Patent application title: REPLIKIN PEPTIDES IN RAPID REPLICATION OF GLIOMA CELLS AND IN INFLUENZA EPIDEMICS

Inventors: Samuel Bogoch (New York, NY, US) Elenore S. Bogoch (New York, NY, US)
IPC8 Class: AA61K39395FI
USPC Class: 4241301
Class name: IMMUNOGLOBULIN, ANTISERUM, ANTIBODY, OR ANTIBODY FRAGMENT, EXCEPT CONJUGATE OR COMPLEX OF THE SAME WITH NONIMMUNOGLOBULIN MATERIAL
Publication date: 10/29/2009
Patent application number: 20090269333

Abstract:

Peptides of influenza virus hemagglutinin protein and Plasmodium falciparum malaria antigen, antibodies specific for the peptides, influenza vaccines, malaria vaccines and methods of stimulating the immune response of a subject to produce antibodies to influenza virus or malaria are disclosed. Also disclosed are methods for formulating vaccines for influenza virus.

Claims:

1-35. (canceled)

36. An isolated or synthesized Plasmodium falciparum Replikin peptide consisting of 7 to about 50 amino acids with a lysine residue on one end of the peptide and a lysine residue or a histidine residue on the other end of the peptide wherein said peptide comprises:(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.

37. The peptide of claim 36 comprising overlapping Replikin peptide sequences.

38. An antibody that specifically binds to a Plasmodium falciparum peptide sequence of claim 36.

39. An antibody cocktail comprising a plurality of antibodies wherein each of the plurality of antibodies specifically binds to a Plasmodium falciparum peptide sequence of claim 36.

40. A composition comprising the antibody of claim 38 and a pharmaceutical composition.

41. A method of stimulating the immune system of a subject to produce antibodies to Plasmodium falciparum comprising administering to the subject an effective amount of at least one Plasmodium falciparum Replikin peptide of claim 36 and a pharmaceutically acceptable carrier.

42. The method of claim 41 wherein the Replikin peptide is located on the merozoite surface or within the parasitophorous vacuole of the Plasmodium falciparum.

43-48. (canceled)

49. A composition comprising the antibody cocktail of claim 39 and a pharmaceutical composition.

Description:

CROSS REFERENCE TO OTHER APPLICATIONS

[0001]This application is a Continuation-In-Part Application of U.S. Ser. No. 09/984,057, filed Nov. 26, 2001, which claims priority from Provisional Application 60/303,396, filed Jul. 9, 2001 and Provisional Application U.S. 60/278,761 filed. Mar. 27, 2001, the subject matter of which is incorporated by reference hereto.

FIELD OF THE INVENTION

[0002]This invention relates to the identification and use of Replikins, 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

[0003]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 future. The impact of pandemic influenza is substantial in terms of morbidity, mortality and economic cost.

[0004]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 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 be used for quantitative warning of epidemics or pandemics or to design more effective and safer vaccines.

[0005]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.

[0006]Another disease which has proved difficult to treat and for which there is no effective 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.

SUMMARY OF THE INVENTION

[0007]In one aspect of the invention there are provided isolated influenza virus peptides containing a Replikin sequence. The influenza virus 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.

[0008]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. In a preferred embodiment the composition comprises at least one peptide that is present in an emerging strain of influenza virus.

[0009]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.

[0010]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

[0011]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.

[0012]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

[0013](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.

[0014]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 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.

[0015]In another aspect, there is provided a method of selecting an influenza virus peptide for inclusion in an influenza virus vaccine comprising

[0016](1) obtaining at least one isolate of each strain of a plurality of strains of influenza virus,

[0017](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,

[0018](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),

[0019](4) identifying the strain of influenza virus having the highest increase in concentration of Replikin sequences during the at least two time periods,

[0020](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.

[0021]The present invention also provides a method of making an influenza virus vaccine comprising

[0022](1) identifying a strain of influenza virus as an emerging strain,

[0023](2) selecting at least one Replikin sequence present in the emerging strain as a peptide template for influenza virus vaccine manufacture,

[0024](3) synthesizing peptides having the amino acid sequence of the at least one Replikin sequence selected in step (2), and

[0025](4) combining a therapeutically effective amount of the peptides of step (4) with a pharmaceutically acceptable carrier and/or adjuvant.

[0026]In another aspect, the invention is directed to a method of identifying an emerging strain of influenza virus for diagnostic or therapeutic purposes comprising

[0027](1) obtaining at least one isolate of each strain of a plurality of strains of influenza virus,

[0028](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,

[0029](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), and

[0030](4) identifying the strain of influenza virus having the highest increase in concentration of Replikin sequences during the at least two time periods.

[0031]In yet another aspect of the invention, 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 carrier and/or adjuvant.

[0032]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 carrier and/or adjuvant.

[0033]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 effective amount of a vaccine comprising at least one isolated Plasmodium falciparum Replikin.

[0034]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.

[0035]As used herein, the term "peptide" refers to a compound of two or more 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 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.

[0036]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 hemagglutinin and/or neuraminidase protein sequence, relative to the concentration of replikins in other strains of influenza virus. The increase in concentration occurs 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

[0037]FIG. 1 is a bar graph depicting the frequency of occurrence of replikins in various protein groups.

[0038]FIG. 2 is a graph depicting the percentage of malignin per milligram total membrane protein during anaerobic replication of glioblastoma cells.

[0039]FIG. 3 is a bar graph showing amount of antimalignin antibody produced in response to exposure to the recognin 16-mer.

[0040]FIG. 4A is a photograph of a blood smear taken with ordinary and fluorescent light. FIG. 4B is a photograph of a blood smear taken with ordinary and fluorescent light illustrating the presence of two leukemic cells. FIG. 4C is a photograph of a dense layer of glioma cells in the presence of antimalignin antibody. FIG. 4D and FIG. 4E are photographs of the layer of cells in FIG. 4C taken at 30 and 45 minutes following addition of antimalignin antibody.

[0041]FIG. 4F is a bar graph showing the inhibition of growth of small cell lung carcinoma cells in vitro by antimalignin antibody.

[0042]FIG. 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.

[0043]FIG. 6 is a box diagram depicting an embodiment of the invention wherein a computer is used to carry out the 3-point-recognition method of identifying replikin sequences.

[0044]FIG. 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 from 1918 through 2001.

[0045]FIG. 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.

DETAILED DESCRIPTION OF THE INVENTION

[0046]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 related to the phenomenon of rapid replication, referred to herein as Replikins, provides new targets for 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.

[0047]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 ten-fold during rapid anaerobic replication of glioblastoma multiforme (glioma) cells. (FIG. 2) Malignin is a 10 KDa 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 al 6-mer peptide sequence, ykagvaflhkndide (SEQ ID NO.: 4), which is referred to herein as the glioma Replikin and which includes the shorter peptide, kagvaflhkk (SEQ ID NO.: 1), both of which apparently are absent in the normal human genome.

[0048]Table 1 illustrates how the sequence of the glioma Replikin, the 16-mer peptide sequence, ykagvaflhkkndide (SEQ ID NO.: 4) was determined.

TABLE-US-00001 TABLE 1 16-mer peptide sequence ykagvaflhkkndide obtained from malignin by hydrolysis and mass spectrometry Method By Which Fragment Obtained Auto- hydrolysis Auto- of malignin hydrolysis immobilized Micro- Seq of malignin on Micro- waved ID Fragment MH+ free in bromoacetyl waved 5 30 NO. Identified (mass) Sequence solution cellulose seconds seconds 19 1-3 381.21 ( )yka(g) + 20 1-5 537.30 ( )ykagv(a) + 21 2-6 445.28 (y)kagva(f) + 22 2-7 592.35 (Y)kagvaf(1) + 23 4-11 899.55 (a)gvaflhkk(n) + 24 5-7 336.19 (g)vaf(1) + 25 6-7 237.12 (v)af(1) + 26 6-10 615.36 (v)aflhk(k) + 27 6-10 615.36 (v)aflhk(k) + 28 6-12 857.50 (v)aflhkkn(d) + 29 6-12 857.50 (v)afhkkn(d) + 30 7-8 279.17 (a)fl(h) + 31 10-16 861.43 (h)kkndide( ) + 32 11-14 489.27 (k)kndi(d) + 33 12-15 476.2- (k)ndid(e) +

[0049]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 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 picograms (femtomolar) per cancer cell. (Bogoch et al., Cancer Detection and Prevention, 26(Supp. 1): 402 (2002).

[0050]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 homologues of the Replikin sequence was undertaken by analysis of published sequences of various organisms.

[0051]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, a new 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 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 by their investigators, See Table 2). No sequences were found to be identical to the malignin 16-mer peptide.

[0052]Table 2 illustrates several Replikin sequences that were identified by the 3-point recognition method of the invention.

TABLE-US-00002 TABLE 2 Examples of Replikins in various organisms-prototype: Glioma Replikin* kagvaflhkk (SEQ ID No.: 1) SEQ ID NO. Algae: 34 Caldophera prolifera kaskftkh 35 Isolepisprolifera kaqaetgeikgh Yeast: 36 Schizosaccharomyces pombe ksfkypkkhk 37 Oryza sativa kkaygnelhk 2 Sacch. cerevisiae replication binding protein hsikrelgiifdk Fungi: Isocitrate lyase ICI I, Penicillium marneffei kvdivthqk 38 DNA-dependent RNA polymerase 11, Diseula destructiva kleedaayhrkk 39 Ophiostoma novo-u1m 1, RNA in Dutch elm disease kvilplrgnikgiffkh 40 fungus Amoeba: 41 Entamoeba invadens, histone H2B klilkgdlnkh Bacteria: 42 Pribosomal protein replication factor, Helicobacter pylori ksvhaflk Replication-associated protein Staph. aureus 10 Mycoplasma pulinonic, chromosome replication kkektthnk 43 Macrophage infectivity potentiator, L. legionella kvhffqlkk 90 Bacillus anthracis kihlisvkk 91 Bacillus anthracis hvkkekeknk 92 Bacillus anthracis khivkievk 93 Bacillus anthracis kkkkikdiygkdallh 94 Bacillus anthracis kwekikqh 95 Bacillus anthracis kldqipppiepkkddiih 96 Bacillus anthracis hnryasnivesayllilnew- knniqsdlikk 97 Bacillus anthracis havddyagylldknqsdlv- tnskk 98 Bacillus anthracis haerlkvqknapk Plants: 44 Arabidopsis thaliana, prolifera kdhdfdgdk 45 Arabidopsis thaliana, cytoplasmic ribosomal krnkglkqkkah 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) hyddvrikndivvsrck 102 Small Pox Virus (Variola) hrfklildski 103 Small Pox Virus (Variola) kerghnyyfek Tumor 48 Rous sarcoma virus tyrosine-protem kinase kklrhek Viruses: 49 v-yes, avian sarcoma kklrhdk 50 c-yes, colon cancer, malignant melanoma kklrhdk 51 v-srcC, avian sarcoma kklrhek 52 c-src, colon, mammary, panrcreatic cancer kklrhek 53 Neuroblastoma RAS viral (v-ras) oncogene kqahelak 54 VPl (major capsid protein) [Polyamavirus sp.] kthrfskh 55 Sindbis knlhekik 56 El [Human papilloamavirus type 71] khrpllqlk 57 v-erbB from AEV and c-erb kspnhvk 58 v-fms (feline sarcoma) knihlekk 59 c-fms (acute and chronic myelomonocytic tumors) knihlekk 60 large t-antigen I [Polyomavirus sp.l kphlaqslek 61 middle t-antlgen [Polyomavirus sp, l- kqhrelkdk 62 small t-antigen [Polyomavirus spJ, kqhrelkdk 63 v-abl, murine acute leukemia kvpvlisptlkh 64 Human T-cell lymphotropic virus typo 2 kslllevdkdish 65 c-kit, GI tumors, small cell lung carcinoma kagitimvkreyh 18 Hepatitis C hyppkpgcivpak 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 (teratocarcinoma) kkkhtvkk 70 TRAF-associated NF•kB activator TANK kaqkdhlsk 71 RFP transforming protein hlkrvkdlkk 72 Transforming protein D (SC) kygspkhrlik 73 Papilloma virus type 11, transforming protein klkhilgkarfik 74 Protein tryosine kinase (EC 2.7.1.112slk kgdhvkhykirk 75 Transforming protein (axl(-)) keklrdvmvdrhk 76 Transforming protein (N-myc) klqarqqqllkkieh 77 Fibroblast growth factor 4 (Kaposi sarcoma) kkgnrvsptmkvth Cancer 78 Matrix metaloproteinase 7 (uterine) keiplhfrk Cell 79 Transcription factor 7-like kkkphikk Proteins: 80 Breast cancer antigen NY-BR-87 ktrhdplak 81 BRCA-1-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 kkkskkhkdk 86 Proto-oncogene tyrosine-protein kinase C-ABLE hksekpalprk 87 Adenomatosis polyposis coli kkkkpsrlkgdnek 88 Gastric cancer transforming protein ktkkgnrvsptmkvth 89 Transforming protein (K-RAS 2B), lung khkekmskdgkkkkkksk

[0053]Identification of an amino acid sequence as a Replikin or as containing a Replikin, i.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 histidine residue; and (3) a composition of at least 6% lysine within an amino acid sequence of 7 to about 50 residues.

[0054]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 individual proteins within each group of PubMed-classified proteins were visually 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 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 "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.

[0055]To permit classification of subtypes of Replikins, additional or "auxiliary 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 seen in Table 2.

[0056]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 were visually examined for the presence of both 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 be conserved in 78% of the 236 isolates reported in PubMed, and each amino acid was found to be conserved in individual isolates as follows: his, 95.6%; lys, 91.8%; gln 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 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 HIV Type 2 (Table 2). Other 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 immunoadsorption from 8,090 human sera from the U.S., U.K., Europe and Asia (e.g., FIG. 5 and U.S. Pat. No. 6,242,578 B1).

[0057]As seen in FIG. 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 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 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) (kekkpskdeimrdiish); 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) (hkinitngqk); and the "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 acids 1-163 of this "replicating protein" contain five Replikins, namely: (SEQ ID NO.: 13) kfrinaknyfltyph, (SEQ ID NO.: 14) knletpvnklfiricrefh, (SEQ ID NO.: 15) hpniqaaksstdvk, (SEQ ID NO.: 16) ksstdvkaymdkdgdvldh, and (SEQ ID NO.: 17) kasalnilrekapkdfvlqfh.

[0058]Table 2 shows that Replikin-containing proteins also are associated frequently with redox functions, and protein synthesis or elongation, as well as with 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) (FIG. 4c-f), all suggest that the Replikins are related to central respiratory functions, which are perhaps less often subjected to the mutations characteristic of proteins of more superficial location or less central survival function.

[0059]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 were observed to occur in the hemagglutinin proteins of isolates of each of the four prevalent strains of influenza virus, influenza B, 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.

TABLE-US-00003 TABLE 3 Replikin Sequences present in hemagglutinins of Influenza B viruses in each year for which amino acid sequences were available (1902-2001). Year Detected in Influenza B strain Influenza B Replikins (Peak in FIG. 7: EB1 EB2) kshfanlk 1902, 19, 24, 38, 40, 43, 51, 59, 75, 76, 77, 89, 90, 93, 97, 98, 99, 00, 01 (SEQ ID NO. 104) kshfanlkgtk 1902, 19, 24, 38, 40, 43, 51, 59, 75, 76, 77, 89, 90, 93, 97, 98, 99, 00, 01 (SEQ ID NO. 105) kshfanlkgtktrgklcpk 1902, 19, 24, 38, 40, 43, 51, 59, 75, 76, 77, 89, 90, 93, 97, 98, 99, 00, 01 (SEQ ID NO. 106) hekygglnk 1902, 19, 24, 38, 40, 43, 51, 59, 75, 76, 77, 89, 90, 93, 97, 98, 99, 00, 01 (SEQ ID NO. 107) hekygglnksk 1902, 19, 24, 38, 40, 43, 51, 59, 75, 76, 77, 89, 90, 93, 97, 98, 99, 00, 01 (SEQ ID NO. 108) hekygglnkskpyytgehak 1902, 19, 24, 38, 40, 43, 51, 59, 75, 76, 77, 89, 90, 93, 97, 98, 99, 00, 01 (SEQ ID NO. 109) hakaigncpiwvk 1902, 19, 24, 38, 40, 43, 51, 59, 75, 76, 77, 89, 90, 93, 97, 98, 99, 00, 01 (SEQ ID NO. 110) hakaigncpiwvktplklangtk 1902, 19, 24, 38, 40, 43, 51, 59, 75, 76, 77, 89, 90, 93, 97, 98, 99, 00, 01 (SEQ ID NO. 111) hakaigncpiwvktplklangtkyrp 1902, 19, 24, 38, 40, 43, 51, 59, 75, 76, 77, 89, 90, 93, 97, 98, 99, 00, 01 pak (SEQ ID NO. 112) hakaigncpiwvktplklangtkyrp 1902, 19, 24, 38, 40, 43, 51, 59, 75, 76, 77, 89, 90, 93, 97, 98, 99, 00, 01 pakllk (SEQ ID NO. 113) hfanlkgtktrgk 1919, 76, 89, 90, 99, 00, 01 (SEQ ID NO. 114) hfanlkgtktrgklcpk 1919, 76, 90 00, 01 (SEQ ID NO. 115) hsdneiqmvklygdsk 1919 (SEQ ID NO. 116) hsdneiqdkmvklygdskpqk 1919 (SEQ ID NO. 117) hsdneiqmvklygdskpqk 1919, 24, 97, 98, 00 (SEQ ID NO. 118) k(a/v)silhevk 1919, 40, 59, 90, 93 (SEQ ID NO. 119) kctgtipsakasilh 1919, 00 (SEQ ID NO. 120) kctgtipsakasilhevk 1919, 93 (SEQ ID NO. 121) kygglnkskpyytgeh 1919 (SEQ ID NO. 122) kvwcasgrskvikgslptigeadclh 1919, 38, 40, 43, 59, 75, 76, 77, 89, 90, 98, 99, 00 (SEQ ID NO. 123) kpyytgehak 1919, 38, 40, 59, 89, 90, 93, 97, 98, 01 (SEQ ID NO. 124) kcmgtipsakasilhevk 1924, 43, 75, 76, 77, 93 (SEQ ID NO. 125) hnvinaekapggpyk 1938, 93, 97, 00 (SEQ ID NO. 126) hsdnetqmaklygdsk 1938, 93, 97, 00 (SEQ ID NO. 127) hgvavaadlkstqeaink 1940, 59, 00 (SEQ ID NO. 128) hgvavaadlkstqeainkdtistqea 1940 ink (SEQ ID NO. 129) klygdskpqkftssangvtth 1943, 75, 76, 77, 93, 97, 00 (SEQ ID NO. 130) hsdnetqmaklygdskpqk 1943, 76, 76, 77, 93 (SEQ ID NO. 131) hfanlkgtqtrgk 1959 (SEQ ID NO. 132) kprsalkckgfh 1988 (SEQ ID NO. 133) kskpyytgehakai(g/a)ncpiwvk 2000 (SEQ ID NO. 134) 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 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. 1951 and 1977 and correlates with increased total replikin concentration (number of replikins per 100 amino acid residues). See FIG. 7.

TABLE-US-00004 TABLE 4 H1N1 Replikin Sequences present in HIN1 hemagglutinins of Influenza viruses in each year for which amino acid sequences were available (1918-2000) Year Detected in Influenza H1N1 Replikin (Peak in FIG. 7: H1N1 Strain P1 E1 E1.1, 1.2, hp(v/i)tigecpkyv(r/k)(s/ 1918, 25, 28, 30, 31, 35, 47, 48, 51, 52, 55, 56, 57, 59, 63, 77, t)(t/a)k (SEQ ID NO. 135) hdsnvknly(e/g)kv(k/r)(n/ 1918, 28, 30, 31, 77, s)ql(k/r)nnak (SEQ ID NO. 136) hdsnvknly(e/g)kv(k/r)(n/ 1918, 28, 30, 31, 77, s)qlk (SEQ ID NO. 137) hkc(nn/dd)(a/t/e)cmesv 1918, 30, 35, 77, (r/k)ngtydypkyseesklnr e(e/k)idgvk (SEQ ID NO. 138) hkc(nn/dd)(a/t/e)cmesv 1918, 30, 35, 77, (r/k)ngtydypkyseesk (SEQ ID NO. 139) hqn(e/g)qgsgyaadqkstqnai 1918, 28, 30, 31, 35, 59, (d/n)gitnkvnsviekmntqfta vgkefnklek (SEQ ID NO. 140) hqn(e/g)qgsgyaadqkstqnai 1918, 28, 30, 31, 35, 59, (d/n)gitnkvnsviek (SEQ ID NO. 141) hqn(e/g)qgsgyaadqkstqnai 1918, 28, 30, 31, 35, 59, (d/n)gitnk (SEQ ID NO. 142) kfeifpktsswpnh 1918, 77 (SEQ ID NO. 143) kg(n/s/t)sypkl(n/s)ksy 1918, 35, 77, (v/t)nnkgkevlvlwgvh (SEQ ID NO. 144) ksy(v/t)nnkgkevlvlwgvh 1918, 35, 77, (SEQ ID NO. 145) hkcnnecmesvkngtydypkysee 1928, 31, sklnrekidgvk (SEQ ID NO. 146) hkcnnecmesvkngtydypkysee 1928, 31, sk (SEQ ID NO. 147) hkcnnecmesvkngtydypk 1928, 31, (SEQ ID NO. 148) hkcnnecmesvk 1928, 31, (SEQ ID NO. 149) hngkssfy(k/r)nllwlt(e/g) 1928, knglypnlsksyvnnkek (SEQ ID NO. 150) hngkssfy(k/r)nllwlt(e/g) 1928, 31, knglypnlsksyvnnk (SEQ ID NO. 151) hngkssfy(k/r)nllwlt(e/g) 1928, 31, knglypnlsk (SEQ ID NO. 152) hngkssfy(k/r)nllwlt(e/g) 1928, 31, k (SEQ ID NO. 153) kssfyknllwlteknglypnlsks 1928, 31, yvnnkekevlvlwgvh (SEQ ID NO. 154) knllwlteknglypnlsksyvnnk 1928, 31, ekevlvlwgvh (SEQ ID NO. 155) knglypnlsksyvnnkekevlvlw 1928, 31, gvh (SEQ ID NO. 156) ksy(v/a)nnkekev(l/-)(v/ 1928, 31, -)lwgvh (SEQ ID NO. 157) kesswpnhtvtk 1928, 31, (SEQ ID NO. 158) het(t/n)kgvtaacpyagassfy 1930, 35 rnllwlvkkensypklsksyvnnk (SEQ ID NO. 159) het(t/n)kgvtaacpyagassfy 1930, 35 rnllwlvkkensypklsk (SEQ ID NO. 160) kfeifpktsswpnevlvlwgvh 1930 (SEQ ID NO. 161) kerswpkh 1947, 51, 52, 55, 56, (SEQ ID NO. 162) klsksyvnnkekevlvlwqvh 1947, 51 (SEQ ID NO. 163) knnkekevlvlwqvh 1947 (SEQ ID NO. 164) h(k/n)(g/q)kssfy(r/k)nll 1948 wltekng(l/s)yp(n/t)lsksy annkek (SEQ ID NO. 165) h(k/n)(g/q)kssfy(r/k)nll 1948 wltek (SEQ ID NO. 166) hakkssfyk 1951, 57, 59 (SEQ ID NO. 167) hngklcrlkgk 1951, 52, 55, 56, 57, 59, (SEQ ID NO. 168) hyklnn(q/g)kk 1956, (SEQ ID NO. 169) hdiyrdeainnrfqiqgvkltqgy 1956 k (SEQ ID NO. 170) kgngcfeifhk 1956 (SEQ ID NO. 171) klnrliektndkyhqiek 1956 (SEQ ID NO. 172) klnrliektndkyh 1956 (SEQ ID NO. 173) kchtdkgslsttk 1956 (SEQ ID NO. 174) kinngdyaklyiwgvh 1956 (SEQ ID NO. 175) hngklcrkgiaplqlgk 1959, (SEQ ID NO. 176) hetnrqvtaacpyagansffrnli 1963, wlvkkessypklsk (SEQ ID NO. 177) hetnrqvtaacpyagansffrnli 1963, wlvkkessypk (SEQ ID NO. 178) hpptstdqqslyqnadayifvgss 1963, kynrkfk (SEQ ID NO. 179) hpptstdqqslyqnadayifvgss 1963, kynrkfkpeia (SEQ ID NO. 180) hdiyrdeainnrfqiqgvkitqgy 1977, k (SEQ ID NO. 181) hqneqgsgyaadqkstqnaidgit 1977 nkvnsviekmntqftavgk (SEQ ID NO. 182) hqneqgsgyaadqkstqnaidgit 1977 nkvnsviek (SEQ ID NO. 183) hqneqgsgyaadqkstqnaingit nkvnsviekmntqftavgkefnkl ek (SEQ ID NO. 184) hngklcrlkgiaplqlgk (SEQ ID NO. 185) hkcnnecmesvk (SEQ ID NO. 186) kfeifpkasswpnh (SEQ ID NO. 187) hdsnvknlyekvrsqlrnnak (SEQ ID NO. 188) kvnsvikkmntqfaavgkefnh (SEQ ID NO. 189) khngklck (SEQ ID NO. 190) kkgtsypklsksythnkgkevlvl wgvh (SEQ ID NO. 191) kgtsypklsksythnkgkevlvlw gvh (SEQ ID NO. 192) klsksythnkgkevlvlwgvh (SEQ ID NO. 193) ksythnkgkevlvlwgvh (SEQ ID NO. 194) kgvtascshk

