is routine and the skilled practitioner can readily ascertain the amount of serum or antibodies needed to achieve the desired effect.

[098] In another aspect of the invention, Replikin structures are used to increase the rephcation of organisms. The present invention demonstrates that in 2 0 influenza virus, for example, increased replication associated with epidemics is associated with increased concentration of Replikins. The increase is due to 1) the reappearance of particular replikin structures, which were present in previous years, but which then disappeared for one or more years; and/or 2) by the appearance of new replikin compositions. In addition, in malaria Replikins, repetition of the same 2 5 Replikin in a single protein occurs.

Thus, the present invention provides methods and compositions for increasing the replication of organisms. For example, the production of crops which are critical to feeding large populations throughout the world, such as rice, for example, can be improved by increasing the concentration (number of 3 0 Replikins/100 amino acid residues) of any particular strain of the food crop. 56 WO 02/085093 PCT/US02/09240 [099] As an example, in the Oryza sativa strain of rice, catalase isolated from immature seeds was observed to contain three different Replikins within the 491 amino acid sequence of the protein. Thus, by using recombinant gene cloning techniques well known in the art, the concentration of Replikin structures in an 5 organism, such as a food crop plant, can be increased, which will promote increased replication of the organism.

[100] The present invention also provides methods for identifying Replikin sequences in an amino acid or nucleic acid sequence. Visual scanning of over four thousand sequences was performed in developing the present 3-point-recognition 10 methods. However, data banks comprising nucleotide and/or amino acid sequences can also be scanned by computer for the presence of sequences meeting the 3 point recognition requirements.

[101] The three point recognition method may also be modified to identify other useful compounds of covalently linked organic molecules, including other 15 covalently linked amino acids, nucleotides, carbohydrates, lipids or combinations thereof. In this embodiment of the invention a sequence is screened for subsequences containing three or more desired structural characteristics. In the case of screening compounds composed of covalently linked amino acids, lipids or carbohydrates the subsequence of 7 to about 50 covalently linked units should 2 0 contain (1) at least one first amino acid, carbohydrate or lipid residue located seven to ten residues from a second of the first amino acid, carbohydrate or lipid residue; (2) encoding at least one second amino acid, lipid or carbohydrate residue; and (3) at least 6% of the first amino acid, carbohydrate or lipid residue. In the case of screening nucleotide sequences, the subsequence of about 21 to about 150 2 5 nucleotides should contain (1) at least one codon encoding a first amino acid located within eighteen to thirty nucleotides from a second codon encoding the first amino acid residue; (2) at least one second amino acid residue; and (3) encodes at least 6% of said first amino acid residue.

[102] According to another embodiment of the invention, the methods 3 0 described herein may be performed by a computer. Figure 6 is a block diagram of a computer available for use with the foregoing embodiments of the present invention. 57 WO 02/085093 PCT/US02/09240

The computer may include a processor, an input/output device and a memory storing executable program instructions representing the 3-point-recognition methods of the foregoing embodiments. The memory may include a static memory, volatile memory and/or a nonvolatile memory. The static memory conventionally may be a 5 read only memory (“ROM”) provided on a magnetic, or an electrical or optical storage medium. The volatile memory conventionally may be a random access memory (“RAM”) and may be integrated as a cache within the processor or provided externally from the processor as a separate integrated circuit. The non-volatile » memory may be an electrical, magnetic or optical storage medium. 10 [103] From a proteomic point of view the construction of a “3-point - recognition” template based on the new glioma peptide sequence led directly to identification of a biology-wide class of proteins having related structures and functions. The operation of the 3-point-recognition method resembles identification hy the use of a “keyword”search; but instead of using the exact spelling of the 15 keyword “kagvaflhkk” (SEQ ID NO.: 1) as in a typical sequence homology search, or in the nucleotide specification of an amino acid, an abstraction of the keyword delimited hy the “3-point-recognition” parameters is used. This delimited abstraction, although derived from a single relatively short amino acid sequence leads to identification of a class of proteins with structures that are defined by the 2 0 same specifications. That particular functions, in this case transformation and replication, in addition to structures, turn out also to be shared by members of the exposed class suggests that these structures and functions are related. Thus, from this newly identified short peptide sequence, a molecular recognition ‘language’ has been formulated, which previously has not been described. Further, the sharing of 2 5 immunological specificity by diverse members of the class, as here demonstrated for the cancer Replikins, suggests that B cells and their product antibodies recognize Replikins by means of a similar recognition language. Since “3-point-recognition” is a proteomic method that specifies a particular class of proteins, using three or more different recognition points for other peptides similarly should provide useful 3 0 information concerning other proteins classes. Further, the “3-point- recognition” 58 WO 02/085093 PCT/US02/09240 method is applicable to other recognins, for example to the TOLL ‘innate’ recognition of lipopolyssacharides of organisms.

[104] Several embodiments of the present invention are specifically illustrated and described herein. However, it will he appreciated that modifications and 5 variations of the present invention are encompassed by the above teachings and within the purview of the appended claims without departing from the spirit and intended scope of the invention. EXAMPLE 1

10 PROCESS FOR EXTRACTION, ISOLATION AND IDENTIFICATION OF REPLIKINS AND THE USE OF REPLIKINS TO TARGET, LABEL OR

DESTROY REPLIKIN-CONTAINING ORGANISMS a) Algae [105] The following algae were collected from Bermuda water sites and either 15 extracted on the same day or frozen at -20 degrees C and extracted the next day. The algae were homogenized in a cold room (at 0 to 5 degrees C) in 1 gram aliquots in neutral buffer, for example 100 cc. of 0.005M phosphate buffer solution, pH 7 (“phosphate buffer”) for 15 minutes in a Waring blender, centrifuged at 3000 rpm, and the supernatant concentrated by perevaporation and dialyzed against phosphate 2 0 buffer in the cold to produce a volume of approximately 15 ml. The volume of this extract solution was noted and an aliquot taken for protein analysis, and the remainder was fractionated to obtain the protein fraction having a pK range between 1 and 4. The preferred method of fractionation is chromatography as follows: [106] The extract solution is fractionated in the cold room (4 degrees C) on a 25 DEAE cellulose (Cellex-D) column 2.5x11.0 cm, which has been equilibrated with 0.005M phosphate buffer. Stepwise eluting solvent changes are made with the following solutions:

Solution 1- 4.04 g. NaH2P04 and 0.5g NaH2P04 are dissolved in 15 litres of distilled water (0.005 molar, pH 7); 3 0 Solution 2-8.57 g. NaH2P04 is dissolved in 2,480 ml. of distilled water;

Solution 3 - 17.1 g. of NaH2P04 is dissolved in 2480 ml of distilled water (0.05 molar, pH 4.7); 59 WO 02/085093 PCT/US02/09240

Solution 4 - 59.65 g. of NaH2P04 is dissolved in 2470 ml distilled water (0.175 molar);

Solution 5 -101.6 g. of NaH2P04 is dissolved in 2455 ml distilled water (pH 4.3); 5 Solution 6 - 340.2 g. of NaH2P04 is dissolved in 2465 of distilled water (1.0 molar, pX-i 4.1);

Solution 7 - 283.63 g. of 80% phosphoric acid (H3P04) is made up in 2460 ml of distilled water (1.0 molar, pH 1.0).

[107] The extract solution, in 6 to 10 ml volume, is passed onto the column and 10 overlayed with Solution 1, and a reservoir of 300 ml of Solution 1 is attached and allowed to drip by gravity onto the column. Three ml aliquots of eluant are collected and analyzed for protein content at OD 280 until all of the protein to be removed with Solution 1 has been removed from the column. Solution 2 is then applied to the column, followed in succession by Solutions 3, 4, 5, 6 aid 7 until all of the protein 15 which can, be removed with each Solution is removed from the column. The eluates from Solution 7 are combined, dialyzed against phosphate buffer, the protein content determined of both dialysand and dialyzate, and both analyzed by gel electrophoresis. One or two bands of peptide or protein of molecular weight between 3,000 and 25,000 Daltons are obtained in Solution 7. For example the algae Caulerpa 2 0 mexicana, Laurencia obtura, Cladophexa prolifera, Sargassum natans, Caulerpa verticillata, Halimeda tuna, and Penicillos capitatus, after extraction and treatment as above, all demonstrated in Solution 7 eluates sharp peptide bands in this molecular weight region with no contaminants. These Solution 7 proteins or their eluted bands are hydrolyzed, and the amino acid composition determined. The peptides so 2 5 obtained, which have a lysine composition of 6% or greater are Replikin precursors. These Replikin peptide precursors are then determined for amino acid sequence and the replikins are determined by hydrolysis and mass spectrometry as detailed in U.S. patent 6,242,578 BI. Those which fulfill the criteria defined by the “ 3-point-recognition” method are identified as Replikins. This procedure can also be applied 30 to obtain yeast, bacterial and any plant Replikins. 60 WO 02/085093 PCT/US02/09240 b) Virus [108] Using the same extraction and column chromatography separation methods as above in a) for algae, Replikens in virus-infected cells are isolated and identified. 5 c) Tumor cells in vivo and in vitro tissue culture [109] Using the same extraction and column chromatography separation methods as above in a) for algae, Replikins in tumor cells are isolated and identified. For example, Replikin precursors of Astrocytin isolated from malignant brain tumors, 10 Malignin (Aglyco 1OB) isolated from glioblastoma tumor cells in tissue cuOlture, MCF7 mammary carcinoma cells in tissue culture, and P3 J Lymphoma cells in tissue culture each treated as above in a) yielded Replikin precursors with lysine content of 9.1%, 6.7%, 6.7%, and 6.5% respectively. Hydrolysis and mass spectrometry of Aglyco 1OB as described in Example 10 U.S. 6,242,578 Bl produced the amino acid 15 sequence, ykagvaflhkkndiide the 16-mer Replikin. EXAMPLE 2: [110] As an example of diagnostic use of Replikins: Aglyco 1OB or the 16-mer Repliken may be used as antigen to capture and quantify the amount of its 2 0 corresponding antibody present in serum for diagnostic purposes are as shown in

Figures 2,3,4 and 7 of U.S. 6,242,578 Bl.

[111] As an example of the production of agents to attach to Replikins for labeling, nutritional or destructive purposes: Injection of the 16-mer Replikin into rabbits to produce the specific antibody to the 16-mer Replikin is shown in Example 25 6 and Figures 9A and 9B of U.S. 6,242,578 Bl.

[112] As an example of the use of agents to label Replikins: The use of antibodies to the 16-mer Replikin to label specific cells which contain this Replikin is shown in Figure 5 and Example 6 of U.S. 6,242,578 Bl.

[Π3] As an example of the use of agents to destroy Replikins: The use of 3 0 antibodies to the 16-mer Replikin to inhibit or destroy specific cells which contain this Replikin is shown in Figure 6 of U.S. 6,242,578 Bl. 61 WO 02/085093 PCT/US02/09240 EXAMPLE 3 [114] Analysis of sequence data of isolates of influenza virus hemagglutinin protein or neuraminidase protein for the presence and concentration of Replikins is 5 carried out by visual scanning of sequences or through use of a computer program based on the 3-point recognition system described herein. Isolates of influenza virus are obtained and the amino acid sequence of the influenza hemagglutinin and/or neuraminidase protein is obtained by any art known method, such as by sequencing the hemagglutinin or neuraminidase gene and deriving the protein sequence 10 therefrom. Sequences are scanned for the presence of new Replikins, conservation of Replikins over time and concentration of Replikins in each isolate. Comparison of the Replikin sequences and concentrations to the amino acid sequences obtained from isolates at an earlier time, such as about six months to about three years earlier, provides data that are used to predict the emergence of strains that are most likely to 15 be the cause of influenza in upcoming flu seasons, and that form the basis for seasonal influenza peptide vaccines or nucleic acid based vaccines. Observation of an increase in concentration, particularly a stepwise increase in concentration of Replikins in a given strain of influenza virus for a period of about six months to about three years or more is a predictor of emergence of the strain as a likely cause 20 of influenza epidemic or pandemic in the fiiture.

[115] Peptide vaccines or nucleic acid-based vaccines based on the Replikins observed in the emerging strain are generated. An emerging strain is identified as the strain of influenza virus having the highest increase in concentration of replikin sequences within the hemagglutinin and/or neuraminidase sequence during the time 2 5 period. Preferably, the peptide or nucleic acid vaccine is based on or includes any

Replikin sequences that are observed to be conserved in the emerging strain. Conserved replikins are preferably those Replikin sequences which are present in the hemagglutinin or neuraminidase protein sequence for about two years and preferably longer. The vaccines may include any combination of Replikin sequences 3 0 identified in the emerging strain., 62 WO 02/085093 PCT/US02/09240 [116] For vaccine production, the Replikin peptide or peptides identified as useful for an effective vaccine are synthesized by any method, including chemical synthesis and molecular biology techniques, including cloning, expression in a host cell and purification therefrom. The peptides are preferably admixed with a 5 pharmaceutically acceptable carrier in an amount determined to induce a therapeutic antibody reaction thereto. Generally, the dosage is about 0.1 pg to about 10 mg.

[Π7] The influenza vaccine is preferably administered to a patient in need thereof prior to the onset of "flu season." Influenza flu season generally occurs in late October and lasts through late April. However, the vaccine maybe administered 10 at any time during the year. Preferably, the influenza vaccine is administered once yearly, and is based on Replikin sequences observed to be present, and preferably conserved in the emerging strain of influenza virus. Another preferred Replikin for inclusion in an influenza vaccine is a Replikin demonstrated to have re-emerged in a strain of influenza after an absence of one or more years. 15 EXAMPLE 4 [118] Analysis of sequence data of isolates of Plasmodium falciparum antigens for the presence and concentration of Replikins is carried out by visual scanning of 2 0 sequences or through use of a computer program based on the 3-point recognition system described herein. Isolates of Plasmodium falciparum are obtained and the amino acid sequence of the protein is obtained by any art known method, such as by sequencing the gene and deriving the protein sequence therefrom. Sequences are scanned for the presence of Replikins, conservation of Replikins over time and 2 5 concentration of Replikins in each isolate. This information provides data that are used to form the basis for anti-malarial peptide vaccines or nucleic acid based vaccines.

[119] Peptide vaccines or nucleic acid-based vaccines based on the Replikins observed in the malaria causing organism are generated. Preferably, the peptide or 3 0 nucleic acid vaccine is based on or includes any Replikin sequences that are observed to he present on a surface antigen of the organism. The vaccines may 63 WO 02/085093 PCT/US02/09240 include any combination of Replikin sequences identified in the malaria causing · strain.

[120] For vaccine production, the Replikin peptide or peptides identified as useful for an effective vaccine are synthesized by any method, including chemical 5 synthesis and molecular biology techniques, including cloning, expression in a host cell and purification therefrom. The peptides are preferably admixed with a pharmaceutically acceptable carrier in an amount determined to induce a therapeutic antibody reaction thereto. Generally, the dosage is about 0.1 pg to about 10 mg.

[121] Then malaria vaccine is preferably administered to a patient in need 10 thereof at any time during the year, and particularly prior to travel to a tropical environment. 64

SEQUENCE LISTING

<110> BOGOCH, SAMUEL BOGOCH, ELENORE S.

<120> REPLIKIN PEPTIDES AND METHODS OE USE <130> 09425-46976 <140> <141> <150> 50/303,39S <151> 2001-07-09 <150> 50/278,751 <151> 2001-03-27 <150> 09/145,755 <151> 1998-09-04 <150> 09/817,144 <151> 2001-03-27 <150> 08/198,139 <151> 1994-02-17 <160> 535 <170> Patentln 2.1 <210> 1 <211> 10

<212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic glioma replikin <400> 1

Lys Ala Gly Val Ala Phe Leu His 1 5

Lys Lys 10 <210> 2 <211> 13

<212> PRT <213 > Saccharomyces cerevisiae <400> 2

His Ser Ile Lys Arg Glu Leu Gly Ile Ile Phe Asp Lys 1 5 10 <210> 3 <211> 10 65

<212 > PRT <213> Gemini· vinis virus <400> 3

His Lys Gin Lys Ile Val Ala Pro Val Lys 15 10 <210> 4 <211> 16

<212> PRT <213> Unknown Organism <220> <223> Description of Unknown Organism: Virus recognin <400> 4

Tyr Lys Ala Gly Val Ala Phe Leu His Lys Lys Asn Asp Ile Asp Glu 15 10 15 <210> 5 <211> 10

<212> PRT <213> Human immunodeficiency virus type 1 <400> 5

Lys Cys Phe Asn Cys Gly Lys Glu Gly His 15 10 <210> 6 <211> 11

<212> PRT <213> Human immunodeficiency virus type 1 <400> 6

Lys Val Tyr Leu Ala Trp Val Pro Ala His Lys 1 5 . 10 <210> 7 <211> 10

<212> PRT <213> Human immunodeficiency virus type 2 <400> 7

Lys Cys Trp Asn Cys Gly Lys Glu Gly His 15 10 <210> 8 <211> 11

<212> PRT <213> Maize streak virus 66 <400> 8

Lys Tyr lie Val Cys Ala Arg Glu Ala His Lys 15 10 <210> 9 <211> 17

<212> PRT <213> Maize streak virus <400> 9

Lys Glu Lys Lys Pro Ser Lys Asp Glu He Met Arg Asp lie lie Ser 15 10 15

His <210:> 10 <211> 9

<212 > PRT <213 > Staphylococcus aureus <400> 10

Lys Lys Glu Lys Thr Thr His Asn Lys 1 5 <210> 11 <211> 10

<212> PRT <213 > Bovine herpesvirus 4 <400> 11

His Lys He Asn He Thr Asn Gly Gin Lys 15 10 <210> 12 <211> 10

<212> PRT <213> Meleagrid herpesvirus 1 <400> 12

His Lys Asp Leu Tyr Arg Leu Leu Met Lys 15 10 <210> 13 <211> 15

<212> PRT <213 > Unknown Organsim <220> <223> Description of Unknown Organism: Virus recognin <400> 13

Lys Phe Arg He Asn Ala Lys Asn Tyr Phe Leu Thr Tyr Pro His 15 10 15 67 <210> 14 <211> 19

<212> PRT <213 > Unknown Organism <220> <223 > Description of Unknown Organism: virus recognin <400> 14

Lys Asn Leu Glu Thr Pro Val Asn Lys Leu Phe lie Arg He Cys Arg 15 10 15

Glu Phe His <210> 15 <211> 14

<212> PRT <213> Unknown Organism <220> <223> Description of Unknown Organism: Virus recognin <400> 15

His Pro Asn lie Gin Ala Ala Lys Ser Ser Thr Asp Val Lys 15 10 <210> 16 <211> 19

<212> PRT <213> Unknown Organism <220> <223> Description of Unknown Organism: Virus recognin <400> 16

Lys Ser Ser Thr Asp Val Lys Ala Tyr Met Asp Lys Asp Gly Asp Val 15 10 15

Leu Asp His <210> 17 <211> 21

<212> PRT <213> Unknown Organism <22D> <223> Description of Unknown Organism: Virus recognin <400> 17

