PLASMODIUM FALCIPARUM AND PLASMODIUM VIVAX VACCINE

Abstract

The present invention relates to a vaccine V comprising (A) at least one isolated polypeptide strand P comprising or consisting of at least nine consecutive amino acid moieties of the repetitive organellar protein, putative of Plasmodium falciparum or the hypothetical protein PVNG_04523 of Plasmodium vivax or a polynucleotide strand encoding for such polypeptide; and (B) at least one pharmaceutically acceptable carrier or excipient. Furthermore, the present invention refers to an antibody binding to the repetitive organellar protein,putative of Plasmodium falciparumor the hypothetical protein PVNG_04523 of Plasmodium vivax or a polynucleotide strand encoding therefor, to a method of generating such antibody and uses thereof.

Description

[0001] The present invention relates to a vaccine V comprising (A) at least one isolated polypeptide strand P comprising or consisting of at least nine consecutive amino acid moieties of the repetitive organellar protein, putative of Plasmodium falciparum or the hypothetical protein PVNK_04523 of Plasmodium vivax or a polynucleotide strand encoding for such polypeptide; and (B) at least one pharmaceutically acceptable carrier or excipient. Furthermore, the present invention refers to an antibody binding to the repetitive organellar protein, putative of Plasmodium falciparum or the hypothetical protein PVNK_04523 of Plasmodium vivax or a polynucleotide strand encoding therefore, and to a method of generating such antibodies and uses thereof.

[0002] Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes. There are 5 parasite species that cause malaria in humans, and 2 of these species, P. falciparum and P. vivax, pose the greatest threat. P. falciparum is responsible for most malaria-related deaths globally. P. vivax is the dominant malaria parasite in most countries outside of sub-Saharan Africa.

[0003] The malaria life cycle begins when the sporozoite stages of the P. falciparum parasite developing inside the salivary glands of an infected Anopheles female mosquito are transmitted to humans during a blood meal. Once inside the bloodstream, sporozoites travel to the liver, where they multiply and transform into infectious stages named merozoites. This represents the liver stage, a pre-erythrocytic stage. Each merozoite released from the liver invades an erythrocyte, inside which it grows and multiplies. Once the intraerythrocytic cycle is completed, the infected erythrocyte membrane lyses, releasing newly formed merozoites that go on to invade more erythrocytes by means of specialized invasion processes. This represents the blood stage. Blood stage parasites are responsible for the clinical manifestations of the disease.

[0004] According to the latest WHO estimates, released in December 2016, there were 212 million cases of malaria in 2015 and about 429 000 deaths. Some population groups are at considerably higher risk of contracting malaria, and developing severe disease, than others. Children under 5 are particularly susceptible to infection, illness and death; more than two thirds (70%) of all malaria deaths occur in this age group. Partial immunity against malaria is developed over years of exposure, and while it never provides complete protection, it does reduce the risk that malaria infection will cause severe disease.

[0005] The control of the mosquitos (the so-called vector) is the main way to prevent and reduce malaria transmission (vector control). Two forms of vector control--insecticide-treated mosquito nets and indoor residual spraying--are effective in a wide range of circumstances. Much of the success in controlling malaria is due to vector control. However, malaria-endemic areas of sub-Saharan Africa and India are causing significant concern due to high levels of malaria transmission and widespread reports of insecticide resistance. Rotational use of different classes of insecticides for IRS is recommended as one approach to manage insecticide resistance.

[0006] Malaria can be prevented through chemoprophylaxis (with antimalarial drugs), which suppresses the blood stage of malaria infections, thereby preventing malaria disease. Resistance to antimalarial medicines is a recurring problem. Resistance of P. falciparum to previous generations of medicines, such as chloroquine and sulfadoxine-pyrimethamine (SP), became widespread in the 1950s and 1960s. A good available treatment, particularly for P. falciparum malaria, is artemisinin-based combination therapy (ACT). An ACT contains both, the drug artemisinin and a partner drug. In recent years, parasite resistance to artemisinin has been detected in 5 countries of the Greater Mekong subregion: Cambodia, Lao People's Democratic Republic, Myanmar, Thailand and Viet Nam. In parallel, there were reports of increased resistance to ACT partner drugs in some settings.

[0007] All these means for treating bear considerable drawbacks. It has also been tried to prepare a variety of vaccines against malaria. Malaria vaccines are considered amongst the most important modalities for potential prevention of malaria disease and reduction of malaria transmission. Research and development in this field has been an area of intense effort by many groups over the last few decades.

[0008] Despite this, there is currently no licensed malaria vaccine. Malaria vaccines can address either the pre-erythrocytic-stage or the blood-stage (more rarely transmission-blocking vaccines are investigated). Also pre-erythrocytic malaria vaccines have been developed. RTS, S/AS01 (RTS, S) is an injectable pre-erythrocytic vaccine, directed against sporozoites, that provides partial protection against malaria in young children. The vaccine is being evaluated in sub-Saharan Africa as a complementary malaria control tool that potentially could be added to (and not replace) the core package of WHO-recommended preventive, diagnostic and treatment measures.

[0009] Furthermore, blood-stage malaria vaccines have been developed. Erythrocyte invasion by merozoites, the blood-stage, is an essential step in Plasmodium falciparum infection and leads to subsequent disease pathology. Proteins both on the merozoite surface and secreted from the apical organelles (micronemes, rhoptries and dense granules) mediate the invasion of erythrocytes; some of the molecules have been regarded as targets in the development of an anti-malaria vaccine.

[0010] Unfortunately, the anti-malaria vaccines known in the art so far bear rather limited effectiveness. Therefore, there is still the need for providing further effective anti-malaria vaccines. It has been shown that several rhoptry polypeptides generally qualify as potential vaccine candidates. This is of particular interest, because there are only about thirty proteins present in the rhoptries. One example could be the Rhoptry-associated membrane antigen (RAMA) (Topolska et al., 2004).

[0011] The rhoptry protein Pch ROPE--Repeated Organellar Protein; Pch ROPE was first identified, described and characterized in a BALB/c mouse model from the rodent malaria parasite Plasmodium chabaudi. Examples for ROPE peptides that could, in principle, have some antigenic properties have been mentioned by Villard et al., 2007, and Kulangara et al., 2009. These documents do, however, not teach a vaccine suitible for efficiently treating or preventing malaria in a patient by means of active immunization. Antigens of Plasmodium vivax are not considered at all.

[0012] U.S. Pat. No. 8,716,443 teaches that the serum of malaria patients may comprise antibodies against malaria proteins, in particular against a truncated version of 844 amino acid moieties or less of a hypothetical protein of Plasmodium falciparum(MAL6P1.37 (PFF0165c)). However, no vaccine based on rhoptry protein Pf ROPE or Pv ROPE is taught or suggested.

[0013] The sequence of ROPE was originally obtained from cDNA--and genomic DNA--libraries of Plasmodium chabaudi 96V (Werner et al., 1998, Mol Biochem Parasitol. 94(2):185-96). (SEQ ID NO: 1): polypeptide sequence of the Repeat Organellar Protein of Plasmodium chabaudi (cf., also GenBank: AAC63403):

TABLE-US-00001 MIFNLKKSKKNEDGSNKDSKKTNETSGIEKKEKSNKWYNKIVNNSTKKDK DKNNDSIVYDDESKVGENDHHMKEYELEDQLKETLKSITALSIKVKEYEV KIEELEKELKLEKEKQINKEYEKELNEKSEFIKRQMELLKEKELNINLKE NKINNKEIITLKREEKLNDIESEYIEKNKEKEKLNYEVTNIKMSLDKLTC EVQEKKDNLEKINKKVIEKENNLRELKEFMKEKNEIIESLDGTINDKKNA YEKLEISFEEKRKMIEMLDSKLIEKEENFANKQAKLEKENEIIIEKLKDI ESREKDFKSKEEKFASMENELNTLKSDLSKNACQMEVYKLEIKDLSQSLV EKEREIFEIKNEYDDKINNMKEKLSSINDKGIDNTVLHSEEEKINKLLKE KETELNEIHKKYNLEIETIKNELNEKEEELEKNKKAHTVEVTNLTKEIKL LEKKTEDAKEGHKNELNELNNQLSKLNKEKDNIKNENTELNDKISSLNSE VNILNKDKQTLGNDIKTLNDLINNLKNEINTSDNKMNKMKEDLAMLNEEM EGKCVVIDEIEKKYKNEIFMLEEKLKEKENYADLNDEISILRNSIYVKEK EFIEMKEFYENKINLFNKNFEEKKNIYENELNSLRLKYDNEQGLIKQIDE LNIQKLKTEEKYLQLYNDNMHMFRSICTKIDMPYSENIKGSDLVDFVTAY IKRRDESSSDANPDTTHKEMVAELEKRHAAIVAELEEKHKEEIAKLGEGH KEVVLRLGEQHKEETIILEEKHKDVVTKLGEQHKENIIKLEEEHKDVVTK LGDQYKEEIAKLKEEHAVVVAELEEKHKLGEGHKEMVDELEKRHADFVEG LEEKHKAETAKLEEGHKSEMNEVEKRHADFVEGLEEKHKAETAKLGEGHR EVVAGLEEKHKEVVAELEEKHKEEIAKLEEGHKEVMAELGEKHKEVVAGL EAKHNLEEGHKEMVAELEKRHADLVAVLEEQHKAEIIKLGEEHKEVVAGI EEKYKVEAIKLAEEHKDVVTKLGEQHKEEIAKLEDGHKEVVNEVEKKNAS LLNMLEENHKNEMIKLKEEHKESASDLVEKLYQKDEEVKNSNNKIEELTN VIKDLNDSIMCYKKQILEEVEKRNEYNEEINKLKIVQNEMKDMNDKKILE KENEIKKLNKKLSNYKVFETKENTYKNSEMVVNENKERIIVDSVCKENIS ESDVEGKGGNLKMTLSLKKKERNIFSINDNKNESSELVDTIKSAYINKIE MYKKEIEDNGKNIEDLKNKILDLSNELINLENMKNVLTDENNNLKKEIEI KDNKLNEKEKNENTEILNLNDDIIKLKKEISEWKDEEEKLTKENIKLKND IEQINKEYKIKEENLMIKFNENINEVTSLKNQIEIEKMKLEELNKNYELL LAEKRETNMSISNDDNKIVENNILEDTDSKQNNLNKNVEDKTGDDINCEK NNDQAKEISYLKDEIKKISMLYGEELNRKNSYDEKVKNLTNELKELKIRN KKGEEAIAELNKLKNIKEKNKSVKQNDESSSNNIITKDGDKTPEYVSNDD KIQKDWKANLVLKLKEKPDLWDNINSLEKENFRVMSIVKENKNVQNDKIV GIYSYFKKCEKELKNDMLVICLVLKDILSILFLNDNFVNLFEKIDKILWK QMYIPTEIRILFLRYFSFLDKLRNYVKCVNEEYVNNERYEYSWALFQTYL ETASNLKKEMIYYVLEKAEKDSCENNSSNFDKPKITDILNFSKDSIRLKT IAQLRKELNFEREAKNILNYDYQIILNKYHECLRKLKIVKNMARELDFNY NVSSKFSIKKELEMCSDENDEFKYNNIKNNEEKNDTIKDPKHNNLIQKII NLQRNKKTEKKKNNLVNEINTMYPGDTTPKGKIFTTNDNSKQNEILKKKD NINNNITHKNVYTGQVKNIFNEPVERKVRISFIHKSPFN

[0014] (Pch ROPE is encoded by an intronless gene. Its dominant structural features are that of a mainly alpha-helical protein, that will build a coiled-coil structure and has a putative transmembrane anchor sequence close to its C-terminal end. Partial sequences of the Pch ROPE DNA sequence were expressed as a recombinant protein in E. coli (Werner et al., 1998). These Pch ROPE partial protein sequences were use to further characterize Pch ROPE.

[0015] Pch ROPE is a Natural Antigen

[0016] BALB/c mice were, after infection with Plasmodium chabaudi 96V, treated with 1 mg of Nivaquine, once 40% of their red blood cells were infected with Plasmodium chabaudi 96V. Here BALB/c mice survived an otherwise 100% lethal infection with Plasmodium chabaudi. Mice were now immune against any further infection with Plasmodium chabaudi 96V. Sera from these mice were immune-sera. It was shown in Western-blot studies that immune-sera recognize recombinant partial Pch ROPE protein sequences, demonstrating that Pch ROPE is a natural antigen occurring during an infection of BALB/c mice with Plasmodium chabaudi 96V (Werner et al., 1998).

[0017] Pch ROPE is a Rhoptry Protein

[0018] Antisera against recombinant fragments of the Pch ROPE protein were raised in Fisher rats. These anti-sera were subsequently used in IF--Indirect Immunofluorescence microscopy on erythrocytes of BALB/c-mice infected with Plasmodium chabaudi 96V. Pch ROPE can be localized in the rhoptry organelles of Plasmodium chabaudi 96V during the more mature blood-stages and Pch ROPE can be localized around the entire erythrocyte membrane during the early stage of the invasion of the BALB/c erythrocyte by Plasmodium chabaudi 96V (Werner et al., 1998).The localization of Pch ROPE in the rhoptry organelles, which are known to be involved in the invasion process, and the localization of Pch ROPE at the membrane of the newly infected erythrocyte suggest a direct role of the Pch ROPE protein during the invasion process of the erythrocyte by Plasmodium chabaudi 96V.

[0019] Pch ROPE is a Protective Antigen

[0020] BALB/c mice, immunized with recombinant parts of Pch ROPE, were protected from an otherwise 100% lethal infection with Plasmodium chabaudi 96V. It is important to emphasize here, that in the presented BALB/c mice--Plasmodium chabaudi 96V model, which we used over a period of about 4 years, not a single unprotected BALB/c mice did ever survive an infection with Plasmodium chabaudi 96V.

[0021] The Pch ROPE Homologues (orthologues) of Plasmodium falciparum and Plasmodium vivax are Potential Vaccine Candidates

[0022] Survival of mice immunized with recombinant parts of Pch ROPE is a direct proof of Pch ROPE being a protective antigen in this model and thus suggesting that the Pch ROPE protein homologue (orthologue) of the human malaria parasites (Plasmodium falciparum and Plasmodium vivax) being potential vaccine candidates for human malaria disease.

[0023] In this context it seems to be noteworthy that Pch ROPE shares some similarities with other vaccine candidates located in the rhoptries, e.g. the Rhoptry-associated membrane antigen (RAMA) (Topolska et al. Infect Immun (2004) June; 72(6):3325-30) of Plasmodium falciparum, for example with respect to its transient location to the erythrocyte membrane during the early invasion stages of the erythrocyte. The homologue (orthologue) of Pch ROPE is the "repetitive organellar protein, putative" of Plasmodium falciparum 3D7 (GenBank: CZT98043.1) [formerly named Plasmodium falciparum 3D7 "Kid domain containing protein" (NCBI Reference Sequence: XP_0013495431)] SEQ ID NO: 2 and SEQ ID NO: 4 and the "hypothetical protein PVNG_04523" of Plasmodium vivax North Korean (GenBank: KNA01322.1) SEQ ID NO: 3 and SEQ ID NO: 5 for the two major human malaria parasite species.

[0024] The three homologues (orthologues) share a comparable size: Pch ROPE with 1939 amino acids the "repetitive organellar protein, putative" of Plasmodium falciparum 3D7 with 1979 amino acids and the "hypothetical protein PVNG_04523" of Plasmodium vivax North Korean with 1887 amino acids. The three homologues (orthologues) share an identical predicted overall secondary structure: large alpha-helical segments, extended non-helical segments at the N- and C-termini of the protein, a predominantly coiled-coil structure and a sequence at identical sites upstream from the C-termini representing a putative trans-membrane segment, thus suggesting further a homologous biological function of the three homologous (orthologous) proteins.