(SEQ ID NO. 195) kgvtascshkgrssfyrnllwlte knglypnlsk (SEQ ID NO. 196) kgnsypklsksyvnnkekevlvlw gih (SEQ ID NO. 197) kefnhlek (SEQ ID NO. 198) hpptstdqqslyqnadayvfvgss kynkkfkpeiatrpk (SEQ ID NO. 199) hpptstdqqslyqnadayvfvgss kynkkfk (SEQ ID NO. 200) hegkssfyrnllwltekegsypkl knsyvnk (SEQ ID NO. 201) hegkssfyrnllwltekegsypk (SEQ ID NO. 202) hkcdnecmesvrngtydypkysee sk (SEQ ID NO. 203) kesswpnhtvtk (SEQ ID NO. 204) knllwlteknglypnlsksyvnnk ekeilvlwgvh (SEQ ID NO. 205) hngkssfy(k/m)(n/-)llwlt (e/g)(-/k)knglypnlsk (SEQ ID NO. 206) hngkssfyknllwltek (SEQ ID NO. 207) htvtkgvtascshngkssfyknll wlteknglypnlsksyvnnkekev lvlwgvh (SEQ ID NO. 208) htvt(k/g)gv(t/s)ascshngk ssfy(k/m)(n/-)llwlt(e/g) k(-n/k)glypnlsk (SEQ ID NO. 209) htvtkgvtascshngkssfyknll wltek (SEQ ID NO. 210) kyvrstklrmvtglrnipsiqsrg lfgaiagfieggwtgmidgwygyh (SEQ ID NO. 211) hqneqgsgyaadqkstqnaingit nkvnsiiekmntqftavgk (SEQ ID NO. 212) hqneqgsgyaadqkstqnaingit nkvnsiiek (SEQ ID NO. 213) hqneqgsgyaadqkstqnaingit nk (SEQ ID NO. 214) hsgarsfyrnllwivkkgnsypk (SEQ ID NO. 215) hsgarsfyrnllwivkkgnsypkl nk (SEQ ID NO. 216) hsgarsfyrnllwivkkgnsypkl nksytndk (SEQ ID NO. 217) hsgarsfyrnllwivkkgnsypkl nksytndkgk (SEQ ID NO. 218) htvskgvttscshngk (SEQ ID NO. 219) katswpnhettk (SEQ ID NO. 220) kqvttscshnqk (SEQ ID NO. 221) kgnsypklnksytndkgkevlviw gvh (SEQ ID NO. 222) klnksytndkgkevlviwgvh (SEQ ID NO. 223) ksytndkgkevlviwgvh (SEQ ID NO. 224) hnqkssfyrnllwlt(e/q)kngl ypnlsksy(v/a)annkek (SEQ ID NO. 225) hpitigecpkyvrsak (SEQ ID NO. 226) hqneqgsgyaadqkstqnaingit nkvnsviekmntqftavgk (SEQ ID NO. 227) hqneqgsgyaadqkstqnaingit nkvnsviek (SEQ ID NO. 228) hngkssfyrnllwlteknglypnl sksyvnnkek (SEQ ID NO. 229) Year Detected in Influenza H1N1 Replikin (Peak in FIG. 7: H1N1 Strain 1.3 E1.4) hp(v/i)tigecpkyv(r/k)(s/ 79, 80, 81, 85, 87, 88, 89, 91, 92, 95, 96, 97, 98, 99, 00 t)(t/a)k (SEQ ID NO. 135) hdsnvknly(e/g)kv(k/r)(n/ 79, 80, 88, 91, 95, 98 s)ql(k/r)nnak (SEQ ID NO. 136) hdsnvknly(e/g)kv(k/r)(n/ 79, 80, 88, 91, 95, 98 s)qlk (SEQ ID NO. 137) hkc(nn/dd)(a/t/e)cmesv 80, 98 (r/k)ngtydypkyseesklnr e(e/k)idgvk (SEQ ID NO. 138) hkc(nn/dd)(a/t/e)cmesv 80, 98 (r/k)ngtydypkyseesk (SEQ ID NO. 139) hqn(e/g)qgsgyaadqkstqnai 79, 95 (d/n)gitnkvnsviekmntqfta vgkefnklek (SEQ ID NO. 140) hqn(e/g)qgsgyaadqkstqnai 79, 95 (d/n)gitnkvnsviek (SEQ ID NO. 141) hqn(e/g)qgsgyaadqkstqnai 79, 95 (d/n)gitnk (SEQ ID NO. 142) kfeifpktsswpnh (SEQ ID NO. 143) kg(n/s/t)sypkl(n/s)ksy 96 (v/t)nnkgkevlvlwgvh (SEQ ID NO. 144) ksy(v/t)nnkgkevlvlwgvh 96 (SEQ ID NO. 145) hkcnnecmesvkngtydypkysee 95 sklnrekidgvk (SEQ ID NO. 146) hkcnnecmesvkngtydypkysee 95 sk (SEQ ID NO. 147) hkcnnecmesvkngtydypk 95 (SEQ ID NO. 148) hkcnnecmesvk 95 (SEQ ID NO. 149) hngkssfy(k/r)nllwlt(e/g) 95, 00 knglypnlsksyvnnkek (SEQ ID NO. 150) hngkssfy(k/r)nllwlt(e/g) 95, 00 knglypnlsksyvnnk (SEQ ID NO. 151) hngkssfy(k/r)nllwlt(e/g) 95, 00 knglypnlsk (SEQ ID NO. 152) hngkssfy(k/r)nllwlt(e/g) 95, 00 k (SEQ ID NO. 153) kssfyknllwlteknglypnlsks 95 yvnnkekevlvlwgvh (SEQ ID NO. 154) knllwlteknglypnlsksyvnnk 95 ekevlvlwgvh (SEQ ID NO. 155) knglypnlsksyvnnkekevlvlw 95, 96, 00 gvh (SEQ ID NO. 156) ksy(v/a)nnkekev(l/-)(v/ 95, 96, 98, 00 -)lwgvh (SEQ ID NO. 157) kesswpnhtvtk 95 (SEQ ID NO. 158) het(t/n)kgvtaacpyagassfy rnllwlvkkensypklsksyvnnk (SEQ ID NO. 159) het(t/n)kgvtaacpyagassfy rnllwlvkkensypklsk (SEQ ID NO. 160) kfeifpktsswpnevlvlwgvh (SEQ ID NO. 161) kerswpkh 79, 82 (SEQ ID NO. 162)

klsksyvnnkekevlvlwqvh (SEQ ID NO. 163) knnkekevlvlwqvh (SEQ ID NO. 164) h(k/n)(g/q)kssfy(r/k)nll 79, 89, 96 wltekng(l/s)yp(n/t)lsksy annkek (SEQ ID NO. 165) h(k/n)(g/q)kssfy(r/k)nll 79, 89, 96 wltek (SEQ ID NO. 166) hakkssfyk (SEQ ID NO. 167) hngklcrlkgk 79 (SEQ ID NO. 168) hyklnn(q/g)kk 00 (SEQ ID NO. 169) hdiyrdeainnrfqiqgvkltqgy k (SEQ ID NO. 170) kgngcfeifhk (SEQ ID NO. 171) klnrliektndkyhqiek (SEQ ID NO. 172) klnrliektndkyh (SEQ ID NO. 173) kchtdkgslsttk (SEQ ID NO. 174) kinngdyaklyiwgvh (SEQ ID NO. 175) hngklcrkgiaplqlgk 82 (SEQ ID NO. 176) hetnrqvtaacpyagansffrnli 81 wlvkkessypklsk (SEQ ID NO. 177) hetnrqvtaacpyagansffrnli 81 wlvkkessypk (SEQ ID NO. 178) hpptstdqqslyqnadayifvgss 81 kynrkfk (SEQ ID NO. 179) hpptstdqqslyqnadayifvgss 81 kynrkfkpeia (SEQ ID NO. 180) hdiyrdeainnrfqiqgvkitqgy 79, 91 k (SEQ ID NO. 181) hqneqgsgyaadqkstqnaidgit nkvnsviekmntqftavgk (SEQ ID NO. 182) hqneqgsgyaadqkstqnaidgit nkvnsviek (SEQ ID NO. 183) hqneqgsgyaadqkstqnaingit 1979, 91 nkvnsviekmntqftavgkefnkl ek (SEQ ID NO. 184) hngklcrlkgiaplqlgk 1979 (SEQ ID NO. 185) hkcnnecmesvk 1979 (SEQ ID NO. 186) kfeifpkasswpnh 1981 (SEQ ID NO. 187) hdsnvknlyekvrsqlrnnak 1981 (SEQ ID NO. 188) kvnsvikkmntqfaavgkefnh 1981 (SEQ ID NO. 189) khngklck 1981 (SEQ ID NO. 190) kkgtsypklsksythnkgkevlvl 1981 wgvh (SEQ ID NO. 191) kgtsypklsksythnkgkevlvlw 1981 gvh (SEQ ID NO. 192) klsksythnkgkevlvlwgvh 1981 (SEQ ID NO. 193) ksythnkgkevlvlwgvh 1981 (SEQ ID NO. 194) kgvtascshk 1985, 87 (SEQ ID NO. 195) kgvtascshkgrssfyrnllwlte 1985, 87 knglypnlsk (SEQ ID NO. 196) kgnsypklsksyvnnkekevlvlw 1988 gih (SEQ ID NO. 197) kefnhlek 1988 (SEQ ID NO. 198) hpptstdqqslyqnadayvfvgss 1988 kynkkfkpeiatrpk (SEQ ID NO. 199) hpptstdqqslyqnadayvfvgss 1988 kynkkfk (SEQ ID NO. 200) hegkssfyrnllwltekegsypkl 1991 knsyvnk (SEQ ID NO. 201) hegkssfyrnllwltekegsypk 1991 (SEQ ID NO. 202) hkcdnecmesvrngtydypkysee 1991 sk (SEQ ID NO. 203) kesswpnhtvtk 1991, 92 (SEQ ID NO. 204) knllwlteknglypnlsksyvnnk 1991, 92, 96 ekeilvlwgvh (SEQ ID NO. 205) hngkssfy(k/m)(n/-)llwlt 1991, 92, 96, 00 (e/g)(-/k)knglypnlsk (SEQ ID NO. 206) hngkssfyknllwltek 1991, 92, 96 (SEQ ID NO. 207) htvtkgvtascshngkssfyknll 1995 wlteknglypnlsksyvnnkekev lvlwgvh (SEQ ID NO. 208) htvt(k/g)gv(t/s)ascshngk 1995, 00 ssfy(k/m)(n/-)llwlt(e/g) k(-n/k)glypnlsk (SEQ ID NO. 209) htvtkgvtascshngkssfyknll 1995 wltek (SEQ ID NO. 210) kyvrstklrmvtglrnipsiqsrg 1995 lfgaiagfieggwtgmidgwygyh (SEQ ID NO. 211) hqneqgsgyaadqkstqnaingit 1995 nkvnsiiekmntqftavgk (SEQ ID NO. 212) hqneqgsgyaadqkstqnaingit 1995 nkvnsiiek (SEQ ID NO. 213) hqneqgsgyaadqkstqnaingit 1995 nk (SEQ ID NO. 214) hsgarsfyrnllwivkkgnsypk 1996 (SEQ ID NO. 215) hsgarsfyrnllwivkkgnsypkl 1996 nk (SEQ ID NO. 216) hsgarsfyrnllwivkkgnsypkl 1996 nksytndk (SEQ ID NO. 217) hsgarsfyrnllwivkkgnsypkl 1996 nksytndkgk (SEQ ID NO. 218) htvskgvttscshngk 1996 (SEQ ID NO. 219) katswpnhettk 1996 (SEQ ID NO. 220) kqvttscshnqk 1996 (SEQ ID NO. 221) kgnsypklnksytndkgkevlviw 1996 gvh (SEQ ID NO. 222) klnksytndkgkevlviwgvh 1996 (SEQ ID NO. 223) ksytndkgkevlviwgvh 1996 (SEQ ID NO. 224) hnqkssfyrnllwlt(e/q)kngl 1997, 98, 99 ypnlsksy(v/a)annkek (SEQ ID NO. 225) hpitigecpkyvrsak 1997 (SEQ ID NO. 226) hqneqgsgyaadqkstqnaingit 1998 nkvnsviekmntqftavgk (SEQ ID NO. 227) hqneqgsgyaadqkstqnaingit 1998 nkvnsviek (SEQ ID NO. 228) hngkssfyrnllwlteknglypnl 1998 sksyvnnkek (SEQ ID NO. 229) 1. Influenza H1N1 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 FIG. 7.

TABLE-US-00005 TABLE 5 Replikin Sequences present in hemagglutinins of Influenza H2N2 viruses in years 1957-2000 Year Detected in Influenza H2N2 strain (Peak in FIG. 8: Influenza H2N2 Replikins P2 E2) khfekvkilpk 1957, 58, 59, 60, 61, 64, 65, 68, 78, 83, 84, 91 (SEQ ID NO. 230) khllssvkhfekvk 1957, 58, 59, 60, 61, 83, 84, 91 (SEQ ID NO. 231) ha(k/q/m)(d/n)ilekthngk 1957, 58, 59, 60, 61, 64, 65, 68, 78, 83, 84, 91, 95 (SEQ ID NO. 232) ha(k/q/m)(d/n)ilekthngklc(k/r) 1957, 58, 59, 60, 61, 64, 65, 68, 78, 83, 84, 91, 95 (SEQ ID NO. 233) hnvhpltigecpkyvksek 1957, 58, 59, 65, 68 (SEQ ID NO. 234) hpltigecpkyvksek 1957, 58, 59, 65, 68, 64, 65, 68, 78, 83, 84, 91 (SEQ ID NO. 235) khllssvkhfekvkilpk 1957, 58, 59, 60, 61, 64, 65, 68, 78 (SEQ ID NO. 236) krqssgimktegtlencetkcqtplgainttlpfhnvh 1957, 59, 83 (SEQ ID NO. 237) kgsnyp(v/i)ak(g/r)synntsgeqmliiwq(v/i)h 1957, 58, 59, 61, 83, 91, 95 (SEQ ID NO. 238) httlgqsracavsgnpsffrnmvwltekgsnypvak 1957 (SEQ ID NO. 239) khfekvk 1957, 59, 65 (SEQ ID NO. 240) kiskrgssgimktegtlencetkcqtplgainttlpfh 1957, 59, 65, 91 (SEQ ID NO. 241) krgssgimktegtlencetkcqtplgainttlpfh 1957, 59, 65, 91 (SEQ ID NO. 242) ktegtlencetkcqtplgainttlpfh 1957, 59, 65, 91 (SEQ ID NO. 243) kiskrgssgimktegtlencetkcqtplgainttlpfh 1957, 59, 65, 91 (SEQ ID NO. 244) ktegtlencetkcqtplgainttlpfhn(v/i)h 1957, 59, 65, 91 (SEQ ID NO. 245) kiskrgssgimktegtlencetkcqtplgainttlpfh 1957, 59, 65, 91 (SEQ ID NO. 246) k(e/g)snypvakgsynntsgeqmliiwgvh 1957, 60, 65 (SEQ ID NO. 247) hpltigecpkyvksek 1957, 60, 65 (SEQ ID NO. 248) kcqtplgaikttlpfh 1957, 65 (SEQ ID NO. 249) hhsndqgsgyaadkestqka(f/i)dgitnkvnsviek- 1961, 65, 68, 83, 84 mntqfeavgklf(n/s)nleklenlnkk (SEQ ID NO. 250) hsndqgsgyaadkestqka(f/i)dgitnkvnsviek- 1961, 65, 68, 83, 84 mntqfeavgklf(n/s)nleklenlnkk (SEQ ID NO. 251) hsndqgsgyaadkestqka(f/i)dgitnk 1961, 65, 68, 83, 84 (SEQ ID NO. 252) hdsnvrnlydkvrmqlrdnak 1964, 68, 76, 84, 91 (SEQ ID NO. 253) hkcddecmnsvkngtydypklnrneikgvk 1964, 65, 68, 76, 83, 84, 91 (SEQ ID NO. 254) hkcddecmnsvkngtydypklnrneik 1964, 65, 68, 76, 83, 84, 91 (SEQ ID NO. 255) hkcddecmnsvkngtydypk 1964, 65, 68, 76, 83, 84, 91 (SEQ ID NO. 256) hkcddecmnsvk 1964, 65, 68, 76, 83, 84, 91 (SEQ ID NO. 257) kgsnypvakgsynntngeqiliiwgvh 1976, 78 (SEQ ID NO. 258) hsndqgsgyaadkestqkavdgitnkvnsviekmntqfeavgk 1976, 91 (SEQ ID NO. 259) krgssgimktegtlencetkcqtplgainttlpfh 1976, 78, 83, 84 (SEQ ID NO. 260) hpltigecpkyvksek 1976 (SEQ ID NO. 261) hakdilekthngklck 1976 (SEQ ID NO. 262) 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 FIG. 8.

TABLE-US-00006 TABLE 6 H3N2 Replikin Sequences present in H3N2 hemagglutinins of Influenza viruses in each year for which amino acid sequences were available (1968-2000) Year Detected in Influenza H3N2 strain Influenza Replikins (Peak in FIG. 8: Influenza H3N2 Replikins P3 E3 E4) hdvyrdealnnrfqikgvelksgyk 1968, 72, 75 96, 97, 98 (SEQ ID NO. 263) htidltdsemnklfertrk 1968 (SEQ ID NO. 264) kfhqiek 1968, 72, 75 77 96, 97, 98 (SEQ ID NO. 265) ktnekfh(g/q)iek 1968 86 98 (SEQ ID NO. 266) klnr(v/l)iektnekfh 1968, 72, 75 77 97, 98 (SEQ ID NO. 267) hqiekefsevegriqdlekyvedtk 1968, 72, 98 (SEQ ID NO. 268) kicnnphk 1975 (SEQ ID NO. 269) klnrvikktnekfh 1975 (SEQ ID NO. 270) hd(I,v)yrdealnnrfqik(g/q)ve(r/k)s(q/g)yk 1975, 76, 77, 86 (SEQ ID NO. 271) hqiekefsevegriqdlekyvedtk 1975 (SEQ ID NO. 272) kyvedtkidlwsynaellvalenqh 1975 (SEQ ID NO. 273) kyvkqnslklatgmrnvpekqtrglfgaiagfiengwegmidgwy 1975 gfrh (SEQ ID NO. 274) kefsevegriqdlekyvedtkidlwsynaellvalenqh 1975 2000 (SEQ ID NO. 275) hqn(s/e)(e/q)g(t/s)g(q/y)aad(l/q)k- 1975 2000 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) hcd(g/q)f(q,r)nekwdlf(v,/i)er(s/t)k 1975, 76, 77, 78, 80, 81, 82, 83, 84, 85, 86, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 (SEQ ID NO. 277) htidltdsemnkklfertrk 1977, (SEQ ID NO. 278) ksgstypvlkvtmpnndnfdklyiwgvh 1977 (SEQ ID NO. 279) klnwltksgntypvlnvtmpnndnfdklviwgvh 1982 (SEQ ID NO. 280) htidltdsemnklfektrk 1986 (SEQ ID NO. 281) klnrliektnekfhqtek 1987 (SEQ ID NO. 282) htgkssvmrsdapidfcnsecitpnqsipndkpfqnvnkitygac 1994 pk (SEQ ID NO. 283) htgkssvmrsdapidfcnsecitpnqsipndkpfqnvnk 1994 (SEQ ID NO. 284) hpstdsdqtslyvrasgrvtvstkrsqqtvipk 1994 (SEQ ID NO. 285) kyvedtkidlwsynaellvalenqh 1997, 98 (SEQ ID NO. 286) klfertrkqlrenaedmgngcfkiyh 1998 (SEQ ID NO. 287) krrsiksffsrlnwlh 1998 (SEQ ID NO. 288) hpvtigecpky(v/r)kstk 2000 (SEQ ID NO. 289) kgnsypklsklsksyiinkkkevlviwgih 2000 (SEQ ID NO. 290) klsklsks(v/y)iinkkkevlviwgih 2000 (SEQ ID NO. 291) klsks(v/y)iinkkkevlviwgih 2000 (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 FIG. 8.

[0060]Both the concentration and type, i.e., composition of Replikins 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 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.

[0061]The concentration of Replikins was found to directly relate to the occurrence of influenza pandemics and epidemics. The concentration of Replikins found in influenza B hemagglutinin and influnza A strain, H1N1, is shown in FIG. 7, and the concentration of Replikins found in the two other common influenza virus A strains, H2N2 and H3N2 is shown in FIG. 8 (H2N2, H3N2). The data in FIG. 8 also demonstrate an emerging new strain of influenza virus as defined by its constituent Replikins (H3N2(R)).

[0062]Each influenza A strain has been responsible for one pandemic: in 1918, 1957, and 1968, respectively. The data in FIGS. 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 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.