Lys Ala Ser Ala Leu Asn He Leu Arg Glu Lys Ala Pro Lys Asp Phe 1 5 10' 15 68

Val Leu Gin Phe His 20 <210> 18 <211> 13

<212> PRT <213 > Hepatitis C virus <400> 18

His Tyr Pro Pro Lys Pro Gly Cys lie Val Pro Ala Lys 15 10 <210> 19 <211> 4

<212> PRT <213> Homo sapiens <400> 19

Tyr Lys Ala Gly 1 <210> 20 <211> 6

<212> PRT <213> Homo sapiens <400> 20

Tyr Lys Ala Gly Val Ala 1 5 <210> 21 <211> 7

<212> PRT <213> Homo sapiens <400> 21

Tyr Lys Ala Gly Val Ala Phe 1 5 <210> 22 <211> 7

<212> PRT <213> Homo sapiens <40Q> 22

Tyr Lys Ala Gly Val Ala Phe 1 5 <210> 23 <211> 9

<212> PRT <213> Homo sapiens 69 <400> 23

Ala Gly Val Ala Phe His Lys Lys Asn 1 5 <210> 24 <211> 4

<212 > PRT <213 > Homo sapiens <400> 24

Gly Val Ala Phe 1 <210> 25 <211> 3

<212> PRT <213> Homo sapiens <400> 25

Val Ala Phe 1 <210> 26 <211> 7

<212> PRT <213> Homo sapiens <400> 26

Val Ala Phe Leu His Lys Lys 1 5 <210> 27 <211> 7

<212> PRT <213> Homo sapiens <400> 27

Val Ala Phe Leu His Lys Lys 1 5 <210> 28 <211> 9

<212> PRT <213> Homo sapiens <400> 28

Val Ala Phe Leu His Lys Lys Asn Asp 1 5 <210> 29 <211> 8 70 / \1.£Λ>

<212> PRT <213> Homo sapiens <400> 29

Val Ala Phe His Lys Lys Asn Asp

1 5 <210> 30 <211> 4 <212> PRT <213 > Homo sapiens <400> 30 Ala Phe Leu His 1 <210> 31 <211> 8 <212> PRT <213> Homo sapiens <400> 31 His Lys Lys Asn Asp lie Asp 1 5 <21O> 32 <211> S <212> PRT <213> Homo sapiens <400> 32 Lys Lys Asn Asp lie Asp 1 5 <210> 33 <211> 6 <212> PRT <213> Homo sapiens <400> 33 Lys Asn Asp lie Asp Glu 1 5 <210> 34 <211> 8 <212> PRT <213> Caldophera prolifera <400> 34

Lys Ala Ser Lys Phe Thr Lys His 1 5 71

OXXX.U <210> 35 <211> 12

<212> PRT <213> Isolepis prolifera <400> 35 Lys Ala Gin Ala Glu Thr Gly Glu lie Lys 1 5 10 <210> 36 <211> 10 <212> PRT <213> Schizosaccharomyces pombe <400> 36 Lys Ser Phe Lys Tyr Pro Lys Lys His Lys 1 5 10 <210> 37 <211> 10 <212> PRT <213 > Oryza estiva <400> 37 Lys Lys Ala Tyr Gly Asn Glu Leu His Lys 1 5 10 <210> 38 <211> 9 <212> PRT <213> Penicillium mameffei <400> 38

Lys Val Asp Ile Val Thr His Gin Lys Ϊ 5 <210> 39 <211> 12

<212> PRT <213> Diseula dcstructiva c400> 39

Lys Leu Glu Glu Asp Ala Ala Tyr His Arg Lys Lys 15 10 <210> 40 <211> 17

<212> PRT <213> Ophiostoma novo-ulmi <400> 40

Lys Val Ile Leu Pro Leu Arg Gly Asn Ile Lys Gly Ile Phe Phe Ly 1 5 10 15 72

His <210> 41 <211> 11

<2125 PRT <213> Entamoeba invadens <4005 41

Lys Leu Ile Leu Lys Gly Asp Leu Asn Lys His 15 10 <2105 42 <211> 8

<212> PRT <213> Helicobacter pylori <400> 42

Lys Ser Val His Ala Phe Leu Lys 1 5 <2105. 43 <2115 9

<2125 PRT <2135. Mycoplasma pulmonis <400> 43

Lys Val His Phe Phe Gin Leu Lys Lys 1 5 <2105 44 <2115 9

<2125 PRT <2135 Arabidopsis thaliana <4005 44

Lys Asp His Asp Phe Asp Gly Asp Lys 1 5 <2105 45 <2115 11

<2125 PRT <2135 Arabidopsis thaliana <4005 45

Lys Met Lys Gly Leu Lys Gin Lys Lys Ala His 15 10 <2105 46 <2115 12

<2125 PRT <2135 Arabidopsis thaliana 73 ιυ\ιζ-υ <400> 46

Lys Glu Leu Ser Ser Thr Thr Gin Glu 1 5 <210> 47 <211> 9 <212> PRT <213> Feline : immunodeficiency virus <400> 47 His Leu Lys Asp Tyr Lys Leu Val Lys 1 5 <210> 48 <211> 7 <212> PRT <213 > Rous sarcoma virus <400> 48 Lys Lys Leu Arg His Glu Lys 1 5 <210> 49 <211> 7 <212> PRT <213> Avian sarcoma virus <400> 49 Lys Lys Leu Arg His Asp Lys 1 5 <210> 50 <211> 7 <212> PRT <213> Homo sapiens <400> 50 Lys Lys Leu Arg His Asp Lys 1 5 <210> 51 <211> 7 <212> PRT <213> Avian.. , sarcoma virus <400> 51 Lys Lys Leu Arg His Glu Lys 1 5 <210> 52 <211> 7

Lys Ser His 10 74

<212> PRT <213> Homo sapiens <400> 52 Lys Lys Leu Arg His Glu Lys 1 5 <210> 53 <211> 8 <212> PRT <213> Homo sapiens <400> 53 Lys Gin Ala His Glu Leu Ala Lys 1 5 <210> 54 <211> 8 <212> PRT <213 > Polyama virus <400> 54 Lys Thr His Arg Phe Ser Lys His 1 5 <210> 55 <211> 8 <212> PRT <213> Sindbis virus <400> 55 Lys Asn Leu His Glu Lys He Lys 1 5 <210> 56 <211> 9 <212> PRT <213> Human papilloamavirus type 71 <400> 56 Lys His Arg Pro Leu Leu Gin Leu Lys 1 5 <210> 57 <211> 7 <212> PRT <213> Avian encephalomyelitis virus <400> 57 Lys Ser Pro Asn His Val Lys 1 5 75 <210> 58 <211> 8

<212> PRT <213> Feline sarcoma virus <400> 58

Lys Asn He His Leu Glu Lys Lys 1 5 <210> 59 <211> 8

<212> PRT <213> Homo sapiens <400> 59

Lys Asn lie His Leu Glu Lys Lys 1 5 <210> 50 <211> 10

<212> PRT <213> Polyoma virus <400> 50

Lys Pro His Leu Ala Gin Ser Leu Glu Lys 15 10 <210> 61 <211> 9

<212> PRT <213> Polyoma virus <400> 61

Lys Gin His Arg'Glu Leu Lys Asp Lys 1 5 <210> 62 <211> 9

<212> PRT <213> Polyoma virus <400> 62

Lys Gin His Arg Glu Leu Lys Asp Lys 1 5 <210> 63 <211> 12

<212> PRT <213> Murine leukemia virus <400> 63

Lys Val Pro Val Leu He Ser Pro Thr Leu Lys His 15 10 76 <210> 54 <211> 13

<212> PRT <213> Human T-cell lymphotropic virus type 2 <400> 54

Lys Ser Leu Leu Leu Glu Val Asp Lys Asp lie Ser His 15 10 <210> 55 <211> 13

<212> PRT <213> Homo sapiens <400> 65

Lys Ala Gly He Thr He Met Val Lys Arg Glu Tyr His 15 10 <210> 66 <211> 8

<212> PRT <213> Homo sapiens <400> 56

Lys Ser Gly Lys His Leu Gly Lys 1 5 <210> 67 <211> 9

<212> PRT <213> Homo sapiens <400> 67

Lys Arg Arg Glu Gin Leu Lys His Lys 1 5 <210> 68 <211> 10

<212> PRT <213> Homo sapiens <400> 68

Lys Ser Phe Glu Val 1 5

He Lys Val lie

His 10 <210> 69 <211> 8

<212> PRT <213> Homo sapiens 77 <400> 69

Lys Lys Lys His Thr Val Lys Lys 1 5 <210> 70 <211> 9

<212> PRT <213> Homo sapiens <400> 70

Lys Ala Gin Lys Asp His Leu Ser Lys 1 5 <210> 71 <211> 10

<212> PRT <213> Homo sapiens <400> 71

His Leu Lys Arg Val Lys Asp Leu Lys Lys 15 10 <210> 72 <211> 11

<212> PRT <213> Homo sapiens <400> 72

Lys Tyr Gly Ser Pro Lys His Arg Leu Ile Lys 15 10 <210> 73 <211> 13

<212> PRT <213> Papilloma virus type 11 <400> 73

Lys Leu Lys His Ile Leu Gly Lys Ala Arg Phe Ile Lys 15 10 <210> 74 <211> 12

<212> PRT <213> Homo sapiens <400> 74

Lys Gly Asp His Val Lys His Tyr Lys Ile Arg Lys 15 10

<210> 75 <211> 13 <212> PRT 78 <213 > Homo sapiens <400> 75

Lys Glu Lys Leu Arg Asp Val Met Val Asp Arg His Lys 15 10 <210> 76 <211> 15

<212> PRT <213> Homo sapiens <400> 76

Lys Leu Gin Ala Arg Gin Gin Gin Leu Leu Lys Lys Ile Glu His 15 10 15 <210> 77 <211> 14

<212> PRT <213> Homo sapiens <400> 77

Lys Lys Gly Asn Arg Val Ser Pro Thr Met Lys Val Thr His 15 10 <210> 78 <211> 3

<212> PRT <213> Homo sapiens <400> 78

Lys Glu Ile .Pro Leu His Phe Arg Lys 1 5 <210> 79 <211> 8

<212> PRT <213> Homo sapiens <400> 79

Lys Lys Lys Pro His Ile Lys Lys 1 5 <210> 80 <211:» 9

<212 > PRT <213> Homo sapiens <400> 80

Lys Thr Arg His Asp Pro Leu Ala Lys 1 5 <210> 81 79 <211> 10

<212 > PRT <213> Homo sapiens <400> 81

Lys His His Pro Lys Asp Asn. Leu He Lys 15 10 <210> 82 <211> 10

<212> PRT <213> Homo sapiens <400> 82

Lys His Lys Arg Lys Lys Phe Arg Gin Lys 1 5 10 <210> 83 <211> 10

<212> PRT <213> Homo sapiens <400> 83

Lys Ala Gly Val Ala Phe Leu His Lys Lys 15 10 <210> 84 <211> 10

<212> PRT <213> Homo sapiens <400> 84

Lys His Lys Arg Lys Lys Phe Arg Gin Lys 15 10 <210> 85 <211> 10

<212> PRT <213> Homo sapiens <400> 85

Lys Lys Lys Ser Lys Lys His Lys Asp 1 5

Lys 10 <210> 86 <211> 11

<212> PRT <213> Homo sapiens <400> 86

His Lys Ser Glu Lys Pro Ala Leu Pro Arg Lys 15 10 80 <210> 87 <211> 14

<212> PRT <213> Homo sapiens <400> 87

Lys Lys Lys Lys Pro Ser Arg Leu Lys Gly Asp Asn Glu Lys 15 10 <210> 88

<211> IS

<212> PRT <213> Homo sapiens <400> 88

Lys Thr Lys Lys Gly Asn Arg Val Ser Pro Thr Met Lys Val Thr His 15 10 15 <210> 89 <211> 18

<212> PRT <213 > Homo sapiens <400> 89

Lys His Lys Glu Lys Met Ser Lys Asp Gly Lys Lys Lys Lys Lys Lys 15 10 15

Ser Lys <210> 90 <211> 9

<212> PRT <213> Legionella sp. <400> 90

Lys He His Leu lie Ser Val Lys Lys 1 5 <210> 91 <211> 10

<212> PRT <213> Bacillus anthracis <400> 91

His Val Lys Lys Glu Lys Glu Lys Asn Lys 1 5 10 <210> 92 <211> 9

<212> PRT <213> Bacillus anthracis 81 <400> 92

Lys His He Val Lys lie Glu Val Lys 1 1 5 <210> 93 <211> 16

<212> PRT <213> Bacillus anthracis <400> 93

Lys Lys Lys Lys He Lys Asp He Tyr Gly Lys Asp Ala Leu Leu His 15 10 15 <210> 94 <211> 8

<212>. PRT <213> Bacillus anthracis <400> 94

Lys Trp Glu Lys. He Lys Gin His 1 5 <210> 95 <211> 18

<212> PRT <213> Bacillus anthracis <400> 95

Lys Lys Leu Gin lie Pro Pro Pro lie Glu Pro Lys Lys Asp Asp He 1 5 10 15

He His <210> 96 <211> 31

<212> PRT <213> Bacillus anthracis <400> 96

His Asn Arg Tyr Ala Ser Asn He Val Glu Ser Ala Tyr Leu Leu He 15 10 15

Leu Asn Glu Trp Lys Asn Asn He Gin Ser Asp Leu He Lys Lys 20 25 30 <210> 97 <211> 24

<212> PRT <213> Bacillus anthracis <400> 97

His Ala Val Asp Asp Tyr Ala Gly Tyr Leu Leu Asp Lys Asn Gin Ser 15 10 15 82

Asp Leu Val Thr Asn Ser Lys Lys 20 <2105 98 <211> 13

<212> PRT <213> Bacillus anthracis <400> 98

His Ala Glu Arg Leu Lys Val Gin Lys Asn Ala Pro Lys 15 10 <210> 99 <211> 10

<212> PRT <213> Variola virus <4005 99

Lys His Tyr Asn Asn Xie Thr Trp Tyr Lys 15 10 <210> 100 <2115 12

<2125 PRT <213> Variola virus <4005 100

Lys Tyr Ser Gin Thr Gly Lys Glu Leu Ile Ile His 15 10 <2105 101 <2115 17

<212> PRT <213> Variola virus <4005 101

His Tyr Asp Asp· Val Arg Ile Lys Asn Asp lie Val Val Ser Arg Cys 15 10 15

Lys <2105 102 <211> 11

<2125 PRT <2135 Variola virus <4005 102

His Arg Phe Lys Leu Ile Leu Asp Ser Lys Ile 15 10 83 <210> 103 <211> 11

<212> PRT <213> Variola virus <400> 103

Lys Glu Arg Gly His Asn Tyr Tyr Phe Glu Lys 15 10 <210> 104 <211> 8

<212> PRT <213> Influenza B virus <400> 104

Lys Ser His Phe Ala Asn Leu Lys 1 5 <210> 105 <211> 11

<212> PRT <213> Influenza B virus <400> 105

Lys Ser His Phe Ala Asn Leu Lys Gly Thr Lys 15 10 <210> 106 <211> 19

<212> PRT <213> Influenza B virus <400> 106

Lys Ser His Phe Ala Asn Leu Lys Gly Thr Lys Thr Arg Gly Lys Leu 15 10 15

Cys Pro Lys <210> 107 <211> 9

<212> PRT <213> Influenza B virus <400> 107

His Glu Lys Tyr Gly Gly Leu Asn Lys 1 5 <210> 108 <211> 11

<212> PRT <213> Influenza B virus 84 <400> 108

His Glu Lys Tyr Gly Gly Leu Asn Lys Ser Lys 15 10 <210> 109 <211> 20

<212> PRT <213 > Influenza B virue <400> 109

His Glu Lys Tyr Gly Gly Leu Asn Lys Ser Lys Pro Tyr Tyr Thr Gly 15 10 15

Glu His Ala Lys 20 <210> 110 <211> 13

<212> PRT <213> Influenza B virus <400> 110

His Ala Lys Ala lie Gly Asn Cys Pro Ile Trp Val Lys 15 10 <210> 111 <211> 23

<212> PRT <213> Influenza B virus <400> 111

His Ala Lys Ala Ile Gly Asn Cys Pro Ile Trp Val Lys Thr Pro Leu 15 10 15

Lys Leu Ala Asn Gly Thr Lys 20 <210> 112 <211> 29

<212> PRT <213 > Influenza B virus <400> 112

His Ala Lys Ala Ile Gly Asn Cys Pro Ile Trp Val Lys Thr Pro Leu 15 10 15

Lys Leu Ala Asn Gly Thr Lys Tyr Arg Pro Pro Ala Lys 20 25 <210> 113 <211> 32

<212 > PRT <213 > Influenza B virus 85

•iiMZAJ <400> 113

His Ala Lys Ala lie Gly Asn Cys Pro He Trp Val Lys Thr Pro Leu. 15 10 15

Lys Leu Ala Asn Gly Thr Lys Tyr Arg Pro Pro Ala Lys Leu Leu Lys 20 25 30 <210> 114 <211> 13

<212> PRT <213> Influenza B virus <400> 114

His Phe Ala Asn Leu Lys Gly Thr Lys Thr Arg Gly Lys 15 10 <210> 115 <211> 17

<212> PRT <213> Influenza B virus <400> 115

His Phe Ala Asn Leu Lys Gly Thr Lys Thr Arg Gly Lys Leu Cys Pro 15 10 15

Lys <210> 116 <211> 16

<212> PRT <213> Influenza B virus <400> 116

His Ser Asp Asn Glu lie Gin Met Val Lys Leu Tyr Gly Asp Ser Lys 15 10 15 <210> 117 <211> 21 <212> PRT <213> Influenza B virus <400> 117 His Ser Asp Asn Glu He Gin Asp Lys Met Val Lys Leu Tyr Gly Asp 1 5 10 15 Ser Lys Pro Gin Lys 20 <210> 118 <211> 19

<212> PRT <213> Influenza B virus 86 <400> 118

His Ser Asp Asn Glu lie Gin Met Val Lys Leu Tyr Gly Asp Ser Lys 15 10 15

Pro Gin Lys

<210> 119 <211> 9 <212> PRT <213> Influenza B virus <220> <221> MOD RES <222> (2) <223s> ala or val <400> 119 Lys Xaa Ser He Leu His 1 5 <210> 120 <211> 15 <212> PRT <213 :> Influenza B virus <400> 120 Lys Cys Thr Gly Thr He 1 5 <210> 121 <211> 18 <212> PRT <213> Influenza B virus <400> 121 Lys Cys Thr Gly Thr He 1 5 Val Lys <210> 122 <211> 16 <212> PRT <213> Influenza B virus <400> 122 Lys Tyr Gly Gly Leu Asn 1 5 <210> 123 <211> 26 <212> PRT 10 15 10 10 15 15 87 z^tuzo <213> Influenza B virus <400> 123

Lys Val Trp Cys Ala Ser Gly Arg Ser Lys Val Ile Lys Gly Ser Leu 15 10 15

Pro Leu lie Gly Glu Ala Asp Cys Leu His 20 25 <210> 124 <211> 10

<212> PRT <213> Influenza B virus <400> 124

Lys Pro Tyr Tyr Thr Gly Glu His Ala Lys 15 10 <210> 125 <211> 18

<212> PRT <213> Influenza B virus <400> 125

Lys Cys Met Gly Thr Ile Pro Ser Ala Lys Ala Ser Ile Leu His Glu • 1 5 10 15

Val Lys <210> 126 <211> 15

<212> PRT <213> Influenza B virus <400> 126

His Asn Val Ile Asn Ala Glu Lys Ala Pro Gly Gly Pro Tyr Lys 15 10 15 <210> 127 <211> 16

<212> PRT <213 > Influenza B virus <400> 127

His Ser Asp Asn Glu Thr Gin Met Ala Lys Leu Tyr Gly Asp Ser Lys 15 10 15 <210> 128 <211> 18

<212> PRT <213> Influenza B virus 88 <400> 128

His Gly Val Ala Val Ala Ala Asp Leu Lys Ser Thr Gin Glu Ala lie 15 10 15

Asn Lys <210> 129 <211> 29

<212> PRT <213> Influenza B virus <400> 129

His Gly Val Ala Val Ala Ala Asp Leu Lys Ser Thr Gin Glu Ala He 15 10 15

Asn Lys Asp Thr He Ser Thr Gin Glu Ala He Asn Lye 20 25 <210> 130 <211> 21

<212> PRT <213> Influenza B virus <400> 130

Lys Leu Tyr Gly Asp Ser Lys Pio Gin Lys Phe Thr Ser Ser Ala Asn 15 10 15

Gly Val Thr Thr His 20 <210> 131 <211> 19

<212> PRT <213> Influenza B virus <400> 131

His Ser Asp Asn Glu Thr Gin Met Ala Lys Leu Tyr Gly Asp Ser Lys 15 10 15

Pro Gin Lys <210> 132 <211> 13

<212> PRT <213> Influenza B virus <400> 132

His Phe Ala Asn Leu Lys Gly Thr Gin Thr Arg Gly Lys 15 10 <210> 133 <211> 12 89 ζ.υ\ι^υ