[0025] A vaccine comprising an isolated polypeptide strand P of at least nine consecutive amino acid moieties of the repetitive organellar protein, putative of Plasmodium falciparum 3D7 or the hypothetical protein PVNG_04523 of Plasmodium vivax North Korean as well as a polynucleotide strand encoding for such polypeptide serve as effective means for targeting Plasmodium falciparum or Plasmodium vivax. This can be used in a medicinal as well as a non-medicinal context for generating antibodies.

[0026] Accordingly, a first aspect of the invention relates to a vaccine V comprising:

[0027] (A) at least one isolated polypeptide strand P comprising or consisting of at least nine consecutive amino acid moieties of the repetitive organellar protein, putative of Plasmodium falciparum 3D7 (SEQ ID NO: 2) and/or the hypothetical protein PVNG_04523 of Plasmodium vivax North Korean (SEQ ID NO: 3) or a polynucleotide strand encoding for said polypeptide strand P; and

[0028] (B) at least one pharmaceutically acceptable carrier or excipient.

[0029] In a preferred embodiment, the vaccine V comprises:

[0030] (A) at least one isolated polypeptide strand P comprising or consisting of at least nine consecutive amino acid moieties of SEQ ID NO: 2 or SEQ ID NO: 3 or a polynucleotide strand encoding for said polypeptide strand P; and

[0031] (B) at least one pharmaceutically acceptable carrier or excipient.

[0032] In another preferred embodiment, the vaccine V comprises:

[0033] (A) at least one isolated polypeptide strand P comprising or consisting of at least nine consecutive amino acid moieties of SEQ ID NO: 2 and (concomitantly) SEQ ID NO: 3 or a polynucleotide strand encoding for said polypeptide strand P; and

[0034] (B) at least one pharmaceutically acceptable carrier or excipient.

[0035] As used herein, the vaccine of the present invention is designated as "vaccine V" in order to ease finding of the vaccine of the present invention in the text. It will be understand that the designation "V" does not have a technical meaning and can also be omitted without altering the scope of the present invention. As used herein, the polypeptide strand of the present invention is designated as "polypeptide strand P" in order to ease finding of the polypeptide strand of the present invention in the text. It will be understand that the designation "P" does not have a technical meaning and can also be omitted without altering the scope of the present invention.

[0036] It will be understood that the term "at least nine consecutive amino acid moieties of" in the context of a certain sequence may embrace any peptide strand that overlaps with nine or more consecutive amino acid moieties of the respective protein sequence.

[0037] The polypeptide sequence of the full repetitive organellar protein, putative of Plasmodium falciparum 3D7 (GenBank: CZT98043.1) (SEQ ID NO: 2):

TABLE-US-00002 MVFTFKNKKKKKEASSDKVSKESFNEEDNENNEKREKSDSWYKKIIETKG KSKTKYKNDNSLDDNINEDIINNNNNNNNDNNNDNNNDNNNDNNNDNNND NNNENNNDNNNFNNYSDEISKNIIHKDNELENQLKDTLKSISSLSNKIVN YESKIEELEKELKEVKDKNIDNNDYENKLKEKEDFVKQKIDMLNEKENLL QEKELDINKREKKINEKEKNIIKKEETFHNIEKEYLEKNKERETISIEII DIKKHLEKLKIEIKEKKEDLENLNKKLLSKENVLKELKGCVKEKNETINS LNDNIIEKEKKYKLLEYELEEKNKQIDLLNKQEKEKEKEKEREKEKEREK EKEKEYDTLIKELKDEKISILEKVHSIKVREMDIEKREHNFLHMEDQLKD LKNSFVKNNNQLKVYKCEIKNLKTELEKKEKELKDIENVSKEEINKLINQ LNEKEKQILAFNKNHKEEIHGLKEELKESVKITKIETQELQEMVDIKQKE LDQLQEKYNAQIESISIELSKKEKEYNQYKNTYIEEINNLNEKLEETNKE YTNLQNNYTNEINMLNNDIHMLNGNIKTMNTQISTLKNDVHLLNEQIDKL NNEKGTLNSKISELNVQIMDLKEEKDFLNNQIVDLSNQIDLLTRKMEEKE NKMLEQENKYKQEMELLRGNIKSSENILNNDEEVCDLKRKLSLKESEMKM MKEEHDKKLAELKDDCDVRIREMNEKNEDKINMLKEEYEDKINTLKEQNE DKINTLKEQNEDKINTLKEEYEHKINTMKEEYEHKINTLNEQNEHKINTL NEQNEHKINTMKEEYEDKMNTLNEQNEDKMNSLKEEYENKINQINSNNEI KIKDVVNEYIEEVDKLKVTLDEKKKQFDKEINYAHIKAHEKEQILLTEME ELKCQRDNKYSDLYEKYIKLIKSICMIINIECCDDIENEDIIRRIEEYIN NNKGLKKEVEEKEHKRHSSFNILKSKEKFFKNSIEDKSHELKKKHEKDLL SKDKEIEEKNKKIKELNNDIKKLQDEILVYKKQSNAQQVDHKKKSWILLK DKSKEKIKDKENQINVEKNEEKDLKKKDDEIRILNEELVKYKTILYNLKK DPLLQNQDLLSKIDINSLTINEGMCVDKIEEHILDYDEEINKSRSNLFQL KNEICSLTTEVMELNNKKNELIEENNKLNLVDQGKKKLKKDVEKQKKEIE KLNKQLTKCNKQIDELNEEVEKLNNENIELITYSNDLNNKFDMKENNLMM KLDENEDNIKKMKSKIDDMEKEIKYREDEKKRNLNEINNLKKKNEDMCIK YNEMNIKYGDICVKYEEMSLTYKETSLKYEQIKVKYDEKCSQYDEIRFQY DEKCFQYDEINKKYGALLNINITNKMVDSKVDRNNNEIISVDNKVEGIAN YLKQIFELNEEIIRLKGEINKISLLYSNELNEKNSYDINMKHIQEQLLFL EKTNKENEEKIINLTSQYSDAYKKKSDESKLCGAQFVDDVNIYGNISNNN IRTNEYKYEEMFDTNIEEKNGMHLSKYIHLLEENKFRCMKIIYENENIKS SNKIIGLYNYSRYYGLREDLCKEEIVPSKIGNISNKNENNNKKNNTCDGY DEKVTIVLCIILNEIIKFLFLNDEYVLLFEKIHKNVWKRMYIPEEIKFFI LKYITLLNNLRDYIISVHNNMKNEKYDECWFLFQHYFERSSDVRKEMVHF LLERKSQENLISFKSKLKSKKEKILTMDILNFSKEHMQLKTIAHLRKEIN YEKLSKDTLNRDYNLLLYKYQECVSKLKRVKNLMKEINQNVFIEKYDDIS KELDNFSDGYNEQNEQHVMDPILLNNNKNKNNKLITEHNNPIINRLTNFT QNRDSKYKNKIMDDVKQRKINSTMNNTNKNGINIIYNHYENLNKPNYNDN INRLNSYHQNIHIANSIHPNRNQNKSFLTNQANSTYSVMKNYINSDKPNL NGKKSVRNIFNEIVDENVNKTFVHKSVFF

[0038] The polypeptide sequence of the full length hypothetical protein PVNG_04523 of Plasmodium vivax North Korean (GenBank: KNA01322.1) (SEQ ID NO: 3):

TABLE-US-00003 MVFKFKKKKKEESSDKLSKQSQNDEGNANEEAEKKDHKSNSWYKKIIDNA IITKSKHDDKEEQEEEKNGEGNDSRAMERNKDYQLEEQLKETLRSITSLS TKIVNYETKIEDLEKELKMEKDKQVDKAYEKELKEKENFIKQKIGMLNEK ENLLNEKELDINMREEKINDREMFISKKEDKLNDMQEQYLEKNKEKEKLH FEIADIKISLEKLKYEVKDKKDCLENVSNKVILKENTLRELKEFIREKNE MIESLNEKITEKEKIYEQLGKDVEEKRKIIELLDMKANEKEKYFEEKIKE LEKEQNALLQKLNNVKMREKEVETRENDFLHMEDELNDLRSSFSKNDCQL KIYKLEIKDLSSALVEKEREILDLKNTYDGEICSLKDQIKEKEKEIAKGS SSGGDVGAQDEPASEVESEEKADPKEEGVENSLTDLLKMKERELHEMKEK YAKEIDTLNSELNEKKKEFVEAKNSHINQINNLNDEIEESESKMAELKSG YEMEIKKLRSEINAVHEEKYLLSNEKQTLSGEIDKLNEEKKSLASEKEEL HNKITTLNSEIGTLHVEKQALTGEINTLNDLIHTLKNEISSSDNLISKLK EQMNAINEEKEGKEKLITEIENNYKNEINALKEKLKDTDNQVSISIREEM DHLKCVLGETEKENKQMKEDYHKKIKQYDEELLSKQQYFEEELNNIRIKS HEKEQILILKNDELKESKLKTEEKYLKLYDDKMSLLRNMCSKVGLPYSDE VSVEELLERVGNYVSGMGEPGGAAHRGEQSEEPHEGQSIVEETNEPLLSA QTADNANSLEDKTTLQALQKELESVQEEYREEVAKMKSYLAMKEKTIEES NHTIAELTGKINSLNDTISFFKVNHSEEKINSYMDEINSLSLTLSELKAN NEQEQLENRNEIARLSEELSGYKRRADEQCRKRSSEKERSESKRGDTRGD SEKEQISESDVEGGGNLKSFLHFPLRKIKGKKRKASKTEKEIQTELRRNE PENEQSEKNEKAPRGDSLEVDQYKKELEEKAKIIEDLKDKICTLTNEVMD LKNLKNELAERDSSLAKAGEEAERQREQLDTLSAQLGGANGEVERLSEEV ERLNEEVEKLKEGEAQSWGEAEKWKGEAEKWKEDAAKWEADTVKLKEDAA KWESDAVKWESDAETWRKEAEELRSSANQLNEELCSKENNYVLKLNENVG VIQKMKDSIDAREKEKENYVREINDLRNELEGLKLKHDALSETYKQLEGK SSPPSGDDPPGGDNYTSEGENKLSIPNENCEMDQAEEANANPGVPKSEIA TEGGVSSLAVNDYISEIAHLKEEINRLTLLYSNELNEKNSSDIRTKELLS QLKELEVRDKENEEKIAALSKMNEKMKAKNEKLKSGKWLSRKDHAPNEEV DIAGEERKKKEKEKVPHPDVKEESLSSEHVNTLEGNTYRVMRIVDESSPA GGGQIIGSYLYTKKVEDLHAVNGANVADAQLAEKNAITVVCLILSEILSL LFLNDQFVNAFERINKSLWKLMYMPEEIKALLLRYFSFMSKLRDYAKEVH GRVENERYEDSQRQDNQRYDDSWLLFQNYLETSSSIKRDLVCFILEEKEN ELAELGEHYGGGMRKGEEVIGGVRGVRGGKIADIINLSKDEMRLKTIAQL RRDLDFEKKSKTLLSRDYQLLLYKYQECVRKLKRVKNMIRQLNLNDHSNR GSFALNRELDRCSEVSNERGFNEEGGDEDSHGNYKNCILQDNNNNSSVNN YNSSNTKLESRENVLIKDLINLRRAQKVKGNNLIHWGRPSMMMGGRCHQD ASHVVRAMVNGPKISSQNIFAHMNRLSNAPKISDHLDDMKKMKNIFNEFV ETRGDVTFVHRSPFCET

[0039] The polynucleotide strand encoding for the at least nine consecutive amino acid moieties of SEQ ID NO: 2 can be any sequence suitable for this purpose. Preferably, it is a part of or the whole sequence according to the repetitive organellar protein, putative of Plasmodium falciparum 3D7 (GenBank: CZT98043.1): 1..1979/locus_tag="PF3D7_0203000"/coded_by="complement (LN999943.1:141625..147564)" (SEQ ID NO: 4):