[0063]Several properties of Replikin concentration are seen in FIG. 7 and FIG. 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 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 example, for the pandemic of 1918, where the influenza virus strain, H1N1, was shown to be responsible, a peak concentration of the Replikins in H1N1 independently occurred (P1); for the pandemic of 1957, where H2N2 emerged and was shown to be responsible, a peak concentration of the Replikins in H2N2 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-pandemic decline is specific for H1N1 immediately following the pandemic (P1) 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 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 (E1); eight years after the 1957 pandemic in an H2N2 `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 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 seen to occur after 1965, but Replikin concentration declined again between 1997 and 2000 (FIG. 7), and this correlates with the low occurrence of influenza B in recent case isolates. H1N1 Replikin concentration peaked in 1978-1979 (FIG. 7) together with the reappearance and prevalence of the H1N1 strain, and then peaked in 1996 coincident with an H1N1 epidemic. (FIG. 7). H1N1 Replikin concentration also declined between 1997 and 2000, and the presence of H1N1 strains decreased in isolates obtained during these years. For H2N2 Replikins, recovery from a 35 year decline has not occurred (FIG. 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 indicates the emergence of a sub-strain of H3N2, which is designated herein as H3N2(R).

[0064]FIGS. 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 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.

[0065]Currently, Replikin concentration in the H3N2(R) strain of influenza virus is increasing (FIG. 8, 1997 to 2000). Three similar previous peak increases in H3N2 Replikin concentration are seen to have occurred in the H3N2-based pandemic of 1968 (FIG. 8), when the strain first emerged, and in the H3N2-based epidemics of 1972 and 1975 (FIG. 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 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 (FIG. 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; 50(48):1084-68 (Dec. 7, 2001).

[0066]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. 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 particular Replikin structure suggests that the Replikins return from another virus host pool rather than through de novo mutation.

[0067]In the case of H1N1 Replikins, the two Replikins present in the P1 peak associated with the 1918 pandemic were not present in the recovery E1 peak of 1933, which contains 12 new Replikins. Constantly conserved Replikins, therefore, 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 the early 1990's, FIG. 7).

[0068]The data in FIGS. 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 concentration of Replikins provides a predictor of influenza pandemics and/or epidemics, as well as a target for influenza vaccine formulation.

[0069]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 present in every influenza B isolate examined from 1902-2001. Overlapping Replikin sequences are listed separately. Lysines and histidines are in bold type to demonstrate homology consistent with the "3-point recognition."

TABLE-US-00007 kshfanlk (SEQ ID NO. 104) kshfanlkgtk (SEQ ID NO. 105) 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) hakaigncpiwvvkktplklangtk (SEQ ID NO. 111) hakaigncpiwvktplklangtkyrppak (SEQ ID NO. 112) hakaigncpiwvktplklangtkyrppakllk (SEQ ID NO. 113)

[0070]Tables 3 and 4 indicate that there appears to be much greater stability of the Replikin structures in influenza B hemagglutinins compared with H1N1 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)).

[0071]Influenza H1N1 Replikins: Only one replikin "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 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 (FIGS. 7 and 8).

[0072]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).

TABLE-US-00008 (SEQ ID NO. 232) ha(k/q/m)(d/n)ilekthngk (SEQ ID NO. 233) ha(k/q/m)(d/n)ilekthngklc(k/r) (SEQ ID No. 238) kgsnyp(v/i)ak(g/r)synntsgeqmliiwq(v/i)h

[0073]However, in contrast to H1N1, only 13 additional Replikins have been found in H2N2 beginning in 1961. This paucity of appearance of new Replikins correlates with the decline in the concentration of the H2N2 Replikins and the appearance of H2N2 in isolates over the years. (FIG. 8).

[0074]Influenza H3N2 Replikins: Influenza H3N2 was responsible for the human pandemic of 1968. Five Replikins which appeared in 1968 disappeared after 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 (FIG. 8), and with the prevalence of the H3N2 strain in recent isolates together with the concurrent disappearance of all Replikins from some of these isolates (FIG. 8), this suggests the emergence of the new substrain H3N2(R).

[0075]FIGS. 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 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.

[0076]It has been believed that changes in the activity of different influenza 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: 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 reassortment is postulated to occur between the viruses of human and non-human hosts. First, the present data suggests that the change in activity of 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 reservoirs, then reappearance. The data show that the epidemic-related increase in replikin concentration is not due to the duplication of existing replikins per hemagglutinin, 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 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 compositions appear (e.g. in H1N1 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 resemblance to the new compositions other than the basic requirements of "3-point recognition" (Tables 2-5). The more prolific nature of H1N1 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.

[0077]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 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 23-6 for the following strain-specific replikins: ten of influenza B, the single replikin of H1N1, and the 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 replikin "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)l(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 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.

[0078]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 10 replikin structures, nor the reappearance in 1993 of a 1919 18mer 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 mechanisms which control this conservation are at present unknown.

[0079]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 replikin "hkqkivapvk" (SEQ ID NO. 3) was found to be conserved in 78% of the 236 isolates reported in PubMed, and each amino acid was found to be conserved in 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 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.

[0080]Data on anti-Replikin antibodies also support Replikin class unity. An anti-Replikin antibody response has been quantified by immunoadsorption of serum antimalignin antibody to immobilized malignin (see Methods in U.S. Pat. No. 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 response (FIG. 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 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.

[0081]Because administration of Replikins stimulates the immune system to produce antibodies having a cytotoxic effect, peptide vaccines based on the 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 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 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.

[0082]Currently, vaccine formulations are changed twice yearly at international 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.

[0083]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. 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 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.

[0084]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 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 Replikin(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 technology, and may include non-Replikin sequences, although vaccines based on peptides containing only Replikin sequences are preferred. Preferably, vaccine compositions of the invention also contain a pharmaceutically acceptable carrier and/or adjuvant.

[0085]The influenza vaccines of the present invention can be administered alone or in combination with antiviral drugs, such as ganciclovir; interferon; 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.

[0086]Analysis of the primary structure of a Plasmodium farciparum malaria antigen located at the merozoite surface and/or within the parasitophorous vacuole 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 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 trypanosome.

[0087]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 within another Replikin sequence.

[0088]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=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 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 (FIG. 7); and tomato-leaf curl gemini virus, which was also observed to have overlapping replikins has only about 3.1/100 amino acids.

[0089]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).

[0090]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 HIV infection has a Replikin concentration of 1.1 (+/-1.6) Replikins per 100 amino acids, Whereas the rapidly-growing high titer strain of HIV (S1, "Lai"), which is prevalent in late stage HIV infection has a Replikin concentration of 6.8 (+/-2.7) Replikins per 100 amino acid residues.

[0091]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 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 be made and perpetuated, leaving key malaria antigens unharmed.

[0092]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 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.

[0093]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 isolates of the organism may contain other Replikin structures.

TABLE-US-00009 TABLE 7 Malaria replikins a) Primary structure of a Plasmodium falciparum malaria antigen located at the merozoite surface and within the parasitophorous vacuole a) i) DECOYS: (C-Terminal) keeeekekekekekeekekeekekeekekekeekekekeekeeekk, (SEQ ID NO. 293) or keeeekekekekekeekekeekekeekekekeekekekeekeeekkek, (SEQ ID NO. 294) or keeeekekekekekeekekeekekekeekekeekekeekeekeeekk, (SEQ ID NO. 295) or keeeekekek (SEQ ID NO. 296) ii) REPLIKINS: Hkklikalkkniesiqnkk (SEQ ID NO. 297) hkklikalkkniesiqnkm (SEQ ID NO. 298) hkklikalkk (SEQ ID NO. 299) hkklikalk (SEQ ID NO. 300) katysfvntkkkiislksqghkk (SEQ ID NO. 301) katysfvntkkkiislksqghk (SEQ ID NO. 302) katysfvntkkkiislksqgh (SEQ ID NO. 303) htyvkgkkapsdpqca dikeeckellkek (SEQ ID NO. 304) kiislksqghk (SEQ ID NO. 305) kkkkfeplkngnvsetiklih (SEQ ID NO. 306) kkkfeplkngnvsetiklih (SEQ ID NO. 307) kkfeplkngnvsetiklih (SEQ ID NO. 308) kngnvsetiklih (SEQ ID NO. 309) klihlgnkdkk (SEQ ID NO. 310) kvkkigvtlkkfeplkngnvsetiklihlgnkdkkh (SEQ ID NO. 311) hliyknksynplllscvkkmnmlkenvdyiqnqnlfkelmnqkatysfvntkkkiislk (SEQ ID NO. 312) hliyknksynplllscvkkmnmlkenvdyiqnqnlfkelmnqkatysfvntk (SEQ ID NO. 313) hliyknksynplllscvkkmnmlkenvdyiqnqnlfkelmnqk (SEQ ID NO. 314) hliyknksynplllscvkkmnmlkenvdyiqknqnlfk (SEQ ID NO. 315) hliyknksynplllscvkkmnmlk (SEQ ID NO. 316) ksannsanngkknnaeemknlvnflqshkklikalkkniesiqnkkh (SEQ ID NO. 317) kknnaeemknlvnflqshkklikalkkniesiqnkkh (SEQ ID NO. 318) knlvnflqshkklikalkkniesiqnkkh (SEQ ID NO. 319) kklikalkkniesiqnkkh (SEQ ID NO. 320) klikalkkniesiqnkkh (SEQ ID NO. 321) kkniesiqnkkh (SEQ ID NO. 322) kniesiqnkkh (SEQ ID NO. 323) knnaeemknlvnflqsh (SEQ ID NO. 324) kklikalkkniesiqnkkqghkk (SEQ ID NO. 325) kknnaeemknlvnflqshk (SEQ ID NO. 326) knnaeemknlvnflqsh (SEQ ID NO. 327) klikalkkniesiqnkkqghkk (SEQ ID NO. 328) kvkkigvtlkkfeplkngnvsetiklih (SEQ ID NO. 329) kngnvsetiklih (SEQ ID NO. 330) klihlgnkdkk (SEQ ID NO. 331) ksannsanngkknnaeemknlvnflqsh (SEQ ID NO. 332) kknnaeemknlvnflqsh (SEQ ID NO. 333) kklikalkkniesiqnkkh (SEQ ID NO. 334) kalkkniesiqnkkh (SEQ ID NO. 335) kkniesiqnkkh (SEQ ID NO. 336) kelmnqkatysfvntkkkiislksqgh (SEQ ID NO. 337) ksqghkk (SEQ ID NO. 338) kkkiislksqgh (SEQ ID NO. 339) kkiislksqgh (SEQ ID NO. 340) kkniesiqnkkh (SEQ ID NO. 341) kniesiqnkkh (SEQ ID NO. 342) htyvkgkkapsdpqcadikeeckellkek (SEQ ID NO. 343) htyvkgkkapsdpqcadikeeckellk (SEQ ID NO. 344) b) "liver stage antigen-3" gene = "LSA-3" Replikins henvlsaalentqseeekkevidvieevk (SEQ ID NO. 345) kenvvttilekveettaesvttfsnileeiqentitndtieekleelh (SEQ ID NO. 346) hylqqmkekfskek (SEQ ID NO. 347) hylqqmkekfskeknnnvievtnkaekkgnvqvtnktekttk (SEQ ID NO. 348) hylqqmkekfskeknnnvievtnkaekkgnvqvtnktekttkvdknnk (SEQ ID NO. 349) hylqqmkekfskeknnnvievtnkaekkgnvqvtnktekttkvdknnkvpkkrrtqk (SEQ ID NO. 350) hylqqmkekfskeknnnvievtnkaekkgnvqvtnktekttkvdknnkvpkkrrtqksk (SEQ ID NO. 351) hvdevmkyvqkidkevdkevskaleskndvtnvlkqnqdffskvknfvkkyk (SEQ ID NO. 352) hvdevmkyvqkidkevdkevskaleskndvtnvlkqnqdffskvknfvkk (SEQ ID NO. 353) hvdevmkyvqkidkevdkevskaleskndvtnvlkqnqdffsk (SEQ ID NO. 354) hvdevmkyvqkidkevdkevskaleskndvtnvlk (SEQ ID NO. 355) hvdevmkyvqkidkevdkevskalesk (SEQ ID NO. 356) hvdevmkyvqkidkevdkevsk (SEQ ID NO. 357) hvdevmkyvqkidkevdk (SEQ ID NO. 358) hvdevmkyvqkidk (SEQ ID NO. 359) kdevidlivqkekriekvkakkkklekkveegvsglkkh (SEQ ID NO. 360) kvkakkkklekkveegvsglkkh (SEQ ID NO. 361) kakkkklekkveegvsglkkh (SEQ ID NO. 362) kkkklekkveegvsglkkh (SEQ ID NO. 363) kkklekkveegvsglkkh (SEQ ID NO. 364) kklekkveegvsglkkh (SEQ ID NO. 365) klekkveegvsglkkh (SEQ ID NO. 366) kkveegvsglkkh (SEQ ID NO. 367) kveegvsglkkh (SEQ ID NO. 368) hveqnvyvdvdvpamkdqflgilneagglkemffnledvfksesdvitveeikdepvqk (SEQ ID NO. 369) hikgleeddleevddlkgsildmlkgdmelgdmdkesledvttklgerveslk (SEQ ID NO. 370) hikgleeddleevddlkgsildmlkgdmelgdmdkesledvttk (SEQ ID NO. 371) hikgleeddleevddlkgsildmlkgdmelgdmdk (SEQ ID NO. 372) hikgleeddleevddlkgsildmlk (SEQ ID NO. 373) hiisgdadvlssalgmdeeqmktrkkaqrpk (SEQ ID NO. 374) hditttldevvelkdveedkiek (SEQ ID NO. 375) kkleevhelk (SEQ ID NO. 376) kleevhelk (SEQ ID NO. 377) ktietdileekkkeiekdh (SEQ ID NO. 378) kkeiekdhfek (SEQ ID NO. 379) kdhfek (SEQ ID NO. 380) kfeeeaeeikh (SEQ ID NO. 381) c) 28 KDA ookinete surface antigen precursor Replikins: kdgdtkctlecaqgkkcikhksdhnhksdhnhksdpnhkkknnnnnk (SEQ ID NO. 382) kdgdtkctlecaqgkkcikhksdhnhksdhnhksdpnhkk (SEQ ID NO. 383) kdgdtkctlecaqgkkcikhksdhnhksdhnhksdpnhk (SEQ ID NO. 384) kdgdtkctlecaqgkkcikhksdhnhksdhnhk (SEQ ID NO. 385) kdgdtkctlecaqgkkcikhksdhnhk (SEQ ID NO. 386) kdgdtkctlecaqgkkcikhk (SEQ ID NO. 387) kdgdtkctlecaqgkk (SEQ ID NO. 388) kdgdtkctlecaqgk (SEQ ID NO. 389) kciqaecnykecgeqkcvwdgih (SEQ ID NO. 390) kecgeqkcvwdgih (SEQ ID NO. 391) hieckcnndyvltnryecepknkctsledtnk (SEQ ID NO. 392) d) Blood stage trophozoites and schizonts Replikins: ksdhnhksdhnhksdhnhksdhnhksdpnhkkknnnnnk (SEQ ID NO. 393) ksdhnhksdhnhksdhnhksdpnhkkknnnnnk (SEQ ID NO. 394) ksdhnhksdhnhksdpnhkkknnnnnk (SEQ ID NO. 395) ksdhnhksdpnhkkknnnnnk (SEQ ID NO. 396) kkknnnnnkdnksdpnhk (SEQ ID NO. 397) kknnnnnkdnksdpnhk (SEQ ID NO. 398) knnnnnkdnksdpnhk (SEQ ID NO. 399) kdnksdpnhk (SEQ ID NO. 400) ksdpnhk (SEQ ID NO. 401) hslyalqqneeyqkvknekdqneikkikqlieknk (SEQ ID NO. 402) hslyalqqneeyqkvknekdqneikkik (SEQ ID NO. 403) hslyalqqneeyqkvknekdqneikk (SEQ ID NO. 404) hslyalqqneeyqkvknekdqneik (SEQ ID NO. 405) hklenleemdk (SEQ ID NO. 406) 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) hikkkegidigyk (SEQ ID NO. 412) kkmwtcklwdnkgneitknih (SEQ ID NO. 413) kkgiqwnllkkmwtcklwdnkgneitknih (SEQ ID NO. 414) kekkdsnenrkkkqkedkknpnklkkieytnkithffkaknnkqqnnvth (SEQ ID NO. 415) kkdsnenrkkkqkedkknpnklkkieytnkithffkaknnkqqnnvth (SEQ ID NO. 416) kdsnenrkkkqkedkknpnklkkieytnkithffkaknnkqqnnvth (SEQ ID NO. 417) kkqkedkknpnklkkieytnkithffkaknnkqqnnvth (SEQ ID NO. 418) kqkedkknpnklkkieytnkithffkaknnkqqnnvth (SEQ ID NO. 419) kedkknpnklkkieytnkithffkaknnkqqnnvth (SEQ ID NO. 420) knpnklkkieytnkithffkaknnkqqnnvth (SEQ ID NO. 421) kkieytnkithffkaknnkqqnnvth (SEQ ID NO. 422) kieytnkithffkaknnkqqnnvth (SEQ ID NO. 423) kithffkaknnkqqnnvth (SEQ ID NO. 424) hknnedikndnskdikndnskdikndnskdikndnnedikndnskdik (SEQ ID NO. 425) hknnedikndnskdikndnskdikndnskdikndnnedikndnsk (SEQ ID NO. 426) hknnedikndnskdikndnskdikndnskdikndnnedik (SEQ ID NO. 427) hknnedikndnskdikndnskdikndnskdik (SEQ ID NO. 428) hknnedikndnskdikndnskdikndnsk (SEQ ID NO. 429) hknnedikndnskdikndnskdik (SEQ ID NO. 430) hknnedikndnskdikndnsk (SEQ ID NO. 431) hknnedikndnskdik (SEQ ID NO. 432) hknnedik (SEQ ID NO. 433) kkyddlqnkynilnklknsleekneelkkyh (SEQ ID NO. 434) kyddlqnkynilnklknsleekneellkkyh (SEQ ID NO. 435) kynilnklknsleekneelkkyh (SEQ ID NO. 436) klknsleekneelkkyh (SEQ ID NO. 437) knsleekneelkkyh (SEQ ID NO. 438) kneelkkyh (SEQ ID NO. 439) hmgnnqdinenvynikpqefkeeeeedismvntkk (SEQ ID NO. 440) knsnelkrindnffklh (SEQ ID NO. 441) kpclykkckisqclykkckisqvwwcmpvkdtfntyernnvlnskienniekiph (SEQ ID NO. 442) hinneytnknpkncllykneernyndnnikdyinsmnfkk (SEQ ID NO. 443) hinneytnknpkncllykneernyndnnikdyinsmnfk (SEQ ID NO. 444) hinneytnknpkncllyk (SEQ ID NO. 445) knktnqskgvkgeyekkketngh (SEQ ID NO. 446) ktnqskgvkgeyekkketngh (SEQ ID NO. 447) kgvkgeyekkketngh (SEQ ID NO. 448) kgeyekkketngh (SEQ ID NO. 449) ksgmytnegnkscecsykkkssssnkvh (SEQ ID NO. 450) kscecsykkkssssnkvh (SEQ ID NO. 451) kkkssssnkvh (SEQ ID NO. 452) kkssssnkvh (SEQ ID NO. 453) kssssnkvh (SEQ ID NO. 454) himlksgmytnegnkscecsykkkssssnk (SEQ ID NO. 455) himlksgmytnegnkscecsykkk (SEQ ID NO. 456) himlksgmytnegnkscecsykk (SEQ ID NO. 457) himlksgmytnegnkscecsyk (SEQ ID NO. 458) kplaklrkrektqinktkyergdviidnteiqkiiirdyhetlnvhkldh (SEQ ID NO. 459) krektqinktkyergdviidnteiqkiiirdyhetlnvhkldh (SEQ ID NO. 460) ktqinktkyergdviidnteiqkiiirdyhetlnvhkldh (SEQ ID NO. 461) kplaklrkrektqinktkyergdviidnteiqkiiirdyhetlnvh (SEQ ID NO. 462) kplaklrkrektqinktkyergdviidnteiqkiiirdyh (SEQ ID NO. 463) klrkrektqinktkyergdviidnteiqkiiirdyh (SEQ ID NO. 464) krektqinktkyergdviidnteiqkiiirdyh (SEQ ID NO. 465) ktqinktkyergdviidnteiqkiiirdyh (SEQ ID NO. 466) kkdkekkkdsnenrkkkqkedkknpndnklkkieytnkith (SEQ ID NO. 467) kdkekkkdsnenrkkkqkedkknpndnklkkieytnkith (SEQ ID NO. 468) kekkkdsnenrkkkqkedkknpndnklkkieytnkith (SEQ ID NO. 469) kkkdsnenrkkkqkedkknpndnklkkieytnkith (SEQ ID NO. 470) kkdsnenrkkkqkedkknpndnklkkieytnkith (SEQ ID NO. 471) kdsnenrkkkqkedkknpndnklkkieytnkith (SEQ ID NO. 472) kkkqkedkknpndnklkkieytnkith (SEQ ID NO. 473) kkqkedkknpndnklkkieytnkith (SEQ ID NO. 474) kqkedkknpndnklkkieytnkith (SEQ ID NO. 475) kedkknpndnklkkieytnkith (SEQ ID NO. 476) kknpndnklkkieytnkith (SEQ ID NO. 477) knpndnklkkieytnkith (SEQ ID NO. 478) klkkieytnkith (SEQ ID NO. 479) kkieytnkith (SEQ ID NO. 480) kieytnkith (SEQ ID NO. 481) hgqikiedvnnenfnneqmknkyndeekmdiskskslksdflek (SEQ ID NO. 482) hgqikiedvnnenfnneqmknkyndeekmdiskskslk (SEQ ID NO. 483) hgqikiedvnnenfnneqmknkyndeekmdisksk (SEQ ID NO. 484) hgqikiedvnnenfnneqmknkyndeekmdisk (SEQ ID NO. 485) kkyddlqnkynilnklknsleekneelkkyh (SEQ ID NO. 486) kyddlqnkynilnklknsleekneelkkyh (SEQ ID NO. 487) kynilnklknsleekneelkkyh (SEQ ID NO. 488) klknsleekneelkkyh (SEQ ID NO. 489) knsleekneelkkyh (SEQ ID NO. 490) kneelkkyh (SEQ ID NO. 491) hmgnnqdinenvynikpqefkeeeeedismvntkkcddiqenik (SEQ ID NO. 492) ktnlyniynnknddkdnildnenreglylcdvmknsnelkrindnffklh (SEQ ID NO. 493) knsnelkrindnffklh (SEQ ID NO. 494) krindnffklh (SEQ ID NO. 495) hinneytnknpkncllykneernyndnnikdyinsmnfkk (SEQ ID NO. 496) hinneytnknpkncllykneernyndnnikdyinsmnfk (SEQ ID NO. 497) hinneytnknpkncllyk (SEQ ID NO. 498) kpclykkckisqvwwcmpvkdtfntyernnvLnskienniekiph (SEQ ID NO. 499) kckisqvwwcmpvkdtfntyernnvlnskienniekiph (SEQ ID NO. 500) kienniekiph (SEQ ID NO. 501) knktngskgvkgeyekkketngh (SEQ ID NO. 502) ktngskgvkgeyekkketngh (SEQ ID NO. 503) kgvkgeyekkketngh (SEQ ID NO. 504) kgeyekkketngh (SEQ ID NO. 505) ktiekinkskswffeeldeidkplaklrkrektqinktkyergdviidnteiqkiirdyh (SEQ ID NO. 506) kinkskswffeeldeidkplaklrkrektqinktkyergdviidnteiqkiirdyh (SEQ ID NO. 507) kplaklrkrektqinktkyergdviidnteiqkiirdyh (SEQ ID NO. 508) himlksqmytnegnkscecsykkkssssnkvh (SEQ ID NO. 509) klrkrektqinktkyergdviidnteiqkiirdyh (SEQ ID NO. 510) krektqinktkyergdviidnteiqkiirdyh (SEQ ID NO. 511) ktqinktkyergdviidnteiqkiirdyh (SEQ ID NO. 512) kplaklrkrektqinktkyergdviidnteiqkiirdyhtlnvhkldh (SEQ ID NO. 513) klrkrektqinktkyergdviidnteiqkiirdyhtlnvhkldh (SEQ ID NO. 514) krektqinktkyergdviidnteiqkiirdyhtlnvhkldh (SEQ ID NO. 515) ktqinktkyergdviidnteiqkiirdyhtlnvhkldh (SEQ ID NO. 516) kplaklrkrektqinktkyergdviidnteiqkiirdyhtlnvh (SEQ ID NO. 517)

klrkrektqinktkyergdviidnteiqkiirdyhtlnvh (SEQ ID NO. 518) krektqinktkyergdviidnteiqkiirdyhtlnvh (SEQ ID NO. 519) ktqinktkyergdviidnteiqkiirdyhtlnvh (SEQ ID NO. 520) himlksqmytnegnkscecsykkkssssnkvh (SEQ ID NO. 521) ksqmytnegnkscecsykkkssssnkvh (SEQ ID NO. 522) kscecsykkkssssnkvh (SEQ ID NO. 523) kkkssssnkvh (SEQ ID NO. 524) kkssssnkvh (SEQ ID NO. 525) kssssnkvh (SEQ ID NO. 526) himlksqmytnegnkscecsykkkssssnk (SEQ ID NO. 527) himlksqmytnegnkscecsykkk (SEQ ID NO. 528) himlksqmytnegnkscecsykk (SEQ ID NO. 529) himlksqmytnegnkscecsyk (SEQ ID NO. 530) hnnhniqiykdkrinfmnphkvmyhdnmsknertek (SEQ ID NO. 531) hnnhniqiykdkrinfmnphkvmyhdnmsk (SEQ ID NO. 532) hnnhniqiykdkrinfmnphk (SEQ ID NO. 533) hkvmyhdnmsknertek (SEQ ID NO. 534) hkvmyhdnmsk (SEQ ID NO. 535)

[0094]Synthetic Replikin vaccines, based on Replikins such as the glioma Replikin (SEQ ID NO.: 1) "kagvaflhkk" or the hepatitis C Replikin (SEQ ID NO.: 18) "hyppkpgcivpak", or HIV Replikins such as (SEQ ID NO.: 5) "kcfncgkegh" or (SEQ ID 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 treatment can then be effective. Similarly, a malaria vaccine, based on Replikins observed in Plasmodium falciparum malaria antigens on the merozoite surface or within the parasitophorous vacuole, for example, can be used to generate cytotoxic antibodies to malaria. 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.