<212 > PRT <213> Influenza B virus <400> 133

Lys Pro Arg Ser Ala Leu Lys Cys Lys Gly Phe His 15 10 <210> 134 <211> 22

<212> PRT <213> Influenza B virus <220>

<221> MOD_RES <222> (15) <223> gly or ala <400> 134

Lys Ser Lys Pro Tyr Tyr Thr Gly Glu His Ala Lys Ala lie Xaa Asn 15 10 15

Cys Pro He Trp Val Lys 20 <210> 135

<211> IS

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (3) <223> val or ile <220>

<221> MOD_RES <222> (13) <223> arg or lys <220>

<221> MOD_RES <222> (14) <223> ser or thr <220>

<221> MOD_RES <222> (15) <223 > thr or ala <400> 135

His Pro Xaa Thr He Gly Glu Cys Pro Lys Tyr Val Xaa Xaa Xaa Lys 15 10 15 <210> 136 <211> 21 90 ί I uzo

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (10) <223> glu or gly <220>

<221> MODJRES <222> (13) <223> lys or arg <220>

<221> MOD_RES <222> (14) <223> asn or ser <220>

<221> MOD_RES <222> (17) <223> lys or arg <400> 136

His Asp Ser Asn Val Lys Asn Leu Tyr Xaa Lys Val Xaa Xaa Gin Leu 15 10 15

Xaa Asn Asn Ala Lys 20 <210> 137 <211> 17

<212> PRT <213> Influenza virus <220>

<221> MODJRES <222> (10) <223> glu or gly <220>

<221> MODJRES <222> (13) <223> lys or arg <220>

<221> MODJRES <222> (14) <223> asn or ser <400> 137

His Asp Ser Asn Val Lys Asn Leu Tyr Xaa Lys Val Xaa Xaa Gin Leu 1,5 10 15

Lys 91 ύο\ίύυ <210> 138 <211> 36

<212> PRT <213> Influenza virus <220> <221> MOD_RES <222> (4) .. (5) <223> asn or asp <220> <221> MOD_RES <222> (6) <223> ala, thr or glu <220> <221> MOD_RES <222> (12) <223> arg or lys <220> <221> MOD_RES <222> (31) <223> glu or lys <400> 138

His Lys Cys Xaa Xaa Xaa Cys Met Glu Ser Val Xaa Asn Gly Thr Tyr 1 5 10 15 Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Xaa Ile 20 25 30 Asp Gly Val Lys 35 <210> 139 <211> 26

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (4) .. (5) <223> asn or asp <220>

<221> MODJRES <222> (6) <223> ala, thr or glu <220>

<221> MOD_RES <222> (12) <223> arg or lys 92 <400> 139

His Lys Cys Xaa Xaa Xaa Cys Met Glu Ser Val Xaa Asn Gly Thr Tyr 15 10 15

Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys 20 25 <210> 140 <211> 50

<212> PRT <213> Influenza virus <220> <221> MOD_RES <222> (4) <223> glu or gly <220> <221> MOD_RES <222> (21) <223> asp or asn <400> 140

His 1 Gin Asn Xaa Gin 5 Gly Ser Gly Tyr Ala 10 Ala Asp Gin Lys Ser 15 Thr Gin Asn Ala He 20 Xaa Gly lie Thr Asn 25 Lys Val Asn Ser Val 30 He Glu Lys Met Asn 35 Thr Gin Phe Thr Ala 40 Val Gly Lys Glu Phe 45 Asn Lys Leu

Glu Lys 50 <210> 141 <211> 33

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (4) <223> glu or gly <220>

<221> MOD_RES <222> (21) <223> asp or asn <400> 141

His Gin Asn Xaa Gin Gly Ser Gly Tyr Ala Ala Asp Gin Lys Ser Thr 15 10 15

Gin Asn Ala lie Xaa Gly He Thr Asn Lys Val Asn Ser Val He Glu 20 25 30 93 3U\12b

Lys <210> 142

<211> 2G

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (4) <223> glu or gly <220>

<221> MOD_RES <222> (21) <223> asp or asn <400> 142

His Gin Asn Xaa Gin Gly Ser Gly Tyr Ala Ala Asp Gin Lys Ser Thr 15 10 15

Gin Asn Ala lie Xaa Gly Ile Thr Asn Lys 20 25 <210> 143 <211> 14

<212> PRT <213> Influenza virus <400> 143

Lys Phe Glu Ile Phe Pro Lys Thr Ser Ser Trp Pro Asn His 1 5 10 <210> 144 <211> 27

<212> PRT <213> Influenza virus <220> <221> MOD_RES <222> (3) <223> asn, ser or thr <220> <221> MOD_RES <222> (9) <223> asn or ser <220>

<221> MOD_RES <222> (13) <223> val or thr 94

JHUU <400> 144

Lys Gly Xaa Ser Tyr Pro Lys Leu Xaa Lys Ser Tyr Xaa Asn Asn Lys 15 10 15

Gly Lys Glu Val Leu Val Leu Trp Gly Val His 20 25 <210> 145 <211> 18

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (4) <223> val or thr <400> 145

Lys Ser Tyr Xaa Asn Asn Lys Gly Lys Glu Val Leu Val Leu Trp Gly 15 10 15

Val His <210> 146 <211> 36

<212 > PRT <213> Influenza virus <400> 146

His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr 1 5 10 15 Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys lie 20 25 30

Asp Gly Val Lys 35 <210> 147 <211> 26

<212> PRT <213> Influenza virus <400> 147

His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr 15 10 15

Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys 20 25 <210> 148 <211> 20

<212> PRT <213> Influenza virus 95 <400> 148

His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr 15 10 15

Asp Tyr Pro Lys 20 <210> 149 <211> 12

<212> PRT <213> Influenza virus <400> 149

His Lye Cys Asn Asn Glu Cys Met Glu Ser Val Lys 15 10 <210> 150 <211> 34

<212> PRT <213> Influenza virus <220> <221> MOD_RES <222> (9) <223> lys or arg <220> <221> MOD_RES <222> (IS) <223> glu or gly <400> 150

His 1 Asn Gly Lys Ser 5 Ser Phe Tyr Xaa Asn 10 Leu Leu Trp Leu Thr 15 Xaa Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys 20 25 30

Glu Lys <210> 151 <211> 32

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (9) <223> lys or arg <220>

<221> MOD_RES <222> (16) <223> glu or gly 96 <400> 151

His Asn Gly Lys Ser Ser Phe Tyr Xaa Asn Leu Leu Trp Leu Thr Xaa 15 10 15

Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys 20 25 30 <210> 152 <211> 26

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (9) <223> lys or arg <220>

<221> MOD_RES <222> (16) <223> glu or gly <400> 152

His Asn Gly Lys Ser Ser Phe Tyr Xaa Asn Leu Leu Trp Leu Thr Xaa 15 10 15

Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys 20 25 <210> 153 <211> 17

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (9) <223 > lys or arg <220>

<221> MOD_RES <222> (16) <223> glu or gly <400> 153

His Asn Gly Lys Ser Ser Phe Tyr Xaa Asn Leu Leu Trp Leu Thr Xaa 15 10 15

Lys <210> 154 <211> 40

<212> PRT <213> Influenza virus 97 ^>-τλχχ»ν <400> 154

Lys Ser Ser Phe Tyr Lys Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly 15 10 15

Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu 20 25 30

Val Leu Val Leu Trp Gly Val His 35 40 <210> 155 <211> 35 <212> PRT <213> Influenza virus <400> 155 Lys Asn Leu Leu Trp Leu Thr Glu 1 5 10 15

Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val Leu Trp 20 25 30

Gly Val His 35 <210> 156 <211> 27

<212> PRT <213> Influenza virus <400> 156

Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys 15 10 15

Glu Lys Glu Val Leu Val Leu Trp Gly Val His 20 25 <210> 157 <211> 18 <212> PRT <213> Influenza · <220> <221> MOD RES <222> (4) <223> val or ala <220>

<221> MOD_RES <222> (12) <223> lys or not present <220>

<221> MOD_RES 98 <222> (13) <223> val or not present <400> 157

Lys Ser Tyr Xaa Asn Asn Lys Glu Lys Glu Val Xaa Xaa Leu Trp Gly 15 10 15

Val His <210> 158 <211> 12

<212> PRT <213> Influenza virus <400> 158

Lys Glu Ser Ser Trp Pro Asn His Thr Val Thr Lys 15 10 <210> 159 <211> 44

<212> PRT <213> Influenza virus <220> <221> MOD_RES <222> (4) <223> thr or asn <400> 159

His Glu Thr 1 Xaa Lys Gly 5 Val Thr Ala Ala Cys Pro Tyr Ala Gly Ala 10 15 Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Val Lys Lys Glu Asn Ser 20 25 30 Tyr Pro Lys Leu Ser Lys Ser Tyr Val Asn Asn Lys 35 40 <210> 160 <211> 38

<212> PRT <213> Influenza virus <220> <221> MODJRES <222> (4) <223> thr or asn <400> 160

His Glu Thr Xaa Lys Gly Val Thr Ala Ala Cys Pro Tyr Ala Gly Ala 1 5 10 15 Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Val Lys Lys Glu Asn Ser 20 25 30 99

Tyr Pro Lys Leu Ser Lys 35 <210> 161 <211> 22

<212> PRT <213> Influenza virus <400> 161

Lys Phe Glu lie Phe Pro Lys Thr Ser Ser Trp Pro Asn Glu Val Leu 15 10 15

Val Leu Trp Gly Val His 20 <210> 162 <211> 8

<212> PRT <213> Influenza virus <400> 162

Lys Glu Arg Ser Trp Pro Lys His 1 5 <210> 163 <211> 21

<212> PRT <213> Influenza virus <400> 163

Lys Leu Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val 15 10 15

Leu Trp Gin Val His 20 <210> 164 <211> 15 <212> PRT <213> Influenza virus <400> 164 Lys Asn Asn Lys Glu Lys Glu Val Leu 1 5

Val 10

Leu Trp Gin Val His 15 <210> 165 <211> 34 <212> PRT <213> Influenza virus <220> <221> MOD RES <222> (2)· 100 <223> lys or asn <220> <221> MOD_RES <222> (3) <223> gly or gin <220> <221> MOD_RES <222> (9) <223> arg or lys <220> <221> MOD_RES <222> (20) <223> lys or ser <220> <221> MOD_RES <222> (23) <223> asn or thr <400> 165

His 1 Xaa Xaa Lys Ser 5 Ser Phe Tyr Xaa Asn 10 Leu Leu Trp Leu Thr 15 Glu Lys Asn Gly Xaa Tyr Pro Xaa Leu Ser Lys Ser Tyr Ala Asn Asn Lys 20 25 30

Glu Lys <210> 166 <211> 17

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (2) <223> lys or asn <220>

<221> MOD_RES <222> (3) <223> gly or gin <220>

<221> MOD_RES <222> (9) <223> arg or lys <400> 166

His Xaa Xaa Lys Ser Ser Phe Tyr Xaa Asn Leu Leu Trp Leu Thr Glu 15 10 15

Lys 101 <210> 167 <211> 9

<212> PRT <2135. Influenza virus <4005. 167

His Ala Lys Lys Ser Ser Phe Tyr Lys 1 5 <210> 168 <211> 11

<212> PRT <213> Influenza virus <400> 168

His Asn Gly Lys Leu Cys Arg Leu Lys Gly Lys 15 10 <210> 169 <211> 9

<2125. PRT <213> Influenza virus <220>

<221> MODJRES <2225» (7) <2235. gin or gly <400> 169

His Tyr Lys Leu Asn Asn Xaa Lys Lys 1 5 <2105. 170 <2115. 25

<212> PRT <213> Influenza virus <400> 170

His Asp lie Tyr Arg Asp Glu Ala He Asn Asn Arg Phe Gin lie Gin 1 5 10 15

Gly Val Lys Leu Thr Gin Gly Tyr Lys 20 25 <210> 171 <211> 11

<2125» PRT <2135- Influenza virus <400> 171

Lys Gly Asn Gly Cys Phe Glu lie Phe His Lys 1 S 10 102 <210> 172 <211> 18

<212> PRT <213> Influenza virus <400> 172

Lys Leu Asn Arg Leu lie Glu Lys Thr Asn Asp Lys Tyr His Gin He 15 10 15

Glu Lys <210> 173 <211> 14

<212> PRT <213> Influenza virus <400> 173

Lys Leu Asn Arg Leu He Glu Lys Thr Asn Asp Lys Tyr His 15 10 <210> 174 <211> 13

<212> PRT <213 > Influenza virus <400> 174

Lys Cys His Thr Asp Lys Gly Ser Leu Ser Thr Thr Lys 15 10 <210> 175 <211> 16

<212> PRT <213> Influenza virus <400> 175

Lys He Asn Asn Gly Asp Tyr Ala Lys Leu Tyr lie Trp Gly Val His 15 10 15 <210> 176 <211> 17

<212> PRT <213> Influenza virus <400> 176

His Asn Gly Lys Leu Cys Arg Lys Gly lie Ala Pro Leu Gin Leu Gly 1 5 10 15

Lys

<210> 177 <211> 38 <212> PRT 103 <213> Influenza virus <400> 177

His Glu Thr Asn Arg Gin Val Thr Ala Ala Cys Pro Tyr Ala Gly Ala 15 10 15

Asn Ser Phe Phe Arg Asn Leu lie Trp Leu Val Lys Lys Glu Ser Ser 20 25 30

Tyr Pro Lys Leu Ser Lys 35 <210> 178 <211> 35

<212> PRT <213> Influenza virus <400> 178

His Glu Thr Asn Arg Gin Val Thr Ala Ala Cys Pro Tyr Ala Gly Ala 15 10 15

Asn Ser Phe Phe Arg Asn Leu He Trp Leu Val Lys Lys Glu Ser Ser 20 25 30

Tyr Pro Lys 35 <210> 179 <211> 31

<212> PRT <213> Influenza virus <400> 179

His Pro Pro Thr Ser Thr Asp Gin Gin Ser Leu Tyr Gin Asn Ala Asp 15 10 15

Ala Tyr He Phe Val Gly Ser Ser Lys Tyr Asn Arg Lys Phe Lys 20 25 30 <210> 180 <211> 35

<212> PRT <213 i» Influenza virus <400> 180

His Pro Pro Thr Ser Thr Asp Gin Gin Ser Leu Tyr Gin Asn Ala Asp 15 10 15

Ala Tyr He Phe Val Gly Ser Ser Lys Tyr Asn Arg Lys Phe Lys Pro 20 25 30

Glu lie Ala 35 104 <210> 181 <211> 25

<212> PRT <213 > Influenza virus <400> 181

His Asp Ile Tyr Arg Asp Glu Ala Ile Asn Asn Arg Phe Gin Ile Gin 15 10 15

Gly Val Lys Ile Thr Gin Gly Tyr Lys 20 25 <210> 182 <211> 43 <212> PRT <213> Influenza virus <400> 182 His Gin Asn Glu Gin Gly Ser Gly Tyr 1 5 Gin Asn Ala Ile Asp Gly Ile Thr Asn 20 25 Lys Met Asn Thr Gin Phe Thr Ala Val 35 40 <210> 183 <211> 33 <212> PRT <213 > Influenza virus <400> 183 His Gin Asn Glu Gin Gly Ser Gly Tyr 1 5 Gin Asn Ala Ile Asp Gly Ile Thr Asn 20 25 Lys <210> 184 <211> 50 <212> PRT <213> Influenza virus 10 10 30 30 15 15 <400> 184

His Gin Asn Glu Gin Gly Ser Gly Tyr Ala Ala Asp Gin Lys Ser Thr 15 10 15

Gin Asn Ala He Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu 20 25 30

Lys Met Asn Thr Gin Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu 35 40 45 105

Glu Lys 50 <210> 1B5 <211> 18

<212> PRT <213> Influenza virus <400> 185

His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile Ala Pro Leu Gin Leu 15 10 15

Gly Lys

<210> 18S <211> 12

<212> PRT <213> Influenza virus

<400> 18G

His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys 15 10 <210> 187 <211> 14

<212> PRT <213> Influenza virus <400> 187

Lys Phe Glu lie Phe Pro Lys Ala Ser Ser Trp Pro Asn His 15 10 <210> 188 <211> 21

<212> PRT <213> Influenza virus <400> 188

His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys Val Arg Ser Gin Leu 1 5 10 15

Arg Asn Asn Ala Lys 20 <210> 189 <211> 22

<212> PRT <213> Influenza virus <400> 189

Lys Val Asn Ser Val Ile Lys Lys Met Asn Thr Gin Phe Ala Ala Val 15 10 15 106

Gly Lys Glu Phe Asn His 20 <210> 190 <211> 8

<212> PRT <213> Influenza virus <400> 190

Lys His Asn Gly Lys Leu Cys Lys 1 5 <210> 191 <211> 28

<212> PRT <213> Influenza virus <400> 191

Lys Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr His Asn 15 10 15

Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His 20 25 <210> 192 <211> 27

<212> PRT <213> Influenza virus <400> 192

Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr His Asn Lye 15 10 15

Gly Lys Glu Val Leu Val Leu Trp Gly Val His 20 25 <210> 193 <211> 21 <212> PRT <213> Influenza virus <400> 193 Lys Leu Ser 1 Lys Ser Tyr Thr His 5 Asn Lys Gly Lys Glu Val 10 Leu Val 15 Leu Trp Gly Val 20 His <210> 194 <211> 18

<212> PRT <213> Influenza virus 107 <400> 194

Lys Ser Tyr Thr His Asn Lys Gly Lys Glu Val Leu Val Leu Trp Gly 15 10 15

Val His <210> 195 <211> 10

<212> PRT <213> Influenza virus <400> 195 ·

Lys Gly Val Thr Ala Ser Cys Ser His Lys 15 10

<210> 19S <211> 34

<212> PRT <213> Influenza virus <400> 196

Lys Gly Val Thr Ala Ser Cys Ser His Lys Gly Arg Ser Ser Phe Tyr 15 10 15

Arg Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Leu Tyr Pro Asn Leu 20 25 30

Ser Lys <210> 197 <211> 27

<212> PRT <213> Influenza virus <400> 197

Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Val Asn Asn Lys 15 10 15

Glu Lys Glu Val Leu Val Leu Trp Gly lie His 20 25 <210> 198 <211> 8

<212> PRT <213> Influenza virus <400> 198

Lys Glu Phe Asn His Leu Glu Lys 1 5 <210> 199 <211> 39 108

<212> PRT <213> Influenza virus <400> 199

His Pro Pro Thr Ser Thr Asp Gin Gin Ser Leu Tyr Gin Asn Ala Asp 15 10 15

Ala Tyr Val Phe Val Gly Ser Ser Lys Tyr Asn Lys Lys Phe Lys Pro 20 25 30

Glu lie Ala Thr Arg Pro Lys 35 <210> 200 <211> 31

<212> PRT <213> Influenza virus <400> 200

His Pro Pro Thr Ser Thr Asp Gin Gin Ser Leu Tyr Gin Asn Ala 1 5 10 15 Ala Tyr Val Phe Val Gly Ser Ser Lys Tyr Asn Lys Lys Phe Lys 20 25 30 <210> 201 <211> 31

<212> PRT <213> Influenza virus <400> 201 His Glu Gly 1

Lys Glu Gly

Lys Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Thr 5 10 15 Ser Tyr Pro Lys Leu Lys Asn Ser Tyr Val Asn Lys 20 25 30 <210> 202 <211> 23

<212> PRT <213> Influenza virus <400> 202

His Glu Gly Lys Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Thr Glu 1 5 10 15 '