TABLE-US-00004 ATGGTATTCACGTTCAAAAATAAGAAAAAGAAAAAAGAAGCTAGTTCAGA TAAAGTAAGCAAAGAATCATTTAATGAGGAAGATAATGAAAATAATGAAA AGAGGGAAAAAAGCGATTCATGGTATAAAAAAATAATAGAAACTAAAGGA AAAAGTAAAACTAAATATAAAAATGATAATTCCTTAGATGATAATATTAA TGAGGACATAATAAATAATAATAATAATAATAATAATGATAATAATAATG ATAACAATAATGATAATAATAATGATAATAATAATGATAATAATAATGAT AATAATAATGAGAATAATAATGATAATAATAATTTTAATAATTATAGCGA TGAAATATCAAAAAATATTATACATAAAGACAATGAGCTAGAAAACCAGC TTAAGGATACATTAAAGTCCATTAGTTCGTTGTCGAATAAAATTGTGAAT TACGAAAGTAAAATTGAAGAATTAGAAAAAGAATTAAAAGAAGTAAAGGA TAAGAATATTGATAATAATGATTATGAAAATAAATTAAAAGAAAAAGAAG ATTTTGTTAAACAAAAAATTGATATGCTAAATGAAAAAGAAAATCTTTTA CAAGAAAAAGAATTAGATATTAATAAAAGAGAAAAGAAAATTAATGAAAA AGAAAAGAATATAATAAAAAAGGAAGAAACATTTCATAATATAGAAAAAG AGTATTTAGAAAAAAATAAAGAAAGAGAAACGATTTCTATAGAAATTATA GATATTAAAAAACATCTAGAAAAACTAAAAATAGAAATAAAAGAAAAAAA AGAAGATTTAGAAAATTTAAATAAAAAATTGTTATCAAAAGAAAATGTAC TAAAAGAATTAAAAGGATGTGTTAAGGAAAAAAATGAAACCATTAATTCA TTGAATGATAATATTATTGAAAAAGAAAAAAAATATAAATTATTAGAATA TGAGTTGGAAGAAAAAAATAAACAAATTGATTTATTAAACAAACAAGAAA AAGAAAAGGAAAAGGAGAAGGAAAGGGAAAAGGAGAAGGAAAGGGAAAAG GAAAAAGAAAAGGAATATGATACATTAATCAAAGAATTAAAAGATGAAAA GATTTCCATTTTAGAAAAAGTTCATTCCATTAAAGTAAGAGAAATGGATA TTGAAAAAAGAGAACATAATTTCCTTCATATGGAAGATCAATTAAAAGAT TTAAAAAATAGTTTTGTAAAGAATAATAATCAATTAAAAGTATATAAATG TGAAATAAAGAATCTTAAAACCGAATTAGAAAAAAAAGAAAAAGAATTAA AAGATATAGAAAATGTATCTAAAGAAGAAATAAATAAATTAATAAACCAA TTAAATGAAAAGGAGAAACAAATTCTTGCGTTTAATAAAAATCATAAAGA AGAAATTCATGGATTGAAAGAAGAATTAAAAGAATCTGTGAAAATAACCA AAATAGAAACACAAGAGTTACAAGAAATGGTAGACATCAAACAAAAAGAG TTAGACCAATTGCAGGAAAAATATAACGCACAAATAGAAAGTATAAGCAT CGAATTAAGTAAAAAAGAGAAGGAATATAATCAATATAAAAATACTTATA TAGAAGAAATAAATAATTTAAATGAAAAATTAGAAGAAACTAATAAAGAA TATACGAATTTACAAAATAATTATACAAATGAAATAAATATGTTAAATAA TGATATACATATGTTAAATGGCAATATAAAAACCATGAATACACAAATAA GTACTTTAAAAAATGATGTACATTTGTTAAATGAACAAATAGATAAATTA AATAATGAAAAGGGTACATTAAATAGTAAAATTAGTGAATTGAATGTTCA AATTATGGATTTAAAAGAGGAAAAAGATTTCTTAAATAATCAAATTGTAG ATTTAAGTAATCAAATTGATTTGTTAACAAGAAAAATGGAAGAGAAGGAA AATAAAATGTTGGAACAGGAGAATAAGTATAAACAAGAGATGGAACTCTT AAGGGGGAATATAAAAAGTTCTGAGAATATTTTAAACAATGACGAAGAGG TGTGTGATTTAAAAAGGAAATTAAGTTTGAAGGAAAGTGAAATGAAAATG ATGAAGGAGGAACATGATAAGAAGTTGGCTGAGTTGAAAGATGATTGTGA TGTGAGGATACGGGAGATGAATGAAAAGAATGAAGATAAAATTAATATGT TAAAGGAAGAATATGAAGATAAAATTAATACGTTGAAGGAACAAAATGAA GATAAAATTAATACGTTAAAGGAACAAAATGAAGATAAAATTAATACATT GAAAGAAGAGTATGAACATAAAATTAATACGATGAAGGAAGAATATGAAC ATAAAATTAATACGTTGAATGAACAAAATGAACATAAAATTAATACGTTG AATGAACAAAATGAACATAAAATTAATACGATGAAGGAAGAATATGAAGA TAAAATGAACACGTTGAATGAACAAAATGAAGATAAAATGAATTCGTTGA AGGAAGAGTATGAAAATAAGATAAATCAAATTAATAGTAATAATGAAATA AAAATAAAAGATGTAGTGAATGAATATATTGAAGAAGTGGACAAATTAAA AGTTACTTTGGATGAAAAAAAAAAACAATTTGATAAAGAAATAAATTACG CACATATCAAAGCTCATGAAAAGGAGCAAATATTATTAACAGAAATGGAA GAATTAAAATGTCAGAGGGATAATAAATATTCAGATTTATATGAGAAATA TATTAAACTAATAAAAAGTATTTGTATGATAATTAACATTGAATGTTGTG ATGATATAGAAAATGAAGATATTATAAGAAGAATTGAAGAATATATAAAT AATAACAAAGGCTTGAAAAAAGAAGTAGAAGAAAAAGAACATAAAAGACA TTCCTCCTTTAATATTTTAAAAAGTAAAGAAAAGTTTTTTAAAAATAGCA TAGAAGATAAAAGTCATGAATTAAAAAAAAAACATGAAAAAGATTTATTA TCAAAAGATAAAGAAATTGAAGAAAAGAATAAAAAAATAAAAGAACTGAA TAATGATATAAAAAAGTTACAAGATGAAATATTAGTATATAAAAAACAAA GTAATGCACAACAAGTAGATCATAAAAAGAAAAGTTGGATTCTTCTTAAA GATAAATCTAAAGAGAAAATAAAAGATAAAGAAAATCAAATAAATGTAGA AAAAAATGAAGAAAAGGATTTAAAAAAAAAAGATGATGAAATAAGAATTT TAAATGAAGAACTTGTAAAATATAAAACAATTTTATATAATTTAAAAAAA GATCCATTATTACAAAATCAAGATTTATTATCAAAAATTGACATAAATTC TTTAACAATAAATGAAGGAATGTGTGTAGATAAAATAGAAGAGCACATTT TGGATTATGATGAAGAAATAAATAAAAGCAGATCTAATTTGTTTCAACTA AAAAATGAAATATGTTCTTTAACAACTGAGGTTATGGAACTTAATAATAA GAAAAATGAATTAATTGAAGAAAATAATAAATTAAATTTAGTAGATCAAG GAAAGAAGAAATTAAAAAAGGATGTGGAAAAACAAAAAAAAGAAATAGAG AAATTAAATAAACAATTAACAAAATGTAATAAACAAATAGATGAATTAAA TGAAGAAGTGGAAAAATTAAATAATGAAAATATTGAATTAATTACATATT CAAATGATTTAAATAACAAATTTGATATGAAAGAAAATAATCTTATGATG AAATTAGATGAAAATGAAGATAATATAAAGAAAATGAAAAGTAAAATTGA TGATATGGAAAAAGAAATAAAATATAGAGAAGATGAAAAAAAAAGAAATT TAAATGAAATTAATAATTTAAAGAAAAAGAATGAAGATATGTGTATTAAA TATAATGAAATGAATATTAAGTATGGAGATATTTGTGTAAAATATGAAGA AATGTCTCTTACGTATAAAGAAACATCTCTTAAATATGAGCAAATTAAAG TGAAATATGATGAAAAGTGTTCTCAATATGACGAAATACGTTTTCAATAT GATGAGAAATGTTTTCAATATGATGAGATAAATAAGAAATATGGTGCTTT ATTAAATATAAATATTACTAATAAAATGGTTGATTCAAAAGTGGATAGAA ATAATAATGAAATAATTTCAGTAGATAATAAAGTAGAAGGAATTGCGAAT TATTTAAAACAAATATTTGAATTAAATGAAGAGATCATACGATTAAAAGG AGAAATAAATAAAATTAGCTTATTATATAGTAATGAATTAAATGAGAAAA ATAGTTATGATATAAACATGAAACATATACAAGAACAATTACTTTTTTTG GAAAAGACAAATAAAGAAAATGAAGAAAAAATAATTAATTTGACTAGCCA ATATTCTGATGCATACAAGAAGAAGAGTGATGAATCTAAATTATGTGGTG CACAGTTTGTTGATGATGTTAATATATATGGAAATATATCAAATAATAAT ATAAGAACAAATGAATATAAATATGAAGAGATGTTTGATACGAATATAGA AGAGAAGAATGGTATGCATTTATCTAAGTATATTCATCTATTAGAAGAAA ATAAATTTCGATGTATGAAAATAATTTATGAAAATGAAAATATAAAAAGT AGTAATAAAATAATTGGATTGTATAATTATTCAAGGTATTATGGGTTAAG AGAAGATTTGTGTAAAGAAGAAATCGTTCCTTCAAAAATAGGAAATATAT CTAATAAAAATGAAAATAATAATAAGAAGAACAACACTTGTGATGGTTAT GATGAGAAGGTTACAATAGTTTTATGCATTATATTAAATGAAATAATAAA ATTTTTATTTTTAAATGACGAATATGTATTATTATTTGAAAAGATTCATA AAAATGTTTGGAAACGAATGTATATCCCAGAAGAAATAAAATTTTTTATC CTAAAATATATTACGCTGTTAAATAACTTGAGAGATTATATAATAAGTGT ACATAATAATATGAAAAATGAGAAATATGATGAATGTTGGTTTTTATTTC AACATTATTTTGAAAGATCGAGTGATGTAAGAAAAGAGATGGTTCATTTC TTATTAGAAAGAAAGAGTCAAGAAAATTTAATATCTTTTAAAAGTAAATT AAAAAGTAAAAAAGAAAAAATATTAACAATGGACATATTGAATTTTAGTA AAGAACATATGCAATTAAAAACCATAGCTCATCTAAGAAAAGAAATAAAT TATGAAAAACTTTCTAAGGATACCTTAAATAGAGATTATAATTTATTATT ATATAAATATCAAGAATGTGTAAGTAAATTAAAAAGGGTAAAAAATTTAA TGAAAGAAATAAATCAAAATGTATTTATAGAAAAATATGATGATATAAGT AAAGAATTAGATAATTTTTCAGATGGATATAATGAACAAAATGAACAACA TGTAATGGATCCTATTTTATTAAATAATAATAAAAACAAAAATAACAAAT TGATAACTGAACATAATAATCCTATAATTAATAGGCTAACTAATTTTACA CAAAACAGAGATTCAAAATATAAAAATAAAATAATGGATGATGTAAAACA AAGAAAAATAAATAGTACAATGAATAATACAAATAAAAATGGTATTAATA TTATATATAATCATTATGAAAATTTAAATAAACCAAACTATAATGATAAT ATAAATAGATTAAATTCATATCATCAAAATATACATATTGCTAATTCAAT TCATCCTAATAGAAATCAAAATAAAAGTTTTCTTACGAATCAAGCAAATA GTACATATAGTGTTATGAAAAATTATATAAATTCAGATAAACCAAATTTA AATGGAAAAAAGAGTGTAAGAAATATTTTTAATGAAATTGTCGATGAAAA TGTAAATAAAACGTTTGTTCATAAAAGTGTATTTTTTTAA

[0040] The N-terminal part of the repetitive organellar protein, putative of Plasmodium falciparum 3D7 (GenBank: CZT98043.1) (SEQ ID NO: 6):

TABLE-US-00005 MVFTFKNKKKKKEASSDKVSKESFNEEDNENNEKREKSDSWYKKIIETKG KSKTKYKNDNSLDDNINEDIINNNNNNNNDNNNDNNNDNNNDNNNDNNND NNNENNNDNNNFNNYSDEISKNIIHKDNELENQLKDTLKSISSLSNKIVN YESKIEELEKELKEVKDKNIDNNDYENKLKEKEDFVKQKIDMLNEKENLL QEKELDINKREKKINEKEKNIIKKEETFHNIEKEYLEKNKERETISIEII DIKKHLEKLKIEIKEKKEDLENLNKKLLSKENVLKELKGCVKEKNETINS LNDNIIEKEKKYKLLEYELEEKNKQIDLLNKQEKEKEKEKEREKEKEREK EKEKEYDTLIKELKDEKISILEKVHSIKVREMDIEKREHNFLHMEDQLKD LKNSFVKNNNQLKVYKCEIKNLKTELEKKEKELKDIENVSKEEINKLINQ LNEKEKQILAFNKNHKEEIHGLKEELKESVKITKIETQELQEMVDIKQKE LDQLQEKYNAQIESISIELSKKEKEYNQYKNTYIEEINNLNEKLEETNKE YTNLQNNYTNEINMLNNDIHMLNGNIKTMNTQISTLKNDVHLLNEQIDKL

[0041] The polynucleotide strand encoding for the at least nine consecutive amino acid moieties of SEQ ID NO: 3 can be any sequence suitable for this purpose. Preferably, it is a part of or the whole sequence according to the polypeptide sequence of the full length hypothetical protein PVNG_04523 of Plasmodium vivax North Korean (GenBank: KNA01322.1; GenBank: KQ235267.1_1:98732-104326 Plasmodium vivax North Korean chromosome Unknown supercont.1.94) (SEQ ID NO: 5):