[0095]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 may be obtained by administering antibodies to Replikin sequences of the identified strain of influenza virus to patients in need. Similarly, passive immunity to malaria may be obtained by administering antibodies to Plasmodium falciparum Replikin(s).

[0096]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 combination with an antiviral agent. Furthermore, combinations of antibodies to different Replikins may be administered as an antibody cocktail.

[0097]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 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 as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, key limpet hemocyanin, dinitrophenol, and potentially useful human adjuvants such as BCG and Corynebacterium parvum.

[0098]Monoclonal antibodies to Replikins may be prepared by using any 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. 77-96). 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 (U.S. Pat. No. 4,946,778) can be adapted to produce Replikin-specific single chain antibodies.

[0099]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, antibodies to any replikins present on malaria antigens and combinations of such antibodies are useful in the prevention and treatment of malaria.

[0100]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 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.

[0101]The fact that antimalignin antibody is increased in concentration in human malignancy regardless of cancer cell type (FIG. 5), and that this antibody binds to malignant cells regardless of cell type now may be explained by the presence of the Replikin structures herein found to be present in most malignancies (FIG. 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 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 (FIG. 4a,b) and is highly cytotoxic to transformed cells in vitro (FIG. 4c-f). Since in these examples the 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.

[0102]Antimalignin does not increase with benign proliferation, but specifically increases only with malignant transformation and replication in breast in vivo and returns from elevated to normal values upon elimination of malignant cells (FIG. 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 may be a part of a mechanism of control of cell transformation and replication. Augmentation of this 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 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 organism. Also, screening for Replikin structures specific for a particular pathological organism, e.g., anthrax., leads to diagnostic detection of the organism in body tissue or in the environment.

[0103]The Replikin sequence structure is associated with the function of replication. Thus, whether the Replikins of this invention are used for targeting 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 structure when seeking to induce antibodies that will recognize and attach to the Replikin fragment and thereby 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.

[0104]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 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; Klenerman et al, Nature 394:421-422 (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 epitopes have many lysine residues, but no histidine residues. Thus, decoy epitopes may bind anti-Replikin antibodies, but keep the antibodies away from histidine-bound respiratory enzymes.

[0105]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. 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.

[0106]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 picograms per cell.

[0107]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 VP1 protein or large segments of the VP1 protein) is that 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 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 be 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 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 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 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.

[0108]The Replikin peptides of the invention, alone or in various combinations 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 μg to about 10 mg, preferably about 10 μg to about 1 mg, and most preferably about 50 μg to about 500 ug. The skilled practitioner can readily determine the dosage and number of dosages needed to produce an effective immune response.

[0109]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 be used in hybridization assays of biopsied tissue or blood, e.g., Southern or Northern analysis, including in situ hybridization assays, to diagnose the presence of a particular organism.

[0110]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 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 route of delivery, although generally i.v. or i.m. delivery is routine. The dosage amount is also readily ascertainable.

[0111]Particularly preferred antisense nucleic acid molecules are those that are complementary to a Replikin sequence contained in a mRNA encoding an influenza 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 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 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.

[0112]In another embodiment of the invention, immune serum containing antibodies to one or more Replikins obtained from an individual exposed to one or 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 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.

[0113]In another aspect of the invention, Replikin structures are used to increase the replication of organisms. The present invention demonstrates that in 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 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 Replikins/100 amino acid residues) of any particular strain of the food crop.

[0114]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 organism, such as a food crop plant, can be increased, which will promote increased replication of the organism.

[0115]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 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.

[0116]The three point recognition method may also be modified to identify other useful compounds of covalently linked organic molecules, including other 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 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 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.

[0117]According to another embodiment of the invention, the methods described herein may be performed by a computer. FIG. 6 is a block diagram of a computer available for use with the foregoing embodiments of the present invention. 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 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.

[0118]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 by the use of a "keyword" search; but instead of using the exact spelling of the 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 by 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 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 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 information concerning other proteins classes. Further, the "3-point-recognition" method is applicable to other recognins, for example to the TOLL `innate` recognition of lipopolyssacharides of organisms.

[0119]Several embodiments of the present invention are specifically illustrated and described herein. However, it will be appreciated that modifications and 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

Process for Extraction, Isolation and Identification of Replikins and the Use of Replikins to Target, Label or Destroy Replikin-Containing Organisms

[0120]a) Algae

[0121]The following algae were collected from Bermuda water sites and either 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 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:

[0122]The extract solution is fractionated in the cold room (4 degrees C.) on a DEAE cellulose (Cellex-D) column 2.5×11.0 cm, which has been equilibrated with 0.005M phosphate buffer. Stepwise eluting solvent changes are made with the following solutions:

[0123]Solution 1--4.04 g. NaH2P04 and 0.5 g NaH2P04 are dissolved in 15 litres of distilled water (0.005 molar, pH 7);

[0124]Solution 2--8.57 g. NaH2P04 is dissolved in 2,480 ml. of distilled water;

[0125]Solution 3--17.1 g. of NaH2P04 is dissolved in 2480 ml of distilled water (0.05 molar, pH 4.7);

[0126]Solution 4--59.65 g. of NaH2P04 is dissolved in 2470 ml distilled water (0.175 molar);

[0127]Solution 5--101.6 g. of NaH2P04 is dissolved in 2455 ml distilled water (pH 4.3);

[0128]Solution 6--0.340.2 g. of NaH2P04 is dissolved in 2465 of distilled water (1.0 molar, pX-i 4.1);

[0129]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).

[0130]The extract solution, in 6 to 10 ml volume, is passed onto the column and 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 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 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 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. Pat. No. 6,242,578 B1. Those which fulfill the criteria defined by the "3-point-recognition" method are identified as Replikins. This procedure can also be applied to obtain yeast, bacterial and any plant Replikins.

[0131]b) Virus

[0132]Using the same extraction and column chromatography separation methods as above in a) for algae, Replikins in virus-infected cells are isolated and identified.

[0133]c) Tumor Cells In Vivo and In Vitro Tissue Culture

[0134]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, Malignin (Aglyco lOB) isolated from glioblastoma tumor cells in tissue culture, MCF7 mammary carcinoma cells in tissue culture, and P₃J 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 lOB as described in Example 10 U.S. Pat. No. 6,242,578 B1 produced the amino acid sequence, ykagvaflhkkndiide the 16-mer Replikin.

Example 2

[0135]As an example of diagnostic use of Replikins: Aglyco lOB or the 16-mer Repliken may be used as antigen to capture and quantify the amount of its corresponding antibody present in serum for diagnostic purposes are as shown in FIGS. 2,3, 4 and 7 of U.S. Pat. No. 6,242,578 B1.

[0136]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 6 and FIGS. 9A and 9B of U.S. Pat. No. 6,242,578 B1.

[0137]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 FIG. 5 and Example 6 of U.S. Pat. No. 6,242,578 B1.

[0138]As an example of the use of agents to destroy Replikins: The use of antibodies to the 16-mer Replikin to inhibit or destroy specific cells which contain this Replikin is shown in FIG. 6 of U.S. Pat. No. 6,242,578 B1.

Example 3

[0139]Analysis of sequence data of isolates of influenza virus hemagglutinin protein or neuraminidase protein for the presence and concentration of Replikins is 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 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 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 of influenza epidemic or pandemic in the future.

[0140]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 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 identified in the emerging strain.

[0141]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 pharmaceutically acceptable carrier in an amount determined to induce a therapeutic antibody reaction thereto. Generally, the dosage is about 0.1 μg to about 10 mg.

[0142]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 may be administered 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.

Example 4

[0143]Analysis of sequence data of isolates of Plasmodium falciparum antigens for the presence and concentration of Replikins is 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 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 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.

[0144]Peptide vaccines or nucleic acid-based vaccines based on the Replikins observed in the malaria causing organism are generated. Preferably, the peptide or nucleic acid vaccine is based on or includes any Replikin sequences that are observed to be present on a surface antigen of the organism. The vaccines may include any combination of Replikin sequences identified in the malaria causing strain.

[0145]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 pharmaceutically acceptable carrier in an amount determined to induce a therapeutic antibody reaction thereto. Generally, the dosage is about 0.1 μg to about 10 mg.

[0146]Then malaria vaccine is preferably administered to a patient in need thereof at any time during the year, and particularly prior to travel to a tropical environment.

Sequence CWU 1

535110PRTArtificial SequenceDescription of Artificial Sequence Synthetic glioma replikin 1Lys Ala Gly Val Ala Phe Leu His Lys Lys1 5 10213PRTSaccharomyces cerevisiae 2His Ser Ile Lys Arg Glu Leu Gly Ile Ile Phe Asp Lys1 5 10310PRTGemini vinis virus 3His Lys Gln Lys Ile Val Ala Pro Val Lys1 5 10416PRTUnknown OrganismDescription of Unknown Organism Virus recognin 4Tyr Lys Ala Gly Val Ala Phe Leu His Lys Lys Asn Asp Ile Asp Glu1 5 10 15510PRTHuman immunodeficiency virus type 1 5Lys Cys Phe Asn Cys Gly Lys Glu Gly His1 5 10611PRTHuman immunodeficiency virus type 1 6Lys Val Tyr Leu Ala Trp Val Pro Ala His Lys1 5 10710PRTHuman immunodeficiency virus type 2 7Lys Cys Trp Asn Cys Gly Lys Glu Gly His1 5 10811PRTMaize streak virus 8Lys Tyr Ile Val Cys Ala Arg Glu Ala His Lys1 5 10917PRTMaize streak virus 9Lys Glu Lys Lys Pro Ser Lys Asp Glu Ile Met Arg Asp Ile Ile Ser1 5 10 15His109PRTStaphylococcus aureus 10Lys Lys Glu Lys Thr Thr His Asn Lys1 51110PRTBovine herpesvirus 4 11His Lys Ile Asn Ile Thr Asn Gly Gln Lys1 5 101210PRTMeleagrid herpesvirus 1 12His Lys Asp Leu Tyr Arg Leu Leu Met Lys1 5 101315PRTUnknown OrgansimDescription of Unknown Organism Virus recognin 13Lys Phe Arg Ile Asn Ala Lys Asn Tyr Phe Leu Thr Tyr Pro His1 5 10 151419PRTUnknown OrganismDescription of Unknown Organism Virus recognin 14Lys Asn Leu Glu Thr Pro Val Asn Lys Leu Phe Ile Arg Ile Cys Arg1 5 10 15Glu Phe His1514PRTUnknown OrganismDescription of Unknown Organism Virus recognin 15His Pro Asn Ile Gln Ala Ala Lys Ser Ser Thr Asp Val Lys1 5 101619PRTUnknown OrganismDescription of Unknown Organism Virus recognin 16Lys Ser Ser Thr Asp Val Lys Ala Tyr Met Asp Lys Asp Gly Asp Val1 5 10 15Leu Asp His1721PRTUnknown OrganismDescription of Unknown Organism Virus recognin 17Lys Ala Ser Ala Leu Asn Ile Leu Arg Glu Lys Ala Pro Lys Asp Phe1 5 10 15Val Leu Gln Phe His201813PRTHepatitis C virus 18His Tyr Pro Pro Lys Pro Gly Cys Ile Val Pro Ala Lys1 5 10194PRTHomo sapiens 19Tyr Lys Ala Gly1206PRTHomo sapiens 20Tyr Lys Ala Gly Val Ala1 5217PRTHomo sapiens 21Tyr Lys Ala Gly Val Ala Phe1 5227PRTHomo sapiens 22Tyr Lys Ala Gly Val Ala Phe1 5239PRTHomo sapiens 23Ala Gly Val Ala Phe His Lys Lys Asn1 5244PRTHomo sapiens 24Gly Val Ala Phe1253PRTHomo sapiens 25Val Ala Phe1267PRTHomo sapiens 26Val Ala Phe Leu His Lys Lys1 5277PRTHomo sapiens 27Val Ala Phe Leu His Lys Lys1 5289PRTHomo sapiens 28Val Ala Phe Leu His Lys Lys Asn Asp1 5298PRTHomo sapiens 29Val Ala Phe His Lys Lys Asn Asp1 5304PRTHomo sapiens 30Ala Phe Leu His1318PRTHomo sapiens 31His Lys Lys Asn Asp Ile Asp Glu1 5326PRTHomo sapiens 32Lys Lys Asn Asp Ile Asp1 5336PRTHomo sapiens 33Lys Asn Asp Ile Asp Glu1 5348PRTCaldophera prolifera 34Lys Ala Ser Lys Phe Thr Lys His1 53512PRTIsolepis prolifera 35Lys Ala Gln Ala Glu Thr Gly Glu Ile Lys Gly His1 5 103610PRTSchizosaccharomyces pombe 36Lys Ser Phe Lys Tyr Pro Lys Lys His Lys1 5 103710PRTOryza sativa 37Lys Lys Ala Tyr Gly Asn Glu Leu His Lys1 5 10389PRTPenicillium marneffei 38Lys Val Asp Ile Val Thr His Gln Lys1 53912PRTDiseula dcstructiva 39Lys Leu Glu Glu Asp Ala Ala Tyr His Arg Lys Lys1 5 104017PRTOphiostoma novo-ulmi 40Lys Val Ile Leu Pro Leu Arg Gly Asn Ile Lys Gly Ile Phe Phe Lys1 5 10 15His4111PRTEntamoeba invadens 41Lys Leu Ile Leu Lys Gly Asp Leu Asn Lys His1 5 10428PRTHelicobacter pylori 42Lys Ser Val His Ala Phe Leu Lys1 5 439PRTMycoplasma pulmonis 43Lys Val His Phe Phe Gln Leu Lys Lys1 5 449PRTArabidopsis thaliana 44Lys Asp His Asp Phe Asp Gly Asp Lys1 5 4511PRTArabidopsis thaliana 45Lys Met Lys Gly Leu Lys Gln Lys Lys Ala His1 5 104612PRTArabidopsis thaliana 46Lys Glu Leu Ser Ser Thr Thr Gln Glu Lys Ser His1 5 10479PRTFeline immunodeficiency virus 47His Leu Lys Asp Tyr Lys Leu Val Lys1 5 487PRTRous sarcoma virus 48Lys Lys Leu Arg His Glu Lys1 5 497PRTAvian sarcoma virus 49Lys Lys Leu Arg His Asp Lys1 5 507PRTHomo sapiens 50Lys Lys Leu Arg His Asp Lys1 5 517PRTAvian sarcoma virus 51Lys Lys Leu Arg His Glu Lys1 5 527PRTHomo sapiens 52Lys Lys Leu Arg His Glu Lys1 5 538PRTHomo sapiens 53Lys Gln Ala His Glu Leu Ala Lys1 5 548PRTPolyama virus 54Lys Thr His Arg Phe Ser Lys His1 5 558PRTSindbis virus 55Lys Asn Leu His Glu Lys Ile Lys1 5 569PRTHuman papilloamavirus type 71 56Lys His Arg Pro Leu Leu Gln Leu Lys1 5 577PRTAvian encephalomyelitis virus 57Lys Ser Pro Asn His Val Lys1 5 588PRTFeline sarcoma virus 58Lys Asn Ile His Leu Glu Lys Lys1 5 598PRTHomo sapiens 59Lys Asn Ile His Leu Glu Lys Lys1 5 6010PRTPolyoma virus 60Lys Pro His Leu Ala Gln Ser Leu Glu Lys1 5 10619PRTPolyoma virus 61Lys Gln His Arg Glu Leu Lys Asp Lys1 5 629PRTPolyoma virus 62Lys Gln His Arg Glu Leu Lys Asp Lys1 5 6312PRTMurine leukemia virus 63Lys Val Pro Val Leu Ile Ser Pro Thr Leu Lys His1 5 106413PRTHuman T-cell lymphotropic virus type 2 64Lys Ser Leu Leu Leu Glu Val Asp Lys Asp Ile Ser His1 5 106513PRTHomo sapiens 65Lys Ala Gly Ile Thr Ile Met Val Lys Arg Glu Tyr His1 5 10668PRTHomo sapiens 66Lys Ser Gly Lys His Leu Gly Lys1 5 679PRTHomo sapiens 67Lys Arg Arg Glu Gln Leu Lys His Lys1 5 6810PRTHomo sapiens 68Lys Ser Phe Glu Val Ile Lys Val Ile His1 5 10698PRTHomo sapiens 69Lys Lys Lys His Thr Val Lys Lys1 5 709PRTHomo sapiens 70Lys Ala Gln Lys Asp His Leu Ser Lys1 5 7110PRTHomo sapiens 71His Leu Lys Arg Val Lys Asp Leu Lys Lys1 5 107211PRTHomo sapiens 72Lys Tyr Gly Ser Pro Lys His Arg Leu Ile Lys1 5 107313PRTPapilloma virus type 11 73Lys Leu Lys His Ile Leu Gly Lys Ala Arg Phe Ile Lys1 5 107412PRTHomo sapiens 74Lys Gly Asp His Val Lys His Tyr Lys Ile Arg Lys1 5 107513PRTHomo sapiens 75Lys Glu Lys Leu Arg Asp Val Met Val Asp Arg His Lys1 5 107615PRTHomo sapiens 76Lys Leu Gln Ala Arg Gln Gln Gln Leu Leu Lys Lys Ile Glu His1 5 10 157714PRTHomo sapiens 77Lys Lys Gly Asn Arg Val Ser Pro Thr Met Lys Val Thr His1 5 10789PRTHomo sapiens 78Lys Glu Ile Pro Leu His Phe Arg Lys1 5 798PRTHomo sapiens 79Lys Lys Lys Pro His Ile Lys Lys1 5 809PRTHomo sapiens 80Lys Thr Arg His Asp Pro Leu Ala Lys1 5 8110PRTHomo sapiens 81Lys His His Pro Lys Asp Asn Leu Ile Lys1 5 108210PRTHomo sapiens 82Lys His Lys Arg Lys Lys Phe Arg Gln Lys1 5 108310PRTHomo sapiens 83Lys Ala Gly Val Ala Phe Leu His Lys Lys1 5 108410PRTHomo sapiens 84Lys His Lys Arg Lys Lys Phe Arg Gln Lys1 5 108510PRTHomo sapiens 85Lys Lys Lys Ser Lys Lys His Lys Asp Lys1 5 108611PRTHomo sapiens 86His Lys Ser Glu Lys Pro Ala Leu Pro Arg Lys1 5 108714PRTHomo sapiens 87Lys Lys Lys Lys Pro Ser Arg Leu Lys Gly Asp Asn Glu Lys1 5 108816PRTHomo sapiens 88Lys Thr Lys Lys Gly Asn Arg Val Ser Pro Thr Met Lys Val Thr His1 5 10 158918PRTHomo sapiens 89Lys His Lys Glu Lys Met Ser Lys Asp Gly Lys Lys Lys Lys Lys Lys1 5 10 15Ser Lys909PRTLegionella sp. 90Lys Ile His Leu Ile Ser Val Lys Lys1 5 9110PRTBacillus anthracis 91His Val Lys Lys Glu Lys Glu Lys Asn Lys1 5 10929PRTBacillus anthracis 92Lys His Ile Val Lys Ile Glu Val Lys1 5 9316PRTBacillus anthracis 93Lys Lys Lys Lys Ile Lys Asp Ile Tyr Gly Lys Asp Ala Leu Leu His1 5 10 15948PRTBacillus anthracis 94Lys Trp Glu Lys Ile Lys Gln His1 5 9518PRTBacillus anthracis 95Lys Lys Leu Gln Ile Pro Pro Pro Ile Glu Pro Lys Lys Asp Asp Ile1 5 10 15Ile His9631PRTBacillus anthracis 96His Asn Arg Tyr Ala Ser Asn Ile Val Glu Ser Ala Tyr Leu Leu Ile1 5 10 15Leu Asn Glu Trp Lys Asn Asn Ile Gln Ser Asp Leu Ile Lys Lys20 25 309724PRTBacillus anthracis 97His Ala Val Asp Asp Tyr Ala Gly Tyr Leu Leu Asp Lys Asn Gln Ser1 5 10 15Asp Leu Val Thr Asn Ser Lys Lys209813PRTBacillus anthracis 98His Ala Glu Arg Leu Lys Val Gln Lys Asn Ala Pro Lys1 5 109910PRTVariola virus 99Lys His Tyr Asn Asn Ile Thr Trp Tyr Lys1 5 1010012PRTVariola virus 100Lys Tyr Ser Gln Thr Gly Lys Glu Leu Ile Ile His1 5 1010117PRTVariola virus 101His Tyr Asp Asp Val Arg Ile Lys Asn Asp Ile Val Val Ser Arg Cys1 5 10 15Lys10211PRTVariola virus 102His Arg Phe Lys Leu Ile Leu Asp Ser Lys Ile1 5 1010311PRTVariola virus 103Lys Glu Arg Gly His Asn Tyr Tyr Phe Glu Lys1 5 101048PRTInfluenza B virus 104Lys Ser His Phe Ala Asn Leu Lys1 5 10511PRTInfluenza B virus 105Lys Ser His Phe Ala Asn Leu Lys Gly Thr Lys1 5 1010619PRTInfluenza B virus 106Lys Ser His Phe Ala Asn Leu Lys Gly Thr Lys Thr Arg Gly Lys Leu1 5 10 15Cys Pro Lys1079PRTInfluenza B virus 107His Glu Lys Tyr Gly Gly Leu Asn Lys1 5 10811PRTInfluenza B virus 108His Glu Lys Tyr Gly Gly Leu Asn Lys Ser Lys1 5 1010920PRTInfluenza B virus 109His Glu Lys Tyr Gly Gly Leu Asn Lys Ser Lys Pro Tyr Tyr Thr Gly1 5 10 15Glu His Ala Lys2011013PRTInfluenza B virus 110His Ala Lys Ala Ile Gly Asn Cys Pro Ile Trp Val Lys1 5 1011123PRTInfluenza B virus 111His Ala Lys Ala Ile Gly Asn Cys Pro Ile Trp Val Lys Thr Pro Leu1 5 10 15Lys Leu Ala Asn Gly Thr Lys2011229PRTInfluenza B virus 112His Ala Lys Ala Ile Gly Asn Cys Pro Ile Trp Val Lys Thr Pro Leu1 5 10 15Lys Leu Ala Asn Gly Thr Lys Tyr Arg Pro Pro Ala Lys20 2511332PRTInfluenza B virus 113His Ala Lys Ala Ile Gly Asn Cys Pro Ile Trp Val Lys Thr Pro Leu1 5 10 15Lys Leu Ala Asn Gly Thr Lys Tyr Arg Pro Pro Ala Lys Leu Leu Lys20 25 3011413PRTInfluenza B virus 114His Phe Ala Asn Leu Lys Gly Thr Lys Thr Arg Gly Lys1 5 1011517PRTInfluenza B virus 115His Phe Ala Asn Leu Lys Gly Thr Lys Thr Arg Gly Lys Leu Cys Pro1 5 10 15Lys11616PRTInfluenza B virus 116His Ser Asp Asn Glu Ile Gln Met Val Lys Leu Tyr Gly Asp Ser Lys1 5 10 1511721PRTInfluenza B virus 117His Ser Asp Asn Glu Ile Gln Asp Lys Met Val Lys Leu Tyr Gly Asp1 5 10 15Ser Lys Pro Gln Lys2011819PRTInfluenza B virus 118His Ser Asp Asn Glu Ile Gln Met Val Lys Leu Tyr Gly Asp Ser Lys1 5 10 15Pro Gln Lys1199PRTInfluenza B virusMOD_RES(2)ala or val 119Lys Xaa Ser Ile Leu His Glu Val Lys1 5 12015PRTInfluenza B virus 120Lys Cys Thr Gly Thr Ile Pro Ser Ala Lys Ala Ser Ile Leu His1 5 10 1512118PRTInfluenza B virus 121Lys Cys Thr Gly Thr Ile Pro Ser Ala Lys Ala Ser Ile Leu His Glu1 5 10 15Val Lys12216PRTInfluenza B virus 122Lys Tyr Gly Gly Leu Asn Lys Ser Lys Pro Tyr Tyr Thr Gly Glu His1 5 10 1512326PRTInfluenza B virus 123Lys Val Trp Cys Ala Ser Gly Arg Ser Lys Val Ile Lys Gly Ser Leu1 5 10 15Pro Leu Ile Gly Glu Ala Asp Cys Leu His20 2512410PRTInfluenza B virus 124Lys Pro Tyr Tyr Thr Gly Glu His Ala Lys1 5 1012518PRTInfluenza B virus 125Lys Cys Met Gly Thr Ile Pro Ser Ala Lys Ala Ser Ile Leu His Glu1 5 10 15Val Lys12615PRTInfluenza B virus 126His Asn Val Ile Asn Ala Glu Lys Ala Pro Gly Gly Pro Tyr Lys1 5 10 1512716PRTInfluenza B virus 127His Ser Asp Asn Glu Thr Gln Met Ala Lys Leu Tyr Gly Asp Ser Lys1 5 10 1512818PRTInfluenza B virus 128His Gly Val Ala Val Ala Ala Asp Leu Lys Ser Thr Gln Glu Ala Ile1 5 10 15Asn Lys12929PRTInfluenza B virus 129His Gly Val Ala Val Ala Ala Asp Leu Lys Ser Thr Gln Glu Ala Ile1 5 10 15Asn Lys Asp Thr Ile Ser Thr Gln Glu Ala Ile Asn Lys20 2513021PRTInfluenza B virus 130Lys Leu Tyr Gly Asp Ser Lys Pro Gln Lys Phe Thr Ser Ser Ala Asn1 5 10 15Gly Val Thr Thr His2013119PRTInfluenza B virus 131His Ser Asp Asn Glu Thr Gln Met Ala Lys Leu Tyr Gly Asp Ser Lys1 5 10 15Pro Gln Lys13213PRTInfluenza B virus 132His Phe Ala Asn Leu Lys Gly Thr Gln Thr Arg Gly Lys1 5 1013312PRTInfluenza B virus 133Lys Pro Arg Ser Ala Leu Lys Cys Lys Gly Phe His1 5 1013422PRTInfluenza B virusMOD_RES(15)gly or ala 134Lys Ser Lys Pro Tyr Tyr Thr Gly Glu His Ala Lys Ala Ile Xaa Asn1 5 10 15Cys Pro Ile Trp Val Lys2013516PRTInfluenza virusMOD_RES(3)val or ile 135His Pro Xaa Thr Ile Gly Glu Cys Pro Lys Tyr Val Xaa Xaa Xaa Lys1 5 10 1513621PRTInfluenza virusMOD_RES(10)glu or gly 136His Asp Ser Asn Val Lys Asn Leu Tyr Xaa Lys Val Xaa Xaa Gln Leu1 5 10 15Xaa Asn Asn Ala Lys2013717PRTInfluenza virusMOD_RES(10)glu or gly 137His Asp Ser Asn Val Lys Asn Leu Tyr Xaa Lys Val Xaa Xaa Gln Leu1 5 10 15Lys13836PRTInfluenza virusMOD_RES(4)..(5)asn or asp 138His Lys Cys Xaa Xaa Xaa Cys Met Glu Ser Val Xaa Asn Gly Thr Tyr1 5 10 15Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Xaa Ile20 25 30Asp Gly Val Lys3513926PRTInfluenza virusMOD_RES(4)..(5)asn or asp 139His Lys Cys Xaa Xaa Xaa Cys Met Glu Ser Val Xaa Asn Gly Thr Tyr1 5 10 15Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys20 2514050PRTInfluenza virusMOD_RES(4)glu or gly 140His Gln Asn Xaa Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr1 5 10 15Gln Asn Ala Ile Xaa Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu20 25 30Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu35 40 45Glu Lys5014133PRTInfluenza virusMOD_RES(4)glu or gly 141His Gln Asn Xaa Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr1 5 10 15Gln Asn Ala Ile Xaa Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu20 25 30Lys14226PRTInfluenza virusMOD_RES(4)glu or gly 142His Gln Asn Xaa Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr1 5 10 15Gln Asn Ala Ile Xaa Gly Ile Thr Asn Lys20 2514314PRTInfluenza virus 143Lys Phe Glu Ile Phe Pro Lys Thr Ser Ser Trp Pro Asn His1 5 1014427PRTInfluenza virusMOD_RES(3)asn, ser or thr 144Lys Gly Xaa Ser Tyr Pro Lys Leu Xaa Lys Ser Tyr Xaa Asn Asn Lys1 5 10 15Gly Lys Glu Val Leu Val Leu Trp Gly Val His20 2514518PRTInfluenza virusMOD_RES(4)val or thr 145Lys Ser Tyr Xaa Asn Asn Lys Gly Lys Glu Val Leu Val Leu Trp Gly1 5 10 15Val His14636PRTInfluenza virus 146His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr1 5 10 15Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn Arg Glu Lys Ile20 25