Lys Glu Gly Ser Tyr Pro Lys 20 <210> 203 <211> 26

<212> PRT <213> Influenza virus 109 <400> 203

His Lys Cys Asp Asn Glu Cys Met Glu Ser Val Arg Asn Gly Thr Tyr 15 10 15

Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys 20 25 <210> 204 <211> 12

<212 > PRT <213> Influenza virus <400> 204

Lys Glu Ser Ser Trp Pro Asn His Thr Val Thr Lys 15 10 <210> 205 <211> 35 <212> PRT <213> Influenza virus <400> 205 Lys Asn Leu Leu Trp Leu Thr 1 5

Ser Lys Ser Tyr Val Asn Asn 20

Gly Val His 35

Glu Lys Asn Gly Leu Tyr Pro Asn Leu 10 15

Lys Glu Lys Glu lie Leu Val Leu Trp 25 30 <210> 206 <211> 27 <212> PRT <213> Influenza virus <220> <221> MOD RES <222> (9) <223> lys or met <220> <221> MOD RES <222> (10) <223> asn or not present <220> <221> MOD RES <222> (15) <223> glu or gly <220> <221> MOD_RES <222> (17) <223> not present or lys 110

"Τ I U.*V <400> 206

Hib Asn Gly Lys Ser Ser Phe Tyr Xaa Xaa Leu Leu Trp Leu Thr Xaa 15 10 15

Xaa Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys 20 25 <210> 207 <211> 17

<212> PRT <213> Influenza virus <400> 207

His Asn Gly Lys Ser Ser Phe Tyr Lys Asn Leu Leu Trp Leu Thr Glu 15 10 15

Lys <210> 208 <211> 55

<212> PRT <213> Influenza virus <400> 208

His 1 Thr Val Thr Lys 5 Gly Val Thr Ala Ser 10 Cys Ser His Asn Gly Lys 15 Ser Ser Phe Tyr 20 Lys Asn Leu Leu Trp 25 Leu Thr Glu Lys Asn 30 Gly Leu Tyr Pro Asn 35 Leu Ser Lys Ser Tyr 40 Val Asn Asn Lys .Glu 45 Lys Glu Val Leu Val Leu Trp Gly Val His 50 55 <210> 209 <211> 38 <212> PRT <213> Influenza i <220> <221> MOD RES <222> (5) <223> lys or gly <220> <221> MOD RES <222> (8) <223> thr or ser <220> <221> MOD_RES <222> (21) 111 *rou*u <223 > lys or met <220>

<221> MOD_RES <222> (22) <223> asn or not present <220>

<221> MOD_RES <222> (28) <223> glu or gly <220>

<221> MOD_RES <222> (30) <223> asn present or not or lys <400> 209

His Thr Val Thr Xaa Gly Val Xaa Ala Ser Cys Ser His Asn Gly Lys 1 5 10 15 Ser Ser Phe Tyr Xaa Xaa Leu Leu Trp Leu Thr Xaa Lys Xaa Gly Leu 20 25 30 Tyr Pro Asn Leu Ser Lys 35 <210> 210 <211> 29

<212> PRT <213> Influenza virus <400> 210

His Thr Val Thr Lys Gly Val Thr Ala Ser Cys Ser His Asn Gly Lys 15 10 15

Ser Ser Phe Tyr Lys Asn Leu Leu Trp Leu Thr Glu Lys 20 25 <210> 211 <211> 48

<212> PRT <213> Influenza virus <400> 211

Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg Asn 15 10 15 lie Pro Ser lie Gin Ser Arg Gly Leu Phe Gly Ala He Ala Gly Phe 20 25 30

He Glu Gly Gly Trp Thr Gly Met He Asp Gly Trp Tyr Gly Tyr His 35 40 45 112 <210> 212 <211> 43

<212> PRT <213> Influenza virus <400> 212

His Gin Asn Glu Gin Gly Ser Gly Tyr Ala Ala Asp Gin Lys Ser Thr 1 5 10 15

Gin Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser lie Ile Glu 20 25 30

Lys Met Asn Thr Gin Phe Thr Ala Val Gly Lys 35 40 <210> 213 <211> 33

<212> PRT <213> Influenza virus <400> 213

His Gin Asn Glu Gin Gly Ser Gly Tyr Ala Ala Asp Gin Lys Ser Thr 1 5 10 15 Gin Asn Ala Ile Asn Gly Tie Thr Asn Lys Val Asn Ser Ile Ile Glu 20 25 30

Lys <210> 214 <211> 26

<212> PRT <213> Influenza virus <400> 214

His Gin Asn Glu Gin Gly Ser Gly Tyr Ala Ala Asp Gin Lys Ser Thr 15 10 15

Gin Asn Ala Ile Asn Gly Ile Thr Asn Lys 20 25 <210> 215 <211> 23

<212> PRT <213> Influenza virus <400> 215

His Ser Gly Ala Arg Ser Phe Tyr Arg Asn Leu Leu Trp Ile Val Lys 15 10 15

Lys Gly Asn Ser Tyr Pro Lys 20 113 w/v <210> 216 <211> 26

<212> PRT <213 > Influenza virus <400> 216

His Ser Gly Ala Arg Ser Phe Tyr Arg Asn Leu Leu Trp lie Val Lys 15 10 15

Lys Gly Asn Ser Tyr Pro Lys Leu Asn Lys 20 25 <210> 217 <211> 32

<212> PRT <213> Influenza virus <400> 217

Hie Ser Gly Ala Arg Ser Phe Tyr Arg Asn Leu Leu Trp He Val Lys 1 5 . 10 15

Lys Gly Asn Ser Tyr Pro Lys Leu Asn Lys Ser Tyr Thr Asn Asp Lys 20 25 30 <210> 218 <211> 34

<212> PRT <213> Influenza virus <400> 218

His Ser Gly Ala Arg Ser Phe Tyr Arg Asn Leu Leu Trp He Val Lys 15 10 15

Lys Gly Asn Ser Tyr Pro Lys Leu Asn Lys Ser Tyr Thr Asn Asp Lys 20 25 30

Gly Lys <210> 219 <211> 16

<212> PRT <213> Influenza virus <400> 219

His Thr Val Ser Lys Gly Val Thr Thr Ser Cys Ser His Asn Gly Lys 15 10 15 <210> 220 <211> 12

<212> PRT <213> Influenza virus 114 <400> 220

Lys Ala Thr Ser Trp Pro Asn His Glu Thr Thr Lys 15 10 <210> 221 <211> 12

<212> PRT <213> Influenza virus <400> 221

Lys Gin Val Thr Thr Ser Cys Ser His Asn Gin Lys 15 10 <210> 222 <211> 27

<212> PRT <213> Influenza virus <400> 222

Lye Gly Asn Ser Tyr Pro Lys Leu Asn Lys Ser Tyr Thr Asn Asp Lys 15 10 15

Gly Lys Glu Val Leu Val Ile Trp Gly Val His 20 25 <210> 223 <211> 21

<212> PRT <213> Influenza virus <400> 223

Lys Leu Asn Lys Ser Tyr Thr Asn Asp Lys Gly Lys Glu Val Leu Val 15 10 15

Ile Trp Gly Val His 20 <210> 224 <211> 18

<212> PRT <213> Influenza virus <400> 224

Lys Ser Tyr Thr Asn Asp Lys Gly Lys Glu Val Leu Val Ile Trp Gly 15 10 15

Val His <210> 225 <211> 35

<212> PRT <213> Influenza virus 115 JL· M.L·^ <220> <221> MOD_RES <222> (16) <223> glu or gin <220> <221> MOD_RES <222> (29? <223 > val or ala <400> 225

His 1 Asn Gin Lys Ser 5 Ser Phe Tyr Arg Asn 10 Leu Leu Trp Leu Thr 15 Xaa Lys Asn Gly Leu 20 Tyr Pro Asn Leu Ser 25 Lys Ser Tyr Xaa Ala 30 Asn Asn

Lys Glu Lys 35 <210> 226 <211> 16

<212> PRT <213> Influenza virus <400> 226

His Pro lie Thr He Gly Glu Cys Pro Lys Tyr Val Arg Ser Ala Lys 1 · 5 10 15 <210> 227 <211> 43

<212> PRT <213> Influenza virus <400> 227

His 1 Gin Asn Glu Gin 5 Gly Ser Gly Tyr Ala 10 Ala Asp Gin Lys Ser 15 Thr Gin Asn Ala He 20 Asn Gly He Thr Asn 25 Lys Val Asn Ser Val 30 He Glu Lys Met Asn Thr Gin Phe Thr Ala Val Gly Lys 35 40 <210> 228 <211> 33

<212> PRT <213> Influenza virus <400> 228

His Gin Asn Glu Gin Gly Ser Gly Tyr Ala Ala Asp Gin Lys Ser Thr 1 5 10 15 Gin Asn Ala He Asn Gly He Thr Asn Lys Val Asn Ser Val He Glu 20 25 30 116

Lye <210> 229 <211> 34

<212> PRT <213> Influenza virus <400> 229

His Asn Gly Lys Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Thr Glu 15 10 15

Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Val Asn Asn Lye 20 25 30

Glu Lys <210> 230 <211> 11

<212> PRT <213> Influenza virus <400> 230

Lys His Phe Glu Lys Val Lys lie Leu Pro Lys 15 10 <210> 231 <211> 14

<212> PRT <213> Influenza virus <400> 231

Lys His Leu Leu Ser Ser Val Lys His Phe Glu LyB Val Lys 15 10 <210> 232 <211> 13

<212> PRT <213> Influenza virus <220>

<221> MODJRES <222> (3) <223> lys, gin or met <220>

<221> MODJRES <222> (4) <223> asp or asn <400> 232

His Ala Xaa Xaa He Leu Glu Lys Thr His Asn Gly Lys 15 10 117 54X126 <21D> 233 <211> 16

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (3) <223> lys, gin or met <220>

<221> MOD_RES <222> (4) <223> asp or asn <220>

<221> MOD_RES <222> (16) <223> lys or arg <400> 233

His Ala Xaa Xaa Ile Leu Glu Lys Thr His Asn Gly Lys Leu Cys Xaa 15 10 15 <210> 234 <211> 19

<212> PRT <213 > Influenza virus <400> 234

His Asn Val His Pro Leu Thr Ile Gly Glu Cys Pro Lys Tyr Val Lys 15 10 15

Ser Glu Lys <210> 235 <211> 16

<212> PRT <213> Influenza virus <400> 235

His Pro Leu Thr Ile Gly Glu Cys Pro Lys Tyr Val Lys Ser Glu Lys 15 10 15 <210> 236 <211> 18

<212> PRT <213> Influenza virus <400> 236

Lys His Leu Leu Ser Ser Val Lys His Phe Glu Lys Val Lys Ile Leu 15 10 15

Pro Lys 118

3JUZ.U <210> 237 <211> 38

<212> PRT <213 > Influenza virus <400> 237

Lys Arg Gin Ser Ser Gly Ile Met Lys Thr Glu Gly Thr Leu Glu Asn 1 5 10 15 Cys Glu Thr Lys Cys Gin Thr Pro Leu Gly Ala Ile Asn Thr Thr Leu 20 25 30 Pro Phe His Asn Val His 35 <210> 238 <211> 27

<212> PRT <213> Influenza virus <220>

<221> MODJRES <222> (7) <223> val or ile <220>

<221> MOD_RES <2225 (10) <223> gly or arg <2205

<2215 MOD_RES <2225 (26) <223> val or ile <400> 238

Lye Gly Ser Asn Tyr Pro Xaa Ala Lys Xaa Ser Tyr Asn Asn Thr Ser 1 5 · 10 15

Gly Glu Gin Met Leu Ile Ile Trp Gin Xaa His 20 25 <210> 239 <211> 36

<212> PRT <213> Influenza virus <4005 239

His Thr Thr Leu Gly Gin Ser Arg Ala Cys Ala Val Ser Gly Asn Pro 1 5 10 15

Ser Phe Phe Arg Asn Met Val Trp Leu Thr Glu Lys Gly Ser Asn Tyr 20 25 30 119

Pro Val Ala Lys 35 <210> 240 <211> 7

<212> PRT <213 > Influenza virus <400> 240

Lys His Phe Glu Lys Val Lys 1 5 <210> 241 <211> 38

<212> PRT <213> Influenza virus <400> 241

Lys Ile Ser Lys Arg Gly Ser Ser Gly Ile Met Lys Thr Glu Gly Thr 1 5 10 15 Leu Glu Asn Cys Glu Thr Lys Cys Gin Thr Pro Leu Gly Ala Ile Asn 20 25 30 Thr Thr Leu Pro Phe Hie 35 <210> 242 <211> 35

<212> PRT <213> Influenza virus <400> 242

Lys Arg Gly Ser Ser Gly lie Met Lys Thr Glu Gly Thr Leu Glu Asn 1 5 10 15 Cys Glu Thr Lys Cys Gin Thr Pro Leu Gly Ala Ile Asn Thr Thr Leu 20 25 30

Pro Phe His 35 <210> 243 <211> 27

<212> PRT <213> Influenza virus <400> 243

Lys Thr Glu Gly Thr Leu Glu Asn Cys Glu Thr Lys Cys Gin Thr Pro 15 10 15

Leu Gly Ala Ile Asn Thr Thr Leu Pro Phe His 20 25 120 <210> 244 <211> 38

<212> PRT <213 > Influenza virus <400> 244

Lys lie Ser Lys Arg Gly Ser Ser Gly lie Met Lys Thr Glu Gly Thr 1 5 10 15 Leu Glu Asn Cys Glu Thr Lys Cys Gin Thr Pro Leu Gly Ala He Asn 20 25 30 Thr Thr Leu Pro Phe His 35 <210> 245 <211> 30 <212> PRT <213> Influenza virus <220> <221> MODJRES <222> (29) <223> val or ile <400> 245 Lys Thr Glu Gly Thr Leu 1 5 Glu Asn Cys Glu 10 Thr Lys Cys Gin Thr Pro 15 Leu Gly Ala He Asn Thr 20 Thr Leu Pro 25 Phe His Asn Xaa His 30 <210> 246 <211> 38

<212> PRT <213> Influenza virus <400> 246

Lys He Ser Lys Arg Gly Ser Ser Gly He Met Lys Thr Glu Gly Thr 1 5 10 15 Leu Glu Asn Cys Glu Thr Lys Cys Gin Thr Pro Leu Gly Ala He Asn 20 25 30 Thr Thr Leu Pro Phe His 35

<210> 247 <2H> 27 <212> PRT <213> Influenza <220> <221> MOD_RES 121 <222> (2) <223> glu. or gly <400> 247

Lys Xaa Ser Asn Tyr Pro Val Ala Lys Gly Ser Tyr Asn Asn Thr Ser 15 10 15

Gly Glu Gin Met Leu lie He Trp Gly Val His 20 25 <210> 248 <2ii> ie

<212> PRT <213> Influenza virus <400> 248

His Pro Leu Thr He Gly Glu Cys Pro Lys Tyr Val Lys Ser Glu Lys 15 10 15 <210> 249 <211> 16

<212> PRT <213 > Influenza virus <400> 249

Lys Cys Gin Thr Pro Leu Gly Ala He Lys Thr Thr Leu Pro Phe His 15 10 15 <21O> 250 <211> 58

<212> PRT <213> Influenza virus <220> <221> MOD_RES <222> (21) <223> phe or ile <220> <221> MOD_RES <222> .(47, <223> aBn or ser <400> 250

His 1 His Ser Asn Asp 5 Gin Gly Ser Gly Tyr 10 Ala Ala Asp Lys Glu 15 Ser Thr Gin Lys Ala 20 Xaa Asp Gly He Thr 25 Asn Lys Val Asn Ser 30 Val lie Glu Lys Met 35 Asn Thr Gin Phe Glu 40 Ala Val Gly Lys Leu 45 Phe Xaa Asn Leu Glu 50 Lys Leu Glu Asn Leu 55 Asn Lys Lys 122

OS>UXO <210> 251 <211> 57

<212 > PRT <213> Influenza virus <220> <221> MOD_RES <222> (20) <223> phe or ile <220> <221> MOD_RES <222> (46) <223> asn or ser <400> 251

His 1 Ser Asn Asp Gin 5 Gly Ser Gly Tyr Ala Ala 10 Asp Lys Glu Ser 15 Thr Gin Lys Ala Xaa 20 Asp Gly Ile Thr Asn 25 Lys Val Asn Ser Val 30 lie Glu Lys Met Asn 35 Thr Gin Phe Glu Ala 40 Val Gly Lys Leu Phe 45 Xaa Asn Leu Glu Lys Leu Glu Asn Leu Asn Lys Lys 50 55 <210> 252 <211> 26

<212> PRT <213> Influenza virus <22 0>

<221> MOD_RES <222> (20) <223> phe or ile <400> 252

His Ser Asn Asp Gin Gly Ser Gly Tyr Ala Ala Asp Lys Glu Ser Thr 15 10 15

Gin Lys Ala Xaa Asp Gly Ile Thr Asn Lys 20 25 <210> 253 <211> 21

<212> PRT <213> Influenza virus <400> 253

His Asp Ser Asn Val Arg Asn Leu Tyr Asp Lys Val Arg Met Gin Leu 15 10 15 123 wilder

Arg Asp Asn Ala Lys 20 <210> 254 <211> 30

<212> PRT <213> Influenza virus <400> 254

His Lys Cys Asp Asp Glu Cys Met Asn Ser Val Lys Asn Gly Thr Tyr 15 10 15

Asp Tyr Pro Lys Leu Asn Arg Asn Glu Ile Lys Gly Val Lys 20 25 30 <210> 255 <211> 27

<212> PRT <213> Influenza virus <400> 255

His Lys Cys Asp Asp Glu Cys Met Asn Ser Val Lys Asn Gly Thr Tyr 15 10 15

Asp Tyr Pro Lys Leu Asn Arg Asn Glu lie Lys 20 25 <210> 256 <211> 20

<212> PRT <213> Influenza virus <400>. 256

His Lys Cys Asp Asp Glu Cys Met Asn Ser Val Lys Asn Gly Thr Tyr 15 10 15

Aep Tyr Pro Lys 20 <210> 257 <211> 12

<212> PRT <213> Influenza virus <400> 257

His Lys Cys Asp Asp Glu Cys Met Asn Ser Val Lys 15 10 <210> 258 <211> 27

<212> PRT <213> Influenza virus 124 <400> 258

Lys Gly Ser Asn Tyr Pro Val Ala Lye Gly Ser Tyr Asn Asn Thr Asn 1 5 10 15

Gly Glu Gin lie Leu lie He Trp Gly Val His 20 25 <210> 259 <211> 43

<212> PRT <213 > Influenza virus <400> 259

His 1 Ser Asn Asp Gin 5 Gly Ser Gly Tyr Ala 10 Ala Asp Lys Glu Ser 15 Thr Gin LyB Ala Val 20 Asp Gly He Thr Asn 25 Lys Val Asn Ser Val 30 lie Glu Lys Met Asn Thr Gin Phe Glu Ala Val Gly Lye 35 40 <210> 260 <211> 35

<212> PRT <213> Influenza virus <400> 260

Lys Arg Gly Ser Ser Gly lie Met Lys Thr Glu Gly Thr Leu Glu Asn 15 10 15

Cys Glu Thr Lys Cys Gin Thr Pro Leu Gly Ala lie Asn Thr Thr Leu 20 25 30

Pro Phe His 35 <210> 261 <211> 16

<212> PRT <213> Influenza virus <400> 261

His Pro Leu Thr He Gly Glu Cys Pro Lys Tyr Val Lys Ser Glu Lys 1 5 · 10 15 <210> 262 <211> 16

<212> PRT <213> Influenza virus <400> 262

His Ala Lys Asp He Leu Glu Lys Thr His Asn Gly Lys Leu Cys Lys 15 10 15 125 <210> 263 <211> 25

<212> PRT <213> Influenza virus <400> 263

His Asp Val Tyr Arg Asp Glu Ala Leu Asn Asn Arg Phe Gin lie Lys 15 10 15

Gly Val Glu Leu Lys Ser Gly Tyr Lys 20 25 <210> 264 <211> 19

<212> PRT <213> Influenza virus <400> 264

His Thr lie Asp Leu Thr Asp Ser Glu Met Asn Lys Leu Phe Glu Arg 1 5 10 15

Thr Arg Lys <210> 265 <211> 7

<212> PRT <213> Influenza virus <400> 265

Lys Phe His Gin lie Glu Lys 1 5 <210> 266 <211> 11

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (8) <223> gly or gin <400> 266