TABLE-US-00006 ATGGTATTCAAATTTAAGAAGAAAAAGAAGGAAGAAAGCTCGGACAAGTT AAGCAAGCAATCGCAAAACGATGAAGGAAATGCCAATGAGGAGGCAGAAA AAAAAGACCACAAGAGTAACTCCTGGTACAAGAAAATAATCGACAATGCA ATTATAACGAAGAGCAAGCATGACGATAAGGAGGAGCAGGAGGAGGAGAA AAATGGCGAAGGAAATGACAGCAGGGCGATGGAAAGAAATAAAGATTATC AATTGGAAGAGCAACTGAAGGAAACCCTAAGGTCAATCACGTCCTTGTCA ACCAAAATTGTGAATTACGAAACGAAGATTGAAGATTTGGAGAAAGAGTT AAAAATGGAAAAAGATAAACAAGTGGATAAGGCATACGAAAAGGAGTTGA AGGAGAAGGAGAATTTTATTAAACAAAAAATTGGCATGCTAAATGAGAAG GAAAATCTGCTAAATGAGAAGGAGCTGGACATAAATATGAGAGAAGAAAA AATTAATGACAGAGAAATGTTCATTTCGAAAAAGGAAGACAAACTGAATG ACATGCAGGAGCAGTACTTGGAAAAAAATAAAGAAAAAGAAAAACTCCAT TTTGAAATTGCAGATATTAAGATTTCCTTAGAAAAGCTAAAGTACGAAGT TAAAGATAAAAAGGACTGCCTAGAAAATGTCAGCAATAAGGTAATTTTGA AGGAAAATACTCTGAGGGAGTTAAAAGAATTTATAAGGGAAAAAAACGAA ATGATAGAATCGCTTAACGAGAAGATAACAGAGAAGGAGAAAATATATGA GCAGTTAGGGAAGGACGTGGAGGAGAAGAGAAAGATCATCGAATTGCTAG ACATGAAGGCAAATGAAAAGGAAAAATATTTCGAAGAAAAAATTAAAGAG TTAGAAAAAGAACAAAATGCGCTTCTGCAAAAGTTAAATAATGTTAAGAT GAGGGAGAAGGAAGTTGAGACGAGGGAAAATGACTTCCTGCACATGGAGG ACGAGCTGAATGATCTTCGCAGTAGCTTCTCGAAGAATGATTGTCAGCTA AAGATCTACAAATTGGAAATAAAAGATTTGAGCAGCGCCCTTGTGGAGAA GGAGAGAGAAATATTGGACTTGAAAAATACCTACGACGGGGAAATCTGCT CATTAAAGGATCAGATAAAGGAAAAGGAAAAGGAAATCGCCAAAGGTAGT TCCTCCGGTGGTGACGTGGGTGCACAAGATGAGCCAGCTAGCGAAGTTGA AAGTGAAGAAAAGGCGGACCCCAAAGAGGAAGGTGTGGAGAACAGCTTGA CCGATTTGCTCAAAATGAAGGAAAGAGAGCTGCACGAAATGAAGGAAAAA TACGCAAAGGAAATAGACACACTGAATAGCGAGCTGAATGAGAAAAAGAA AGAATTCGTGGAGGCAAAAAATAGCCACATCAACCAGATAAACAACCTAA ATGATGAAATTGAGGAGAGCGAAAGCAAAATGGCAGAACTGAAAAGTGGC TACGAAATGGAGATCAAAAAACTGCGCAGCGAAATTAATGCAGTGCACGA GGAGAAGTACCTCTTGAGCAACGAAAAACAAACACTCAGTGGAGAGATAG ACAAGCTGAATGAAGAGAAGAAGTCCCTGGCCAGCGAGAAGGAGGAGCTA CATAACAAAATAACCACGTTGAACAGCGAAATTGGGACGTTACATGTGGA GAAACAGGCACTCACTGGAGAAATAAACACCTTAAACGATCTGATTCACA CCCTGAAGAATGAAATCAGCTCGTCGGATAACCTGATTAGCAAATTGAAA GAGCAAATGAACGCCATCAACGAAGAAAAGGAAGGAAAGGAAAAACTCAT CACAGAGATAGAAAATAATTATAAAAATGAAATAAACGCGCTGAAGGAAA AATTAAAAGACACGGACAATCAAGTGAGCATAAGTATTAGGGAAGAGATG GACCACCTCAAATGCGTCCTTGGCGAAACGGAAAAGGAAAACAAACAGAT GAAGGAGGACTACCACAAAAAGATAAAACAGTATGATGAAGAATTGCTAT CGAAGCAGCAATATTTTGAAGAAGAATTAAATAACATACGCATCAAATCG CACGAAAAGGAACAAATTTTGATTTTAAAAAATGACGAGTTGAAGGAGTC GAAGCTAAAGACGGAGGAGAAGTACCTCAAGCTGTACGATGACAAAATGA GTCTCCTCAGGAATATGTGCTCCAAAGTGGGGCTCCCCTACAGCGATGAA GTTTCGGTGGAGGAGCTTCTCGAGCGGGTGGGCAACTACGTAAGTGGGAT GGGTGAACCGGGGGGTGCGGCACACAGGGGGGAGCAAAGTGAGGAGCCGC ATGAGGGGCAGTCGATTGTGGAGGAGACGAATGAACCCCTTTTGAGCGCC CAAACGGCCGACAATGCTAATAGCCTAGAGGACAAGACAACCCTACAGGC GCTACAGAAAGAACTGGAAAGTGTGCAAGAAGAGTACAGAGAAGAGGTAG CCAAAATGAAGAGCTATTTGGCGATGAAGGAAAAAACGATAGAGGAGTCG AACCACACAATCGCCGAGTTGACCGGAAAGATAAACAGCCTGAATGATAC CATTTCGTTTTTTAAGGTTAACCACTCTGAGGAGAAAATTAATTCCTATA TGGACGAAATTAACAGCTTGAGCTTGACGCTTAGCGAGCTGAAGGCTAAT AATGAACAGGAGCAGTTGGAGAATCGAAACGAAATTGCCAGGCTGTCGGA AGAGCTCAGCGGGTATAAGCGGCGTGCTGATGAGCAATGTAGAAAGAGGA GCAGCGAGAAGGAGAGAAGCGAGTCCAAGAGGGGAGACACAAGAGGTGAC TCCGAGAAGGAACAAATCTCCGAGTCGGACGTGGAAGGGGGGGGCAATTT AAAATCCTTTTTACACTTTCCCCTTCGAAAAATAAAAGGGAAAAAAAGAA AGGCCTCTAAAACTGAGAAGGAAATACAAACGGAGCTTAGGAGAAACGAG CCAGAGAATGAACAGAGTGAGAAAAATGAGAAGGCGCCTAGAGGAGACAG CCTGGAGGTGGACCAGTACAAAAAGGAATTGGAGGAAAAGGCGAAGATTA TTGAGGACTTGAAGGACAAAATATGCACCCTGACGAATGAGGTTATGGAT TTGAAGAATTTGAAGAACGAGCTGGCTGAGCGGGATAGCAGCTTGGCGAA GGCGGGCGAGGAGGCGGAAAGGCAAAGAGAGCAGTTGGACACGCTGAGCG CCCAACTGGGGGGTGCAAACGGAGAGGTGGAGAGACTCAGCGAAGAGGTG GAGAGGCTCAACGAAGAGGTGGAGAAGCTGAAGGAGGGAGAGGCACAATC GTGGGGGGAAGCGGAGAAGTGGAAAGGGGAAGCAGAGAAGTGGAAAGAAG ACGCAGCGAAGTGGGAAGCGGACACAGTGAAATTGAAAGAGGACGCAGCG AAATGGGAATCGGACGCAGTGAAGTGGGAATCGGACGCCGAGACGTGGAG GAAAGAAGCGGAGGAACTGAGAAGCAGCGCGAATCAATTGAACGAAGAAT TATGCTCGAAGGAAAATAACTACGTGTTGAAGCTGAACGAAAATGTGGGA GTTATACAAAAAATGAAGGACTCAATTGATGCACGTGAAAAGGAGAAGGA GAATTACGTTCGCGAGATAAACGATTTGAGAAACGAACTCGAAGGGTTGA AATTGAAGCATGATGCGTTGAGTGAGACGTATAAGCAGTTGGAGGGGAAG AGCAGCCCCCCCAGTGGAGATGACCCCCCTGGTGGAGATAACTACACCAG TGAGGGAGAGAATAAATTAAGCATCCCAAATGAGAATTGCGAAATGGACC AAGCGGAGGAAGCGAATGCCAACCCAGGTGTTCCCAAGAGCGAAATTGCC ACCGAGGGGGGTGTCTCCTCATTGGCAGTGAACGATTACATAAGCGAAAT AGCGCACCTGAAGGAAGAAATAAACAGACTAACCCTACTGTATAGCAACG AACTGAACGAAAAAAACAGCTCTGATATTAGGACCAAAGAGCTGCTGAGC CAGTTGAAGGAACTCGAAGTGAGGGATAAAGAAAATGAGGAAAAGATTGC TGCGCTGAGCAAAATGAATGAGAAAATGAAAGCGAAAAATGAAAAGCTGA AATCGGGGAAGTGGTTATCTAGGAAGGACCACGCGCCGAATGAAGAGGTA GATATCGCAGGGGAGGAGCGTAAGAAGAAGGAGAAGGAGAAAGTGCCTCA CCCGGATGTGAAAGAGGAGAGTCTGTCTTCAGAGCATGTGAACACACTGG AAGGAAACACCTACCGCGTGATGAGAATAGTTGATGAAAGTAGCCCCGCG GGAGGAGGCCAAATAATAGGGTCCTACTTGTACACCAAAAAGGTGGAAGA TTTACACGCAGTAAATGGAGCAAATGTGGCAGATGCACAGCTGGCTGAGA AAAACGCAATCACAGTTGTGTGTCTAATTCTAAGCGAAATCTTAAGCCTC CTATTTTTGAACGATCAATTTGTTAACGCCTTTGAACGGATAAACAAAAG TCTGTGGAAGCTTATGTACATGCCTGAAGAGATTAAAGCGCTGCTTCTGA GGTATTTTTCCTTTATGAGTAAGCTCAGGGATTATGCCAAGGAGGTGCAC GGGAGGGTGGAAAATGAGAGGTATGAAGACAGCCAAAGGCAGGACAACCA ACGGTACGACGATTCGTGGTTACTTTTTCAAAACTATTTGGAGACGTCGA GTAGTATCAAGAGGGACCTGGTGTGCTTCATTTTGGAAGAGAAGGAAAAT GAACTAGCCGAGCTGGGCGAGCACTATGGTGGTGGAATGAGAAAGGGAGA GGAAGTAATCGGGGGAGTACGCGGAGTGCGCGGGGGAAAAATCGCCGACA TCATAAACCTTTCAAAGGACGAAATGAGATTGAAGACCATAGCACAGTTA AGAAGAGACCTAGATTTTGAAAAGAAATCGAAAACATTGCTAAGCAGGGA TTATCAGTTGTTACTTTATAAGTACCAGGAATGCGTGAGGAAGCTAAAGA GGGTAAAAAATATGATAAGGCAGCTAAATCTGAACGACCATTCAAATAGA GGCAGTTTCGCCTTAAACAGGGAGCTGGACAGGTGTTCCGAAGTGAGCAA CGAGCGAGGTTTTAACGAGGAGGGGGGTGATGAAGATTCGCACGGAAATT ACAAAAACTGCATTCTGCAAGACAATAATAATAATAGCAGTGTAAATAAC TATAATAGTAGTAACACCAAATTGGAGAGTCGGGAAAATGTTCTAATCAA GGACCTAATCAATTTGAGGAGGGCGCAAAAGGTGAAGGGAAATAATTTGA TCCACTGGGGCCGTCCCAGCATGATGATGGGGGGCAGGTGTCACCAAGAC GCTTCCCATGTGGTAAGGGCGATGGTAAATGGACCCAAAATAAGCAGCCA GAATATCTTCGCACACATGAACAGGCTGAGCAATGCGCCCAAAATTAGCG ACCACTTGGATGACATGAAAAAAATGAAAAATATTTTTAACGAATTTGTT GAAACCAGAGGGGACGTTACGTTTGTGCACAGGAGTCCCTTCTGCGAAAC GTGA

[0042] As used herein, the term "isolated" may be understood in the broadest sense as any increase in purity. The isolated polypeptide strand P does not form part of a plasmodium or larger sized fragments of 100 or more nm thereof. Preferably, the isolated polypeptide strand P represents at least 5% by weight, more preferably at least 10% by weight, even more preferably at least 25% by weight, even more preferably at least 50% by weight, even more preferably at least 75% by weight, in particular at least 90% by weight of the whole polypeptide content of the vaccine V.

[0043] The terms "polypeptide", "protein" and "peptide" may be understood interchangeably throughout the invention in the broadest sense as any chemical entity mainly composed of amino acid residues and comprising at least nine amino acid residues consecutively linked with another via amide bonds. It will be understood that a protein in the sense of the present invention may or may not be subjected to one or more posttranslational modification(s) and/or be conjugated with one or more non-amino acid moiety/moieties. The termini of the protein may, optionally, be capped by any means known in the art, such as, e.g., amidation, acetylation, methylation, acylation. Posttranslational modifications are well-known in the art and may be but may not be limited to lipidation, phosphorylation, sulfatation, glycosylation, truncation, oxidation, reduction, decarboxylation, acetylation, amidation, deamidation, disulfide bond formation, amino acid addition, cofactor addition (e.g., biotinylation, heme addition, eicosanoid addition, steroid addition) and complexation of metal ions, non-metal ions, peptides or small molecules and addition of iron-sulphide clusters. Moreover, optionally, co-factors, in particular cyclic guanidinium monophosphate (cGMP), but optionally also such as, e.g., ATP, ADP, NAD.sup.+, NADH+H.sup.+, NADP.sup.+, NADPH+H.sup.+, metal ions, anions, lipids, etc. may be bound to the protein, irrespective on the biological influence of these co-factors. In the context of Glu-plasminogen in particular glycosylation may play a role. In a particularly preferred embodiment, the isolated polypeptide strand P does not bear posttranslational modifications, i.e., consists of the plain polypeptide sequence consisting of consecutive amino acid moieties.

[0044] As used herein, the terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "carrier" and "excipient" may be understood interchangeably in the broadest sense as any substance that may support the pharmacological acceptance of the vaccine V. A pharmaceutically acceptable carrier may exemplarily be selected from the list consisting of an aqueous buffer, saline, water, dimethyl sulfoxide (DMSO), ethanol, vegetable oil, paraffin oil or combinations of two or more thereof. Furthermore, the pharmaceutically acceptable carrier may optionally contain one or more detergent(s), one or more foaming agent(s) (e.g., sodium lauryl sulfate (SLS), sodium doceyl sulfate (SDS)), one or more coloring agent(s) (e.g., food coloring), one or more vitamin(s), one or more salt(s) (e.g., sodium, potassium, calcium, zinc salts), one or more humectant(s) (e.g., sorbitol, glycerol, mannitol, propylenglycol, polydextrose), one or more enzyme(s), one or more preserving agent(s) (e.g., benzoic acid, methylparabene, one or more antioxidant(s), one or more herbal and plant extract(s), one or more stabilizing agent(s), one or more chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA), and/or one or more uptake mediator(s) (e.g., polyethylene imine (PEI), a cell-penetrating peptide (CPP), a protein transduction domain (PTD), an antimicrobial peptide, etc.). In addition, the excipient of the vaccine V may or may not comprise one or more adjuvants. An excipient may be an adjuvant such as, e.g., alum.

[0045] As used herein, the term "adjuvant" may be understood in the broadest sense as any that supports immunologic stimulation. It may be a solution or emulsion of antigen emulsified in mineral oil and used as an immunopotentiator (booster). An adjuvant may also comprise muramyl peptide (MDP). An adjuvant typically significantly enhances the immune response to the isolated polypeptide strand P. Typically, immune response is at least two-fold higher compared to a comparable vaccine lacking the adjuvant.

[0046] In a preferred embodiment, the vaccine V comprises an adjuvant supporting immunologic stimulation. In a preferred embodiment, the excipient of the vaccine V comprises at least one adjuvant, such as, e.g., alum. In a preferred embodiment, the vaccine V comprises at least one adjuvant supporting immunologic stimulation selected from the group consisting of alum and an immunostimulatory peptide, and optionally one or more further pharmaceutically acceptable carriers. The combination of an adjuvant such as alum and one or more immunostimulatory peptides may also be designated as composite adjuvant. In a preferred embodiment, an adjuvant in the sense of the present invention is a composite adjuvant. In a preferred embodiment, such composite adjuvant includes alum and one or more further immunostimulatory agents. In a preferred embodiment, such composite adjuvant includes alum and one or more immunostimulatory peptides (e.g., muramyl peptide (MDP) and/or monophosphoryl lipid A (MPL), a modified bacterial coat molecule). In a preferred embodiment, an immunostimulatory peptide is selected from the group consisting of muramyl peptide (MDP) and/or monophosphoryl lipid A (MPL).

[0047] It is known that alum bears several technical disadvantages such as rather unsatisfactory enlisting of cytotoxic T cells that may be helpful for fighting malaria (Leslie, 2013). It will be, thus, understood that alum may be replaced by another adjuvant that at least partly overcomes these drawbacks. Such replacement of an adjuvant would not alter the sense of the present invention.

[0048] As experimentally evidenced, peptides derived from SEQ ID NO: 2 or SEQ ID NO: 3 are particularly strong immunogens. Therefore, in some preferred embodiments, an adjuvant such as, e.g., muramyl peptide (MDP), may also be omitted. This may avoid undesired side effects and/or may be more cost-efficient. Accordingly, in another preferred embodiment, the vaccine V does (essentially) not comprise (thus, is (essentially) free of) muramyl peptide (MDP).

[0049] In an alternative preferred embodiment, the vaccine V does (essentially) not comprise (thus, is (essentially) free of) an adjuvant.

[0050] In a preferred embodiment, the vaccine V comprises at least one isolated polypeptide strand P comprising or consisting of at least nine consecutive amino acid moieties of the repetitive organellar protein, putative of Plasmodium falciparum 3D7 (SEQ ID NO: 2) or the hypothetical protein PVNG_04523 of Plasmodium vivax North Korean (SEQ ID NO: 3) or a polynucleotide strand encoding for said polypeptide strand P.

[0051] In a preferred embodiment, the vaccine V comprises or consists of:

[0052] (A) at least one isolated polypeptide strand P comprising or consisting of at least nine consecutive amino acid moieties of SEQ ID NO: 2; and

[0053] (B) at least one pharmaceutically acceptable carrier or excipient.

[0054] In another preferred embodiment, the vaccine V comprises or consists of:

[0055] (A) at least one isolated polypeptide strand P comprising or consisting of at least nine consecutive amino acid moieties of SEQ ID NO: 3; and

[0056] (B) at least one pharmaceutically acceptable carrier or excipient.

[0057] In another preferred embodiment, the vaccine V comprises or consists of:

[0058] (A) at least one polynucleotide strand encoding for a polypeptide strand P comprising or consisting of at least nine consecutive amino acid moieties of SEQ ID NO: 2; and

[0059] (B) at least one pharmaceutically acceptable carrier or excipient.

[0060] In another preferred embodiment, the vaccine V comprises or consists of:

[0061] (A) at least one polynucleotide strand encoding for a polypeptide strand P comprising or consisting of at least nine consecutive amino acid moieties of SEQ ID NO: 3; and

[0062] (B) at least one pharmaceutically acceptable carrier or excipient.

[0063] Preferably, the isolated polypeptide strand P is not too short in order to provide various antigens and to improve antigenicity. In a preferred embodiment, the isolated polypeptide strand P comprises or consists of at least 10, at least 15, at least 20, at least 50 or at least 100 consecutive amino acid moieties of SEQ ID NO: 2 and/or SEQ ID NO: 3.