30Asp Gly Val Lys3514726PRTInfluenza virus 147His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr1 5 10 15Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys20 2514820PRTInfluenza virus 148His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys Asn Gly Thr Tyr1 5 10 15Asp Tyr Pro Lys2014912PRTInfluenza virus 149His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys1 5 1015034PRTInfluenza virusMOD_RES(9)lys or arg 150His Asn Gly Lys Ser Ser Phe Tyr Xaa Asn Leu Leu Trp Leu Thr Xaa1 5 10 15Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys20 25 30Glu Lys15132PRTInfluenza virusMOD_RES(9)lys or arg 151His Asn Gly Lys Ser Ser Phe Tyr Xaa Asn Leu Leu Trp Leu Thr Xaa1 5 10 15Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys20 25 3015226PRTInfluenza virusMOD_RES(9)lys or arg 152His Asn Gly Lys Ser Ser Phe Tyr Xaa Asn Leu Leu Trp Leu Thr Xaa1 5 10 15Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys20 2515317PRTInfluenza virusMOD_RES(9)lys or arg 153His Asn Gly Lys Ser Ser Phe Tyr Xaa Asn Leu Leu Trp Leu Thr Xaa1 5 10 15Lys15440PRTInfluenza virus 154Lys Ser Ser Phe Tyr Lys Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly1 5 10 15Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu20 25 30Val Leu Val Leu Trp Gly Val His35 4015535PRTInfluenza virus 155Lys Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Leu Tyr Pro Asn Leu1 5 10 15Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val Leu Trp20 25 30Gly Val His3515627PRTInfluenza virus 156Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys1 5 10 15Glu Lys Glu Val Leu Val Leu Trp Gly Val His20 2515718PRTInfluenza virusMOD_RES(4)val or ala 157Lys Ser Tyr Xaa Asn Asn Lys Glu Lys Glu Val Xaa Xaa Leu Trp Gly1 5 10 15Val His15812PRTInfluenza virus 158Lys Glu Ser Ser Trp Pro Asn His Thr Val Thr Lys1 5 1015944PRTInfluenza virusMOD_RES(4)thr or asn 159His Glu Thr Xaa Lys Gly Val Thr Ala Ala Cys Pro Tyr Ala Gly Ala1 5 10 15Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Val Lys Lys Glu Asn Ser20 25 30Tyr Pro Lys Leu Ser Lys Ser Tyr Val Asn Asn Lys35 4016038PRTInfluenza virusMOD_RES(4)thr or asn 160His Glu Thr Xaa Lys Gly Val Thr Ala Ala Cys Pro Tyr Ala Gly Ala1 5 10 15Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Val Lys Lys Glu Asn Ser20 25 30Tyr Pro Lys Leu Ser Lys3516122PRTInfluenza virus 161Lys Phe Glu Ile Phe Pro Lys Thr Ser Ser Trp Pro Asn Glu Val Leu1 5 10 15Val Leu Trp Gly Val His201628PRTInfluenza virus 162Lys Glu Arg Ser Trp Pro Lys His1 516321PRTInfluenza virus 163Lys Leu Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val1 5 10 15Leu Trp Gln Val His2016415PRTInfluenza virus 164Lys Asn Asn Lys Glu Lys Glu Val Leu Val Leu Trp Gln Val His1 5 10 1516534PRTInfluenza virusMOD_RES(2)lys or asn 165His Xaa Xaa Lys Ser Ser Phe Tyr Xaa Asn Leu Leu Trp Leu Thr Glu1 5 10 15Lys Asn Gly Xaa Tyr Pro Xaa Leu Ser Lys Ser Tyr Ala Asn Asn Lys20 25 30Glu Lys16617PRTInfluenza virusMOD_RES(2)lys or asn 166His Xaa Xaa Lys Ser Ser Phe Tyr Xaa Asn Leu Leu Trp Leu Thr Glu1 5 10 15Lys1679PRTInfluenza virus 167His Ala Lys Lys Ser Ser Phe Tyr Lys1 5 16811PRTInfluenza virus 168His Asn Gly Lys Leu Cys Arg Leu Lys Gly Lys1 5 101699PRTInfluenza virusMOD_RES(7)gln or gly 169His Tyr Lys Leu Asn Asn Xaa Lys Lys1 5 17025PRTInfluenza virus 170His Asp Ile Tyr Arg Asp Glu Ala Ile Asn Asn Arg Phe Gln Ile Gln1 5 10 15Gly Val Lys Leu Thr Gln Gly Tyr Lys20 2517111PRTInfluenza virus 171Lys Gly Asn Gly Cys Phe Glu Ile Phe His Lys1 5 1017218PRTInfluenza virus 172Lys Leu Asn Arg Leu Ile Glu Lys Thr Asn Asp Lys Tyr His Gln Ile1 5 10 15Glu Lys17314PRTInfluenza virus 173Lys Leu Asn Arg Leu Ile Glu Lys Thr Asn Asp Lys Tyr His1 5 1017413PRTInfluenza virus 174Lys Cys His Thr Asp Lys Gly Ser Leu Ser Thr Thr Lys1 5 1017516PRTInfluenza virus 175Lys Ile Asn Asn Gly Asp Tyr Ala Lys Leu Tyr Ile Trp Gly Val His1 5 10 1517617PRTInfluenza virus 176His Asn Gly Lys Leu Cys Arg Lys Gly Ile Ala Pro Leu Gln Leu Gly1 5 10 15Lys17738PRTInfluenza virus 177His Glu Thr Asn Arg Gln Val Thr Ala Ala Cys Pro Tyr Ala Gly Ala1 5 10 15Asn Ser Phe Phe Arg Asn Leu Ile Trp Leu Val Lys Lys Glu Ser Ser20 25 30Tyr Pro Lys Leu Ser Lys3517835PRTInfluenza virus 178His Glu Thr Asn Arg Gln Val Thr Ala Ala Cys Pro Tyr Ala Gly Ala1 5 10 15Asn Ser Phe Phe Arg Asn Leu Ile Trp Leu Val Lys Lys Glu Ser Ser20 25 30Tyr Pro Lys3517931PRTInfluenza virus 179His Pro Pro Thr Ser Thr Asp Gln Gln Ser Leu Tyr Gln Asn Ala Asp1 5 10 15Ala Tyr Ile Phe Val Gly Ser Ser Lys Tyr Asn Arg Lys Phe Lys20 25 3018035PRTInfluenza virus 180His Pro Pro Thr Ser Thr Asp Gln Gln Ser Leu Tyr Gln Asn Ala Asp1 5 10 15Ala Tyr Ile Phe Val Gly Ser Ser Lys Tyr Asn Arg Lys Phe Lys Pro20 25 30Glu Ile Ala3518125PRTInfluenza virus 181His Asp Ile Tyr Arg Asp Glu Ala Ile Asn Asn Arg Phe Gln Ile Gln1 5 10 15Gly Val Lys Ile Thr Gln Gly Tyr Lys20 2518243PRTInfluenza virus 182His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr1 5 10 15Gln Asn Ala Ile Asp Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu20 25 30Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys35 4018333PRTInfluenza virus 183His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr1 5 10 15Gln Asn Ala Ile Asp Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu20 25 30Lys18450PRTInfluenza virus 184His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr1 5 10 15Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu20 25 30Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu35 40 45Glu Lys5018518PRTInfluenza virus 185His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile Ala Pro Leu Gln Leu1 5 10 15Gly Lys18612PRTInfluenza virus 186His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys1 5 1018714PRTInfluenza virus 187Lys Phe Glu Ile Phe Pro Lys Ala Ser Ser Trp Pro Asn His1 5 1018821PRTInfluenza virus 188His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys Val Arg Ser Gln Leu1 5 10 15Arg Asn Asn Ala Lys2018922PRTInfluenza virus 189Lys Val Asn Ser Val Ile Lys Lys Met Asn Thr Gln Phe Ala Ala Val1 5 10 15Gly Lys Glu Phe Asn His201908PRTInfluenza virus 190Lys His Asn Gly Lys Leu Cys Lys1 5 19128PRTInfluenza virus 191Lys Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr His Asn1 5 10 15Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His20 2519227PRTInfluenza virus 192Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr His Asn Lys1 5 10 15Gly Lys Glu Val Leu Val Leu Trp Gly Val His20 2519321PRTInfluenza virus 193Lys Leu Ser Lys Ser Tyr Thr His Asn Lys Gly Lys Glu Val Leu Val1 5 10 15Leu Trp Gly Val His2019418PRTInfluenza virus 194Lys Ser Tyr Thr His Asn Lys Gly Lys Glu Val Leu Val Leu Trp Gly1 5 10 15Val His19510PRTInfluenza virus 195Lys Gly Val Thr Ala Ser Cys Ser His Lys1 5 1019634PRTInfluenza virus 196Lys Gly Val Thr Ala Ser Cys Ser His Lys Gly Arg Ser Ser Phe Tyr1 5 10 15Arg Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Leu Tyr Pro Asn Leu20 25 30Ser Lys19727PRTInfluenza virus 197Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Val Asn Asn Lys1 5 10 15Glu Lys Glu Val Leu Val Leu Trp Gly Ile His20 251988PRTInfluenza virus 198Lys Glu Phe Asn His Leu Glu Lys1 5 19939PRTInfluenza virus 199His Pro Pro Thr Ser Thr Asp Gln Gln Ser Leu Tyr Gln Asn Ala Asp1 5 10 15Ala Tyr Val Phe Val Gly Ser Ser Lys Tyr Asn Lys Lys Phe Lys Pro20 25 30Glu Ile Ala Thr Arg Pro Lys3520031PRTInfluenza virus 200His Pro Pro Thr Ser Thr Asp Gln Gln Ser Leu Tyr Gln Asn Ala Asp1 5 10 15Ala Tyr Val Phe Val Gly Ser Ser Lys Tyr Asn Lys Lys Phe Lys20 25 3020131PRTInfluenza virus 201His Glu Gly Lys Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Thr Glu1 5 10 15Lys Glu Gly Ser Tyr Pro Lys Leu Lys Asn Ser Tyr Val Asn Lys20 25 3020223PRTInfluenza virus 202His Glu Gly Lys Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Thr Glu1 5 10 15Lys Glu Gly Ser Tyr Pro Lys2020326PRTInfluenza virus 203His Lys Cys Asp Asn Glu Cys Met Glu Ser Val Arg Asn Gly Thr Tyr1 5 10 15Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys20 2520412PRTInfluenza virus 204Lys Glu Ser Ser Trp Pro Asn His Thr Val Thr Lys1 5 1020535PRTInfluenza virus 205Lys Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Leu Tyr Pro Asn Leu1 5 10 15Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Ile Leu Val Leu Trp20 25 30Gly Val His3520627PRTInfluenza virusMOD_RES(9)lys or met 206His Asn Gly Lys Ser Ser Phe Tyr Xaa Xaa Leu Leu Trp Leu Thr Xaa1 5 10 15Xaa Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys20 2520717PRTInfluenza virus 207His Asn Gly Lys Ser Ser Phe Tyr Lys Asn Leu Leu Trp Leu Thr Glu1 5 10 15Lys20855PRTInfluenza virus 208His Thr Val Thr Lys Gly Val Thr Ala Ser Cys Ser His Asn Gly Lys1 5 10 15Ser Ser Phe Tyr Lys Asn Leu Leu Trp Leu Thr Glu Lys Asn Gly Leu20 25 30Tyr Pro Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val35 40 45Leu Val Leu Trp Gly Val His50 5520938PRTInfluenza virusMOD_RES(5)lys or gly 209His Thr Val Thr Xaa Gly Val Xaa Ala Ser Cys Ser His Asn Gly Lys1 5 10 15Ser Ser Phe Tyr Xaa Xaa Leu Leu Trp Leu Thr Xaa Lys Xaa Gly Leu20 25 30Tyr Pro Asn Leu Ser Lys3521029PRTInfluenza virus 210His Thr Val Thr Lys Gly Val Thr Ala Ser Cys Ser His Asn Gly Lys1 5 10 15Ser Ser Phe Tyr Lys Asn Leu Leu Trp Leu Thr Glu Lys20 2521148PRTInfluenza virus 211Lys Tyr Val Arg Ser Thr Lys Leu Arg Met Val Thr Gly Leu Arg Asn1 5 10 15Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe20 25 30Ile Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr His35 40 4521243PRTInfluenza virus 212His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr1 5 10 15Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Ile Ile Glu20 25 30Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys35 4021333PRTInfluenza virus 213His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr1 5 10 15Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Ile Ile Glu20 25 30Lys21426PRTInfluenza virus 214His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr1 5 10 15Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys20 2521523PRTInfluenza virus 215His Ser Gly Ala Arg Ser Phe Tyr Arg Asn Leu Leu Trp Ile Val Lys1 5 10 15Lys Gly Asn Ser Tyr Pro Lys2021626PRTInfluenza virus 216His Ser Gly Ala Arg Ser Phe Tyr Arg Asn Leu Leu Trp Ile Val Lys1 5 10 15Lys Gly Asn Ser Tyr Pro Lys Leu Asn Lys20 2521732PRTInfluenza virus 217His Ser Gly Ala Arg Ser Phe Tyr Arg Asn Leu Leu Trp Ile Val Lys1 5 10 15Lys Gly Asn Ser Tyr Pro Lys Leu Asn Lys Ser Tyr Thr Asn Asp Lys20 25 3021834PRTInfluenza virus 218His Ser Gly Ala Arg Ser Phe Tyr Arg Asn Leu Leu Trp Ile Val Lys1 5 10 15Lys Gly Asn Ser Tyr Pro Lys Leu Asn Lys Ser Tyr Thr Asn Asp Lys20 25 30Gly Lys21916PRTInfluenza virus 219His Thr Val Ser Lys Gly Val Thr Thr Ser Cys Ser His Asn Gly Lys1 5 10 1522012PRTInfluenza virus 220Lys Ala Thr Ser Trp Pro Asn His Glu Thr Thr Lys1 5 1022112PRTInfluenza virus 221Lys Gln Val Thr Thr Ser Cys Ser His Asn Gln Lys1 5 1022227PRTInfluenza virus 222Lys Gly Asn Ser Tyr Pro Lys Leu Asn Lys Ser Tyr Thr Asn Asp Lys1 5 10 15Gly Lys Glu Val Leu Val Ile Trp Gly Val His20 2522321PRTInfluenza virus 223Lys Leu Asn Lys Ser Tyr Thr Asn Asp Lys Gly Lys Glu Val Leu Val1 5 10 15Ile Trp Gly Val His2022418PRTInfluenza virus 224Lys Ser Tyr Thr Asn Asp Lys Gly Lys Glu Val Leu Val Ile Trp Gly1 5 10 15Val His22535PRTInfluenza virusMOD_RES(16)glu or gln 225His Asn Gln Lys Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Thr Xaa1 5 10 15Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Xaa Ala Asn Asn20 25 30Lys Glu Lys3522616PRTInfluenza virus 226His Pro Ile Thr Ile Gly Glu Cys Pro Lys Tyr Val Arg Ser Ala Lys1 5 10 1522743PRTInfluenza virus 227His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr1 5 10 15Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu20 25 30Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys35 4022833PRTInfluenza virus 228His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr1 5 10 15Gln Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu20 25 30Lys22934PRTInfluenza virus 229His Asn Gly Lys Ser Ser Phe Tyr Arg Asn Leu Leu Trp Leu Thr Glu1 5 10 15Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Val Asn Asn Lys20 25 30Glu Lys23011PRTInfluenza virus 230Lys His Phe Glu Lys Val Lys Ile Leu Pro Lys1 5 1023114PRTInfluenza virus 231Lys His Leu Leu Ser Ser Val Lys His Phe Glu Lys Val Lys1 5 1023213PRTInfluenza virusMOD_RES(3)lys, gln or met 232His Ala Xaa Xaa Ile Leu Glu Lys Thr His Asn Gly Lys1 5 1023316PRTInfluenza virusMOD_RES(3)lys, gln or met 233His Ala Xaa Xaa Ile Leu Glu Lys Thr His Asn Gly Lys Leu Cys Xaa1 5 10 1523419PRTInfluenza virus 234His Asn Val His Pro Leu Thr Ile Gly Glu Cys Pro Lys Tyr Val Lys1 5 10 15Ser Glu Lys23516PRTInfluenza virus 235His Pro Leu Thr Ile Gly Glu Cys Pro Lys Tyr Val Lys Ser Glu Lys1 5 10 1523618PRTInfluenza virus 236Lys His Leu Leu Ser Ser Val Lys His Phe Glu Lys Val Lys Ile Leu1 5 10 15Pro Lys23738PRTInfluenza virus 237Lys Arg Gln Ser Ser Gly Ile Met Lys Thr Glu Gly Thr Leu Glu Asn1