Lys Thr Asn Glu Lys Phe His Xaa He Glu Lys 15 10 <210> <211> <212> <213> 267 14 PRT Influenza virus <220> 126

<221s» MOD RES <222> (5) <223i> val or leu <400> 267 Lys Leu Asn Arg Xclel He 1 5 <210> 268 <211> 25 <212> PRT <213> Influenza virus <400> 268 His Gin lie Glu Lys Glu • 1 5 Leu Glu Lys Tyr Val Glu 20 <210> 269 <211> 8 <212> PRT <213> Influenza virus <400> 269 Lys He Cys Asn Asn Pro 1 5 <210> 270 <211> 14 <212> PRT <213 > Influenza virus <400> 270 Lys Leu Asn Arg Val lie 1 5 <210> 271 <211> 24 <212> PRT <213> Influenza virus <220> <221> MOD RES <222> (3) <223> ile or val <220> <221> MOD RES <222> (17) <223> gly or gin <220> 25 10 10 10 15 127

<221> MODJRES <222> (20) <223> arg or lys <220>

<221> MODJRES <222> (22) <223> gin or gly <400> 271

His Asp Xaa Tyr Arg Asp Glu Ala Leu Asn Asn Arg Phe Gin lie Lys 15 10 15

Xaa Val Glu Xaa Ser Xaa Tyr Lys 20 <210> 272 <211> 25

<212> PRT <213> Influenza virus <400> 272

His Gin Ile Glu Lys Glu Phe Ser Glu Val Glu Gly Arg lie Gin Asp 15 10 15

Leu Glu Lys Tyr Val Glu Asp Thr Lys 20 25 <210> 273 <211> 25

<212> PRT <213> Influenza virus <400> 273

Lys Tyr Val Glu Asp Thr Lys Ile Asp Leu Trp Ser Tyr Asn Ala Glu 15 10 15

Leu Leu Val Ala Leu Glu Asn Gin His 20 25 <210> 274 <211> 49

<212> PRT <213> Influenza virus <400> 274

Lys Tyr Val Lys Gin Asn Ser Leu Lys Leu Ala Thr Gly Met Arg Asn 1 5 10 15 Val Pro Glu Lys Gin Thr Arg Gly Leu Phe Gly Ala lie Ala Gly Phe 20 25 30 Ile Glu Asn Gly Trp Glu Gly Met lie Asp Gly Trp Tyr Gly Phe Arg 35 40 45 128

His <210> 275 <211> 39

<212> PRT <213> Influenza virus <400> 275

Lys Glu Phe Ser Glu Val Glu Gly Arg lie Gin Asp Leu Glu Lys Tyr 15 10 15

Val Glu Asp Thr Lys lie Asp Leu Trp Ser Tyr Asn Ala Glu Leu Leu 20 25 30

Val Ala Leu Glu Asn Gin His 35 <210> 275 <211> 33 <212> PRT <213> Influenza v <22D> <221> MOD RES <222> (4) <223> ser or glu <220> <221> MOD RES <222 > (5) <223> glu or gin <220> <221> MOD RES <222> (7) <223> thr or ser <220> <221> MOD RES <222> <9)~ <223> gin or tyr <220> <221> MOD RES <222> (13) <223> leu or gin <220> <221> MOD RES <222> (18) <223> ala or asn <220> <221> MOD RES <222> (20) <223> ile or leu 129 <220>

<221> MOD_RES <222> (22) <223 > gin or gly <220>

<221> MOD_RES <222> (24) <223> asn or thr <220>

<221> MOD_RES <222> (25) <223> gly or asn <220>

<221> MOD_RES <222> (27) <223> leu or val <220>

<221> MOD_RES <222> (29) <223> arg or ser <220>

<221> MOD_RES <222> (32) <223> glu or cys <400> 276

His Gin Asn Xaa Xaa Gly Xaa Gly Xaa Ala Ala Asp Xaa Lys Ser Thr 15 10 15

Gin Xaa Ala Xaa Asp Xaa lie Xaa Xaa Lys Xaa Asn Xaa Val Ile Xaa 20 25 30

Lys <210> 277 <211> 18

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (4) <223> gly or gin <220>

<221> MOD_RES <222> (6) <223 > gin or arg <220>

<221> MOD_RES 130 <222> (14) <223> val or ile <22 0>

<221> MODJRES <222> (17) <223> ser or thr <400> 277

His Cys Asp Xaa Phe Xaa Asn Glu Lys Trp Asp Leu Phe Xaa Glu Arg 15 10 15

Xaa Lys <2ί0> 278 <211> 20

<212> PRT <213> Influenza virus <400> 278

His Thr Ile Asp Leu Thr Asp Ser Glu Met Asn Lys Lys Leu Phe Glu 15 10 15

Arg Thr Arg Lys 20 <210> 279 <211> 28

<212> PRT <213> Influenza virus <400> 279

Lys Ser Gly Ser Thr Tyr Pro Val Leu Lys Val Thr Met Pro Asn Asn 15 10 15

Asp Asn Phe Asp Lys Leu Tyr Ile Trp Gly Val His 20 25 <210> 280 <211> 34

<212> PRT <213> Influenza virus <400;· 280

Lys Leu Asn Trp Leu Thr Lys Ser Gly Asn Thr Tyr Pro Val Leu Asn 15 10 15

Val Thr Met Pro Asn Asn Asp Asn Phe Asp Lys Leu Val Ile Trp Gly 20 25 30

Val His <210> 281 <211> 19 131

VUXXXrV

<212> PRT <213> Influenza virus <400> 281

His Thr lie Asp Leu Thr Asp Ser Glu Met Asn Lys Leu Phe Glu Lys 15 10 15

Thr Arg Lys <210> 282 <211> 18

<212> PRT <213> Influenza virus <400> 282

Lys Leu Asn Arg Leu He Glu Lys Thr Asn Glu Lys Phe His Gin Thr 15 10 15

Glu Lys <210> 283 <211> 47

<212> PRT <213> Influenza virus <400> 283

His 1 Thr Gly Lys Ser 5 Ser Val Met Arg Ser 10 Asp Ala Pro He Asp 15 Phe Cys Asn Ser Glu 20 Cys He Thr Pro Asn 25 Gin Ser He Pro Asn 30 Asp Lys Pro Phe Gin 35 Asn Val Asn Lys He 40 Thr Tyr Gly Ala Cys 45 Pro Lys <210> 284 <211> 39

<212> PRT <213> Influenza virus <400> 284

His Thr Gly Lys Ser Ser Val Met Arg Ser Asp Ala Pro lie Asp Phe 1 5 10 15 Cys Asn Ser Glu Cys He Thr Pro Asn Gin Ser lie Pro Asn Asp Lys 20 25 30 Pro Phe Gin Asn Val Asn Lys 35 <210> 285 <211> 33

<212> PRT <213> Influenza virus 132

U5UX.V <400> 285

His Pro Ser Thr Asp Ser Asp Gin Thr Ser Leu Tyr Val Arg Ala Ser 1 5 10 15 Gly Arg Val Thr Val Ser Thr Lys Arg Ser Gin Gin Thr Val Ile Pro 20 25 30

Lye <2105 286 <211> 25

<212> PRT <213> Influenza virus <400> 286

Lys Tyr Val Glu Asp Thr Lys Ile Asp Leu Trp Ser Tyr Asn Ala Glu 15 10 15

Leu Leu Val Ala Leu Glu Asn Gin His 20 25 <210> 287 <211> 26

<212> PRT <213> Influenza virus <400> 287

Lys Leu Phe Glu Arg Thr Arg Lys Gin Leu Arg Glu Asn Ala Glu Asp 15 10 15

Met Gly Asn Gly Cys Phe Lys Ile Tyr His 20 25 <210> 288 <211> 16 <212> PRT <213> Influenza virus <400> 288 Lys Arg Arg Ser Ile Lys 1 5

Phe

Phe Ser 10

Arg Leu Asn

Trp

Leu His 15 <210> 289 <2115 16 <212> PRT <213> Influenza virus <2205 <2215 MOD_RES <2225 (12) <223> val or arg 133 / ν\ιχ.υ <400s> 289

His Pro Val Thr Ile Gly Glu Cys Pro Lys Tyr Xaa Lys Ser Thr Lys 15 10 15 <210> 290 <211> 30

<212> PRT <213> Influenza virus <400> 290

Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lye Leu Ser Lys Ser Tyr 15 10 15

Ile Asn Lys Lys Lys Glu Val Leu Val Ile Trp Gly lie His 20 25 30 <210> 291 <211> 24

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (9) <223> val or tyr <400> 291

Lys Leu Ser Lys Leu Ser Lys Ser Xaa Ile lie Asn Lys Lys Lys 15 10 15

Val Leu Val

Ile Trp Gly Ile His 20

Ile

Glu <210> 292 <211> 21

<212> PRT <213> Influenza virus <220>

<221> MOD_RES <222> (6) <223> val or tyr <400> 292

Lys Leu Ser Lys Ser Xaa Ile lie Asn Lys Lys Lys Glu Val Leu Val 1 5 10 15

Ile Trp Gly Ile His 20 <210> 293 <211> 46

<212> PRT <213 > Plasmodium falciparum 134 ! ί <4005. 293 Lys Glu Glu 1 Glu Glu 5 Lys Glu Lys Glu Lys 10 Glu Lys Glu Lys Glu 15 Glu Lys Glu Lys Glu Glu Lys Glu Lys Glu Glu Lys Glu Lys Glu Lys Glu 20 25 30 Glu Lys Glu Lys Glu Lys Glu Glu Lys Glu Glu Glu Lys Lys 35 40 45 <210> 294 <211> 48

<212> PRT <213 > Plasmodium falciparum <400> 294

Lys Glu Glu Glu Glu Lys Glu Lys Glu Lys Glu Lys Glu Lys Glu Glu 1 5 10 15 Lys Glu Lys Glu Glu Lys Glu Lys Glu Glu Lys Glu Lye Glu Lys Glu 20 25 30 Glu Lys Glu Lys Glu Lys Glu Glu Lys Glu Glu Glu LyB Lys Glu Lys 35 40 45 <210> 295 <211> 47

<212> PRT <213 > Plasmodium falciparum <4005» 295

Lys Glu Glu Glu Glu Lys Glu Lys Glu Lys Glu Lys Glu Lys Glu Glu 1 5 10 15 Lys Glu Lys Glu Glu Lys Glu Lys Glu Lys Glu Glu Lys Glu Lys Glu 20 25 30 Glu Lys Glu Lys Glu Glu Lys Glu Glu Lys Glu Glu Glu Lys Lys 35 40 45 <210> 296 <211> 10

<212> PRT <213> Plasmodium falciparum <400> 296

Lys Glu Glu Glu Glu Lys Glu Lys Glu Lys 1 5 10 <210> 297 <211> 19

<2125. PRT <213> Plasmodium falciparum 135 !ί\ίίΌ <400> 297

His Lys Lys Leu Ile Lys Ala Leu Lys Lys Asn lie Glu Ser Ile Gin 15 10 15

Asn Lys Lys <210> 298 <211> 19

<212> PRT <213> Plasmodium falciparum <400> 298

His Lys Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gin 15 10 15

Asn Lys Met <210> 299 <211> 10

<212> PRT <213 > Plasmodium falciparum <400> 299

His Lys Lys Leu Ile Lys Ala Leu Lys Lys 15 10 <210> 300 <211> 9

<212> PRT <213> Plasmodium falciparum <400> 300

His Lys Lys Leu Ile Lys Ala Leu Lys 1 5 <210> 301 <211> 23

<212> PRT <213> Plasmodium falciparum <400> 301

Lys Ala Thr Tyr Ser Phe Val Asn Thr Lys Lys Lys lie lie Ser Leu 15 10 15

Lys Ser Gin Gly His Lys Lys 20 <210> 302 <211> 22

<212> PRT <213> Plasmodium falciparum 136 73X126 <400> 302

Lys Ala Thr Tyr Ser Phe Val Asn Thr Lys Lye Lys Ile Ile Ser Leu 15 10 15

Lys Ser Gin Gly His Lys 20 <210> 303 <211> 21

<212> PRT <213 > Plasmodium falciparum <400> 303

Lys Ala Thr Tyr Ser Phe Val Asn Thr Lys Lys Lys Ile Ile Ser Leu 1 5 10 15

Lys Ser Gin Gly His 20 <210> '304 <211> 29

<212> PRT <213> Plasmodium falciparum <400> 304

His Thr Tyr Val Lys Gly Lys Lys Ala Pro Ser Asp Pro Gin Cys Ala 15 10 15

Asp Ile Lys Glu Glu Cys Lys Glu Leu Leu Lys Glu Lys 20 25 <210> 305 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 305

Lys Ile Ile Ser Leu Lys Ser Gin Gly His Lys 15 10 <210> 306 <211> 21

<212> PRT <213> Plasmodium falciparum <400> 306

Lys Lys Lys Lys Phe Glu Pro Leu Lys Asn Gly Asn Val Ser Glu Thr 1’5 10 15

Ile Lys Leu Ile His 20 <210> 307 137 74UZ0 <211> 20

<212> PRT <213> Plasmodium falciparum <400> 307

Lys Lys Lys Phe Glu Pro Leu Lys Asn Gly Asn Val Ser Glu Thr lie 1 5 10 15

Lys Leu lie His 20 <210> 308 <211> 19

<212> PRT <213> Plasmodium falciparum <400> 308

Lys Lys Phe Glu Pro Leu Lys Asn Gly Asn Val Ser Glu Thr Ile Lys 15 10 15

Leu lie His <210> 309 <211> 13

<212> PRT <213> Plasmodium falciparum <400> 309

Lys Asn Gly Asn Val Ser Glu Thr Ile Lys Leu Ile His 1 5 10 <210> 310 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 310

Lys Leu Ile His Leu Gly Asn Lys Asp Lys Lys 15 10 <210> 311 <211> 36

<212> PRT <213> Plasmodium falciparum <400> 311

Lys Val Lys Lys Ile Gly Val Thr Leu Lys Lys Phe Glu Pro Leu Lys 15 10 15

Asn Gly Asn Val Ser Glu Thr Ile Lys Leu Ile His Leu Gly Asn Lys 20 25 30

Asp Lys Lys His 35 138 <210> 312 <211> 59

<212> PRT <213> Plasmodium falciparum <400> 312

His 1 Leu Ile Tyr Lys 5 Asn Lys Ser Tyr Asn 10 Pro Leu Leu Leu Ser 15 Cys Val Lys Lys Met 20 Asn Met Leu Lys Glu 25 Asn Val Asp Tyr Ile 30 Gin Asn Gin Asn Leu 35 Phe Lys Glu Leu Met 40 Asn Gin Lys Ala Thr 45 Tyr Ser Phe Val Asn Thr Lys Lys Lys lie Ile Ser Leu Lys 50 55 <210> 313 <211> 52

<212> PRT <213> Plasmodium falciparum <400> 313

His 1 Leu lie Tyr Lys 5 Asn Lys Ser Tyr Asn 10 Pro Leu Leu Leu Ser 15 Cys Val Lys Lys Met 20 Asn Met Leu Lys Glu 25 Asn Val Asp Tyr Ile 30 Gin Asn Gin Asn Leu 35 Phe Lys Glu Leu Met 40 Asn Gin Lys Ala Thr 45 Tyr Ser Phe Val Asn Thr Lys 50 <210> 314 <211> 43

<212> PRT <213> Plasmodium falciparum <400> 314

His Leu Ile Tyr Lys Asn Lys Ser Tyr Asn Pro Leu Leu Leu Ser Cys 1 5 10 15 Val Lys Lys Met Asn Met Leu Lys Glu Asn Val Asp Tyr lie Gin Asn 20 25 30 Gin Asn Leu Phe Lys Glu Leu Met Asn Gin Lys <210> 315 <211> 38 35 40 139

<212 > PRT <213> Plasmodium falciparum <400> 315

His Leu Ile Tyr Lys Asn Lys Ser Tyr Asn Pro Leu Leu Leu Ser Cys 15 10 15

Val Lys Lys Met Asn Met Leu Lys Glu Asn Val Asp Tyr Ile Gin Lys 20 25 30

Asn Gin Asn Leu Phe Lys 35 <210> 316 <211> 24

<212> PRT <213> Plasmodium falciparum <400> 316

His Leu lie Tyr Lys Asn Lys Ser Tyr Asn Pro Leu Leu Leu Ser Cys 1 5 10. 15

Val Lys Lys Met Asn Met Leu Lys 20 <210> 317 <211> 47

<212> PRT <213> Plasmodium falciparum <400> 317

Lys 1 Ser Ala Asn Asn 5 Ser Ala Asn Asn Gly Lys Lys 10 Asn Asn Ala 15 Glu Met Lys Asn Leu Val Asn Phe Leu Gin Ser His Lys Lys Leu 20 25 30 Lys Ala Leu Lys Lys Asn lie Glu Ser Ile Gin Asn Lys Lys His 35 40 45

Glu

Ile <210> 318 <211> 37

<212> PRT <213> Plasmodium falciparum <400> 318

Lys Lys Asn Asn Ala Glu Glu Met Lys Asn Leu Val Asn Phe Leu Gin 15 10 15

Ser His Lys Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile 20 25 30

Gin Asn Lys Lys His 35 140 <210> 319 <211> 29

<212> PRT <213> Plasmodium falciparum <400> 319

Lys Asn Leu Val Asn Phe Leu Gin Ser His Lys Lys Leu Ile Lys Ala 15 10 15

Leu Lys Lys Asn Ile Glu Ser Ile Gin Asn Lys Lys His 20 25 <210> 320 <211> 19

<212> PRT <21'3> Plasmodium falciparum <400> 320

Lys Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gin Asn 15 10 15

Lys Lys His <210> 321 <211> 18

<212> PRT <213 > Plasmodium falciparum <400> 321

Lys Leu Ile Lys Ala Leu Lys Lys Asn lie Glu Ser lie Gin Asn Lys 15 10 15

Lys His <210> 322 <211> 12

<212> PRT <213> Plasmodium falciparum <400> 322

Lys Lys Asn Ile Glu Ser Ile Gin Asn Lys Lys His 15 10 <210> 323 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 323

Lys Asn Ile Glu Ser Ile Gin Asn Lys Lys His 1.5 10 141 <210> 324 <211> 17

<212> PRT <213> Plasmodium falciparum <400> 324

Lys Asn Asn Ala Glu Glu Met Lys Asn Leu Val Asn Phe Leu Gin Ser 15 10 15

His <210> 325 <211> 23

<212> PRT <213> Plasmodium falciparum <400> 325

Lys Lys Leu He Lys Ala Leu Lys Lys Asn lie Glu Ser He Gin Asn 15 10 15

Lys Lys Gin Gly His Lys Lys 20 <210> 326 <211> 19

<212> PRT <213> Plasmodium falciparum <400> 326

Lys Lys Asn Asn Ala Glu Glu Met Lys Asn Leu Val Asn Phe Leu Gin 15 10 15

Ser His Lys <210> 327 <211> 17

<212> PRT <213> Plasmodium falciparum <400> 327 '

Lys Asn Asn Ala Glu Glu Met Lys Asn Leu Val Asn Phe Leu Gin Ser 15 10 15

His

<210> 32B <211> 22

<212> PRT <213> Plasmodium falciparum <400> 328

Lys Leu He Lys Ala Leu Lys Lys Asn lie Glu Ser lie Gin Asn Lys 15 10 15 142

Lys Gin Gly His Lys Lys 20 <210> 329 <211> 28

<212> PRT <213> Plasmodium falciparum <400> 329

Lys Val Lys Lys Ile Gly Val Thr Leu Lys Lys Phe Glu Pro Leu Lys 15 10 15

Asn Gly Asn Val Ser Glu Thr Ile Lys Leu Ile His 20 25 <210> 330 <211> 13

<212> PRT <213> Plasmodium falciparum <400> 330

Lys Asn Gly Asn Val Ser Glu Thr Ile Lys Leu Ile His 15 10 <210> 331 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 331