[0064] In a preferred embodiment, the polypeptide strand P comprises or consists of from 10 to 250, from 10 to 100, from 15 to 75, from 20 to 50, or from 25 to 45 consecutive amino acid moieties of SEQ ID NO: 2. In another preferred embodiment, the polypeptide strand P comprises or consists of from 10 to 250, of from 11 to 100, from 15 to 75, from 20 to 50, or from 25 to 45 consecutive amino acid moieties of SEQ ID NO: 3. In another preferred embodiment, the polypeptide strand P comprises or consists of from 10 to 250, of from 11 to 100, from 15 to 75, from 20 to 50, or from 25 to 45 consecutive amino acid moieties of SEQ ID NO: 6.

[0065] In a preferred embodiment, the isolated polypeptide strand P comprises (or consists of) at least 100, at least 200, at least 500, at least 1000, or at least 1800 consecutive amino acids having at least 80%, more preferably at least 90%, even more preferably at least 95%, more preferably at least 98% or homology to or even sequence identity with the polypeptide sequence of SEQ ID NO: 2 and/or SEQ ID NO: 3.

[0066] In a preferred embodiment, the isolated polypeptide strand P comprises or consists of an amino acid sequence having at least 80%, more preferably at least 90%, even more preferably at least 95%, more preferably at least 98% or homology to or even sequence identity with the polypeptide sequence of SEQ ID NO: 2.

[0067] In another preferred embodiment, the isolated polypeptide strand P comprises or consists of an amino acid sequence having at least 80%, more preferably at least 90%, even more preferably at least 95%, more preferably at least 98% or homology to or even sequence identity with the polypeptide sequence of SEQ ID NO: 3.

[0068] In a highly preferred embodiment, the isolated polypeptide strand P consists of an amino acid sequence having the polypeptide sequence of SEQ ID NO: 2. In a highly preferred embodiment, the isolated polypeptide strand P consists of an amino acid sequence having the polypeptide sequence of SEQ ID NO: 2 obtained from heterologous expression. In a highly preferred embodiment, the isolated polypeptide strand P consists of an amino acid sequence having the polypeptide sequence of SEQ ID NO: 2 obtained from heterologous expression in a bacterium, in particular in Escherichia coli (E. coli).

[0069] In a highly preferred embodiment, the isolated polypeptide strand P consists of an amino acid sequence having the polypeptide sequence of SEQ ID NO: 3. In a highly preferred embodiment, the isolated polypeptide strand P consists of an amino acid sequence having the polypeptide sequence of SEQ ID NO: 3 obtained from heterologous expression. In a highly preferred embodiment, the isolated polypeptide strand P consists of an amino acid sequence having the polypeptide sequence of SEQ ID NO: 3 obtained from heterologous expression in a bacterium, in particular in Escherichia coli (E. coli).

[0070] In a highly preferred embodiment, the vaccine V comprises two isolated polypeptide strands P consisting of amino acid sequence having the polypeptide sequences of SEQ ID NO: 2 and SEQ ID NO: 3. In a highly preferred embodiment, the vaccine V comprises two isolated polypeptide strands P consisting of amino acid sequence having the polypeptide sequences of SEQ ID NO: 2 and SEQ ID NO: 3 each obtained from heterologous expression, preferably obtained from heterologous expression in a bacterium, in particular in Escherichia coli (E. coli).

[0071] In another preferred embodiment, the isolated polypeptide strand P comprises or consists of an amino acid sequence having at least 80%, more preferably at least 90%, even more preferably at least 95%, more preferably at least 98% or homology to or even sequence identity with the polypeptide sequence of SEQ ID NO: 6.

[0072] In an alternative preferred embodiment, the isolated polypeptide strand P comprises or consists of an amino acid sequence having at least 80%, more preferably at least 90%, even more preferably at least 95%, more preferably at least 98% or homology to or even sequence identity with the polypeptide sequence of SEQ ID NO: 1.

[0073] In an alternative preferred embodiment, the isolated polypeptide strand P comprises or consists of an amino acid sequence having amino acids of positions 1283-1516 (234 amino acids) of SEQ ID NO: 1.

[0074] In a preferred embodiment, the nucleotide sequence usable as antigen encodes for such polypeptide sequence of SEQ ID NO: 2 and/or SEQ ID NO: 3. In a preferred embodiment, the nucleotide sequence usable as antigen (including an indirect antigen encoding the polypeptide strand P (that may serve as antigen)) bears at least 300, at least 600, at least 1500, at least 3000, or at least 5000 consecutive nucleotides having at least 80%, more preferably at least 90%, even more preferably at least 95%, more preferably at least 98% or homology to or even sequence identity with the sequence of SEQ ID NO: 4 and/or SEQ ID NO: 5. As indicated herein, such sequence may optionally be embedded in a larger polynucleotide sequence. In a preferred embodiment, the nucleotide sequence encodes for the polypeptide strand P (that may serve as antigen).

[0075] In a preferred embodiment, the nucleotide sequence encoding the polypeptide strand P bears at least 300, at least 600, at least 1500, at least 3000, or at least 5000 consecutive nucleotides having at least 80%, more preferably at least 90%, even more preferably at least 95%, more preferably at least 98% or homology to or even sequence identity with the sequence of SEQ ID NO: 4. In a preferred embodiment, the nucleotide sequence encoding the polypeptide strand P bears at least 300, at least 600, at least 1500, at least 3000, or at least 5000 consecutive nucleotides having at least 80%, more preferably at least 90%, even more preferably at least 95%, more preferably at least 98% or homology to or even sequence identity with the sequence of SEQ ID NO: 5.

[0076] In a preferred embodiment, the at least one isolated polypeptide strand P consists of or comprises a peptide strand having at least 80% sequence homology to sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression. In a preferred embodiment, the at least one isolated polypeptide strand P consists of or comprises a peptide strand having at least 90% sequence homology to sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression. In a preferred embodiment, the at least one isolated polypeptide strand P consists of or comprises a peptide strand having at least 95% sequence homology to sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression. In a preferred embodiment, the at least one isolated polypeptide strand P consists of or comprises a peptide strand having at least 98% sequence homology to sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression. In a preferred embodiment, the at least one isolated polypeptide strand P consists of or comprises a peptide strand having a sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression.

[0077] The person skilled in the art will notice that the isolated polypeptide strand P as used in a vaccine V of the present invention may also form part of a fusion protein, a multi-antigen vaccine, or a viral vector.

[0078] In a highly preferred embodiment, the isolated polypeptide strand P comprises (essentially) the whole polypeptide sequence of SEQ ID NO: 2 and/or SEQ ID NO: 3. In a highly preferred embodiment, the nucleotide sequence usable as antigen comprises (essentially) the whole polypeptide sequence of SEQ ID NO: 4 and/or SEQ ID NO: 5.

[0079] The isolated polypeptide strand P may be obtained by any means. In order to obtain a rather pure and polypeptide one effective mean is to employ an effective (over)expression technique. The person skilled in the art is aware of numerous methods suitable for this purpose. In a preferred embodiment, the isolated polypeptide strand P is obtained from heterologous expression.

[0080] As used herein, "heterologous expression" may be understood in the broadest sense as expression of a gene encoding for the polypeptide according to SEQ ID NO: 2 and/or SEQ ID NO: 3 or fragment thereof in a host organism, which does not naturally have this gene or gene fragment. Insertion of the gene in the heterologous host may be performed by recombinant DNA technology which is well-known to the person skilled in the art. For this purpose, the gene may be inserted to the host, wherein it may be integrated into the host DNA causing permanent expression, or may not be integrated causing transient expression of this gene.

[0081] In a more preferred embodiment, the isolated polypeptide strand P is obtained from heterologous expression in bacterial or eukaryotic cells. In a highly preferred embodiment, the isolated polypeptide strand P is obtained from heterologous expression in bacterial cells such as E. coli. Such host organism comprising the gene encoding for the polypeptide strand P may also be designated as "expression system". An advantage of such heterologous expression is that high amounts of the peptide are obtainable in good purity. In contrast to peptide synthesis, toxic agents can be avoided. On the other hand, in particular when expressed in bacteria, the peptides are typically not glycosylated.

[0082] In a preferred embodiment, the vaccine V of the present invention comprises or consists of:

[0083] (A) at least one isolated polypeptide strand P comprising or consisting of a peptide strand having at least 80% sequence homology to a sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression; and

[0084] (B) at least one adjuvant supporting immunologic stimulation and optionally one or more further pharmaceutically acceptable carriers.

[0085] In view of the further preferred embodiments described herein, it will be understood that the isolated polypeptide strand P may also have a higher homology and/or any of the other properties described herein. Further, in view of the further preferred embodiments described herein, the pharmaceutically acceptable carrier and/or the adjuvant may bear more specific properties.

[0086] In a preferred embodiment, the vaccine V comprises or consists of:

[0087] (A) at least one isolated polypeptide strand P comprising or consisting of a peptide strand of sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression; and

[0088] (B) at least one adjuvant supporting immunologic stimulation selected from the group consisting of alum and an immunostimulatory peptide, and optionally one or more further pharmaceutically acceptable carriers.

[0089] In a preferred embodiment, the vaccine V comprises or consists of:

[0090] (A) at least one isolated polypeptide strand P comprising or consisting of a peptide strand of sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression in bacteria; and

[0091] (B) a composite adjuvant supporting immunologic stimulation comprising alum and at least one immunostimulatory peptide, and optionally one or more further pharmaceutically acceptable carriers.

[0092] Alternatively, the polypeptide strand P may also be isolated from Plasmodium falciparum or Plasmodium vivax. This may optionally be performed by chromatographic means.

[0093] In a preferred embodiment, the at least one isolated polypeptide strand P comprises or consists of at least nine consecutive amino acid moieties of a sequence having at least 80% sequence homology to a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0094] The sequences of SEQ ID Nos 7 to 15 are the following:

TABLE-US-00007 (SEQ ID NO: 7) KQEKEKEKEKEREKEKEREKEKEKEY (SEQ ID NO: 8) KNLKTELEKKEKELKDIENVSKEEINKL (SEQ ID NO: 9) SKKEKEYNQYKNTYIEEINNLNEKLEETNKEYTNLQNNYTN (SEQ ID NO: 10) KEEYEDKMNTLNEQNEDKMNSLKEEYENK (SEQ ID NO: 11) KGLKKEVEEKEHKRHSSFNILKSKEKFFKNSIEDKSHELKKKHE (SEQ ID NO: 12) KDKSKEKIKDKENQINVEKNEEKDLKKKDD (SEQ ID NO: 13) EDEKKRNLNEINNLKKKNEDMCIKYNEMN (SEQ ID NO: 14) KTNKENEEKIINLTSQYSDAYKKKSDES (SEQ ID NO: 15) SNNNIRTNEYKYEEMFDTNIEEKNG (SEQ ID NO: 16) GNISNKNENNNKKNNTCDGYDEKVT

[0095] These sequences are described in more detail in the experimental part below.

[0096] In a preferred embodiment, the at least one isolated polypeptide strand P comprises or consists of at least nine consecutive amino acid moieties of a sequence having at least 90% sequence homology to a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0097] In a preferred embodiment, the at least one isolated polypeptide strand P comprises or consists of at least nine consecutive amino acid moieties of a sequence having at least 95% sequence homology to a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0098] In a preferred embodiment, the at least one isolated polypeptide strand P comprises or consists of at least nine consecutive amino acid moieties of a sequence having at least 98% sequence homology to a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0099] In a preferred embodiment, the at least one isolated polypeptide strand P comprises or consists of at least nine consecutive amino acid moieties of a sequence having a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0100] In a preferred embodiment, the above peptides may also be at least ten consecutive amino acid moieties, at least 15 consecutive amino acid moieties, at least 20 consecutive amino acid moieties, at least 25 consecutive amino acid moieties, at least 50 consecutive amino acid moieties, or at least 100 consecutive amino acid moieties as far as the respective sequence provided above is long enough.

[0101] In another preferred embodiment, the at least one isolated polypeptide strand P comprises or consists of a sequence having at least 80% sequence homology to a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0102] In a preferred embodiment, the at least one isolated polypeptide strand P comprises or consists of a sequence having at least 90% sequence homology to a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0103] In a preferred embodiment, the at least one isolated polypeptide strand P comprises or consists of a sequence having at least 95% sequence homology to a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0104] In a preferred embodiment, the at least one isolated polypeptide strand P comprises or consists of a sequence having at least 98% sequence homology to a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0105] In a preferred embodiment, the at least one isolated polypeptide strand P comprises or consists of a sequence having a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0106] In a preferred embodiment, the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising at least one peptide sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0107] In a preferred embodiment, the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising at least two peptide sequences selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16. In a preferred embodiment, the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising at least sequences of SEQ ID NO: 7 and 8, SEQ ID NO: 7 and 9, SEQ ID NO: 7 and 10, SEQ ID NO: 7 and 11, SEQ ID NO: 7 and 12, SEQ ID NO: 7 and 13, SEQ ID NO: 7 and 14, SEQ ID NO: 7 and 15, SEQ ID NO: 7 and 16, SEQ ID NO: 8 and 9, SEQ ID NO: 8 and 10, SEQ ID NO: 8 and 11, SEQ ID NO: 8 and 12, SEQ ID NO: 8 and 13, SEQ ID NO: 8 and 14, SEQ ID NO: 8 and 15, SEQ ID NO: 8 and 16, SEQ ID NO: 9 and 10, SEQ ID NO: 9 and 11, SEQ ID NO: 9 and 12, SEQ ID NO: 9 and 13, SEQ ID NO: 9 and 14, SEQ ID NO: 9 and 15, SEQ ID NO: 9 and 16, SEQ ID NO: 10 and 11, SEQ ID NO: 10 and 12, SEQ ID NO: 10 and 13, SEQ ID NO: 10 and 14, SEQ ID NO: 10 and 15, SEQ ID NO: 10 and 16, SEQ ID NO: 11 and 12, SEQ ID NO: 11 and 13, SEQ ID NO: 11 and 14, SEQ ID NO: 11 and 15, SEQ ID NO: 11 and 16, SEQ ID NO: 12 and 13, SEQ ID NO: 12 and 14, SEQ ID NO: 12 and 15, SEQ ID NO: 12 and 16, SEQ ID NO: 13 and 14, SEQ ID NO: 13 and 15, SEQ ID NO: 13 and 16, SEQ ID NO: 14 and 15, SEQ ID NO: 14 and 16, or SEQ ID NO: 15 and 16.

[0108] As used throughout the present invention, the term "truncated version of SEQ ID NO: 2" means a peptide comprising or consisting of a fraction of SEQ ID NO: 2 truncated by at least one amino acid moiety in length. In other words, in a t truncated version of SEQ ID NO: 2, at least one amino acid moiety is missing. Even if the truncated peptide sequence is extended by one or more amino acid moieties, these are not the same as those of SEQ ID NO: 2.

[0109] In a preferred embodiment, a truncated version of SEQ ID NO: 2 comprises or consists of a fraction of SEQ ID NO: 2 truncated by at least two, at least three, at least five, at least ten, at least 20, at least 50, at least 75, at least 100, at least 200, at least 500, or at least 1000 amino acid moieties in length. In a preferred embodiment, the polypeptide strand P which is a truncated version of SEQ ID NO: 2 comprises or consists of from 32 to 1900, from 40 to 1800, from 50 to 1700, from 60 to 1600, from 70 to 1500, from 80 to 1400, from 90 to 1300, from 100 to 1200, from 200 to 1100, from 300 to 1000 amino acid moieties in length.

[0110] In a preferred embodiment, a truncated version of SEQ ID NO: 2 comprises or consists of a fraction of SEQ ID NO: 2 truncated by at least 100 amino acid moieties in length.