5 10 15Cys Glu Thr Lys Cys Gln Thr Pro Leu Gly Ala Ile Asn Thr Thr Leu20 25 30Pro Phe His Asn Val His3523827PRTInfluenza virusMOD_RES(7)val or ile 238Lys Gly Ser Asn Tyr Pro Xaa Ala Lys Xaa Ser Tyr Asn Asn Thr Ser1 5 10 15Gly Glu Gln Met Leu Ile Ile Trp Gln Xaa His20 2523936PRTInfluenza virus 239His Thr Thr Leu Gly Gln Ser Arg Ala Cys Ala Val Ser Gly Asn Pro1 5 10 15Ser Phe Phe Arg Asn Met Val Trp Leu Thr Glu Lys Gly Ser Asn Tyr20 25 30Pro Val Ala Lys352407PRTInfluenza virus 240Lys His Phe Glu Lys Val Lys1 5 24138PRTInfluenza virus 241Lys Ile Ser Lys Arg Gly Ser Ser Gly Ile Met Lys Thr Glu Gly Thr1 5 10 15Leu Glu Asn Cys Glu Thr Lys Cys Gln Thr Pro Leu Gly Ala Ile Asn20 25 30Thr Thr Leu Pro Phe His3524235PRTInfluenza virus 242Lys Arg Gly Ser Ser Gly Ile Met Lys Thr Glu Gly Thr Leu Glu Asn1 5 10 15Cys Glu Thr Lys Cys Gln Thr Pro Leu Gly Ala Ile Asn Thr Thr Leu20 25 30Pro Phe His3524327PRTInfluenza virus 243Lys Thr Glu Gly Thr Leu Glu Asn Cys Glu Thr Lys Cys Gln Thr Pro1 5 10 15Leu Gly Ala Ile Asn Thr Thr Leu Pro Phe His20 2524438PRTInfluenza virus 244Lys Ile Ser Lys Arg Gly Ser Ser Gly Ile Met Lys Thr Glu Gly Thr1 5 10 15Leu Glu Asn Cys Glu Thr Lys Cys Gln Thr Pro Leu Gly Ala Ile Asn20 25 30Thr Thr Leu Pro Phe His3524530PRTInfluenza virusMOD_RES(29)val or ile 245Lys Thr Glu Gly Thr Leu Glu Asn Cys Glu Thr Lys Cys Gln Thr Pro1 5 10 15Leu Gly Ala Ile Asn Thr Thr Leu Pro Phe His Asn Xaa His20 25 3024638PRTInfluenza virus 246Lys Ile Ser Lys Arg Gly Ser Ser Gly Ile Met Lys Thr Glu Gly Thr1 5 10 15Leu Glu Asn Cys Glu Thr Lys Cys Gln Thr Pro Leu Gly Ala Ile Asn20 25 30Thr Thr Leu Pro Phe His3524727PRTInfluenza virusMOD_RES(2)glu or gly 247Lys Xaa Ser Asn Tyr Pro Val Ala Lys Gly Ser Tyr Asn Asn Thr Ser1 5 10 15Gly Glu Gln Met Leu Ile Ile Trp Gly Val His20 2524816PRTInfluenza virus 248His Pro Leu Thr Ile Gly Glu Cys Pro Lys Tyr Val Lys Ser Glu Lys1 5 10 1524916PRTInfluenza virus 249Lys Cys Gln Thr Pro Leu Gly Ala Ile Lys Thr Thr Leu Pro Phe His1 5 10 1525058PRTInfluenza virusMOD_RES(21)phe or ile 250His His Ser Asn Asp Gln Gly Ser Gly Tyr Ala Ala Asp Lys Glu Ser1 5 10 15Thr Gln Lys Ala Xaa Asp Gly Ile Thr Asn Lys Val Asn Ser Val Ile20 25 30Glu Lys Met Asn Thr Gln Phe Glu Ala Val Gly Lys Leu Phe Xaa Asn35 40 45Leu Glu Lys Leu Glu Asn Leu Asn Lys Lys50 5525157PRTInfluenza virusMOD_RES(20)phe or ile 251His Ser Asn Asp Gln Gly Ser Gly Tyr Ala Ala Asp Lys Glu Ser Thr1 5 10 15Gln Lys Ala Xaa Asp Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu20 25 30Lys Met Asn Thr Gln Phe Glu Ala Val Gly Lys Leu Phe Xaa Asn Leu35 40 45Glu Lys Leu Glu Asn Leu Asn Lys Lys50 5525226PRTInfluenza virusMOD_RES(20)phe or ile 252His Ser Asn Asp Gln Gly Ser Gly Tyr Ala Ala Asp Lys Glu Ser Thr1 5 10 15Gln Lys Ala Xaa Asp Gly Ile Thr Asn Lys20 2525321PRTInfluenza virus 253His Asp Ser Asn Val Arg Asn Leu Tyr Asp Lys Val Arg Met Gln Leu1 5 10 15Arg Asp Asn Ala Lys2025430PRTInfluenza virus 254His Lys Cys Asp Asp Glu Cys Met Asn Ser Val Lys Asn Gly Thr Tyr1 5 10 15Asp Tyr Pro Lys Leu Asn Arg Asn Glu Ile Lys Gly Val Lys20 25 3025527PRTInfluenza virus 255His Lys Cys Asp Asp Glu Cys Met Asn Ser Val Lys Asn Gly Thr Tyr1 5 10 15Asp Tyr Pro Lys Leu Asn Arg Asn Glu Ile Lys20 2525620PRTInfluenza virus 256His Lys Cys Asp Asp Glu Cys Met Asn Ser Val Lys Asn Gly Thr Tyr1 5 10 15Asp Tyr Pro Lys2025712PRTInfluenza virus 257His Lys Cys Asp Asp Glu Cys Met Asn Ser Val Lys1 5 1025827PRTInfluenza virus 258Lys Gly Ser Asn Tyr Pro Val Ala Lys Gly Ser Tyr Asn Asn Thr Asn1 5 10 15Gly Glu Gln Ile Leu Ile Ile Trp Gly Val His20 2525943PRTInfluenza virus 259His Ser Asn Asp Gln Gly Ser Gly Tyr Ala Ala Asp Lys Glu Ser Thr1 5 10 15Gln Lys Ala Val Asp Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu20 25 30Lys Met Asn Thr Gln Phe Glu Ala Val Gly Lys35 4026035PRTInfluenza virus 260Lys Arg Gly Ser Ser Gly Ile Met Lys Thr Glu Gly Thr Leu Glu Asn1 5 10 15Cys Glu Thr Lys Cys Gln Thr Pro Leu Gly Ala Ile Asn Thr Thr Leu20 25 30Pro Phe His3526116PRTInfluenza virus 261His Pro Leu Thr Ile Gly Glu Cys Pro Lys Tyr Val Lys Ser Glu Lys1 5 10 1526216PRTInfluenza virus 262His Ala Lys Asp Ile Leu Glu Lys Thr His Asn Gly Lys Leu Cys Lys1 5 10 1526325PRTInfluenza virus 263His Asp Val Tyr Arg Asp Glu Ala Leu Asn Asn Arg Phe Gln Ile Lys1 5 10 15Gly Val Glu Leu Lys Ser Gly Tyr Lys20 2526419PRTInfluenza virus 264His Thr Ile Asp Leu Thr Asp Ser Glu Met Asn Lys Leu Phe Glu Arg1 5 10 15Thr Arg Lys2657PRTInfluenza virus 265Lys Phe His Gln Ile Glu Lys1 5 26611PRTInfluenza virusMOD_RES(8)gly or gln 266Lys Thr Asn Glu Lys Phe His Xaa Ile Glu Lys1 5 1026714PRTInfluenza virusMOD_RES(5)val or leu 267Lys Leu Asn Arg Xaa Ile Glu Lys Thr Asn Glu Lys Phe His1 5 1026825PRTInfluenza virus 268His Gln Ile Glu Lys Glu Phe Ser Glu Val Glu Gly Arg Ile Gln Asp1 5 10 15Leu Glu Lys Tyr Val Glu Asp Thr Lys20 252698PRTInfluenza virus 269Lys Ile Cys Asn Asn Pro His Lys1 5 27014PRTInfluenza virus 270Lys Leu Asn Arg Val Ile Lys Lys Thr Asn Glu Lys Phe His1 5 1027124PRTInfluenza virusMOD_RES(3)ile or val 271His Asp Xaa Tyr Arg Asp Glu Ala Leu Asn Asn Arg Phe Gln Ile Lys1 5 10 15Xaa Val Glu Xaa Ser Xaa Tyr Lys2027225PRTInfluenza virus 272His Gln Ile Glu Lys Glu Phe Ser Glu Val Glu Gly Arg Ile Gln Asp1 5 10 15Leu Glu Lys Tyr Val Glu Asp Thr Lys20 2527325PRTInfluenza virus 273Lys Tyr Val Glu Asp Thr Lys Ile Asp Leu Trp Ser Tyr Asn Ala Glu1 5 10 15Leu Leu Val Ala Leu Glu Asn Gln His20 2527449PRTInfluenza virus 274Lys Tyr Val Lys Gln Asn Ser Leu Lys Leu Ala Thr Gly Met Arg Asn1 5 10 15Val Pro Glu Lys Gln Thr Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe20 25 30Ile Glu Asn Gly Trp Glu Gly Met Ile Asp Gly Trp Tyr Gly Phe Arg35 40 45His27539PRTInfluenza virus 275Lys Glu Phe Ser Glu Val Glu Gly Arg Ile Gln Asp Leu Glu Lys Tyr1 5 10 15Val Glu Asp Thr Lys Ile Asp Leu Trp Ser Tyr Asn Ala Glu Leu Leu20 25 30Val Ala Leu Glu Asn Gln His3527633PRTInfluenza virusMOD_RES(4)ser or glu 276His Gln Asn Xaa Xaa Gly Xaa Gly Xaa Ala Ala Asp Xaa Lys Ser Thr1 5 10 15Gln Xaa Ala Xaa Asp Xaa Ile Xaa Xaa Lys Xaa Asn Xaa Val Ile Xaa20 25 30Lys27718PRTInfluenza virusMOD_RES(4)gly or gln 277His Cys Asp Xaa Phe Xaa Asn Glu Lys Trp Asp Leu Phe Xaa Glu Arg1 5 10 15Xaa Lys27820PRTInfluenza virus 278His Thr Ile Asp Leu Thr Asp Ser Glu Met Asn Lys Lys Leu Phe Glu1 5 10 15Arg Thr Arg Lys2027928PRTInfluenza virus 279Lys Ser Gly Ser Thr Tyr Pro Val Leu Lys Val Thr Met Pro Asn Asn1 5 10 15Asp Asn Phe Asp Lys Leu Tyr Ile Trp Gly Val His20 2528034PRTInfluenza virus 280Lys Leu Asn Trp Leu Thr Lys Ser Gly Asn Thr Tyr Pro Val Leu Asn1 5 10 15Val Thr Met Pro Asn Asn Asp Asn Phe Asp Lys Leu Val Ile Trp Gly20 25 30Val His28119PRTInfluenza virus 281His Thr Ile Asp Leu Thr Asp Ser Glu Met Asn Lys Leu Phe Glu Lys1 5 10 15Thr Arg Lys28218PRTInfluenza virus 282Lys Leu Asn Arg Leu Ile Glu Lys Thr Asn Glu Lys Phe His Gln Thr1 5 10 15Glu Lys28347PRTInfluenza virus 283His Thr Gly Lys Ser Ser Val Met Arg Ser Asp Ala Pro Ile Asp Phe1 5 10 15Cys Asn Ser Glu Cys Ile Thr Pro Asn Gln Ser Ile Pro Asn Asp Lys20 25 30Pro Phe Gln Asn Val Asn Lys Ile Thr Tyr Gly Ala Cys Pro Lys35 40 4528439PRTInfluenza virus 284His Thr Gly Lys Ser Ser Val Met Arg Ser Asp Ala Pro Ile Asp Phe1 5 10 15Cys Asn Ser Glu Cys Ile Thr Pro Asn Gln Ser Ile Pro Asn Asp Lys20 25 30Pro Phe Gln Asn Val Asn Lys3528533PRTInfluenza virus 285His Pro Ser Thr Asp Ser Asp Gln Thr Ser Leu Tyr Val Arg Ala Ser1 5 10 15Gly Arg Val Thr Val Ser Thr Lys Arg Ser Gln Gln Thr Val Ile Pro20 25 30Lys28625PRTInfluenza virus 286Lys Tyr Val Glu Asp Thr Lys Ile Asp Leu Trp Ser Tyr Asn Ala Glu1 5 10 15Leu Leu Val Ala Leu Glu Asn Gln His20 2528726PRTInfluenza virus 287Lys Leu Phe Glu Arg Thr Arg Lys Gln Leu Arg Glu Asn Ala Glu Asp1 5 10 15Met Gly Asn Gly Cys Phe Lys Ile Tyr His20 2528816PRTInfluenza virus 288Lys Arg Arg Ser Ile Lys Ser Phe Phe Ser Arg Leu Asn Trp Leu His1 5 10 1528916PRTInfluenza virusMOD_RES(12)val or arg 289His Pro Val Thr Ile Gly Glu Cys Pro Lys Tyr Xaa Lys Ser Thr Lys1 5 10 1529030PRTInfluenza virus 290Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Leu Ser Lys Ser Tyr Ile1 5 10 15Ile Asn Lys Lys Lys Glu Val Leu Val Ile Trp Gly Ile His20 25 3029124PRTInfluenza virusMOD_RES(9)val or tyr 291Lys Leu Ser Lys Leu Ser Lys Ser Xaa Ile Ile Asn Lys Lys Lys Glu1 5 10 15Val Leu Val Ile Trp Gly Ile His2029221PRTInfluenza virusMOD_RES(6)val or tyr 292Lys Leu Ser Lys Ser Xaa Ile Ile Asn Lys Lys Lys Glu Val Leu Val1 5 10 15Ile Trp Gly Ile His2029346PRTPlasmodium falciparum 293Lys Glu Glu Glu Glu Lys Glu Lys Glu Lys Glu Lys Glu Lys Glu Glu1 5 10 15Lys Glu Lys Glu Glu Lys Glu Lys Glu Glu Lys Glu Lys Glu Lys Glu20 25 30Glu Lys Glu Lys Glu Lys Glu Glu Lys Glu Glu Glu Lys Lys35 40 4529448PRTPlasmodium falciparum 294Lys Glu Glu Glu Glu Lys Glu Lys Glu Lys Glu Lys Glu Lys Glu Glu1 5 10 15Lys Glu Lys Glu Glu Lys Glu Lys Glu Glu Lys Glu Lys Glu Lys Glu20 25 30Glu Lys Glu Lys Glu Lys Glu Glu Lys Glu Glu Glu Lys Lys Glu Lys35 40 4529547PRTPlasmodium falciparum 295Lys Glu Glu Glu Glu Lys Glu Lys Glu Lys Glu Lys Glu Lys Glu Glu1 5 10 15Lys Glu Lys Glu Glu Lys Glu Lys Glu Lys Glu Glu Lys Glu Lys Glu20 25 30Glu Lys Glu Lys Glu Glu Lys Glu Glu Lys Glu Glu Glu Lys Lys35 40 4529610PRTPlasmodium falciparum 296Lys Glu Glu Glu Glu Lys Glu Lys Glu Lys1 5 1029719PRTPlasmodium falciparum 297His Lys Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gln1 5 10 15Asn Lys Lys29819PRTPlasmodium falciparum 298His Lys Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gln1 5 10 15Asn Lys Met29910PRTPlasmodium falciparum 299His Lys Lys Leu Ile Lys Ala Leu Lys Lys1 5 103009PRTPlasmodium falciparum 300His Lys Lys Leu Ile Lys Ala Leu Lys1 5 30123PRTPlasmodium falciparum 301Lys Ala Thr Tyr Ser Phe Val Asn Thr Lys Lys Lys Ile Ile Ser Leu1 5 10 15Lys Ser Gln Gly His Lys Lys2030222PRTPlasmodium falciparum 302Lys Ala Thr Tyr Ser Phe Val Asn Thr Lys Lys Lys Ile Ile Ser Leu1 5 10 15Lys Ser Gln Gly His Lys2030321PRTPlasmodium falciparum 303Lys Ala Thr Tyr Ser Phe Val Asn Thr Lys Lys Lys Ile Ile Ser Leu1 5 10 15Lys Ser Gln Gly His2030429PRTPlasmodium falciparum 304His Thr Tyr Val Lys Gly Lys Lys Ala Pro Ser Asp Pro Gln Cys Ala1 5 10 15Asp Ile Lys Glu Glu Cys Lys Glu Leu Leu Lys Glu Lys20 2530511PRTPlasmodium falciparum 305Lys Ile Ile Ser Leu Lys Ser Gln Gly His Lys1 5 1030621PRTPlasmodium falciparum 306Lys Lys Lys Lys Phe Glu Pro Leu Lys Asn Gly Asn Val Ser Glu Thr1 5 10 15Ile Lys Leu Ile His2030720PRTPlasmodium falciparum 307Lys Lys Lys Phe Glu Pro Leu Lys Asn Gly Asn Val Ser Glu Thr Ile1 5 10 15Lys Leu Ile His2030819PRTPlasmodium falciparum 308Lys Lys Phe Glu Pro Leu Lys Asn Gly Asn Val Ser Glu Thr Ile Lys1 5 10 15Leu Ile His30913PRTPlasmodium falciparum 309Lys Asn Gly Asn Val Ser Glu Thr Ile Lys Leu Ile His1 5 1031011PRTPlasmodium falciparum 310Lys Leu Ile His Leu Gly Asn Lys Asp Lys Lys1 5 1031136PRTPlasmodium falciparum 311Lys Val Lys Lys Ile Gly Val Thr Leu Lys Lys Phe Glu Pro Leu Lys1 5 10 15Asn Gly Asn Val Ser Glu Thr Ile Lys Leu Ile His Leu Gly Asn Lys20 25 30Asp Lys Lys His3531259PRTPlasmodium falciparum 312His Leu Ile Tyr Lys Asn Lys Ser Tyr Asn Pro Leu Leu Leu Ser Cys1 5 10 15Val Lys Lys Met Asn Met Leu Lys Glu Asn Val Asp Tyr Ile Gln Asn20 25 30Gln Asn Leu Phe Lys Glu Leu Met Asn Gln Lys Ala Thr Tyr Ser Phe35 40 45Val Asn Thr Lys Lys Lys Ile Ile Ser Leu Lys50 5531352PRTPlasmodium falciparum 313His Leu Ile Tyr Lys Asn Lys Ser Tyr Asn Pro Leu Leu Leu Ser Cys1 5 10 15Val Lys Lys Met Asn Met Leu Lys Glu Asn Val Asp Tyr Ile Gln Asn20 25 30Gln Asn Leu Phe Lys Glu Leu Met Asn Gln Lys Ala Thr Tyr Ser Phe35 40 45Val Asn Thr Lys5031443PRTPlasmodium falciparum 314His Leu Ile Tyr Lys Asn Lys Ser Tyr Asn Pro Leu Leu Leu Ser Cys1 5 10 15Val Lys Lys Met Asn Met Leu Lys Glu Asn Val Asp Tyr Ile Gln Asn20 25 30Gln Asn Leu Phe Lys Glu Leu Met Asn Gln Lys35 4031538PRTPlasmodium falciparum 315His Leu Ile Tyr Lys Asn Lys Ser Tyr Asn Pro Leu Leu Leu Ser Cys1 5 10 15Val Lys Lys Met Asn Met Leu Lys Glu Asn Val Asp Tyr Ile Gln Lys20 25 30Asn Gln Asn Leu Phe Lys3531624PRTPlasmodium falciparum 316His Leu Ile Tyr Lys Asn Lys Ser Tyr Asn Pro Leu Leu Leu Ser Cys1 5 10 15Val Lys Lys Met Asn Met Leu Lys2031747PRTPlasmodium falciparum 317Lys Ser Ala Asn Asn Ser Ala Asn Asn Gly Lys Lys Asn Asn Ala Glu1 5 10 15Glu Met Lys Asn Leu Val Asn Phe Leu Gln Ser His Lys Lys Leu Ile20 25 30Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gln Asn Lys Lys His35 40 4531837PRTPlasmodium falciparum 318Lys Lys Asn Asn Ala Glu Glu Met Lys Asn Leu Val Asn Phe Leu Gln1 5 10 15Ser His Lys Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile20 25 30Gln Asn Lys Lys His3531929PRTPlasmodium falciparum 319Lys Asn Leu Val Asn Phe Leu Gln Ser His Lys Lys Leu Ile Lys Ala1 5 10 15Leu Lys Lys Asn Ile Glu Ser Ile Gln Asn