Lys Leu Ile His Leu Gly Asn Lys Asp Lys Lys 15 10 <210> 332 <211> 28

<212> PRT <213> Plasmodium falciparum <400> 332

Lys Ser Ala Asn Asn Ser Ala Asn Asn Gly Lys Lys Asn Asn Ala Glu 15 10 15

Glu Met Lys Asn Leu Val Asn Phe Leu Gin Ser His 20 25 <210> 333 <211> 18

<212> PRT <213> Plasmodium falciparum <400> 333

Lys Lys Asn Asn Ala Glu Glu Met Lys Asn Leu Val Asn Phe Leu Gin 15 10 15 143

W IXXrU

Ser His <210> 334 <211> 19

<212> PRT <213> Plasmodium falciparum <400> 334

Lys Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gin Asn 15 10 15

Lys Lys His <210> 335 <211> 15

<212> PRT <213 > Plasmodium falciparum <400> 335

Lys Ala Leu Lys Lys Asn lie Glu Ser Ile Gin Asn Lys Lys His 15 10 15 <210> 336 <211> 12

<212> PRT <213> Plasmodium falciparum <400> 336

Lys Lys Asn Ile Glu Ser Ile Gin Asn Lys Lys His 15 10 <210> 337 <211> 27

<212> PRT <213> Plasmodium falciparum <400> 337

Lys Glu Leu Met Asn Gin Lys Ala Thr Tyr Ser Phe Val Asn Thr 1 5 10 15 Lys Lys Ile lie Ser Leu Lys Ser Gin Gly His 20 25 <210> 338 <211> 7

<212> PRT <213> Plasmodium falciparum <400> 338

Lys Ser Gin Gly His Lys Lys 1 5 144

Ui uxu <210> 339 <211> 12

<212> PRT <213> Plasmodium falciparum <400> 339

Lys Lys Lys lie Ile Ser Leu Lys Ser Gin Gly His 15 10 <210> 340 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 340

Lys Lys Ile Ile Ser Leu Lys Ser Gin Gly His 15 10 <210> 341 <211> 12

<212> PRT <213> Plasmodium falciparum <400> 341

Lys Lys Asn Ile Glu Ser Ile Gin Asn Lys Lys His 15 10 <210> 342 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 342

Lys Asn Ile Glu Ser Ile Gin Asn Lys Lys His 15 10 <210> 343 <211> 29

<212> PRT <213> Plasmodium falciparum <400> 343

His Thr Tyr Val Lys Gly Lys Lys Ala Pro Ser Asp Pro Gin Cys Ala 1 5 10 15

Asp lie Lys Glu Glu Cys Lys Glu Leu Leu Lys Glu Lys 20 25 <210> 344 <211> 27

<212> PRT <213> Plasmodium falciparum 145 <400> 344

His Thr Tyr Val Lys Gly Lys Lys Ala 1 5

Asp Ile Lys Glu Glu Cys Lys Glu Leu 20 25

Pro Ser Asp Pro 10

Leu Lys

Gin Cys Ala 15 <210> 345 <211> 29

<212> PRT <213> Plasmodium falciparum <400> 345

His Glu Asn Val Leu Ser Ala Ala Leu Glu Asn Thr Gin Ser Glu Glu 1 5 10 15

Glu Lys Lys Glu Val Ile Asp Val Ile Glu Glu Val Lys 20 25 <210> 346 <211> 48

<212> PRT <213> Plasmodium falciparum <400> 346

Lys Glu Asn Val Val Thr Thr Ile Leu Glu Lys Val Glu Glu Thr Thr 1 5 10 15 Ala Glu Ser Val Thr Thr Phe Ser Asn Ile Leu Glu Glu Ile Gin Glu 20 25 30 Asn Thr Ile Thr Asn Asp Thr Ile Glu Glu Lys Leu Glu Glu Leu His 35 40 45 <210> 347 <211> 14

<212> PRT <213> Plasmodium falciparum <400> 347

His Tyr Leu Gin Gin Met Lys Glu Lys Phe Ser Lys Glu Lys 15 10 <210> 348 <211> 42

<212> PRT <213> Plasmodium falciparum <400> 348

His Tyr Leu Gin Gin Met Lys Glu Lys Phe Ser Lys Glu Lys Asn Asn 15 10 15 146

Asn Val Ile Glu Val Thr Asn Lys Ala Glu Lys Lys Gly Asn Val Gin 20 25 30

Val Thr Asn Lys Thr Glu Lys Thr Thr Lys 35 40 <210> 349 <211> 48

<212> PRT <213> Plasmodium falciparum <400> 349

His 1 Tyr Leu Gin Gin 5 Met Lys Glu Lys Phe 10 Ser Lys Glu Lys Asn 15 Asn Asn Val Ile Glu 20 Val Thr Asn Lys Ala 25 Glu Lys Lys Gly Asn 30 Val Gin Val Thr Asn Lys Thr Glu Lys Thr Thr Lys Val Asp Lys Asn Asn Lys 35 40 45 <210> 350 <211> 57

<212> PRT <213> Plasmodium falciparum <400> 350

His 1 Tyr Leu Gin Gin 5 Met Lys Glu Lys Phe 10 Ser Lys Glu Lys Asn 15 Asn Asn Val Ile Glu 20 Val Thr Asn Lys Ala 25 Glu Lys Lys Gly Asn 30 Val Gin Val Thr Asn 35 Lys Thr Glu Lys Thr 40 Thr Lys Val Asp Lys 45 Asn Asn Lys Val Pro Lys Lys Arg Arg Thr Gin Lys 50 55 <210> 351 <211> 59

<212> PRT <213> Plasmodium falciparum <400> 351

His Tyr Leu Gin Gin Met Lys Glu Lys Phe Ser Lys Glu Lys Asn Asn 15 10 15

Asn Val Ile Glu Val Thr Asn Lys Ala Glu Lys Lys Gly Asn Val Gin 20 25 30

Val Thr Asn Lys Thr Glu Lys Thr Thr Lys Val Asp Lys Asn Asn Lys 35 40 45 147

O^UZD

Val Pro Lys Lys Arg Arg Thr Gin Lys Ser Lys 50 55 <210> 352 <211> 52

<212> PRT <213> Plasmodium falciparum <400> 352

His Val Asp Glu Val Met Lys Tyr Val Gin Lye Ile Asp Lys Glu Val 1 5 10 15 Asp Lys Glu Val Ser Lys Ala Leu Glu Ser Lys Asn Asp Val Thr Asn 20 25 30 Val Leu Lys Gin Asn Gin Asp Phe Phe Ser Lys Val Lys Asn Phe Val 35 40 45

Lys Lys Tyr Lys 50 <210> 353 <211> 50

<212> PRT <213> Plasmodium falciparum <400> 353

His Val Asp Glu Val Met Lys Tyr Val Gin Lys Ile Asp Lys Glu Val 1 5 10 15 Asp Lys Glu Val Ser Lys Ala Leu Glu Ser Lys Asn Asp Val Thr Asn 20 25 30 Val Leu Lys Gin Asn Gin Asp Phe Phe Ser Lys Val Lys Asn Phe Val 35 40 45

Lys Lys 50 <210> 354 <211> 43

<212> PRT <213> Plasmodium falciparum <400> 354

His 1 Val Asp Glu Val 5 Met Lys Tyr Val Gin 10 Lys Ile Asp Lys Glu 15 Asp Lys Glu Val 20 Ser Lys Ala Leu Glu 25 Ser Lys Asn Asp Val 30 Thr Val Leu Lys Gin Asn Gin Asp Phe Phe Ser Lys 35 40 148 ou\xx.u <210> 355 <211> 35

<212> PRT <213 > Plasmodium falciparum <400> 355

His Val Asp Glu Val Met Lys Tyr Val Gin Lys lie Asp Lys Glu Val 1 5 . 10 15

Asp Lys Glu Val Ser Lys Ala Leu Glu Ser Lys Asn Asp Val Thr Asn 20 25 30

Val Leu Lys 35 <210> 356 <211> 27

<212> PRT <213> Plasmodium falciparum <400> 356

His Val Asp Glu Val Met Lys Tyr Val Gin Lys He Asp Lys Glu Val 1 5 10 15

Asp Lys Glu Val Ser Lys Ala Leu Glu Ser Lys 20 25 <210> 357 <211> 22

<212> PRT <213> Plasmodium falciparum <400> 357

His Val Asp Glu Val Met Lys Tyr Val Gin Lys He Asp Lys Glu Val 15 10 15

Asp Lys Glu Val Ser Lys 20 <210> 358 <211> 18

<212> PRT <213> Plasmodium falciparum <400> 358

His Val Asp Glu Val Met Lys Tyr Val Gin Lys lie Asp Lys Glu Val 1 5 10 15 'Asp Lys <210> 359 <211> 14

<212> PRT <213> Plasmodium falciparum 149 <400> 359

His Val Asp Glu Val Met Lys Tyr Val Gin Lys Ile Asp Lys 15 10 <210> 360 <211> 39

<212> PRT <213> Plasmodium falciparum <400> 360

Lys 1 Asp Glu Val Ile 5 Asp Leu Ile Val Gin 10 Lys Glu Lys Arg Ile 15 Glu Lys Val Lys Ala 20 Lys Lys Lys Lys Leu 25 Glu Lys Lys Val Glu 30 Glu Gly Val Ser Gly 35 Leu Lys Lys His <210> 361 <211> 23

<212> PRT <213> Plasmodium falciparum <400> 361

Lys Val Lys Ala Lys Lys Lys Lys Leu Glu Lys Lys Val Glu Glu Gly 15 10 15

Val Ser Gly Leu Lys Lys His 20 <210> 362 <211> 21

<212> PRT <213> Plasmodium falciparum <400> 362

Lys Ala Lys Lys Lys Lys Leu Glu Lys Lys Val Glu Glu Gly Val Ser 15 10 15

Gly Leu Lys Lys His 20 <210> 363 <211> 19

<212> PRT <213> Plasmodium falciparum <400> 363

Lys Lys Lys Lys Leu Glu Lys Lys Val Glu Glu Gly Val Ser Gly Leu 15 10 15

Lys Lys His 150 <210> 364 <211> 18

<212> PRT <213> Plasmodium falciparum <400> 364

Lys Lys Lys Leu Glu Lys Lys Val Glu Glu Gly Val Ser Gly Leu Lys 15 10 15

Lys His <210> 365 <211> 17

<212> PRT <213> Plasmodium falciparum <400> 365

Lys Lys Leu Glu Lys Lys Val Glu Glu Gly Val Ser Gly Leu Lys Lys 15 10 15

His <210> 366 <211> 16

<212> PRT <213> Plasmodium falciparum <400> 366

Lys Leu Glu Lys Lys Val Glu Glu Gly Val Ser Gly Leu Lys Lys His 15 10 15 <210> 367 <211> 13

<212> PRT <213> Plasmodium falciparum <400> 367

Lys Lys Val Glu Glu Gly Val Ser Gly Leu Lys Lys His 15 10 <210> 368 <211> 12

<212> PRT <213> Plasmodium falciparum <400> 368

Lys Val Glu Glu Gly Val Ser Gly Leu Lys Lys His 15 10 <210> 369 <211> 59 151

<212> PRT <213 > Plasmodium falciparum <400> 369 ΗΪΒ 1 Val Glu Gin Asn 5 Val Tyr Val Asp Val 10 Asp Val Pro Ala Met 15 Lys Asp Gin Phe Leu 20 Gly lie Leu Asn Glu 25 Ala Gly Gly Leu Lys 30 Glu Met Phe Phe Asn 35 Leu Glu Asp Val Phe 40 Lys Ser Glu Ser Asp 45 Val lie Thr Val Glu Glu Xie Lys Asp Glu Pro Val Gin Lys 50 55 <210> 370 <211> 53

<212> PRT <213> Plasmodium falciparum <400> 370

His 1 lie Lys Gly Leu 5 Glu Glu Asp Asp Leu 10 Glu Glu Val Asp Asp 15 Leu Lys Gly Ser lie 20 Leu Asp Met Leu Lys 25 Gly Asp Met Glu Leu 30 Gly Asp Met Asp Lys 35 Glu Ser Leu Glu Asp 40 Val Thr Thr Lys Leu 45 Gly Glu Arg Val Glu Ser Leu Lys 50 <210> 371 <211> 44

<212> PRT <213> Plasmodium falciparum <400> 371

His He Lys Gly Leu Glu Glu Asp Asp Leu Glu Glu Val Asp Asp Leu 1 5 10 15 Lys Gly Ser He Leu Asp Met Leu Lys Gly Asp Met Glu Leu Gly Asp 20 25 30 Met Asp Lys Glu Ser Leu Glu Asp Val Thr Thr Lys 35 40 <210> 372 <211> 35

<212> PRT <213> Plasmodium falciparum 152 <400> 372

His Ile Lys Gly Leu Glu Glu Asp Asp Leu Glu Glu Val Asp Asp Leu 15 10 15

Lys Gly Ser Ile Leu Asp Met Leu Lys Gly Asp Met Glu Leu Gly Asp 20 25 30

Met Asp Lys 35 <210> 373 <211> 25

<212> PRT <213> Plasmodium falciparum <400> 373

His Ile Lys Gly Leu Glu Glu Asp Asp Leu Glu Glu Val Asp Asp Leu 15 10 15

Lys Gly Ser Ile Leu Asp Met Leu Lys 20 25 <210> 374 <211> 31

<212> PRT <213> Plasmodium falciparum <400> 374

His Ile Ile Ser Gly Asp Ala Asp Val Leu Ser Ser Ala Leu Gly Met 15 10 15

Asp Glu Glu Gin Met Lys Thr Arg Lys Lys Ala Gin Arg Pro Lys 20 25 30 <210> 375 <211> 23

<212> PRT <213> Plasmodium falciparum <400> 375

His Asp Ile Thr Thr Thr Leu Asp Glu Val Val Glu Leu Lys Asp Val 15 10 15

Glu Glu Asp Lys Ile Glu Lys 20 <210> 376 <211> 10

<212> PRT <213 > Plasmodium falciparum <400> 376

Lys Lys Leu Glu Glu Val His Glu Leu Lys 15 10 153 <210> 377 <211> 9

<212> PRT <213> Plasmodium falciparum <400> 377

Lys Leu Glu Glu Val His Glu Leu Lys 1 5 <210> 378 <211> 19

<212> PRT <213> Plasmodium falciparum <400> 378

Lys Thr Ile Glu Thr Asp Ile Leu Glu Glu Lys Lys Lys Glu Ile Glu 15 10 15

Lys Asp His <210> 379 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 379

Lys Lys Glu Ile Glu Lys Asp His Phe Glu Lys 15 10 <210> 380 <211> 6

<212> PRT <213> Plasmodium falciparum <400> 380

Lys Asp His Phe Glu Lys 1 5 <210> 381 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 381

Lys Phe Glu Glu Glu Ala Glu Glu Ile Lys His 15 10 <210> 382 <211> 47

<212> PRT <213> Plasmodium falciparum 154 <400> 382 Lys 1 Asp Gly Asp Thr 5 Lys Cys Thr Leu Glu 10 Cys Ala Gin Gly Lys 15 Lys Cys Ile Lys His 20 Lys Ser Asp His Asn 25 His Lys Ser Asp His 30 Asn His Lys Ser Asp 35 Pro Asn His Lys Lys 40 Lys Asn Asn Asn Asn 45 Asn Lys <210> 383 <211> 40

<212> PRT <213> Plasmodium falciparum <400> 383

Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gin Gly Lys Lys 1 5 10 15 Cys Ile Lys His Lys Ser Asp His Asn Hxb Lys Ser Asp His Asn His 20 25 30 Lys Ser Asp Pro Asn His Lys Lys 35 40 <210> 384 <211> 39

<212> PRT <213> Plasmodium falciparum <400> 384

Lys 1 Asp Gly Asp Thr 5 Lys Cys Thr Leu Glu 10 Cys Ala Gin Gly Lys 15 Lys Cys Ile Lys His 20 Lys Ser Asp His Asn 25 His Lys Ser Asp His 30 Asn His Lys Ser Asp 35 Pro Asn His Lys <210> 385 <211> 33

<212> PRT <213> Plasmodium falciparum <400> 385

Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gin Gly Lys Lys 15 10 15

Cys Ile Lys His Lys Ser Asp His Asn His Lys 'Ser Asp His Asn His 20 25 30

Lys 155

74.\IiU <210> 386 <211> 27

<212> PRT <213> Plasmodium falciparum <400> 3B6

Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gin Gly LyB Lys 1. 5 10 15

Cys Ile Lys His Lys Ser Asp His Asn His Lys 20 25 <210> 387 <211> 21

<212> PRT <213> Plasmodium falciparum <400> 387

Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gin Gly Lys Lys 15 10 15

Cys Ile Lys His Lys 20 <210> 388 <211> 16

<212> PRT <213> Plasmodium falciparum <400> 388

Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gin Gly Lys Lys • 1 5 10 15 <210> 389 <211> 15

<212> PRT <213> Plasmodium falciparum <400> 389

Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gin Gly Lys 1 5 10 15 <210> 390 <211> 23

<212> PRT <213> Plasmodium falciparum <400> 390

Lys Cys Ile Gin Ala Glu Cys Asn Tyr Lys Glu Cys Gly Glu Gin Lys 1 5 10 15

Cys Val Trp Asp Gly Ile His 20 156 <210> 391 <211> 14

<212> PRT <213> Plasmodium falciparum <400> 391

Lys Glu Cys Gly Glu Gin Lys Cys Val Trp Asp Gly lie His 15 10 <210> 392 <211> 32

<212> PRT <213> Plasmodium falciparum <400> 392

His He Glu Cys Lys Cys Asn Asn Asp Tyr Val Leu Thr Asn Arg Tyr 1 5 10 · 15

Glu Cys Glu Pro Lys Asn Lys Cys Thr Ser Leu Glu Asp Thr Asn Lys 20 25 30 <210> 393 <211> 39

<212> PRT <213> Plasmodium falciparum <400> 393

Lys Ser Asp His Asn His Lys Ser Asp His Asn His Lys Ser Asp His 1 5 10 15 Asn His Lys Ser Asp His Asn His Lys Ser Asp Pro Asn His Lys Lye 20 25 30 Lys Asn Asn Asn Asn Asn Lys 35 <210> 394 <211> 33

<212 > PRT <213 > Plasmodium falciparum <400> 394

Lys 1 Ser Asp His Asn His Lys Ser Asp His Asn His Lys Ser Asp 5 10 15 Asn His Lys Ser Asp Pro Asn His Lys Lys Lys Asn Asn Asn Asn 20 25 30

Lys <210> 395 <211> 27 157

<212 > PRT <213 s· Plasmodium falciparum <400> 395

Lys Ser Asp His Asn His Lys Ser Asp His Asn His Lys Ser Asp Pro 15 10 15

Asn His Lys Lys Lys Asn Asn Asn Asn Asn Lys 20 25 <210> 396 <211> 21

<212> PRT <213> Plasmodium falciparum <400> 396

Lye Ser Asp His Asn His Lys Ser Asp Pro Asn His Lys Lys Lys Asn 15 10 15

Asn Asn Asn Asn Lys 20 <210> 397 <211> 18

<212> PRT <213> Plasmodium falciparum <400> 397

Lys Lys Lys Asn Asn Asn Asn Asn Lys Asp Asn Lys Ser Asp Pro Asn 1 5 10 15

His Lys <210> 398 <211> 17

<212> PRT <213> Plasmodium falciparum <400> 398

Lys Lys Asn Asn Asn Asn Asn Lys Asp Asn Lys Ser Asp Pro Asn His 15 10 15

Lys <210> 399 <211> 16

<212> PRT <213> Plasmodium falciparum <400> 399

Lys Asn Asn Asn Asn Asn Lys Asp Asn Lys Ser Asp Pro Asn His Lys 15 10 15 158

iOUZO <210> 400 <211> 10

<212> PRT <213 > Plasmodium falciparum <400> 400

Lys Asp Asn Lys Ser Asp Pro Asn His Lys 15 10 <210> 401 <211> 7

<212s· PRT <213> Plasmodium falciparum <400> 401

Lys Ser Asp Pro Asn His Lys 1 5 <210> 402 <211s» 35

<212> PRT <213 > Plasmodium falciparum <400> 402

His Ser Leu Tyr Ala Leu Gin Gin Asn Glu Glu Tyr Gin Lys Val Lys 1 5 10 15 Asn Glu Lys Asp Gin Asn Glu Ile Lys Lys lie Lys Gin Leu Ile Glu 20 25 30