[0111] In a preferred embodiment, the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising or consisting of a fraction of SEQ ID NO: 2 truncated by at least 100 amino acid moieties in length and comprising at least two peptide sequences selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0112] In a preferred embodiment, the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising or consisting of a fraction of SEQ ID NO: 2 truncated by at least 100 amino acid moieties in length and comprising all of the peptide sequences SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0113] In a preferred embodiment, the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising at least three peptide sequences selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0114] In a preferred embodiment, the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising at least four peptide sequences selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16. In a preferred embodiment, the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising at least five peptide sequences selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16. In a preferred embodiment, the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising at least six, at least seven, at least eight, or least nine, peptide sequences selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0115] In a preferred embodiment, the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising all of the peptide sequences SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0116] As indicated herein, the polypeptide strand P may also be obtained by means of heterologous expression. It has been surprisingly found that also polypeptide strands P which were obtained from heterologous expression in bacteria led to a remarkable effectivity. Therefore, also non-glycosylated peptide strands P showed activity as experimentally evidenced.

[0117] Accordingly, in a preferred embodiment, the polypeptide strand P does not comprise (i.e., is (essentially) free of glycosylation.

[0118] Alternatively, it will be understood that glycosylated peptides are, however, also suitable. Therefore, in an alternative preferred embodiment, the polypeptide strand P comprises one or more glycosylated sides.

[0119] In a preferred embodiment, the polypeptide strand P comprises or consists of an easily assessable epitope. Accordingly, it preferably bears a sequence as laid out above. This is evidenced further by bioinformatic means as laid out in the experimental section below. In a preferred embodiment, the polypeptide strand P is not a hardly assessable sequence.

[0120] Thus, in a preferred embodiment, in particular when the polypeptide strand P is not the full-length protein (of any of SEQ ID NOs: 2 or 3), the polypeptide strand P is not and/or comprises no peptide strand that has a length of nine or more consecutive amino acid moieties of at least 80% homology of any of SEQ ID NOs: 17-24. In a preferred embodiment, in particular when the polypeptide strand P is not the full-length protein (of any of SEQ ID NOs: 2 or 3), the polypeptide strand P is not and/or comprises no peptide strand that has a length of nine or more consecutive amino acid moieties of at least 80% homology of any of SEQ ID NOs: 17-21.

[0121] In a preferred embodiment, in particular when the polypeptide strand P is not the full-length protein (of any of SEQ ID NOs: 2 or 3), the polypeptide strand P is not and/or comprises no peptide strand that has a length of nine or more consecutive amino acid moieties of at least 98% homology of any of SEQ ID NOs: 17-21. In a preferred embodiment, in particular when the polypeptide strand P is not the full-length protein (of any of SEQ ID NOs: 2 or 3), the polypeptide strand P is not and/or comprises no peptide strand that has a length of nine or more consecutive amino acid moieties of at least 98% homology of any of SEQ ID NOs: 17-24. In a preferred embodiment, in particular when the polypeptide strand P is not the full-length protein (of any of SEQ ID NOs: 2 or 3), the polypeptide strand P is not and/or comprises no peptide strand that has a length of nine or more consecutive amino acid moieties of any of SEQ ID NOs: 17-21. In a preferred embodiment, in particular when the polypeptide strand P is not the full-length protein (of any of SEQ ID NOs: 2 or 3), the polypeptide strand P is not and/or comprises no peptide strand that has a length of nine or more consecutive amino acid moieties of any of SEQ ID NOs: 17-24.

[0122] In a preferred embodiment, the polypeptide strand P is not a sequence having at least 80% sequence homology to a peptide sequence selected from the group consisting of one or more of SEQ ID NOs: 17-24. In a preferred embodiment, the polypeptide strand P is not a peptide strand of a sequence having at least 80% sequence homology to all of SEQ ID NOs: 17-21. In a preferred embodiment, the polypeptide strand P is not a peptide strand of a sequence having at least 80% sequence homology to all of SEQ ID NOs: 17-24.

[0123] SEQ ID NOs: 17-24 refer to the following sequences:

TABLE-US-00008 (SEQ ID NO: 17) IKTMNTQISTLKNDVHLLNEQDKLNNEKGTLNSKISELNVQI MDL (SEQ ID NO: 18) LLSKDKEIEEKNKKIKELNNDIKKL (SEQ ID NO: 19) ICSLTTEVMELNNKKNELIEENNKLNLVDQGKKKLKKDVEK QKKEIEKL (SEQ ID NO: 20) VDKIEEHILDYDEEINKSRSNLFQLKNEICSLTTEVMELNNKK NELIEENNKLNLVDQGKKKLKKDVEKQKKEIEKL (SEQ ID NO: 21) LDENEDNIKKMKSKIDDMEKEIKYR (SEQ ID NO: 22) TISSLSNKIVNYESKIEELEKELKEVK (SEQ ID NO: 23) IIDIKKHLEKLKIEIKEKKEDLENL (SEQ ID NO: 24) IKTMNTQISTLKNDVHLLNEQDKLNNEKGTLNSKISEL

[0124] In a preferred embodiment, the polypeptide strand P does not have a sequence of SEQ ID NOs: 17-21. In a preferred embodiment, the polypeptide strand P does not have a sequence of SEQ ID NOs: 17-24.

[0125] A vaccine V based on a polynucleotide strand encoding for the polypeptide strand P may be any kind of polynucleotide. In a preferred embodiment, the polynucleotide strand encoding for said polypeptide strand P is double or single stranded DNA or double or single stranded RNA, or an analogue of double or single stranded DNA or double or single stranded RNA.

[0126] Such nucleotide analogue may exemplarily comprise or even consist of nucleotide analogues such as, e.g., peptide nucleic acid (PNA), Morpholino and locked nucleic acid (LNA), as well as glycol nucleic acid (GNA) and threose nucleic acid (TNA).

[0127] In a preferred embodiment, the polynucleotide strand encoding for said polypeptide strand P is a plasmid.

[0128] In a preferred embodiment, the at least one polynucleotide strand encoding for the polypeptide strand P is a polynucleotide strand encoding for a sequence having at least 80% sequence homology, at least 90% sequence homology, at least 95% sequence homology, or at least 98% sequence homology to a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0129] In a preferred embodiment, the at least one polynucleotide strand encoding for the polypeptide strand P is a polynucleotide strand encoding for a sequence having a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0130] As indicated above, it will be understood that the vaccine V of the present invention is well suitible for preventing malaria in a patient.

[0131] Accordingly, as indicated above, a further aspect of the present invention relates to the vaccine V of the present invention for use in a method for preventing malaria in a patient.

[0132] In other words, the present invention relates to a method for preventing malaria in a patient, wherein a sufficient amount of the vaccine V is administered to said patient. This method may be understood as active immunization.

[0133] As throughout the present invention, malaria is preferably malaria caused by Plasmodium falciparum or Plasmodium vivax. The person skilled in eth art will notice that the respective vaccine V (comprising at least one isolated polypeptides P or at least one nucleotide encoding for such) will provide at least partly protection against Plasmodia of the respective type. A vaccine V comprising at least one isolated polypeptides P of a sequence homolog to Plasmodium falciparum or at least one nucleotide encoding for such will particularly prevent the patient from malaria caused by Plasmodium falciparum.

[0134] A vaccine V comprising at least one isolated polypeptides P of a sequence homolog to Plasmodium vivax or at least one nucleotide encoding for such will particularly prevent the patient from malaria caused by Plasmodium vivax.

[0135] As used herein, "preventing" does not necessarily means that the disease is completely prohibited, but means, in the broadest sense, that the symptoms of malaria are diminish, when the patient is exposed to the respective plasmodia (e.g., Plasmodium falciparum and/or Plasmodium vivax (and/or, regarding rodents, Plasmodium chabaudi)). The effect of diminishing symptoms is the reduction in comparison to a comparable patient exposed to a comparable amount of the respective plasmodia (e.g., Plasmodium falciparum and/or Plasmodium vivax (and/or, regarding rodents, Plasmodium chabaudi)) without administration of the vaccine V.

[0136] As used herein, a "sufficient amount" may be understood in the broadest sense as an amount that is suitible to provoke an immune response against plasmodia. Preferably, a sufficient amount vaccine V is suitible to diminish the quantity of the respective plasmodia (e.g., Plasmodium falciparum and/or Plasmodium vivax (and/or, regarding rodents, Plasmodium chabaudi)) when the patient is exposed to plasmodia.

[0137] In a preferred embodiment, at each administration, the patient is administered with an amount of an isolated polypeptide strand P in the range of from 0.1 .mu.g/kg to 1 g/kg, of from 1 .mu.g/kg to 100 mg/kg, of from 5 .mu.g/kg to 50 mg/kg, of from 10 .mu.g/kg to 25 mg/kg, of from 25 .mu.g/kg to 20 mg/kg, of from 50 .mu.g/kg to 10 mg/kg, or of from 100 .mu.g/kg to 5 mg/kg.

[0138] In a preferred embodiment, the patient is administered with a sufficient amount of the vaccine V to diminish the symptoms of malaria or even to prohibit the outbreak of malaria completely. In other words, this may be sufficient to confer protection.

[0139] The patient may be administered with the vaccine V of the present invention once, twice, three times of more often. The patient may also be administered on a regular basis (e.g., once per month, once per two months, one per three months, once per half a year, once per year or once every five years).

[0140] In a preferred embodiment, the patient is administered only once. This may already be sufficient for developing an immune response to diminish the quantity of the respective plasmodia (e.g., Plasmodium falciparum and/or Plasmodium vivax (and/or, regarding rodents, Plasmodium chabaudi)) when the patient is exposed to plasmodia. This may diminish the symptoms of malaria or even to prohibit the outbreak of malaria completely. In other words, this may be sufficient to confer protection.

[0141] In a preferred embodiment, the vaccine V is administered at least once to the patient before exposure to the respective plasmodia (e.g., Plasmodium falciparum and/or Plasmodium vivax (and/or, regarding rodents, Plasmodium chabaudi)). In another preferred embodiment, the vaccine V is administered to the patient during and/or after exposure to the respective plasmodia. In a preferred embodiment, the vaccine V is administered at least once to the patient before exposure to the respective plasmodia and during and/or after exposure to the respective plasmodia

[0142] As indicated above, the vaccine V of the present invention may be very well be used for generating antibodies binding to Plasmodium falciparum or Plasmodium vivax. As used in the context of antibodies, terms like "binding to", "directed to", "targeted" or the like may be understood interchangeably in the broadest sense as interacting selectively and non-covalently with a binding affinity of a dissociation constant (Kd) of 1000 nM or less. Accordingly, the present invention also refers to the generation of antibodies by means of a vaccine V of the present invention. In other words, the present invention also refers to the use of a vaccine V of the present invention for preparing an antibody AB binding to Plasmodium falciparum or Plasmodium vivax , in particular, binding to the repetitive organellar protein, putative of Plasmodium falciparum 3D7 or the hypothetical protein PVNG_04523 of Plasmodium vivax North Korean.

[0143] Accordingly, a further aspect of the present invention refers a method for preparing an antibody AB, binding to Plasmodium falciparum or Plasmodium vivax comprising the following steps:

[0144] (i) providing:

[0145] (a) a vaccine V according to the present invention, and

[0146] (b) an organism O suitible for generating antibodies;

[0147] (ii) administering the organism O with the vaccine V;

[0148] (iii) waiting until the subjected organism of step (ii) shows an immune response against the antigens of the vaccine V;

[0149] (iv) obtaining antibody-generating cells C of the organism O of step (iii);

[0150] (v) optionally hybridizing the antibody-generating cells of step (iv) with myeloma cells obtaining immortalized antibody-generating cells C1;

[0151] (vi) optionally isolating the nucleotide encoding for the antibody AB of interest and transfer it to another antibody-generating cell type C2 suitible for expressing the antibody AB;

[0152] (vii) cultivating the antibody-generating cells C, C1 or C2 of any of steps (iv) to

[0153] (vi) under conditions enabling the production of the antibody AB; and

[0154] (viii) isolating the antibody from step (vii).

[0155] In the context of such method, the organism O may be any organism suitible for generating antibodies. Preferably, the organism is a (typically non-human) mammalian. Exemplarily, the organism O may be selected from the group consisting of a mouse, a rat, a rabbit, a goat, a hamster, a donkey, a cow, a pig, or a camel.

[0156] Preferably, administration of step (ii) is systemic administration (e.g., intravenously (i.v.), intraarterially (i.a.), intraperitoneally (i.p.), intramusculary (i.m.), subcutaneously (s.c.), transdermally, nasally). Alternatively, administration may also be local administration (e.g., intrathecally or intravitreally). Preferably, administration is systemic administration, in particular intravenous injection.

[0157] The waiting time depends on the vaccine V, the species of the organism O and the like. Typically it will take several days up to several weeks until an immune response is obtained. Exemplarily, the waiting time may be between 1 day and twenty weeks, preferably between 2 days and ten weeks, more preferably between 3 days and five weeks, exemplarily between 4 days and three weeks. During this time, the animals are kept under suitable conditions for maintain health for this species.

[0158] Obtaining antibody-generating cells C of the organism O of step (iii) may be performed by any means known for this purpose in the art. Optionally, the cells C may be obtained from the blood of the immunized organism O. Alternatively, the cells C may be obtained from the lymph and/or spleen of the immunized organism O. Depending on the method used the organism O may be kept alive or may be sacrificed.

[0159] The antibodies AB of interest may be directly obtained from the cells C or may be obtained from further processed cells.

[0160] In a preferred embodiment, the method comprised the further step (v) of hybridizing the antibody-generating cells of step (iv) with myeloma cells obtaining immortalized antibody-generating cells C1. This may enable obtaining monoclonal antibodies. The person skilled in the art is well aware of methods usable for preparing such hybridoma cells C1.

[0161] In a preferred embodiment, the method comprised the further step (vi) of isolating the nucleotide encoding for the antibody AB of interest and transfer it to another antibody-generating cell type C2 suitible for expressing the antibody AB. This may enable heterologous expression of the antibody AB or fragments thereof. Optionally, also the Fc part of the antibody may be altered. Exemplarily, the antibody AB may than be humanized. The person skilled in the art is well aware of methods usable for this purpose. Further, the person skilled in the art will notice that the optional steps (v) and (vi) may optionally also be combined with another.

[0162] In any case, the antibody-generating cells C, C1 or C2 of any of steps (iv) to (vi) are cultivated under conditions enabling the production of the antibody AB followed by isolating the antibody AB. Such isolation step may be performed by any means such as, e.g., by means of chromatographic means such as affinity chromatography using a stationary phase comprising the antigen of the antibody AB.

[0163] In a further aspect, the present invention also embraces each of the antibody-generating cells C, C1 or C2.

[0164] It will be noted that the present invention also refers to an anti-repetitive organellar protein, putative of Plasmodium falciparum 3D7 or anti-hypothetical protein PVNG_04523 of Plasmodium vivax North Korean antibody.

[0165] Accordingly, a still further aspect of the present invention refers to an antibody or antibody fragment AB binding a polypeptide strand P of SEQ ID NO: 2 or SEQ ID NO: 3 or a polynucleotide strand encoding for said polypeptide strand P with a dissociation constant of not more than 1000 nM.

[0166] Preferably, the antibody or antibody fragment AB binding a polypeptide strand P of SEQ ID NO: 2 or SEQ ID NO: 3 or a polynucleotide strand encoding for said polypeptide strand P with a dissociation constant of not more than 100 nM, more preferably not more than 100 nM, even more preferably not more than 50 nM or not more than 20 nM.

[0167] As used in the context of the present invention, the term "antibody" may be understood in the broadest sense as any type of immunoglobulin or antigen-binding fraction or mutant thereof known in the art.