Lys Lys His20 2532019PRTPlasmodium falciparum 320Lys Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gln Asn1 5 10 15Lys Lys His32118PRTPlasmodium falciparum 321Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gln Asn Lys1 5 10 15Lys His32212PRTPlasmodium falciparum 322Lys Lys Asn Ile Glu Ser Ile Gln Asn Lys Lys His1 5 1032311PRTPlasmodium falciparum 323Lys Asn Ile Glu Ser Ile Gln Asn Lys Lys His1 5 1032417PRTPlasmodium falciparum 324Lys Asn Asn Ala Glu Glu Met Lys Asn Leu Val Asn Phe Leu Gln Ser1 5 10 15His32523PRTPlasmodium falciparum 325Lys Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gln Asn1 5 10 15Lys Lys Gln Gly His Lys Lys2032619PRTPlasmodium falciparum 326Lys Lys Asn Asn Ala Glu Glu Met Lys Asn Leu Val Asn Phe Leu Gln1 5 10 15Ser His Lys32717PRTPlasmodium falciparum 327Lys Asn Asn Ala Glu Glu Met Lys Asn Leu Val Asn Phe Leu Gln Ser1 5 10 15His32822PRTPlasmodium falciparum 328Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gln Asn Lys1 5 10 15Lys Gln Gly His Lys Lys2032928PRTPlasmodium falciparum 329Lys Val Lys Lys Ile Gly Val Thr Leu Lys Lys Phe Glu Pro Leu Lys1 5 10 15Asn Gly Asn Val Ser Glu Thr Ile Lys Leu Ile His20 2533013PRTPlasmodium falciparum 330Lys Asn Gly Asn Val Ser Glu Thr Ile Lys Leu Ile His1 5 1033111PRTPlasmodium falciparum 331Lys Leu Ile His Leu Gly Asn Lys Asp Lys Lys1 5 1033228PRTPlasmodium falciparum 332Lys Ser Ala Asn Asn Ser Ala Asn Asn Gly Lys Lys Asn Asn Ala Glu1 5 10 15Glu Met Lys Asn Leu Val Asn Phe Leu Gln Ser His20 2533318PRTPlasmodium falciparum 333Lys Lys Asn Asn Ala Glu Glu Met Lys Asn Leu Val Asn Phe Leu Gln1 5 10 15Ser His33419PRTPlasmodium falciparum 334Lys Lys Leu Ile Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gln Asn1 5 10 15Lys Lys His33515PRTPlasmodium falciparum 335Lys Ala Leu Lys Lys Asn Ile Glu Ser Ile Gln Asn Lys Lys His1 5 10 1533612PRTPlasmodium falciparum 336Lys Lys Asn Ile Glu Ser Ile Gln Asn Lys Lys His1 5 1033727PRTPlasmodium falciparum 337Lys Glu Leu Met Asn Gln Lys Ala Thr Tyr Ser Phe Val Asn Thr Lys1 5 10 15Lys Lys Ile Ile Ser Leu Lys Ser Gln Gly His20 253387PRTPlasmodium falciparum 338Lys Ser Gln Gly His Lys Lys1 5 33912PRTPlasmodium falciparum 339Lys Lys Lys Ile Ile Ser Leu Lys Ser Gln Gly His1 5 1034011PRTPlasmodium falciparum 340Lys Lys Ile Ile Ser Leu Lys Ser Gln Gly His1 5 1034112PRTPlasmodium falciparum 341Lys Lys Asn Ile Glu Ser Ile Gln Asn Lys Lys His1 5 1034211PRTPlasmodium falciparum 342Lys Asn Ile Glu Ser Ile Gln Asn Lys Lys His1 5 1034329PRTPlasmodium falciparum 343His Thr Tyr Val Lys Gly Lys Lys Ala Pro Ser Asp Pro Gln Cys Ala1 5 10 15Asp Ile Lys Glu Glu Cys Lys Glu Leu Leu Lys Glu Lys20 2534427PRTPlasmodium falciparum 344His Thr Tyr Val Lys Gly Lys Lys Ala Pro Ser Asp Pro Gln Cys Ala1 5 10 15Asp Ile Lys Glu Glu Cys Lys Glu Leu Leu Lys20 2534529PRTPlasmodium falciparum 345His Glu Asn Val Leu Ser Ala Ala Leu Glu Asn Thr Gln Ser Glu Glu1 5 10 15Glu Lys Lys Glu Val Ile Asp Val Ile Glu Glu Val Lys20 2534648PRTPlasmodium falciparum 346Lys Glu Asn Val Val Thr Thr Ile Leu Glu Lys Val Glu Glu Thr Thr1 5 10 15Ala Glu Ser Val Thr Thr Phe Ser Asn Ile Leu Glu Glu Ile Gln Glu20 25 30Asn Thr Ile Thr Asn Asp Thr Ile Glu Glu Lys Leu Glu Glu Leu His35 40 4534714PRTPlasmodium falciparum 347His Tyr Leu Gln Gln Met Lys Glu Lys Phe Ser Lys Glu Lys1 5 1034842PRTPlasmodium falciparum 348His Tyr Leu Gln Gln Met Lys Glu Lys Phe Ser Lys Glu Lys Asn Asn1 5 10 15Asn Val Ile Glu Val Thr Asn Lys Ala Glu Lys Lys Gly Asn Val Gln20 25 30Val Thr Asn Lys Thr Glu Lys Thr Thr Lys35 4034948PRTPlasmodium falciparum 349His Tyr Leu Gln Gln Met Lys Glu Lys Phe Ser Lys Glu Lys Asn Asn1 5 10 15Asn Val Ile Glu Val Thr Asn Lys Ala Glu Lys Lys Gly Asn Val Gln20 25 30Val Thr Asn Lys Thr Glu Lys Thr Thr Lys Val Asp Lys Asn Asn Lys35 40 4535057PRTPlasmodium falciparum 350His Tyr Leu Gln Gln Met Lys Glu Lys Phe Ser Lys Glu Lys Asn Asn1 5 10 15Asn Val Ile Glu Val Thr Asn Lys Ala Glu Lys Lys Gly Asn Val Gln20 25 30Val Thr Asn Lys Thr Glu Lys Thr Thr Lys Val Asp Lys Asn Asn Lys35 40 45Val Pro Lys Lys Arg Arg Thr Gln Lys50 5535159PRTPlasmodium falciparum 351His Tyr Leu Gln Gln Met Lys Glu Lys Phe Ser Lys Glu Lys Asn Asn1 5 10 15Asn Val Ile Glu Val Thr Asn Lys Ala Glu Lys Lys Gly Asn Val Gln20 25 30Val Thr Asn Lys Thr Glu Lys Thr Thr Lys Val Asp Lys Asn Asn Lys35 40 45Val Pro Lys Lys Arg Arg Thr Gln Lys Ser Lys50 5535252PRTPlasmodium falciparum 352His Val Asp Glu Val Met Lys Tyr Val Gln Lys Ile Asp Lys Glu Val1 5 10 15Asp Lys Glu Val Ser Lys Ala Leu Glu Ser Lys Asn Asp Val Thr Asn20 25 30Val Leu Lys Gln Asn Gln Asp Phe Phe Ser Lys Val Lys Asn Phe Val35 40 45Lys Lys Tyr Lys5035350PRTPlasmodium falciparum 353His Val Asp Glu Val Met Lys Tyr Val Gln Lys Ile Asp Lys Glu Val1 5 10 15Asp Lys Glu Val Ser Lys Ala Leu Glu Ser Lys Asn Asp Val Thr Asn20 25 30Val Leu Lys Gln Asn Gln Asp Phe Phe Ser Lys Val Lys Asn Phe Val35 40 45Lys Lys5035443PRTPlasmodium falciparum 354His Val Asp Glu Val Met Lys Tyr Val Gln Lys Ile Asp Lys Glu Val1 5 10 15Asp Lys Glu Val Ser Lys Ala Leu Glu Ser Lys Asn Asp Val Thr Asn20 25 30Val Leu Lys Gln Asn Gln Asp Phe Phe Ser Lys35 4035535PRTPlasmodium falciparum 355His Val Asp Glu Val Met Lys Tyr Val Gln Lys Ile Asp Lys Glu Val1 5 10 15Asp Lys Glu Val Ser Lys Ala Leu Glu Ser Lys Asn Asp Val Thr Asn20 25 30Val Leu Lys3535627PRTPlasmodium falciparum 356His Val Asp Glu Val Met Lys Tyr Val Gln Lys Ile Asp Lys Glu Val1 5 10 15Asp Lys Glu Val Ser Lys Ala Leu Glu Ser Lys20 2535722PRTPlasmodium falciparum 357His Val Asp Glu Val Met Lys Tyr Val Gln Lys Ile Asp Lys Glu Val1 5 10 15Asp Lys Glu Val Ser Lys2035818PRTPlasmodium falciparum 358His Val Asp Glu Val Met Lys Tyr Val Gln Lys Ile Asp Lys Glu Val1 5 10 15Asp Lys35914PRTPlasmodium falciparum 359His Val Asp Glu Val Met Lys Tyr Val Gln Lys Ile Asp Lys1 5 1036039PRTPlasmodium falciparum 360Lys Asp Glu Val Ile Asp Leu Ile Val Gln Lys Glu Lys Arg Ile Glu1 5 10 15Lys Val Lys Ala Lys Lys Lys Lys Leu Glu Lys Lys Val Glu Glu Gly20 25 30Val Ser Gly Leu Lys Lys His3536123PRTPlasmodium falciparum 361Lys Val Lys Ala Lys Lys Lys Lys Leu Glu Lys Lys Val Glu Glu Gly1 5 10 15Val Ser Gly Leu Lys Lys His2036221PRTPlasmodium falciparum 362Lys Ala Lys Lys Lys Lys Leu Glu Lys Lys Val Glu Glu Gly Val Ser1 5 10 15Gly Leu Lys Lys His2036319PRTPlasmodium falciparum 363Lys Lys Lys Lys Leu Glu Lys Lys Val Glu Glu Gly Val Ser Gly Leu1 5 10 15Lys Lys His36418PRTPlasmodium falciparum 364Lys Lys Lys Leu Glu Lys Lys Val Glu Glu Gly Val Ser Gly Leu Lys1 5 10 15Lys His36517PRTPlasmodium falciparum 365Lys Lys Leu Glu Lys Lys Val Glu Glu Gly Val Ser Gly Leu Lys Lys1 5 10 15His36616PRTPlasmodium falciparum 366Lys Leu Glu Lys Lys Val Glu Glu Gly Val Ser Gly Leu Lys Lys His1 5 10 1536713PRTPlasmodium falciparum 367Lys Lys Val Glu Glu Gly Val Ser Gly Leu Lys Lys His1 5 1036812PRTPlasmodium falciparum 368Lys Val Glu Glu Gly Val Ser Gly Leu Lys Lys His1 5 1036959PRTPlasmodium falciparum 369His Val Glu Gln Asn Val Tyr Val Asp Val Asp Val Pro Ala Met Lys1 5 10 15Asp Gln Phe Leu Gly Ile Leu Asn Glu Ala Gly Gly Leu Lys Glu Met20 25 30Phe Phe Asn Leu Glu Asp Val Phe Lys Ser Glu Ser Asp Val Ile Thr35 40 45Val Glu Glu Ile Lys Asp Glu Pro Val Gln Lys50 5537053PRTPlasmodium falciparum 370His Ile Lys Gly Leu Glu Glu Asp Asp Leu Glu Glu Val Asp Asp Leu1 5 10 15Lys Gly Ser Ile Leu Asp Met Leu Lys Gly Asp Met Glu Leu Gly Asp20 25 30Met Asp Lys Glu Ser Leu Glu Asp Val Thr Thr Lys Leu Gly Glu Arg35 40 45Val Glu Ser Leu Lys5037144PRTPlasmodium falciparum 371His Ile Lys Gly Leu Glu Glu Asp Asp Leu Glu Glu Val Asp Asp Leu1 5 10 15Lys Gly Ser Ile Leu Asp Met Leu Lys Gly Asp Met Glu Leu Gly Asp20 25 30Met Asp Lys Glu Ser Leu Glu Asp Val Thr Thr Lys35 4037235PRTPlasmodium falciparum 372His Ile Lys Gly Leu Glu Glu Asp Asp Leu Glu Glu Val Asp Asp Leu1 5 10 15Lys Gly Ser Ile Leu Asp Met Leu Lys Gly Asp Met Glu Leu Gly Asp20 25 30Met Asp Lys3537325PRTPlasmodium falciparum 373His Ile Lys Gly Leu Glu Glu Asp Asp Leu Glu Glu Val Asp Asp Leu1 5 10 15Lys Gly Ser Ile Leu Asp Met Leu Lys20 2537431PRTPlasmodium falciparum 374His Ile Ile Ser Gly Asp Ala Asp Val Leu Ser Ser Ala Leu Gly Met1 5 10 15Asp Glu Glu Gln Met Lys Thr Arg Lys Lys Ala Gln Arg Pro Lys20 25 3037523PRTPlasmodium falciparum 375His Asp Ile Thr Thr Thr Leu Asp Glu Val Val Glu Leu Lys Asp Val1 5 10 15Glu Glu Asp Lys Ile Glu Lys2037610PRTPlasmodium falciparum 376Lys Lys Leu Glu Glu Val His Glu Leu Lys1 5 103779PRTPlasmodium falciparum 377Lys Leu Glu Glu Val His Glu Leu Lys1 537819PRTPlasmodium falciparum 378Lys Thr Ile Glu Thr Asp Ile Leu Glu Glu Lys Lys Lys Glu Ile Glu1 5 10 15Lys Asp His37911PRTPlasmodium falciparum 379Lys Lys Glu Ile Glu Lys Asp His Phe Glu Lys1 5 103806PRTPlasmodium falciparum 380Lys Asp His Phe Glu Lys1 538111PRTPlasmodium falciparum 381Lys Phe Glu Glu Glu Ala Glu Glu Ile Lys His1 5 1038247PRTPlasmodium falciparum 382Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gln Gly Lys Lys1 5 10 15Cys Ile Lys His Lys Ser Asp His Asn His Lys Ser Asp His Asn His20 25 30Lys Ser Asp Pro Asn His Lys Lys Lys Asn Asn Asn Asn Asn Lys35 40 4538340PRTPlasmodium falciparum 383Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gln Gly Lys Lys1 5 10 15Cys Ile Lys His Lys Ser Asp His Asn His Lys Ser Asp His Asn His20 25 30Lys Ser Asp Pro Asn His Lys Lys35 4038439PRTPlasmodium falciparum 384Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gln Gly Lys Lys1 5 10 15Cys Ile Lys His Lys Ser Asp His Asn His Lys Ser Asp His Asn His20 25 30Lys Ser Asp Pro Asn His Lys3538533PRTPlasmodium falciparum 385Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gln Gly Lys Lys1 5 10 15Cys Ile Lys His Lys Ser Asp His Asn His Lys Ser Asp His Asn His20 25 30Lys38627PRTPlasmodium falciparum 386Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gln Gly Lys Lys1 5 10 15Cys Ile Lys His Lys Ser Asp His Asn His Lys20 2538721PRTPlasmodium falciparum 387Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gln Gly Lys Lys1 5 10 15Cys Ile Lys His Lys2038816PRTPlasmodium falciparum 388Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gln Gly Lys Lys1 5 10 1538915PRTPlasmodium falciparum 389Lys Asp Gly Asp Thr Lys Cys Thr Leu Glu Cys Ala Gln Gly Lys1 5 10 1539023PRTPlasmodium falciparum 390Lys Cys Ile Gln Ala Glu Cys Asn Tyr Lys Glu Cys Gly Glu Gln Lys1 5 10 15Cys Val Trp Asp Gly Ile His2039114PRTPlasmodium falciparum 391Lys Glu Cys Gly Glu Gln Lys Cys Val Trp Asp Gly Ile His1 5 1039232PRTPlasmodium falciparum 392His Ile Glu Cys Lys Cys Asn Asn Asp Tyr Val Leu Thr Asn Arg Tyr1 5 10 15Glu Cys Glu Pro Lys Asn Lys Cys Thr Ser Leu Glu Asp Thr Asn Lys20 25 3039339PRTPlasmodium falciparum 393Lys Ser Asp His Asn His Lys Ser Asp His Asn His Lys Ser Asp His1 5 10 15Asn His Lys Ser Asp His Asn His Lys Ser Asp Pro Asn His Lys Lys20 25 30Lys Asn Asn Asn Asn Asn Lys3539433PRTPlasmodium falciparum 394Lys Ser Asp His Asn His Lys Ser Asp His Asn His Lys Ser Asp His1 5 10 15Asn His Lys Ser Asp Pro Asn His Lys Lys Lys Asn Asn Asn Asn Asn20 25 30Lys39527PRTPlasmodium falciparum 395Lys Ser Asp His Asn His Lys Ser Asp His Asn His Lys Ser Asp Pro1 5 10 15Asn His Lys Lys Lys Asn Asn Asn Asn Asn Lys20 2539621PRTPlasmodium falciparum 396Lys Ser Asp His Asn His Lys Ser Asp Pro Asn His Lys Lys Lys Asn1 5 10 15Asn Asn Asn Asn Lys2039718PRTPlasmodium falciparum 397Lys Lys Lys Asn Asn Asn Asn Asn Lys Asp Asn Lys Ser Asp Pro Asn1 5 10 15His Lys39817PRTPlasmodium falciparum 398Lys Lys Asn Asn Asn Asn Asn Lys Asp Asn Lys Ser Asp Pro Asn His1 5 10 15Lys39916PRTPlasmodium falciparum 399Lys Asn Asn Asn Asn Asn Lys Asp Asn Lys Ser Asp Pro Asn His Lys1 5 10 1540010PRTPlasmodium falciparum 400Lys Asp Asn Lys Ser Asp Pro Asn His Lys1 5 104017PRTPlasmodium falciparum 401Lys Ser Asp Pro Asn His Lys1 5 40235PRTPlasmodium falciparum 402His Ser Leu Tyr Ala Leu Gln Gln Asn Glu Glu Tyr Gln Lys Val Lys1 5 10 15Asn Glu Lys Asp Gln Asn Glu Ile Lys Lys Ile Lys Gln Leu Ile Glu20 25 30Lys Asn Lys3540328PRTPlasmodium falciparum 403His Ser Leu Tyr Ala Leu Gln Gln Asn Glu Glu Tyr Gln Lys Val Lys1 5 10 15Asn Glu Lys Asp Gln Asn Glu Ile Lys Lys Ile Lys20 2540426PRTPlasmodium falciparum 404His Ser Leu Tyr Ala Leu Gln Gln Asn Glu Glu Tyr Gln Lys Val Lys1 5 10 15Asn Glu Lys Asp Gln Asn Glu Ile Lys Lys20 2540525PRTPlasmodium falciparum 405His Ser Leu Tyr Ala Leu Gln Gln Asn Glu Glu Tyr Gln Lys Val Lys1 5 10 15Asn Glu Lys Asp Gln Asn Glu Ile Lys20 2540611PRTPlasmodium falciparum 406His Lys Leu Glu Asn Leu Glu Glu Met Asp Lys1 5 1040711PRTPlasmodium falciparum 407Lys His Phe Asp Asp Asn Thr Asn Glu Gln Lys1 5 104088PRTPlasmodium falciparum 408Lys Lys Glu Asp Asp Glu Lys His1 540913PRTPlasmodium falciparum 409Lys Glu Glu Asn Asn Lys Lys Glu Asp Asp Glu Lys His1 5 1041021PRTPlasmodium falciparum 410Lys Thr Ser Ser Gly Ile Leu Asn Lys