Lys Asn Lys 35 <210> 403 <211> 28

<212> PRT <213> Plasmodium falciparum <400> 403

His 1 Ser Leu Tyr Ala 5 Leu Gin Gin Asn Glu 10 Glu Tyr Asn Glu Lys Asp Gin Asn Glu Ile Lys Lys Ile Lys 20 25 15 <210> 404 <211> 26

<212> PRT <213> Plasmodium falciparum <400> 404

His Ser Leu Tyr Ala Leu Gin Gin Asn Glu Glu Tyr Gin Lys Val Lys 15 10 15 159

Asn Glu Lys Asp Gin Asn Glu Ile Lys Lys 20 25 <210> 405 <211> 25

<212> PRT <213> Plasmodium falciparum <400> 405

His Ser Leu Tyr Ala Leu Gin Gin Asn Glu Glu Tyr Gin Lys Val Lys 1 . 5 10 15

Asn Glu Lys Asp Gin Asn Glu Ile Lys 20 25 <210> 406 <211> 11

<212 > PRT <213> Plasmodium falciparum <400> 406

His Lys Leu Glu Asn Leu Glu Glu Met Asp Lys 15 10 <210> 407 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 407

Lys His Phe Asp Asp Asn Thr Asn Glu Gin Lys 15 10 <210> 408 <211> 8

<212> PRT <213> Plasmodium falciparum <400> 408

Lys Lys Glu Asp Asp Glu Lys His 1 5 <210> 409 <211> 13

<212> PRT <213> Plasmodium falciparum <400> 409

Lys Glu Glu Asn Asn Lys Lys Glu Asp Asp Glu Lys His 15 10 160 y/uzo <210> 410 <211> 21

<212 > PRT <213> Plasmodium falciparum <400> 410

Lys Thr Ser Ser Gly lie Leu Asn Lys Glu Glu Asn Asn Lys Lys Glu 15 10 15

Asp Asp Glu Lys His 20 <210> 411 <211> 7

<212> PRT <213 > Plasmodium falciparum <400> 411

Lys Asn Ile His Ile Lys Lys 1 5 <210> 412 <211> 13

<212> PRT <213> Plasmodium falciparum <400> 412

His lie Lys Lys Lys Glu Gly Ile Asp Ile Gly Tyr Lys 15 10 <210> 413 <211> 21

<212> PRT <213> Plasmodium falciparum <400> 413

Lys Lys Met Trp Thr Cys Lys Leu Trp Asp Asn Lys Gly Asn Glu lie 15 10 15

Thr Lys Asn Ile His 20 <210> 414 <211> 30

<212> PRT <213> Plasmodium falciparum <400> 414

Lys Lys Gly Ile Gin Trp Asn Leu Leu Lys Lys Met Trp Thr Cys Lys 15 10 15

Leu Trp Asp Asn Lys Gly Asn Glu lie Thr Lys Asn Ile His 20 25 30 161 <210> 415 c211> 50

<212> PRT <213 > Plasmodium falciparum <4D0> 415

Lys 1 Glu Lys Lys Asp 5 Ser Asn Glu Asn Arg 10 Lys Lys Lys Gin Lys 15 Glu Asp Lys Lys Asn 20 Pro Asn Lys Leu Lys 25 Lys Ile Glu Tyr Thr 30 Asn Lys Ile Thr His Phe Phe Lys Ala Lys Asn Asn Lys Gin Gin Asn Asn Val 35 40 45

Thr His 50 <210> 416 <211> 48

<212> PRT <213> Plasmodium falciparum <400> 416

Lys 1 Lys Asp Ser Asn 5 Glu Asn Arg Lys Lys 10 Lys Gin Lys Glu Asp 15 Lys Lys Asn Pro Asn 20 Lys Leu Lys Lys Ile 25 Glu Tyr Thr Asn Lys 30 Ile Thr His Phe Phe 35 Lys Ala Lys Asn Asn 40 Lys Gin Gin Asn Asn 45 Val Thr His <210> 417 <211> 47

<212> PRT <213 > Plasmodium falciparum <400> 417

Lys 1 Asp Ser Asn Glu 5 Asn Arg Lys Lys Lys 10 Gin Lys Glu Asp Lys 15 Lys Asn Pro Asn Lys 20 Leu Lys Lys Ile Glu 25 Tyr Thr Asn Lys Ile 30 Thr His Phe Phe Lys Ala Lys Asn Asn Lys Gin Gin Asn Asn Val Thr His 35 40 45 <210> 418 <211> 39

<212> PRT <213> Plasmodium falciparum 162 yyuzo <400> 418

Lys Lys Gin Lys Glu Asp Lys Lys Asn Pro Asn Lys Leu Lys Lys Ile 1 5 10 15 Glu Tyr Thr Asn Lys Ile Thr His Phe Phe Lys Ala Lys Asn Asn Lys 20 25 30 Gin Gin Asn Asn Val Thr His 35 <210> 419 <211> 38

<212> PRT <213> Plasmodium falciparum <400> 419

Lys Gin Lys Glu Asp Lys Lys Asn Pro Asn Lys Leu Lys Lys Ile Glu 1 5 10 15 Tyr Thr Asn Lys Ile Thr His Phe Phe Lys Ala Lys Asn Asn Lys Gin 20 25 30 Gin Asn Asn Val Thr His 35 <210> 420 <211> 36

<212> PRT <213 > Plasmodium falciparum <400> 420

Lys Glu Asp Lys Lys Asn Pro Asn Lys Leu Lys Lys Ile Glu Tyr Thr 1 5 10 15 Asn Lys Ile Thr His Phe Phe Lys Ala Lys Asn Asn Lys Gin Gin Asn 20 25 30

Asn Val Thr His 35 <210> 421 <211> 32

<212> PRT <213> Plasmodium falciparum <400> 421

Lys Asn Pro Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys Ile Thr 15 10 15

His Phe Phe Lys Ala Lys Asn Asn Lys Gin Gin Asn Asn Val Thr His 20 25 30 <210> 422 <211> 26 163

J.UUUZO

<212> PRT <213> Plasmodium falciparum <400> 422

Lys Lys Ile Glu Tyr Thr Asn Lys Ile Thr Hie Phe Phe Lys Ala Lys 15 10 15

Asn Asn Lys

Gin Gin Asn Asn Val 20

Thr His 25 <210> 423 <212> 25

<212> PRT <213> Plasmodium falciparum <400> 423

Lys Ile Glu Tyr Thr Asn Lys Ile Thr His Phe Phe Lys Ala Lys Asn 15 10 15

Asn Lys Gin Gin Asn Asn Val Thr His 20 25 <210> 424 <211> 19

<212> PRT <213> Plasmodium falciparum <400> 424

Lys Ile Thr His Phe Phe Lys Ala Lys Asn Asn Lys Gin Gin Asn Asn 15 10 15

Val Thr His <210> 425 <211> 48

<212> PRT <213> Plasmodium falciparum <400> 425

His Lys Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys 1 5 10 15 Asn Asp Asn Ser Lys Asp Ile Lys Asn Asp Asn Ser Lys Αθρ Ile Lys 20 25 30 Asn Asp Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys 35 40 45 <210> 426 <211> 45

<212> PRT <213> Plasmodium falciparum 164

iUI UZD <400> 426 He Lys Asn Asp Asn Ser Lys Asp lie Lys His Lys 1 Asn Asn Glu 5 Asp 10 15 Asn Asp Asn Ser Lys Asp He Lys Asn Asp Asn Ser Lys Asp He Lye 20 25 30 Asn Asp Asn Asn Glu Asp lie Lys Asn Asp Abu Ser Lys 35 40 45 <210> 427 <211> 40

<212> PRT <213> Plasmodium falciparum <400> 427

His Lys Asn Asn Glu Asp lie Lys Asn Asp Asn Ser Lys Asp lie Lys 1 5 10 15 Asn Asp Asn Ser Lys Asp He Lys Asn Asp Asn Ser Lys Asp He Lys 20 25 30 Asn Asp Asn Asn Glu Asp He Lye 35 40 <210> 428 <211> 32

<212> PRT <213> Plasmodium falciparum <400> 428

His Lys Asn Asn Glu Asp lie Lys Asn Asp Asn Ser Lys Asp He Lys 1 5 10 15

Aan Asp Asn Ser Lys Asp He Lys Asn Asp Asn Ser Lys Asp He Lys 20 25 30 <210> 429 <211> 29

<212> PRT <213> Plasmodium falciparum <400> 429

His Lys Asn Asn Glu Asp He Lys Asn Asp Asn Ser Lys Asp He Lys 15 10 15

Asn Asp Asn Ser Lys Asp lie Lys Asn Asp Asn Ser Lys 20 25 <210> 430 <211> 24

<212> PRT <213> Plasmodium falciparum 165 ιυζηζο <400> 430

His Lys Αβπ Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys 1 5 10 ’ 15

Asn Asp Asn Ser Lys Asp Ile Lys 20 <210> 431 <211> 21

<212> PRT <213> Plasmodium falciparum <400> 431

His Lys Asn Asn Glu Asp lie Lys Asn Asp Asn Ser Lys Asp lie Lys 15 10 15

Asn Asp Asn Ser Lys 20 <210> 432 <211> 16

<212> PRT <213> Plasmodium falciparum <400> 432

His Lys Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys 15 10 15 <210> 433 <2115 8

<212> PRT <213> Plasmodium falciparum <4005 433

His Lys Asn Asn Glu Asp Ile Lys 1 5 <2105 434 <2115 31

<212> PRT <2135 Plasmodium falciparum <400> 434

Lys Lys Tyr Asp Asp Leu Gin Asn Lys Tyr Asn Ile Leu Asn Lys Leu 15 10 15

Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His 20 25 30 <2105 435 <2115 30

<2125 PRT <2135 Plasmodium falciparum 166 <400> 435

Lys Tyr Asp Asp Leu Gin Asn Lys Tyr Asn lie Leu Asn Lys Leu Lys 15 10 15

Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His 20 25 30 <210> 436 <211> 23

<212> PRT <213> Plasmodium falciparum <400> 436

Lys Tyr Asn Ile Leu Asn Lys Leu Lys Asn Ser Leu Glu Glu Lys Asn 15 10 15

Glu Glu Leu Lys Lys Tyr His 20 <210> 437 <211> 17

<212> PRT <213> Plasmodium falciparum <400> 437

Lys Leu Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr 15 10 15

His <210> 438 <211> 15

<212> PRT <213> Plasmodium falciparum <400> 438

Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His 15 10 15 <210> 439 <211> 9

<212> PRT <213> Plasmodium falciparum <400> 439

Lys Asn Glu Glu Leu Lys Lys Tyr His 1 5 <210> 440 <211> 35

<212> PRT <213> Plasmodium falciparum 167

i\TT\14/U <400> 440

His Met Gly Asn Asn Gin Asp Ile 1 5

Pro Gin Glu Phe Lys Glu Glu Glu 20

Thr Lys Lys 35

Asn Glu Asn Val 10

Glu Glu Asp Ile 25

Tyr Asn Ile Lys 15

Ser Met Val Asn 30 <210> 441 <211> 17

<212> PRT <213> Plasmodium falciparum <400> 441

Lys Asn Ser Asn Glu Leu Lys Arg Ile Asn Asp Asn Phe Phe Lys Leu 15 10 15

His <210> 442 <211> 55

<212> PRT <213> Plasmodium falciparum <400> 442

Lys 1 Pro Cys Leu Tyr 5 Lys Lys Cys Lys Ile 10 Ser Gin Cys Leu Tyr 15 Lys Lys Cys Lys Ile 20 Ser Gin Val Trp Tip 25 Cys Met Pro Val Lys 30 Asp Thr Phe Asn Thr 35 Tyr Glu Arg Asn Asn 40 Val Leu Asn Ser Lys 45 lie Glu Asn Asn lie Glu Lys lie Pro His 50 55 <210> 443 <211> 40

<212> PRT <213> Plasmodium falciparum <400> 443

His Ile Asn Asn Glu Tyr Thr Asn Lys Asn Pro Lys Asn Cys Leu 1 5 10 15 Tyr Lys Asn Glu Glu Arg Asn Tyr Asn Asp Asn Asn Ile Lys Asp 20 25 30 Ile Asn Ser Met Asn Phe Lys Lys

Leu

Tyr 35 40 168

iU3\IZO <210> 444 <211> 39

<212> PRT <213> Plasmodium falciparum <400> 444

His lie Asn Asn Glu Tyr Thr Asn Lys Asn Pro Lys Asn Cys Leu Leu 1 5 10 15 Tyr Lys Asn Glu Glu Arg Asn Tyr Asn Asp Asn Asn · He Lys Asp Tyr 20 25 30 He Asn Ser Met Asn Phe Lys 35 <210> 445 <211> 18 <212> PRT 1 <213 > Plasmodium falciparum <400> 445

His lie Asn Asn Glu Tyr Thr Asn Lys Asn Pro Lys Asn Cys Leu Leu 15 10 15

Tyr Lys <210> 446 <211> 23

<212> PRT <213> Plasmodium falciparum <400> 446

Lys Asn Lys Thr Asn Gin Ser Lys Gly Val Lys Gly Glu Tyr Glu Lys 15 10 15

Lys Lys Glu Thr Asn Gly His 20 <210> 447 <211> 21

<212> PRT <213> Plasmodium falciparum <400> 447

Lys Thr Asn Gin Ser Lys Gly Val Lys Gly Glu Tyr Glu Lys Lys Lys 1 5 10 .15

Glu Thr Asn Gly His 20

<210> 448 <211> 16 <212> PRT 169 106\126 <213 > Plasmodium falciparum <400> 448

Lys Gly Val Lys Gly Glu Tyr Glu Lys LyB Lys Glu Thr Asn Gly His 15 10 15 <210> 449 <211> 13

<212> PRT <213> Plasmodium falciparum <400> 449

Lys Gly Glu Tyr Glu Lys Lys Lys Glu Thr Asn Gly His 15 10 <210> 450 <211> 28

<212> PRT <213> Plasmodium falciparum <400> 450

Lye Ser Gly Met Tyr Thr Asn Glu Gly Asn Lys Ser Cys Glu Cys Ser 15 10 15

Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys Val His 20 25 <210> 451 <211> 18

<212> PRT <213> Plasmodium falciparum <400> 451

Lys Ser Cys Glu Cys Ser Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys 15 10 15

Val His <210> 452 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 452

Lys Lys Lys Ser Ser Ser Ser Asn Lys Val His 15 10 <210> 453 <211> 10

<212> PRT <213> Plasmodium falciparum 170 107X126 <400> 453

Lye Lys Ser Ser Ser Ser Asn Lys Val His 15 10 <210> 454 <211> 9

<212> PRT <213> Plasmodium falciparum <400> 454

Lys Ser Ser Ser Ser Asn Lys Val His 1 5 <210> 455 <211> 30

<212> PRT <213 > Plasmodium falciparum <400> 455

His Ile Met Leu Lys Ser Gly Met Tyr Thr Asn Glu Gly Asn Lys Ser 15 10 15

Cys Glu Cys Ser Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys 20 25 30

<210> 45S <211> 24

<212> PRT <213> Plasmodium falciparum <400> 456

His Ile Met Leu Lys Ser Gly Met Tyr Thr Asn Glu Gly Asn Lys Ser 1 5 10 15

Cys Glu Cys Ser Tyr Lys Lys Lys 20 <210> 457 <211> 23

<212> PRT <213> Plasmodium falciparum <400> 457

His Ile Met Leu Lys Ser Gly Met Tyr Thr Asn Glu Gly Asn Lys Ser 1 5 10 '15

Cys Glu Cys Ser Tyr Lys Lys 20 <210> 458 <211> 22

<212> PRT <213 > Plasmodium falciparum 171 108X126 <400> 458

His Ile Met Leu Lys Ser Gly Met Tyr Thr Asn Glu Gly Asn Lys Ser 15 10 15

Cys Glu Cys Ser Tyr Lys 20 <210> 459 <211> 50

<212> PRT <213> Plasmodium falciparum <400> 459

Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gin lie Asn Lys 1 5 10 15 Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gin 20 25 30 Lys Ile Ile Ile Arg Asp Tyr His Glu Thr Leu Asn Val His Lys Leu 35 40 .45

Asp His 50 <210> 460 <211> 43

<212> PRT <213 > Plasmodium falciparum <400> 460

Lys Arg Glu Lys Thr Gin Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp 1 5 10 15 Val lie Ile Asp Asn Thr Glu Ile Gin Lys Ile Ile Ile Arg Asp Tyr 20 25 30 His Glu Thr Leu Asn Val His Lys Leu Asp His 35 40 <210> 461 <211> 40

<212> PRT <213> Plasmodium falciparum <400> 461

Lys Thr Gin Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile 1 5 10 15 Asp Asn Thr Glu Ile Gin Lys Ile lie Ile Arg Asp Tyr His Glu Thr 20 25 30 Leu Asn Val His Lys Leu Asp His 35 40 172 I09X1Z6 <210> 462 <211> 46

<212;- PRT <213 > Plasmodium falciparum <400> 462

Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gin Ile Asn Lys 1 5 10 15 Thr Lys Tyr Glu Arg Gly Asp Val Ile lie Asp Asn Thr Glu Ile Gin 20 25 30 Lys Ile lie Ile Arg Asp Tyr His Glu Thr Leu Asn Val His 35 40 45 <210> 463 <211> 40

<212> PRT <213> Plasmodium falciparum <400> 463

Lys Pro Leu Ala Lys Leu Arg Lys 1 5

Thr Lys Tyr Glu Arg Gly Asp Val 20

Lys Ile lie Ile Arg Asp Tyr His 35 40

Arg Glu 10 Lys Thr Gin Ile Asn 15 Lys Ile 25 Ile Asp Asn Thr Glu 30 Ile Gin <210> 464 <211> 36

<212> PRT <213> Plasmodium falciparum <400> 464

Lys Leu Arg Lys Arg Glu Lys Thr Gin Ile Asn Lys Thr Lys Tyr 1 5 10 15 Afg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gin Lys He Ile 20 25 30

Arg Asp Tyr His 35 <210> 465 <211> 33

<212> PRT <213> Plasmodium falciparum <400> 465

Lys Arg Glu Lys Thr Gin Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp 15 10 15 173 ί ιυ\ιζο

Val lie He Asp Asn Thr Glu He 20

His

Gin Lys lie He lie Arg Asp Tyr 25 30 <210> 466 <211> 30

<212> PRT <213> Plasmodium falciparum <400> 466

Lys Thr Gin He Asn Lys Thr Lys 1 5

Asp Asn Thr Glu lie Gin Lys He 20

Tyr Glu Arg Gly Asp Val He He 10 15

He He Arg Asp Tyr His 25 30 <210> 467 <211> 41

<212> PRT <213> Plasmodium falciparum <400> 467

Lys 1 Lys Asp Lys Glu 5 Lys Lys Lys Lys Gin Lys Glu 20 Asp Lys Lys Asn lie Glu Tyr 35 Thr Asn Lys He Thr 40

Asp Ser Asn Glu Asn Arg Lys Lys 10 15 Pro Asn Asp Asn Lys Leu Lys Lys 25 30 His <210> 468 <211> 40