[0168] Exemplarily, the antibody of the present invention may be an immunoglobulin A (IgA), immunoglobulin D (IgD), immunoglobulin E (IgE), immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin Y (IgY) or immunoglobulin W (IgW). Preferably, the antibody is an IgA, IgG or IgD. More preferably, the antibody is an IgG. However, it will be apparent that the type of antibody may be altered by biotechnological means by cloning the gene encoding for the antigen-binding domains of the antibody of the present invention into a common gene construct encoding for any other antibody type.

[0169] The binding between the antibody and its molecular target structure (i.e., its antigen based on the polypeptide strand P of SEQ ID NO: 2 or SEQ ID NO: 3 or a polynucleotide strand encoding for said polypeptide strand P) typically is a non-covalent binding. Preferably, the binding affinity of the antibody to its antigen has a dissociation constant (Kd) of less than 1000 nM, less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 40 nM, less than 30 nM or even less than 20 nM.

[0170] The term "antibody" as used herein may be understood in the broadest sense and also includes what may be designated as an antibody mutant. As used in the context of the present invention, an antibody mutant may be understood in the broadest sense as any antibody mimetic or antibody with altered sequence known in the art. The antibody mutant may have at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90% or at least 95% of the binding affinity of a corresponding antibody, i.e., bear a dissociation constant (Kd) of less than 10 .mu.M, less than 1 .mu.M, less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 40 nM, less than 30 nM or even less than 20 nM.

[0171] As used herein, the term "antibody fragment" may be understood in the broadest sense as any fragment of an antibody that still bears binding affinity to its molecular target (i.e., its antigen based on the polypeptide strand P of SEQ ID NO: 2 or SEQ ID NO: 3 or a polynucleotide strand encoding for said polypeptide strand P). Exemplarily, the antibody fragment may be a fragment antigen binding (Fab fragment), Fc, F(ab').sub.2, Fab', scFv, a truncated antibody comprising one or both complementarity determining region(s) (CDR(s)) or the variable fragment (Fv) of an antibody. Variable domains (Fvs) are the smallest fragments with an intact antigen-binding domain consisting of one V.sub.L and one V.sub.H. Such fragments, with only the binding domains, can be generated by enzymatic approaches or expression of the relevant gene fragments, e.g. in bacterial and eukaryotic cells. Different approaches can be used, e.g. either the Fv fragment alone or `Fab`-fragments comprising one of the upper arms of the "Y" that includes the Fv plus the first constant domains. These fragments are usually stabilized by introducing a polypeptide link between the two chains which results in the production of a single chain Fv (scFv). Alternatively, disulfide-linked Fv (dsFv) fragments may be used. The binding domains of fragments can be combined with any constant domain in order to produce full length antibodies or can be fused with other proteins and polypeptides. A recombinant antibody fragment is the single-chain Fv (scFv) fragment. Dissociation of scFvs results in monomeric scFvs, which can be complexed into dimers (diabodies), trimers (triabodies) or larger aggregates such as TandAbs and Flexibodies. The antibody may be a Fab, a Fab', a F(ab')2, a Fv, a disulfide-linked Fv, a scFv, a (scFv).sub.2, a bivalent antibody, a bispecific antibody, a multispecific antibody, a diabody, a triabody, a tetrabody or a minibody.

[0172] As mentioned above, the term "antibody" may also include an antibody mimetic which may be understood in the broadest sense as organic compounds that, like antibodies, can specifically bind antigens and that typically have a molecular mass in a range of from approximately 3 kDa to approximately 25 kDa. Antibody mimetics may be, e.g., affibody molecules (affibodies), affilins, affitins, anticalins, avimers, DARPins, Fynomers, Kunitz domain peptides, single-domain antibodies (e.g., VHH antibodies or VNAR antibodies, nanobodies), monobodies, diabodies, triabodies, flexibodies and tandabs. The antibody mimetics may be of natural origin, of gene technologic origin and/or of synthetical origin. The antibody mimetics may also include polynucleotide-based binding units. Optionally, the antibody may also be a CovX-body. Optionally, the antibody may also be a cameloid species antibody.

[0173] In a preferred embodiment, the antibody or antibody fragment AB binds to its antigen based on the polypeptide strand P of SEQ ID NO: 2 or SEQ ID NO: 3 or a polynucleotide strand encoding for said polypeptide strand P with an at least 10-fold, even more preferably at least 100-fold, even more preferably at least 1000-fold higher binding affinity than to the corresponding (i.e., sequence homologue) antigen of a polypeptide SEQ ID NO: 2 or SEQ ID NO: 3 or the respective polynucleotide strand encoding for said polypeptide.

[0174] The antibody or antibody fragment AB may be obtained by any means. In a preferred embodiment, the antibody or antibody fragment AB is obtained from a method of the present invention.

[0175] Optionally, the antibody of the present invention may be a monoclonal antibody, a chimeric antibody and/or a humanized antibody. Monoclonal antibodies are monospecific antibodies that are identical because they are produced by one type of immune cell that are all clones of a single parent cell. A chimeric antibody is an antibody in which at least one region of an immunoglobulin of one species is fused to another region of an immunoglobulin of another species by genetic engineering in order to reduce its immunogenicity. For example murine V.sub.L and V.sub.H regions may be fused to the remaining part of a human immunoglobulin. A particularly preferred type of chimeric antibodies are humanized antibodies. Humanized antibodies are produced by merging the DNA that encodes the CDRs of a non-human antibody with human antibody-producing DNA. The resulting DNA construct can then be used to express and produce antibodies that are usually not as immunogenic as the non-human parenteral antibody or as a chimeric antibody, since merely the CDRs are non-human.

[0176] In a preferred embodiment, the antibody or antibody fragment AB is a monoclonal humanized antibody.

[0177] Preferably, the antibody or antibody fragment AB bears a high affinity to the polypeptide strand P of SEQ ID NO: 2 or SEQ ID NO: 3. In a preferred embodiment, the antibody or antibody fragment AB bears a binding affinity to a polypeptide strand P of SEQ ID NO: 2 or SEQ ID NO: 3 of a dissociation constant of not more than 100 nM, not more than 50 nM, not more than 20 nM, not more than 10 nM, or not more than 5 nM.

[0178] The antibody or antibody fragment AB may be provided and stored in any suitable form. The antibody or antibody fragment AB, independent on its chemical nature, may optionally be dissolved in any medium suitable for storing said antibody such as, e.g., water, an aqueous buffer (e.g., a Hepes, Tris, or phosphate buffer (e.g. phosphate buffered saline (PBS)), an organic solvent (e.g., dimethyl sulfoxide (DMSO), dimethylformide (DMF)) or a mixture of two or more thereof. The antibody or mutant thereof according to the present invention may be of any species or origin. It may bind to any epitope(s) comprised by its molecular target structure (e.g., linear epitope(s), structural epitope(s), primary epitope(s), secondary epitope(s), e.g., based on SEQ ID NO: 2 or SEQ ID NO: 3 or a nucleotide encoding therefor). Preferably, the antibody or mutant thereof may recognize the naturally folded molecular target structure or a domain or fragment thereof (e.g., SEQ ID NO: 2 or SEQ ID NO: 3 or a nucleotide encoding therefor in its natural environment inside the plasmodia). The antibody or mutant thereof may be of any origin an antibody may be obtained from such as, e.g., natural origin, a gene technologic origin and/or a synthetic origin. Optionally, the antibody may also be commercially available. The person skilled in the art will understand that the antibody may further comprise one or more posttranscriptional modification(s) and/or may be conjugated to one or more further structures such as label moieties or cell-penetrating peptides (CPPs). Optionally, the antibody or antibody fragment may be added to a support, particularly a solid support such as an array, bead (e.g. glass or magnetic), a fiber, a film etc. The skilled person will be able to adapt the antibody of the present invention and a further component to the intended use by choosing a suitable further component.

[0179] Optionally, the antibody or antibody fragment AB may be conjugated with any kind of detectable label moiety. Then, the antibody or antibody fragment AB and the label moiety may be covalently or non-covalently conjugated with another, either directly of via a spacer.

[0180] As used throughout the present invention, the term "conjugated with" may be understood in the broadest sense as any kind of covalent or non-covalent attachment or linkage of one component with another component. Such conjugate can be obtained by chemical means and/or by genetic engineering and biotechnological means. The label moiety may be any moiety that is detectable, preferably detectable by an imaging method.

[0181] Exemplarily, the label moiety may be a fluorescent moiety. Exemplarily, a fluorescent moiety may be a fluorescent polypeptide moiety (e.g., cyan fluorescent protein (CFP), green fluorescent protein (GFP) or yellow fluorescent protein (YFP), red fluorescent protein (RFP), mCherry, etc.), a small-molecule dye moiety (e.g., an Atto dye moiety (e.g., ATTO 390, ATTO 425, ATTO 465, ATTO 488, ATTO 495, ATTO 520, ATTO 532, ATTO 550, ATTO 565, ATTO 590, ATTO 594, ATTO 610, ATTO 611X, ATTO 620, ATTO 633, ATTO 635, ATTO 637, ATTO 647, ATTO 647N, ATTO 655, ATTO 665, ATTO 680, ATTO 700, ATTO 725, ATTO 740), a Cy dye moiety (e.g., Cy3, Cy5, Cy5.5, Cy 7), an Alexa dye moiety (e.g., Alexa Fluor 488, Alexa Fluor 546, Alexa Fluor 647, Alexa Fluor 680, Alexa Fluor 750), a VisEn dye moiety (e.g. VivoTag680, VivoTag750), an S dye (e.g., S0387), a DyLight fluorophore moiety (e.g., DyLight 750, DyLight 800), an IRDye moiety (e.g., IRDye 680, IRDye 800), a fluorescein dye moiety (e.g., fluorescein, carboxyfluorescein, fluorescein isothiocyanate (FITC)), a rhodamine dye moiety (e.g., rhodamine, tetramethylrhodamine (TAMRA)), a HOECHST dye moiety, a quantum dot moiety or a combination of two or more thereof. Such fluorescent label moiety may be used in fluorescence microscopy.

[0182] Alternatively or additionally, the label moiety may be metal atom, metal ion or metal bead (e.g., a (colloidal) gold such as a gold bead). Such metal bead may be used in electron microscopy.

[0183] Alternatively or additionally, the label moiety may be radioactive label such as, e.g., .sup.3H, .sup.14C, .sup.123I, .sup.124I, .sup.131I, .sup.32P, .sup.99mTc or lanthanides (e.g., .sup.64Gd). In this context, a radioactive label may or may not be suitable for scintillation assays, computer tomography (CT), single-photon emission computed tomography (SPECT) or as a label suitable for Positron Emission Tomography (PET) (e.g., .sup.11.sub.C, .sup.13.sub.N, .sup.15O, .sup.18F, .sup.82Rb).

[0184] As indicated above, the present invention also refers to the medicinal and non-medicinal uses of the antibody or antibody fragment AB of the present invention.

[0185] Accordingly, a still further aspect of the present invention refers to an antibody or antibody fragment AB of the present invention for use in a method for treating or preventing malaria in a patient.

[0186] The present invention refers to a method for treating or preventing malaria in a patient, said method comprising administration of antibody or antibody fragment AB of the present invention to said patient in an amount suitible for treating or preventing malaria in said patient.

[0187] Preferably, administration is systemic administration (e.g., intravenously (i.v.), intraarterially (i.a.), intraperitoneally (i.p.), intramusculary (i.m.), subcutaneously (s.c.), transdermally, nasally). Alternatively, administration may also be local administration (e.g., intrathecally or intravitreally). Preferably, administration is systemic administration, in particular intravenous injection. The administration frequency may be adapted to the individual patient. Administration may be performed once, twice, or more often or continuously (e.g., via drip). Exemplarily, administration may be performed three times daily, twice daily, or every two days or less often.

[0188] A still further aspect of the present invention refers to an antibody or antibody fragment AB for use in a method for diagnosing malaria in a patient.

[0189] In other words, the present invention refers to a method for diagnosing malaria in a patient, said method comprising administration of antibody or antibody fragment AB of the present invention to said patient in an amount suitible for detecting Plasmodium falciparum or Plasmodium vivax in said patient.

[0190] For detecting the antibody or antibody fragment AB used for diagnostic purposes, the antibody or antibody fragment AB is preferably labelled, i.e., conjugated to a label moiety, as described above.

[0191] The antibody or antibody fragment AB according to the present invention may also be used for staining in vitro.

[0192] For example, detection may be performed by enzyme-linked immunosorbent assay (ELISA), flow cytometry, fluorescence activated cell sorting (FACS), magnetic activated cell sorting (MACS), antibody-based dipsticks, etc.

[0193] Accordingly, a further aspect of the present invention relates to a method for staining Plasmodium falciparum or Plasmodium vivax in vitro, said method comprising the steps of:

[0194] (i) providing

[0195] (a) an optionally fixed sample S containing Plasmodium falciparum or Plasmodium vivax, and

[0196] (b) an optionally stained antibody or antibody fragment AB according to the present invention;

[0197] (ii) contacting the sample S with the optionally stained antibody or antibody fragment AB; and

[0198] (iii) optionally contacting the treated sample of step (ii) with a second antibody or antibody fragment AB2 which is stained and selectively binds to the antibody or antibody fragment AB.

[0199] When at least one of AB1 or AB2 is fluorescently labelled, the sample may be investigated by fluorescence microscopy of flow cytometry. Exemplarily, fluorescence microscopy may comprise one or more of the following methods: laser scanning microscopy (LSM), two-photon fluorescence microscopy, fluorescence molecular imaging (FMI), fluorescence energy transfer (FRET), fluorescence correlation spectroscopy (FCS), and/or fluorescence cross-correlation spectroscopy (FCCS). All these techniques as such are well-known to those skilled in the art. In the imaging step, the polypeptide strand P of SEQ ID NO: 1, SEQ ID NO: 2, SEQ IND NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16 or nucleotide encoding for at least one thereof may be fluorescently stained by a fluorescently labeled antibody AB1 or unlabeled AB1 in combination with labelled AB2. The excess fluorescently labeled antibody may be washed away and the localization and intensity is determined spatially resolved in the sample.

[0200] A still further aspect of the present invention refers to the (preferably in vitro) use of any of the polypeptides of the present invention as described herein (e.g. a polypeptide selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and/or SEQ ID NO: 16) for detecting Plasmodium falciparum or Plasmodium vivax in a patient's body fluid.

[0201] In a preferred embodiment, patient's body fluid is blood, blood plasm, blood serum or a fraction thereof.

[0202] A still further aspect of the present invention refers to a method of detecting Plasmodium falciparum or Plasmodium vivax (preferably in vitro), said method comprising the step of detecting the presence of any of the polypeptides of the present invention as described herein (e.g. a polypeptide selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and/or SEQ ID NO: 16) in a patient's body fluid. A further step may optionally be treating malaria in the patient accordingly.

[0203] A still further aspect of the present invention refers to a polypeptide of the present invention as described herein (e.g. a polypeptide selected from the group consisting of (SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and/or SEQ ID NO: 16) for use in a method for diagnosing a Plasmodium falciparum or Plasmodium vivax infection in a patient. Optionally the patient is further subjected to a malaria treatment.

[0204] A still further aspect of the present invention refers to a method of detecting Plasmodium falciparum or Plasmodium vivax (preferably in vitro), said method comprising the step of detecting the presence of an antibody specific for any of the polypeptides of the present invention as described herein (e.g. a polypeptide selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and/or SEQ ID NO: 16) in a patient's body fluid. A further step may optionally be treating malaria in the patient accordingly.