Glu Glu Asn Asn Lys Lys Glu1 5 10 15Asp Asp Glu Lys His204117PRTPlasmodium falciparum 411Lys Asn Ile His Ile Lys Lys1 541213PRTPlasmodium falciparum 412His Ile Lys Lys Lys Glu Gly Ile Asp Ile Gly Tyr Lys1 5 1041321PRTPlasmodium falciparum 413Lys Lys Met Trp Thr Cys Lys Leu Trp Asp Asn Lys Gly Asn Glu Ile1 5 10 15Thr Lys Asn Ile His2041430PRTPlasmodium falciparum 414Lys Lys Gly Ile Gln Trp Asn Leu Leu Lys Lys Met Trp Thr Cys Lys1 5 10 15Leu Trp Asp Asn Lys Gly Asn Glu Ile Thr Lys Asn Ile His20 25 3041550PRTPlasmodium falciparum 415Lys Glu Lys Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys Gln Lys Glu1 5 10 15Asp Lys Lys Asn Pro Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys20 25 30Ile Thr His Phe Phe Lys Ala Lys Asn Asn Lys Gln Gln Asn Asn Val35 40 45Thr His5041648PRTPlasmodium falciparum 416Lys Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys Gln Lys Glu Asp Lys1 5 10 15Lys Asn Pro Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys Ile Thr20 25 30His Phe Phe Lys Ala Lys Asn Asn Lys Gln Gln Asn Asn Val Thr His35 40 4541747PRTPlasmodium falciparum 417Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys Gln Lys Glu Asp Lys Lys1 5 10 15Asn Pro Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys Ile Thr His20 25 30Phe Phe Lys Ala Lys Asn Asn Lys Gln Gln Asn Asn Val Thr His35 40 4541839PRTPlasmodium falciparum 418Lys Lys Gln Lys Glu Asp Lys Lys Asn Pro Asn Lys Leu Lys Lys Ile1 5 10 15Glu Tyr Thr Asn Lys Ile Thr His Phe Phe Lys Ala Lys Asn Asn Lys20 25 30Gln Gln Asn Asn Val Thr His3541938PRTPlasmodium falciparum 419Lys Gln Lys Glu Asp Lys Lys Asn Pro Asn Lys Leu Lys Lys Ile Glu1 5 10 15Tyr Thr Asn Lys Ile Thr His Phe Phe Lys Ala Lys Asn Asn Lys Gln20 25 30Gln Asn Asn Val Thr His3542036PRTPlasmodium falciparum 420Lys Glu Asp Lys Lys Asn Pro Asn Lys Leu Lys Lys Ile Glu Tyr Thr1 5 10 15Asn Lys Ile Thr His Phe Phe Lys Ala Lys Asn Asn Lys Gln Gln Asn20 25 30Asn Val Thr His3542132PRTPlasmodium falciparum 421Lys Asn Pro Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys Ile Thr1 5 10 15His Phe Phe Lys Ala Lys Asn Asn Lys Gln Gln Asn Asn Val Thr His20 25 3042226PRTPlasmodium falciparum 422Lys Lys Ile Glu Tyr Thr Asn Lys Ile Thr His Phe Phe Lys Ala Lys1 5 10 15Asn Asn Lys Gln Gln Asn Asn Val Thr His20 2542325PRTPlasmodium falciparum 423Lys Ile Glu Tyr Thr Asn Lys Ile Thr His Phe Phe Lys Ala Lys Asn1 5 10 15Asn Lys Gln Gln Asn Asn Val Thr His20 2542419PRTPlasmodium falciparum 424Lys Ile Thr His Phe Phe Lys Ala Lys Asn Asn Lys Gln Gln Asn Asn1 5 10 15Val Thr His42548PRTPlasmodium falciparum 425His Lys Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys1 5 10 15Asn Asp Asn Ser Lys Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys20 25 30Asn Asp Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys35 40 4542645PRTPlasmodium falciparum 426His Lys Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys1 5 10 15Asn Asp Asn Ser Lys Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys20 25 30Asn Asp Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys35 40 4542740PRTPlasmodium falciparum 427His Lys Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys1 5 10 15Asn Asp Asn Ser Lys Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys20 25 30Asn Asp Asn Asn Glu Asp Ile Lys35 4042832PRTPlasmodium falciparum 428His Lys Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys1 5 10 15Asn Asp Asn Ser Lys Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys20 25 3042929PRTPlasmodium falciparum 429His Lys Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys1 5 10 15Asn Asp Asn Ser Lys Asp Ile Lys Asn Asp Asn Ser Lys20 2543024PRTPlasmodium falciparum 430His Lys Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys1 5 10 15Asn Asp Asn Ser Lys Asp Ile Lys2043121PRTPlasmodium falciparum 431His Lys Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys1 5 10 15Asn Asp Asn Ser Lys2043216PRTPlasmodium falciparum 432His Lys Asn Asn Glu Asp Ile Lys Asn Asp Asn Ser Lys Asp Ile Lys1 5 10 154338PRTPlasmodium falciparum 433His Lys Asn Asn Glu Asp Ile Lys1 543431PRTPlasmodium falciparum 434Lys Lys Tyr Asp Asp Leu Gln Asn Lys Tyr Asn Ile Leu Asn Lys Leu1 5 10 15Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His20 25 3043530PRTPlasmodium falciparum 435Lys Tyr Asp Asp Leu Gln Asn Lys Tyr Asn Ile Leu Asn Lys Leu Lys1 5 10 15Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His20 25 3043623PRTPlasmodium falciparum 436Lys Tyr Asn Ile Leu Asn Lys Leu Lys Asn Ser Leu Glu Glu Lys Asn1 5 10 15Glu Glu Leu Lys Lys Tyr His2043717PRTPlasmodium falciparum 437Lys Leu Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr1 5 10 15His43815PRTPlasmodium falciparum 438Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His1 5 10 154399PRTPlasmodium falciparum 439Lys Asn Glu Glu Leu Lys Lys Tyr His1 544035PRTPlasmodium falciparum 440His Met Gly Asn Asn Gln Asp Ile Asn Glu Asn Val Tyr Asn Ile Lys1 5 10 15Pro Gln Glu Phe Lys Glu Glu Glu Glu Glu Asp Ile Ser Met Val Asn20 25 30Thr Lys Lys3544117PRTPlasmodium falciparum 441Lys Asn Ser Asn Glu Leu Lys Arg Ile Asn Asp Asn Phe Phe Lys Leu1 5 10 15His44255PRTPlasmodium falciparum 442Lys Pro Cys Leu Tyr Lys Lys Cys Lys Ile Ser Gln Cys Leu Tyr Lys1 5 10 15Lys Cys Lys Ile Ser Gln Val Trp Trp Cys Met Pro Val Lys Asp Thr20 25 30Phe Asn Thr Tyr Glu Arg Asn Asn Val Leu Asn Ser Lys Ile Glu Asn35 40 45Asn Ile Glu Lys Ile Pro His50 5544340PRTPlasmodium falciparum 443His Ile Asn Asn Glu Tyr Thr Asn Lys Asn Pro Lys Asn Cys Leu Leu1 5 10 15Tyr Lys Asn Glu Glu Arg Asn Tyr Asn Asp Asn Asn Ile Lys Asp Tyr20 25 30Ile Asn Ser Met Asn Phe Lys Lys35 4044439PRTPlasmodium falciparum 444His Ile Asn Asn Glu Tyr Thr Asn Lys Asn Pro Lys Asn Cys Leu Leu1 5 10 15Tyr Lys Asn Glu Glu Arg Asn Tyr Asn Asp Asn Asn Ile Lys Asp Tyr20 25 30Ile Asn Ser Met Asn Phe Lys3544518PRTPlasmodium falciparum 445His Ile Asn Asn Glu Tyr Thr Asn Lys Asn Pro Lys Asn Cys Leu Leu1 5 10 15Tyr Lys44623PRTPlasmodium falciparum 446Lys Asn Lys Thr Asn Gln Ser Lys Gly Val Lys Gly Glu Tyr Glu Lys1 5 10 15Lys Lys Glu Thr Asn Gly His2044721PRTPlasmodium falciparum 447Lys Thr Asn Gln Ser Lys Gly Val Lys Gly Glu Tyr Glu Lys Lys Lys1 5 10 15Glu Thr Asn Gly His2044816PRTPlasmodium falciparum 448Lys Gly Val Lys Gly Glu Tyr Glu Lys Lys Lys Glu Thr Asn Gly His1 5 10 1544913PRTPlasmodium falciparum 449Lys Gly Glu Tyr Glu Lys Lys Lys Glu Thr Asn Gly His1 5 1045028PRTPlasmodium falciparum 450Lys Ser Gly Met Tyr Thr Asn Glu Gly Asn Lys Ser Cys Glu Cys Ser1 5 10 15Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys Val His20 2545118PRTPlasmodium falciparum 451Lys Ser Cys Glu Cys Ser Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys1 5 10 15Val His45211PRTPlasmodium falciparum 452Lys Lys Lys Ser Ser Ser Ser Asn Lys Val His1 5 1045310PRTPlasmodium falciparum 453Lys Lys Ser Ser Ser Ser Asn Lys Val His1 5 104549PRTPlasmodium falciparum 454Lys Ser Ser Ser Ser Asn Lys Val His1 545530PRTPlasmodium falciparum 455His Ile Met Leu Lys Ser Gly Met Tyr Thr Asn Glu Gly Asn Lys Ser1 5 10 15Cys Glu Cys Ser Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys20 25 3045624PRTPlasmodium falciparum 456His Ile Met Leu Lys Ser Gly Met Tyr Thr Asn Glu Gly Asn Lys Ser1 5 10 15Cys Glu Cys Ser Tyr Lys Lys Lys2045723PRTPlasmodium falciparum 457His Ile Met Leu Lys Ser Gly Met Tyr Thr Asn Glu Gly Asn Lys Ser1 5 10 15Cys Glu Cys Ser Tyr Lys Lys2045822PRTPlasmodium falciparum 458His Ile Met Leu Lys Ser Gly Met Tyr Thr Asn Glu Gly Asn Lys Ser1 5 10 15Cys Glu Cys Ser Tyr Lys2045950PRTPlasmodium falciparum 459Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gln Ile Asn Lys1 5 10 15Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gln20 25 30Lys Ile Ile Ile Arg Asp Tyr His Glu Thr Leu Asn Val His Lys Leu35 40 45Asp His5046043PRTPlasmodium falciparum 460Lys Arg Glu Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp1 5 10 15Val Ile Ile Asp Asn Thr Glu Ile Gln Lys Ile Ile Ile Arg Asp Tyr20 25 30His Glu Thr Leu Asn Val His Lys Leu Asp His35 4046140PRTPlasmodium falciparum 461Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile1 5 10 15Asp Asn Thr Glu Ile Gln Lys Ile Ile Ile Arg Asp Tyr His Glu Thr20 25 30Leu Asn Val His Lys Leu Asp His35 4046246PRTPlasmodium falciparum 462Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gln Ile Asn Lys1 5 10 15Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gln20 25 30Lys Ile Ile Ile Arg Asp Tyr His Glu Thr Leu Asn Val His35 40 4546340PRTPlasmodium falciparum 463Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gln Ile Asn Lys1 5 10 15Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gln20 25 30Lys Ile Ile Ile Arg Asp Tyr His35 4046436PRTPlasmodium falciparum 464Lys Leu Arg Lys Arg Glu Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu1 5 10 15Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gln Lys Ile Ile Ile20 25 30Arg Asp Tyr His3546533PRTPlasmodium falciparum 465Lys Arg Glu Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp1 5 10 15Val Ile Ile Asp Asn Thr Glu Ile Gln Lys Ile Ile Ile Arg Asp Tyr20 25 30His46630PRTPlasmodium falciparum 466Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile1 5 10 15Asp Asn Thr Glu Ile Gln Lys Ile Ile Ile Arg Asp Tyr His20 25 3046741PRTPlasmodium falciparum 467Lys Lys Asp Lys Glu Lys Lys Lys Asp Ser Asn Glu Asn Arg Lys Lys1 5 10 15Lys Gln Lys Glu Asp Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys20 25 30Ile Glu Tyr Thr Asn Lys Ile Thr His35 4046840PRTPlasmodium falciparum 468Lys Asp Lys Glu Lys Lys Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys1 5 10 15Gln Lys Glu Asp Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile20 25 30Glu Tyr Thr Asn Lys Ile Thr His35 4046938PRTPlasmodium falciparum 469Lys Glu Lys Lys Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys Gln Lys1 5 10 15Glu Asp Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu Tyr20 25 30Thr Asn Lys Ile Thr His3547036PRTPlasmodium falciparum 470Lys Lys Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys Gln Lys Glu Asp1 5 10 15Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn20 25 30Lys Ile Thr His3547135PRTPlasmodium falciparum 471Lys Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys Gln Lys Glu Asp Lys1 5 10 15Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys20 25 30Ile Thr His3547234PRTPlasmodium falciparum 472Lys Asp Ser Asn Glu Asn Arg Lys Lys Lys Gln Lys Glu Asp Lys Lys1 5 10 15Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys Ile20 25 30Thr His47327PRTPlasmodium falciparum 473Lys Lys Lys Gln Lys Glu Asp Lys Lys Asn Pro Asn Asp Asn Lys Leu1 5 10 15Lys Lys Ile Glu Tyr Thr Asn Lys Ile Thr His20 2547426PRTPlasmodium falciparum 474Lys Lys Gln Lys Glu Asp Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys1 5 10 15Lys Ile Glu Tyr Thr Asn Lys Ile Thr His20 2547525PRTPlasmodium falciparum 475Lys Gln Lys Glu Asp Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys1 5 10 15Ile Glu Tyr Thr Asn Lys Ile Thr His20 2547623PRTPlasmodium falciparum 476Lys Glu Asp Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu1 5 10 15Tyr Thr Asn Lys Ile Thr His2047720PRTPlasmodium falciparum 477Lys Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn1 5 10 15Lys Ile Thr His2047819PRTPlasmodium falciparum 478Lys Asn Pro Asn Asp Asn Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys1 5 10 15Ile Thr His47913PRTPlasmodium falciparum 479Lys Leu Lys Lys Ile Glu Tyr Thr Asn Lys Ile Thr His1 5 1048011PRTPlasmodium falciparum 480Lys Lys Ile Glu Tyr Thr Asn Lys Ile Thr His1 5 1048110PRTPlasmodium falciparum 481Lys Ile Glu Tyr Thr Asn Lys Ile Thr His1 5 1048244PRTPlasmodium falciparum 482His Gly Gln Ile Lys Ile Glu Asp Val Asn Asn Glu Asn Phe Asn Asn1 5 10 15Glu Gln Met Lys Asn Lys Tyr Asn Asp Glu Glu Lys Met Asp Ile Ser20 25 30Lys Ser Lys Ser Leu Lys Ser Asp Phe Leu Glu Lys35 4048338PRTPlasmodium falciparum 483His Gly Gln Ile Lys Ile Glu Asp Val Asn Asn Glu Asn Phe Asn Asn1 5 10 15Glu Gln Met Lys Asn Lys Tyr Asn Asp Glu Glu Lys Met Asp Ile Ser20 25 30Lys Ser Lys Ser Leu Lys3548435PRTPlasmodium falciparum 484His Gly Gln Ile Lys Ile Glu Asp Val Asn Asn Glu Asn Phe Asn Asn1 5 10 15Glu Gln Met Lys Asn Lys Tyr Asn Asp Glu Glu Lys Met Asp Ile Ser20 25 30Lys Ser Lys3548533PRTPlasmodium falciparum 485His Gly Gln Ile Lys Ile Glu Asp Val Asn Asn Glu Asn Phe Asn Asn1 5 10 15Glu Gln Met Lys Asn Lys Tyr Asn Asp Glu Glu Lys Met Asp Ile Ser20 25 30Lys48631PRTPlasmodium falciparum 486Lys Lys Tyr Asp Asp Leu Gln Asn Lys Tyr Asn Ile Leu Asn Lys Leu1 5 10 15Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His20 25 3048730PRTPlasmodium falciparum 487Lys Tyr Asp Asp Leu Gln Asn Lys Tyr Asn Ile Leu Asn Lys Leu Lys1 5 10 15Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His20 25 3048823PRTPlasmodium falciparum 488Lys Tyr Asn Ile Leu Asn Lys Leu Lys Asn Ser Leu Glu Glu Lys Asn1 5 10 15Glu Glu Leu Lys Lys Tyr His2048917PRTPlasmodium falciparum

489Lys Leu Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr1 5 10 15His49015PRTPlasmodium falciparum 490Lys Asn Ser Leu Glu Glu Lys Asn Glu Glu Leu Lys Lys Tyr His1 5 10 154919PRTPlasmodium falciparum 491Lys Asn Glu Glu Leu Lys Lys Tyr His1 549244PRTPlasmodium falciparum 492His Met Gly Asn Asn Gln Asp Ile Asn Glu Asn Val Tyr Asn Ile Lys1 5 10 15Pro Gln Glu Phe Lys Glu Glu Glu Glu Glu Asp Ile Ser Met Val Asn20 25 30Thr Lys Lys Cys Asp Asp Ile Gln Glu Asn Ile Lys35 4049350PRTPlasmodium falciparum 493Lys Thr Asn Leu Tyr Asn Ile Tyr Asn Asn Lys Asn Asp Asp Lys Asp1 5 10 15Asn Ile Leu Asp Asn Glu Asn Arg Glu Gly Leu Tyr Leu Cys Asp Val20 25 30Met Lys Asn Ser Asn Glu Leu Lys Arg Ile Asn Asp Asn Phe Phe Lys35 40 45Leu His5049417PRTPlasmodium falciparum 494Lys Asn Ser Asn Glu Leu Lys Arg Ile Asn Asp Asn Phe Phe Lys Leu1 5 10 15His49511PRTPlasmodium falciparum 495Lys Arg Ile Asn Asp Asn Phe Phe Lys Leu His1 5 1049640PRTPlasmodium falciparum 496His Ile Asn Asn Glu Tyr Thr Asn Lys Asn Pro Lys Asn Cys Leu Leu1 5 10 15Tyr Lys Asn Glu Glu Arg Asn Tyr Asn Asp Asn Asn Ile Lys Asp Tyr20 25 30Ile Asn Ser Met Asn Phe Lys Lys35 4049739PRTPlasmodium falciparum 497His Ile Asn Asn Glu Tyr Thr Asn Lys Asn Pro Lys Asn Cys Leu Leu1 5 10 15Tyr Lys Asn Glu Glu Arg Asn Tyr Asn Asp Asn Asn Ile Lys Asp Tyr20 25 30Ile Asn Ser Met Asn Phe Lys3549818PRTPlasmodium falciparum 498His Ile Asn Asn Glu Tyr Thr Asn Lys Asn Pro Lys Asn Cys Leu Leu1 5 10 15Tyr Lys49945PRTPlasmodium falciparum 499Lys Pro Cys Leu Tyr Lys Lys Cys Lys Ile Ser Gln Val Trp Trp Cys1 5 10 15Met Pro Val Lys Asp Thr Phe Asn Thr Tyr Glu Arg Asn Asn Val Leu20 25 30Asn Ser Lys Ile Glu Asn Asn Ile Glu Lys Ile Pro His35 40 4550039PRTPlasmodium falciparum 500Lys Cys Lys Ile Ser Gln Val Trp Trp Cys Met Pro Val Lys Asp Thr1 5 10 15Phe Asn Thr Tyr Glu Arg Asn Asn Val Leu Asn Ser Lys Ile Glu Asn20 25 30Asn Ile Glu Lys Ile Pro His3550111PRTPlasmodium falciparum 501Lys Ile Glu Asn Asn Ile Glu Lys Ile Pro His1 5 1050223PRTPlasmodium falciparum 502Lys Asn Lys Thr Asn Gly Ser Lys Gly Val Lys Gly Glu Tyr Glu Lys1 5 10 15Lys Lys Glu Thr Asn Gly His2050321PRTPlasmodium falciparum 503Lys Thr Asn Gly Ser Lys Gly Val Lys Gly Glu Tyr Glu Lys Lys Lys1 5 10 15Glu Thr Asn Gly His2050416PRTPlasmodium falciparum 504Lys Gly Val Lys Gly Glu Tyr Glu Lys Lys Lys Glu Thr Asn Gly His1 5 10 1550513PRTPlasmodium falciparum 505Lys Gly Glu Tyr Glu Lys Lys Lys Glu Thr Asn Gly His1 5 1050660PRTPlasmodium falciparum 506Lys Thr Ile Glu Lys Ile Asn Lys Ser Lys Ser Trp Phe Phe Glu Glu1 5 10 15Leu Asp Glu Ile Asp Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys20 25 30Thr Gln Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile Asp35 40 45Asn Thr Glu Ile Gln Lys Ile Ile Arg Asp Tyr His50 55 6050756PRTPlasmodium falciparum 507Lys Ile Asn Lys Ser Lys Ser Trp Phe Phe Glu Glu Leu Asp Glu Ile1 5 10 15Asp Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gln Ile Asn20 25 30Lys Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile35 40 45Gln Lys Ile Ile Arg Asp Tyr His50 5550839PRTPlasmodium falciparum 508Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gln Ile Asn Lys1 5 10 15Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gln20 25 30Lys Ile Ile Arg Asp Tyr His3550932PRTPlasmodium falciparum 509His Ile Met Leu Lys Ser Gln Met Tyr Thr Asn Glu Gly Asn Lys Ser1 5 10 15Cys Glu Cys Ser Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys Val His20 25 3051035PRTPlasmodium falciparum 510Lys Leu Arg Lys Arg Glu Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu1 5 10 15Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gln Lys Ile Ile Arg20 25 30Asp Tyr His3551132PRTPlasmodium falciparum 511Lys Arg Glu Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp1 5 10 15Val Ile Ile Asp Asn Thr Glu Ile Gln Lys Ile Ile Arg Asp Tyr His20 25 3051229PRTPlasmodium falciparum 512Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile1 5 10 15Asp Asn Thr Glu Ile Gln Lys Ile Ile Arg Asp Tyr His20 2551348PRTPlasmodium falciparum 513Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gln Ile Asn Lys1 5 10 15Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gln20 25 30Lys Ile Ile Arg Asp Tyr His Thr Leu Asn Val His Lys Leu Asp His35 40 4551444PRTPlasmodium falciparum 514Lys Leu Arg Lys Arg Glu Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu1 5 10 15Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gln Lys Ile Ile Arg20 25 30Asp Tyr His Thr Leu Asn Val His Lys Leu Asp His35 4051541PRTPlasmodium falciparum 515Lys Arg Glu Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp1 5 10 15Val Ile Ile Asp Asn Thr Glu Ile Gln Lys Ile Ile Arg Asp Tyr His20 25 30Thr Leu Asn Val His Lys Leu Asp His35 4051638PRTPlasmodium falciparum 516Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile1 5 10 15Asp Asn Thr Glu Ile Gln Lys Ile Ile Arg Asp Tyr His Thr Leu Asn20 25 30Val His Lys Leu Asp His3551744PRTPlasmodium falciparum 517Lys Pro Leu Ala Lys Leu Arg Lys Arg Glu Lys Thr Gln Ile Asn Lys1 5 10 15Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gln20 25 30Lys Ile Ile Arg Asp Tyr His Thr Leu Asn Val His35 4051840PRTPlasmodium falciparum 518Lys Leu Arg Lys Arg Glu Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu1 5 10 15Arg Gly Asp Val Ile Ile Asp Asn Thr Glu Ile Gln Lys Ile Ile Arg20 25 30Asp Tyr His Thr Leu Asn Val His35 4051937PRTPlasmodium falciparum 519Lys Arg Glu Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp1 5 10 15Val Ile Ile Asp Asn Thr Glu Ile Gln Lys Ile Ile Arg Asp Tyr His20 25 30Thr Leu Asn Val His3552034PRTPlasmodium falciparum 520Lys Thr Gln Ile Asn Lys Thr Lys Tyr Glu Arg Gly Asp Val Ile Ile1 5 10 15Asp Asn Thr Glu Ile Gln Lys Ile Ile Arg Asp Tyr His Thr Leu Asn20 25 30Val His52132PRTPlasmodium falciparum 521His Ile Met Leu Lys Ser Gln Met Tyr Thr Asn Glu Gly Asn Lys Ser1 5 10 15Cys Glu Cys Ser Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys Val His20 25 3052228PRTPlasmodium falciparum 522Lys Ser Gln Met Tyr Thr Asn Glu Gly Asn Lys Ser Cys Glu Cys Ser1 5 10 15Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys Val His20 2552318PRTPlasmodium falciparum 523Lys Ser Cys Glu Cys Ser Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys1 5 10 15Val His52411PRTPlasmodium falciparum 524Lys Lys Lys Ser Ser Ser Ser Asn Lys Val His1 5 1052510PRTPlasmodium falciparum 525Lys Lys Ser Ser Ser Ser Asn Lys Val His1 5 105269PRTPlasmodium falciparum 526Lys Ser Ser Ser Ser Asn Lys Val His1 5 52730PRTPlasmodium falciparum 527His Ile Met Leu Lys Ser Gln Met Tyr Thr Asn Glu Gly Asn Lys Ser1 5 10 15Cys Glu Cys Ser Tyr Lys Lys Lys Ser Ser Ser Ser Asn Lys20 25 3052824PRTPlasmodium falciparum 528His Ile Met Leu Lys Ser Gln Met Tyr Thr Asn Glu Gly Asn Lys Ser1 5 10 15Cys Glu Cys Ser Tyr Lys Lys Lys2052923PRTPlasmodium falciparum 529His Ile Met Leu Lys Ser Gln Met Tyr Thr Asn Glu Gly Asn Lys Ser1 5 10 15Cys Glu Cys Ser Tyr Lys Lys2053022PRTPlasmodium falciparum 530His Ile Met Leu Lys Ser Gln Met Tyr Thr Asn Glu Gly Asn Lys Ser1 5 10 15Cys Glu Cys Ser Tyr Lys2053136PRTPlasmodium falciparum 531His Asn Asn His Asn Ile Gln Ile Tyr Lys Asp Lys Arg Ile Asn Phe1 5 10 15Met Asn Pro His Lys Val Met Tyr His Asp Asn Met Ser Lys Asn Glu20 25 30Arg Thr Glu Lys3553230PRTPlasmodium falciparum 532His Asn Asn His Asn Ile Gln Ile Tyr Lys Asp Lys Arg Ile Asn Phe1 5 10 15Met Asn Pro His Lys Val Met Tyr His Asp Asn Met Ser Lys20 25 3053321PRTPlasmodium falciparum 533His Asn Asn His Asn Ile Gln Ile Tyr Lys Asp Lys Arg Ile Asn Phe1 5 10 15Met Asn Pro His Lys2053417PRTPlasmodium falciparum 534His Lys Val Met Tyr His Asp Asn Met Ser Lys Asn Glu Arg Thr Glu1 5 10 15Lys53511PRTPlasmodium falciparum 535His Lys Val Met Tyr His Asp Asn Met Ser Lys1 5 10

Patent applications by Elenore S. Bogoch, New York, NY US

Patent applications by Samuel Bogoch, New York, NY US

Patent applications in class IMMUNOGLOBULIN, ANTISERUM, ANTIBODY, OR ANTIBODY FRAGMENT, EXCEPT CONJUGATE OR COMPLEX OF THE SAME WITH NONIMMUNOGLOBULIN MATERIAL

Patent applications in all subclasses IMMUNOGLOBULIN, ANTISERUM, ANTIBODY, OR ANTIBODY FRAGMENT, EXCEPT CONJUGATE OR COMPLEX OF THE SAME WITH NONIMMUNOGLOBULIN MATERIAL

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Patent application title: REPLIKIN PEPTIDES IN RAPID REPLICATION OF GLIOMA CELLS AND IN INFLUENZA EPIDEMICS

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