<212> PRT <213> Plasmodium falciparum <400> 468

Lys 1 Asp Lys Glu Lys 5 Lys Lys Asp Gin Lys Glu Asp 20 Lys Lys Asn Pro Glu Tyr Thr 35 Asn Lys lie Thr His 40

Ser· Asn Glu Asn Arg Lys Lys Lys 10 15

Asn Asp Asn Lys Leu Lys Lys lie 25 30 <210> 469 <211> 38

<212> PRT <213> Plasmodium falciparum 174 ιη\ιχο <400> 469

Lys Glu Lys Lys Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys Gin Lys 1 5 10 15 Glu Asp Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu Tyr 20 25 30 Thr Asn Lys Ile Thr His 35 <210> 470 <211> 36

<212> PRT <213> Plasmodium falciparum <400> 470

Lys Lys Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys Gin Lys Glu Asp 1 5 10 15

Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn 20 25 30

Lys Ile Thr His 35 <210> 471 <211> 35

<212> PRT <213> Plasmodium falciparum <400> 471

Lys Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys Gin Lys Glu Asp Lys 15 10 15

Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys 20 25 30 lie Thr His 35 <210> 472 <211> 34

<212> PRT <213> Plasmodium falciparum <400> 472

Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys Gin Lys Glu Asp Lys Lys 15 10 15

Asn Pro Asn Asp Asn Lys Leu Lys Lys lie Glu Tyr Thr Asn Lys Ile 20 25 30

Thr His 175 <2105 473 <211> 27

<2125 PRT <213> Plasmodium falciparum <400> 473

Lys Lys Lys Gin Lys Glu Asp LyB Lys Asn Pro Asn Asp Asn Lys Leu 15 ID 15

Lys Lys lie Glu Tyr Thr Aen Lys Ile Thr His 20 25 <21D> 474 <211> 26

<212> PRT <213> Plasmodium falciparum <400> 474

Lys Lys Gin Lys Glu Asp Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys 15 ID 15

Lys Ile Glu Tyr Thr Asn Lys Ile Thr His 20 25 <210> 475 <2115 25

<2125 PRT <2135 Plasmodium falciparum <4005 475

Lye Gin Lys Glu Asp Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys 1 ' 5 10 15

Ile Glu Tyr Thr Asn Lys Ile Thr His 20 25 <210> 476 <2115 23

<2125 PRT <213> Plasmodium falciparum <400> 476

Lys Glu Asp Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu 15 10 15

Tyr Thr Asn Lys Ile Thr His 20 <2105 477 <211> 20

<212> PRT <2135 Plasmodium falciparum 176 <400> 477

Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn 15 10 15

Lys lie Thr His 20 <210> 478 <211> 19

<212> PRT <213> Plasmodium falciparum <400> 478

Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys 15 10 15

Ile Thr His <210> 479 <211> 13

<212> PRT <213> Plasmodium falciparum <400> 479

Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys Ile Thr His 15 10 <2105 480 <2115 11

<212> PRT <2135 Plasmodium falciparum <400> 480

Lys Lys Ile Glu Tyr Thr Asn Lys Ile Thr His 15 10 <210> 481 <211> 10

<212> PRT <213> Plasmodium falciparum <400> 481

Lys Ile Glu Tyr Thr Asn Lys lie Thr His 15 10 <210> 482 <211> 44

<212 > PRT <213> Plasmodium falciparum <400> 482

His Gly Gin Ile Lys Ile Glu Asp Val Asn Asn Glu Asn Phe Asn Asn 15 10 15 177

ll^UZO

Glu Gin Met Lys Asn Lys Tyr Asn Asp Glu Glu Lys Met Asp Ile Ser 20 25 30

Lys Ser Lys Ser Leu Lys Ser Asp Phe Leu Glu Lys 35 40 <210> 483 <211> 38

<212> PRT <213> Plasmodium falciparum <400> 483

His 1 Gly Gin Ile Lys 5 Ile Glu Asp Val Asn 10 Asn. Glu Asn Phe Asn 15 Glu Gin Met Lys Asn Lys Tyr Asn Asp Glu Glu Lys Met Asp Ile 20 25 30 Lys Ser Lys Ser Leu Lys 35 <210i- 484 <211> 35

<212> PRT <213 s- Plasmodium falciparum <400> 484

His Gly Gin Ile Lys Ile Glu Asp Val Asn Asn Glu Asn Phe Asn Asn 15 10 15

Glu Gin Met Lys Asn Lys Tyr Asn Asp Glu Glu Lys Met Asp Ile Ser 20 25 30

Lys Ser Lys 35 <210> 485 <211> 33 .

<212> PRT <213> Plasmodium falciparum <400> 485

His Gly Gin Ile Lys Ile Glu Asp Val Asn Asn Glu Asn Phe Asn Asn 15 10 15

Glu Gin Met Lys Asn Lys Tyr Asn Asp Glu Glu Lys Met Asp lie Ser 20 25 30

Lys <210> 486 <211> 31 <212> PRT 178

113UZO <213 > Plasmodium falciparum <400> 485

Lys Lys Tyr Asp Asp Leu Gin Asn Lys Tyr Asn Ile Leu Asn Lys Leu 15 10 15

Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His 20 25 30 <210> 487 <211> 30

<212> PRT <213> Plasmodium falciparum <400> 487

Lys Tyr Asp Asp Leu Gin Asn Lys Tyr Asn Ile Leu Asn Lys Leu Lys 1 5 10 15 Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His 20 25 30 <210> 488 <211> 23

<212> PRT <213> Plasmodium falciparum <400> 488

Lys Tyr Asn Ile Leu Asn Lys Leu Lys Asn Ser Leu Glu Glu Lys Asn 1 5 10 15

Glu Glu Leu Lys Lys Tyr His 20 <210> 489 <211> 17

<212> PRT <213> Plasmodium falciparum <400> 489

Lys Leu Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr 15 10 15

His <210> 490 <211> 15

<212> PRT <213> Plasmodium falciparum <400> 490

Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His 15 10 15 179

liOUZO <210> 491 <211> 9

<212> PRT <213> Plasmodium falciparum <400> 491

Lys Asn Glu Glu Leu Lys Lys Tyr His 1 5 <210> 492 <211> 44

<212> PRT <213> Plasmodium falciparum <400> 492

His 1 Met Gly Asn Asn 5 Gin Asp He Asn Glu 10 Asn Val Tyr Asn He 15 Lys Pro Gin Glu Phe 20 Lys Glu Glu Glu Glu 25 Glu Asp lie Ser Met 30 Val Asn Thr Lys Lys Cys Asp Asp lie Gin GlU Abu He Lys 35 40 <210> 493 <211> 50

<212> PRT <213> Plasmodium falciparum <400> 493

Lys Thr Asn Leu Tyr Asn lie Tyr Asn Asn Lys Asn Asp Asp Lys Asp 1 5 10 15 Asn lie Leu Asp Asn Glu Asn Arg Glu Gly Leu Tyr Leu Cys Asp Val 20 25 30 Met Lys Asn Ser Asn Glu Leu Lys Arg He Asn Asp Asn Phe Phe Lys 35 40 45

Leu His 50 <210> 494 <211> 17

<212> PRT <213> Plasmodium falciparum <400> 494

Lys Asn Ser Asn Glu Leu Lys Arg lie Asn Asp Asn Phe Phe Lys Leu 15 10 15

His 180 11 / \iiu <210> 495 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 495

Lys Arg Ile Asn Asp Asn Phe Phe Lys Leu His 15 10 <210> 496 <211> 40

<212> PRT <213> Plasmodium falciparum <400> 496

His 1 Ile Asn Asn Glu 5 Tyr Thr Asn Lys Asn 10 Pro Lys ASXl Cys Leu 15 Leu Tyr Lys Asn Glu 20 Glu Arg Asn Tyr Asn 25 Asp Asn Asn lie Lys 30 Asp Tyr lie Asn Ser Met Asn Phe Lys Lys 35 40 <210> 497 <211> 39

<212> PRT <213> Plasmodium falciparum <400> 497

His lie Asn Asn Glu Tyr Thr Asn Lys Asn Pro Lys Asn Cys Leu Leu 1 5 10 15 Tyr Lys Asn Glu Glu Arg Asn Tyr Asn Asp Asn Asn Ile Lys Asp Tyr 20 25 30 Ile Asn Ser Met Asn Phe Lys 35 <210> 496 <211> 18

<212> PRT <213> Plasmodium falciparum <400> 498

His Ile Asn Asn Glu Tyr Thr Asn Lys Asn Pro Lys Asn Cys Leu Leu 15 10 15

Tyr Lys <210> 499 <211> 45

<212> PRT <213> Plasmodium falciparum 181 ί ι ο \ίύυ <400> 499

Lys Pro Cys Leu Tyr Lys Lys Cys Lys Ile Ser Gin Val Trp Trp Cys 1 5 10 15 Met Pro Val Lys Asp Thr Phe Asn Thr Tyr Glu Arg Asn Aen Val Leu 20 25 30 Asn Ser Lys Ile Glu Asn Asn lie Glu Lys Ile Pro His 35 ' 40 45 <210> 500 <211> 39

<212 > PRT <213> Plasmodium falciparum <400> 500

Lys Cys Lys Ile Ser Gin Val Trp Trp Cys Met Pro Val Lys Asp Thr 1 5 10 15 Phe Asn Thr Tyr Glu Arg Asn Asn Val Leu Asn Ser Lys Ile Glu Asn 20 25 30 Asn Ile Glu Lys Ile Pro His 35 <210> 501 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 501

Lys Ile Glu Asn Asn lie Glu Lys Ile Pro His 15 10 <210> 502 <211> 23

<212> PRT <213> Plasmodium falciparum <400> 502

Lys Asn Lys Thr Asn Gly Ser Lys Gly Val Lys Gly Glu Tyr Glu Lys 15 10 15

Lys Lys Glu Thr Asn Gly His 20 <210> 503 <211> 21

<212> PRT <213> Plasmodium falciparum 182 X x.x \x^v <400> 503

Lys Thr Asn Gly Ser Lys Gly Val Lys Gly Glu Tyr Glu Lys Lys Lys 15 10 15

Glu Thr Asn Gly His 20 <210> 504 <211> 16

<212> PRT <213> Plasmodium falciparum <400> 504

Lys Gly Val Lys Gly Glu Tyr Glu Lys Lys Lys Glu Thr Asn Gly His 15 10 15 <210> 505 <211> 13

<212> PRT <213> Plasmodium falciparum <400> 505

Lys Gly Glu Tyr Glu Lys Lys Lys Glu Thr Asn Gly His 15 10 <210> 506 <211> 60

<212> PRT <213> Plasmodium falciparum <400> 506

Lys 1 Thr Ile Glu Lys 5 lie Asn Lys Ser Lys 10 Ser Tarp Phe Phe Glu 15 Glu Leu Asp Glu Ile 20 Asp Lys Pro Leu Ala 25 Lys Leu Arg Lys Arg 30 Glu Lys Thr Gin Ile 35 Asn Lys Thr Lys Tyr 40 Glu Arg Gly Asp Val 45 Ile Ile Asp Αθη Thr 50 Glu Ile Gin Lys Ile 55 Ile Arg Asp Tyr His 60 <210> 507 <211> 56

<212> PRT <213 > Plasmodium falciparum <400> 507

Lys Ile Asn Lys Ser Lys Ser Trp Phe Phe Glu Glu Leu Asp Glu Ile 1 5 10 15 Asp Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gin Ile Asn 20 25 30 183 i-ΛΛί

Lys Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile 35 40 45

Gin Lys Ile Ile Arg Asp Tyr His 50 55 <210> 508 <211> 39

<212> PRT <213> Plasmodium falciparum <400> 508

Lys 1 Pro Leu Ala Lys 5 Leu Arg Lys Arg Glu 10 Lys Thr Gin Ile Asn 15 Lys Thr Lys Tyr Glu 20 Arg Gly Asp Val Ile 25 Ile Asp Asn Thr Glu 30 lie Gin Lys Ile Ile 35 Arg Asp Tyr His <210=. 509 <211=. 32

<212> PRT <213=. Plasmodium falciparum <400=> 509

His 1 lie Met Leu Lys Ser Gin 5 Met Tyr Thr Asn Glu Gly Asn Lys Ser 10 15 Cys Glu Cys Ser Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys Val His 20 25 30 <210=· 510 <211> 35

<212> PRT <213> Plasmodium falciparum <400=· 510

Lys Leu Arg Lys Arg Glu Lys Thr Gin Ile Asn Lys Thr Lys Tyr Glu 1 5 . 10 15

Arg Gly Asp Val lie Ile Asp Asn Thr Glu Ile Gin Lys Ile Ile Arg 20 25 30

Asp Tyr His 35 <210> 511 <211> 32

<212=> PRT <213 > Plasmodium falciparum 184 <4D0> 511

Lys Arg Glu Lys Thr Gin lie Asn 1 5

Val Ile Ile Asp Asn Thr Glu Ile 20

Lys Thr Lys 10

Gin Lys Ile 25

Tyr Glu Arg

Ile Arg Asp 30

Gly Asp 15

Tyr His <210> 512 <211> 29

<212> PRT <213 > Plasmodium falciparum <400> 512

Lys Thr Gin Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile 15 10 15

Asp Asn Thr Glu lie Gin Lys lie lie Arg Asp Tyr His 20 25 <210> 513 <211> 48

<212> PRT <213> Plasmodium falciparum <400> 513 Lys 1 Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gin Ile Asn 15 Lys 5 10 Thr Lys Tyr Glu 20 Arg Gly Asp Val Ile Ile Asp 25 Asn Thr Glu 30 Ile Gin Lys Ile Ile Arg Asp Tyr His Thr Leu Asn Val His Lys Leu Asp His 35 40 45 <210> 514 <211> 44

<212> PRT <213> Plasmodium falciparum <400> 514 Lys 1 Leu Arg Lys Arg Glu Lys Thr Gin Ile Asn Lys Thr Lys Tyr 15 Glu 5 10 Arg Gly Asp Val Ile Ile Asp Asn Thr Glu lie Gin Lys Ile Ile Arg 20 25 30 Asp Tyr His Thr Leu Asn Val His Lys Leu Asp His 35 40 <210> 515 <211> 41

<212> PRT <213> Plasmodium falciparum 185 <400> 515 Ile Asn Lys Thr 10 Lys Tyr Glu Arg Lys 1 Arg Glu Lye Thr Gin 5 Val lie lie Asp 20 Asn Thr Glu Ile Gin 25 Lys Ile Ile Arg Asp 30 Thr Leu Asn Val His Lys Leu Asp His 35 40

Gly Asp 15

Tyr His <210> 516 <211> 38

<212> PRT <213> Plasmodium falciparum <400> 516

Lys Thr Gin Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile 15 10 15

Asp Asn Thr Glu Ile Gin Lys Ile lie Arg Asp Tyr His Thr Leu Asn 20 25 30

Val His Lys Leu Asp His 35 <210> 517 <211> 44

<212> PRT <213> Plasmodium falciparum <400> 517

Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gin Ile Asn Lys 1 ' 5 10 15

Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gin 20 25 30

Lys Ile Ile Arg Asp Tyr His Thr Leu Asn Val His 35 40 <210> 518 <211> 40

<212> PRT <213> Plasmodium falciparum <400> 518 Lys 1 Leu Arg Lys Arg Glu 5 Lys Thr Gin lie Asn Lys Thr Lys Tyr Glu 10 15 Arg Gly Asp Val lie lie Asp Asn Thr Glu lie Gin Lys lie lie Arg 20 25 30 Asp Tyr His Thr Leu Asn Val His 35 40 186 <210> 519 <211> 37

<212> PRT <213> Plasmodium falciparum <400> 519

Lys Arg Glu Lys Thr Gin lie Asn Lys Thr Lys Tyr Glu Arg Gly Asp 1 5 10 15 Val He He Asp Asn Thr Glu He Gin Lys He He Arg Asp Tyr His 20 25 30 Thr Leu Asn Val His 35 <210> 520 <211> 34

<212 > PRT <213 > Plasmodium falciparum <400> 520

Lys Thr Gin lie Asn Lys Thr Lys Tyr Glu Arg Gly Asp Val He lie 15 10 15

Asp Asn Thr Glu He Gin Lys lie He Arg Asp Tyr His Thr Leu Asn 20 25 30

Val His <210> 521 <211> 32

<212> PRT <213> Plasmodium falciparum <400> 521 His He Met 1

Cys Glu Cys

Leu Lys Ser Gin Met 5

Ser Tyr Lys Lys Lys 20

Tyr Thr Asn Glu Gly Asn Lys Ser 10 15

Ser Ser Ser Ser Asn Lys Val His 25 30 <210> 522 <211> 28

<212> PRT <213> Plasmodium falciparum <400> 522

Lys Ser Gin Met Tyr Thr Asn Glu Gly Asn Lys Ser Cys Glu Cys Ser 1 5 10 15

Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys Val His 20 25 187 <210> 523 <211> 18

<212> PRT <213> Plasmodium falciparum <400> 523

Lys Ser Cys Glu Cys Ser Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys 15 10 15

Val His <210> 524 <211> 11

<212> PRT <213> Plasmodium falciparum <400> 524

Lys Lys Lys Ser Ser Ser Ser Asn Lys Val His 15 10 <210> 525 <211> 10

<212> PRT <213> Plasmodium falciparum <400> 525

Lys Lys Ser Ser Ser Ser Asn Lys Val His 15 10 <210> 526 <211> 9

<212> PRT <213> Plasmodium falciparum <400> 526

Lys Ser Ser Ser Ser Asn Lys Val His 1 5 <210> 527 <211> 30

<212> PRT <213> Plasmodium falciparum <400> 527

His lie Met Leu Lys Ser Gin Met Tyr Thr Asn Glu Gly Asn Lys 1 5 10 15 Cys Glu Cys Ser Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys 20 25 30

<210> 528 <211> 24 <212> PRT 188 <213 > Plasmodium falciparum <400> 528

His lie Met Leu Lys Ser Gin Met Tyr Thr Asn Glu Gly Asn Lys Ser 15 10 15

Cys Glu Cys Ser Tyr Lys Lys Lys 20 <210> 529 <211> 23

<212> PRT <213> Plasmodium falciparum <400> 529

His Ile Met Leu Lys Ser Gin Met Tyr Thr Asn Glu Gly Asn Lys Ser 15 10 15

Cys Glu Cys Ser Tyr Lys Lys 20 <210> 530 <211> 22

<212> PRT <213 > Plasmodium falciparum <400> 530

His lie Met Leu Lys Ser Gin Met Tyr Thr Asn Glu Gly Asn Lys Ser 1 5 10-15

Cys Glu Cys Ser Tyr Lys 20 <210> 531 <211> 35

<212> PRT <213> Plasmodium falciparum <400> 531

His Asn Asn His Asn Ile Gin Ile Tyr Lys Asp Lys Arg lie Asn Phe 1 5 10 15 Met Asn Pro His Lys Val Met Tyr His Asp Asn Met Ser Lys Asn Glu 20 25 30 Arg Thr Glu Lys 35 <210> 532 <211> 30

<212> PRT <213> Plasmodium falciparum 189 126U26 :400> 532 .iis Asn Asn His Asn lie Gin Ile Tyr Lys Asp Lys Arg Ile Asn'''Phe 1 5 10 15 4et Asn Pro His Lys Val Met Tyr His Asp Asn Met Ser Lys 20 25 30· c210> 533 ;211> 21 ;212> PRT ;213> Plasmodium falciparum :400> 533 Iis Asn Asn His Asn Xie Gin Ile Tyr Lys Asp Lys Arg Ile Asn Phe 1 5 10 15 4et Asn Pro His Lys 20 =210> 534 <211> 17

e212> PRT c2l3> Plasmodium falciparum =400> 534 3is Lys Val Met Tyr His Asp Asn Met Ser Lys Asn Glu Arg Thr Glu 15 10 15

Lys <210> 535 <211> 11

<212> PRT <213 > Plasmodium falciparum <400> 535

Hie Lys Val Met Tyr His Asp Asn Met Ser Lys 15 10 190