[0205] A still further aspect of the present invention refers to an antibody specific for any of the polypeptides of the present invention as described herein (e.g. a polypeptide selected from the group consisting of (SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and/or SEQ ID NO: 16) for use in a method for diagnosing a Plasmodium falciparum or Plasmodium vivax infection in a patient. Optionally the patient is further subjected to a malaria treatment.

[0206] A still further aspect of the present invention refers to a primer that is complementary to a fraction of any of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6 for detecting Plasmodium falciparum or Plasmodium vivax in a patient's body fluid.

[0207] In a preferred embodiment, the primer is a single chain nucleotide strand of a length of between five to 50 nucleotide moieties in length, between seven to 40 nucleotide moieties in length, between eight to 35 nucleotide moieties in length, or between nine to 30 nucleotide moieties in length.

[0208] A still further aspect of the present invention refers to a pair of primers that are both complementary to a fraction of any of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6 for detecting Plasmodium falciparum or Plasmodium vivax in a patient's body fluid.

[0209] A still further aspect of the present invention refers to a method of detecting Plasmodium falciparum or Plasmodium vivax (preferably in vitro) in a patient, said method comprising the steps of

[0210] (i) contacting the nucleotides contained in a patient's body fluid with a pair of primers of which at least one is complementary to a fraction of any of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6;

[0211] (ii) conducting polymerase chain reaction (PCR) with the sample obtained in step (i); and

[0212] (iii) detecting the presence or absence of amplification product comprising the primers; and

[0213] (iv) optionally treating malaria in the patient accordingly.

[0214] A still further aspect of the present invention refers to a method of detecting Plasmodium falciparum or Plasmodium vivax (preferably in vitro) in a patient, said method comprising the steps of

[0215] (i) contacting the nucleotides contained in a patient's body fluid with a pair of primers which are both complementary to a fraction of any of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6;

[0216] (ii) conducting polymerase chain reaction (PCR) with the sample obtained in step (i); and

[0217] (iii) detecting the presence or absence of amplification product comprising the primers; and

[0218] (iv) optionally treating malaria in the patient accordingly.

[0219] The Examples provided below and the claims illustrate further embodiments of the present invention.

EXAMPLES

Example 1

Protective Effect of the Immunization with Pch ROPE

[0220] Immunization experiment with Pch ROPE in Balb/c mice.

[0221] A cDNA library of a Plasmodium chabaudi 96V was constructed in pBluescript SK (Werner et al. 1998). From the cDNA library the recombinant plasmid pBluescript SK (-) 70 was isolated by screening. It contains part of the Pch ROPE sequence coding for amino acids 1283-1516 (234 amino acids) as an insert.

[0222] The insert was sub cloned in the pGEX-1T vector, transformed in E. coli JM 109 bacteria and expressed as a glutathione-S-transferase fusion protein in E. coli JM 109. The fusion protein was isolated using glutathione-agarose beads, followed by thrombin cleavage to obtain the 234 amino acid Pch ROPE protein fragment in a pure form, called rec 700.

[0223] Mice were immunized at day 0 and day 21 with:

[0224] 7.5 .mu.g rec 700

[0225] 60 .mu.g Alum

[0226] in 200 .mu.l PBS pH 7.4

[0227] At day 35, mice were infected with 5.times.10.sup.6 Plasmodium chabaudi 96V parasitized erythrocytes. Balb/c mice were immunized only two times and without any supplementation of an adjuvant such as muramyl peptide (MDP).

[0228] Results

[0229] All of the non-immunized mice died. 50% of the immunized Balb/c survived and 50% died. The fact that a high number of Balb/c mice survived an otherwise deadly infection with this extremely virulent Plasmodium chabaudi 96V strain using a weak immunization protocol, was surprising.

[0230] It is noteworthy in this context to mention that in other experiments, not a single untreated mouse survived an infection with the Plasmodium chabaudi 96V strain over a period of about four years of conducting regular experiments with this strain (Watier et al., 1992).

[0231] Particularly surprising was the finding that a protective effect of the immunization could still be observed when adjuvants like muramyl peptide (MDP) were omitted. Such adjuvants are typically considered to be a relevant component to illicit a stronger immune response against an antigen used as a vaccine.

[0232] Furthermore it was recently shown that, in the case of malaria, alum (used in above immunization) is a comparably poor adjuvant for fighting diseases like malaria (Leslie, 2013). This shows that ROPE is a particularly effective immunogen. It is indicating a very high protection capacity of the ROPE protein when used as a malaria vaccine. Moreover, ROPE is very effective for generating specific antibodies.

[0233] It will be understood that an infection with Plasmodium chabaudi in rodents is a well-established model system for infections with Plasmodium falciparum or Plasmodium vivax in humans. For this reason, it is reasonable to assume that ROPE has a protective effect for mammals (including humans) immunized with Plasmodium falciparum or Plasmodium vivax recombinant ROPE against infection with these parasites. As shown immunization was highly efficient. Ideally a single immunization step using a strong immunization protocol would be sufficient to confer protection.

Example 2

Further Development of a Pf ROPE or Pv ROPE Malaria Vaccine

[0234] Steps towards the development of a Pf ROPE or Pv ROPE malaria vaccine include generation and testing of antibodies against ROPE fragments, testing of antibodies against ROPE peptide-microarrays covering the entire ROPE sequence, and preclinical and clinical trials.

[0235] a.) Generation and Testing of Antibodies Against ROPE Fragments

[0236] Synthesizing parts of Plasmodium falciparum (Pf) ROPE as peptides, raising soluble scFvs (single chain fragment variable) antibodies against these peptides and testing the capacity to block invasion of human red blood cells by Plasmodium falciparum in vitro in culture. Antibodies showing the strongest inhibition will be used to produce antibodies that can be used for passive immunization in humans, similar to an anti-malaria drug.

[0237] Several peptides are produced from the Pf ROPE amino acid sequence. To analyze the Pf B cell epitopes, the Pf ROPE sequence was analyzed using the PROTEAN subroutine in the DNASTAR package. This subroutine uses (Wang et al., 2016):

[0238] Predicted alpha-regions (Gamier and Robson, 1989; Chou and Fasman, 1978)

[0239] Hydrophilicity (Kyte and Doolittle, 1982)

[0240] Flexibility (Karpus and Schulz, 1985)

[0241] Surface probability (Emini et al., 1985)

[0242] Antigenicity (Jameson and Wolf, 1988).

[0243] Based on this analysis the following peptides with good hydrophilicity, high accessibility, high flexibility, and strong antigenicity were selected as the antigen epitopes as shown in Table 1.

TABLE-US-00009 TABLE 1 Epitopes derived from ROPE Amino acid position Length in (amino Sequence ROPE Sequence acids) No. 331-356 KQEKEKEKEKEREKEKEREKEKEKEY 26 SEQ ID NO: 7 420-447 KNLKTELEKKEKELKDIENVSKEEINKL 28 SEQ ID NO: 8 520-560 SKKEKEYNQYKNTYIEEINNLNEKLEE 41 SEQ ID NO: 9 TNKEYTNLQNNYTN 812-840 KEEYEDKMNTLNEQNEDKMNSLKEEY 29 SEQ ID NO: 10 ENK 953-996 KGLKKEVEEKEHKRHSSFNILKSKEKFF 44 SEQ ID NO: 11 KNSIEDKSHELKKKHE 1050-1079 KDKSKEKIKDKENQINVEKNEEKDLKKK 30 SEQ ID NO: 12 DD 1277-1305 EDEKKRNLNEINNLKKKNEDMCIKYNEMN 29 SEQ ID NO: 13 1452-1479 KTNKENEEKIINLTSQYSDAYKKKSDES 28 SEQ ID NO: 14 1497-1521 SNNNIRTNEYKYEEMFDTNIEEKNG 25 SEQ ID NO: 15 1581-1605 GNISNKNENNNKKNNTCDGYDEKVT 25 SEQ ID NO: 16

[0244] It is reasonable that these peptides or fragments thereof are particularly suitable as a polypeptide strand P usable in a vaccine V.

[0245] Human antibodies are generated against above Pf ROPE peptides by phage display using human antibody gene libraries (Kugler et al. 2015).

[0246] In brief, biotinylated Pf ROPE peptides are immobilized on streptavidin coated microtiter plates. The libraries are incubated with the peptides, non-binding antibody phage particles removed by rigid washing steps. The bound antibody phages are eluted by trypsin and re-amplified using E. coli XL1-Blue and the M13-K07 helper phage. Subsequently, two further panning rounds are performed. Monoclonal antibodies are produced as soluble scFvs (single chain fragment variable) antibodies, using the phage display vector pHAL30 and identified by screening ELISA on the immobilized Pf ROPE peptides. This step is needed to discard non-specific binders of the corresponding antibody phage particles.

[0247] For further tests the monoclonal scFvs--single chain fragment variable-antibodies are re-cloned into the bivalent scFv-Fc format and produced in mammalian cells. The mammalian vector pCSE2.6-hIgG-Fc-XP and HEK293 6E cells are used. This is an IgG like bivalent molecule and also effector functions are established. (Jager et al., 2013). These IgG-like antibodies are used to test for their capacity to block invasion of human red blood cells by Plasmodium falciparum in vitro in culture. An in vitro growth inhibition activity assay (GIA) is used to measure the efficacy of the soluble scFvs antibodies directed against our peptides in blocking merozoite invasion (Kennedy et al., 2002).

[0248] Peptides identified as protective in the context of this in vitro inhibition can be used for the production of chemically synthesized vaccines, either as single peptides or as a fusion of several peptides or can be used as diagnostics.

[0249] b.) Testing of Antibodies Against ROPE Fragments in Microarrays

[0250] Peptide microarrays covering the entire Pf ROPE sequence are prepared. Sera from malaria patients are used to identify the immunodominant parts of the Pf ROPE protein during the course of an infection with Plasmodium falciparum.

[0251] The whole amino acid sequence of the target protein is retrieved from a public database and translated into 15-mer peptides with a peptide-peptide overlap of e.g. 12 amino acids. The peptide arrays with the corresponding peptides are produced by the company PEPperPRINT GmbH (Heidelberg, Germany) in a laser printing process on glass slides, coated with a PEGMA/PMMA graft copolymer, which are functionalized with a Ala- Ala-linker.

[0252] A layer of amino acid particles, containing Fmoc-amino acid pentafluorophenyl esters, is printed layer after layer onto the functionalized glass slides, with intermittent melting (i.e. coupling) steps at 90.degree. C. and chemical washing and capping steps (Stadler et al., 2008), based on the same principle as Merrifield's solid-phase peptide synthesis. Peptides are generated in duplicates on the arrays, which are screened for IgG and IgM responses in human sera.

[0253] Therefore, peptide microarrays are placed in incubation trays (PEPperPRINT GmbH, Heidelberg, Germany) and blocked for 30 min at room temperature with western blot blocking buffer MB-070 (Rockland, USA). Then, sera are diluted 1:1000 in PBS buffer with 0.05% Tween 20 pH 7.4 (PBS-T) and 10% blocking buffer, incubating the sera for 16 h at 4.degree. C. and 50 RPM orbital shaking. Peptide microarrays are washed three times shortly with PBS-T, followed by an incubation with a 1:2500 dilution of the secondary fluorescently labeled antibody, together with a control antibody for 30 min at room temperature. The peptide microarrays are washed with PBST and rinsed with deionized water. After drying in a stream of air, fluorescent images are acquired using an Odyssey Imaging System (LI-COR, USA) at 700 nm. Image analysis and quantification is performed with the PepSlide Analyzer software (Sicasys Software GmbH, Heidelberg, Germany).

[0254] c.) Further Preclinical and Clinical Trials with Recombinant Pf ROPE Protein

[0255] The result of this mapping will determine which part of the long Pf ROPE protein (1979 amino acids) will be expressed as a recombinant protein in E. coli and be used as an anti-malaria vaccine in Aotus monkeys and once proven to be efficient in human trials.

[0256] The DNA sequence coding for the entire Pf ROPE protein or parts of it is amplified by PCR of genomic Pf DNA and cloned into the pET-21a (+)-plasmid at the multiple cloning site (MCS). The MCS is under the control of a T7 promoter and flanked by a T7- and a HIS-tag. The recombinant pET-21a (+)-plasmid containing a sequence coding for Pf ROPE is transformed into E. coli BL21(DE3), a strain that allows high-efficiency protein expression of any gene that is under the control of a T7 promoter. The expressed recombinant Pf ROPE protein carries a histidine-tag at its C-terminus and is purified on a Nickel-column.

[0257] The recombinant Pf ROPE protein is mixed with a pharmaceutically acceptable carrier or excipient. A vaccine is obtained. This is applied to Aotus monkeys and once proven to be efficient in human trials.

REFERENCES

[0258] U.S. Pat. No. 8,716,443

[0259] Chou P Y, Fasman G D (1978) Prediction of the secondary structure of proteins from their amino acid sequence. Adv Enzymol 47:45-148.

[0260] Emini E A, Hughes J V, Perlow D S, Boger J (1985) Induction of hepatitis A virus-neutralizing antibody by virus specific synthetic peptide. J Virol 55:836-839

[0261] Gamier J, Robson B (1989) The GOR method for predicting secondary structures in proteins. In Fasman G D ed., Prediction of protein structure and the principles of protein conformation. New York, USA. Plenum Press. pp 417-465.

[0262] Jager V, Bussow K, Wagner A, Weber S, Hust M, Frenzel A and Schirrmann (2013) High level transient production of recombinant antibodies and antibody fusion proteins in HEK293 cells. BMC Biotechnology 13:52, 1472-6750/13/52

[0263] Jameson B A, Wolf (1988) The antigenic index: a novel algorithm for predicting antigenic determinants. Comput Appl Biosci 4(1):181-186

[0264] Kulangara, C., A. V. Kajava, G. Corradin, and I. Felger (2009) Sequence conservation in Plasmodium falciparum alpha-helical coiled coil domains proposed for vaccine development. PLoS One 4:e5419.

[0265] Karplus P A, Schulz G E. (1985) Prediction of chain flexibility in proteins: tool for the selection of peptide antigens. Naturwissenschaften 72:212-213.

[0266] Kennedy M C, Jin Wang, Yanling Zhang, Miles A P, Chitsaz F, Saul A, Long C A, Miller L H, Stowers A W (2002) In vitro studies with recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1): Production and activity of an AMA1 vaccine and generation of a multiallelic response. Infect Immun 70(12):6948-6960.

[0267] Kugler J, Wilke S, Meier D, Tomszak F, Frenzel A, Schirrmann T, Dubel S, Garritsen H, Hock B, Toleikis L, Schutte M, Hust M (2015) Generation and analysis of the improved human HAL9/10 antibody phage display libraries Biotechnology 15:10; DOI 10.1186/s12896-015-0125-0

[0268] Kyte J, Doolittle R F. (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105-132.

[0269] Leslie, M. (2013) Solution to Vaccine Mystery Starts to Crystallize. Science 341:26-27

[0270] Stadler V et al. (2008) Combinatorial synthesis of peptide arrays with a laser printer. Angew. Chem. Int. Ed. Engl. 47(37):7132-7135

[0271] Topolska A E, Richie T L, Nhan D H, Coppel, R L. (2004), Associations between responses to the rhoptry-associated membrane antigen of Plasmodium falciparum and immunity to malaria infection. Infect Immun 72(6):3325-3330

[0272] Villard V, Agak G W, Frank G, Jafarshad A, Servis C, Servis C, Nebie I, Sirima S B, Felger I, Arevalo-Herrera M, Herrera S, Heitz F, Backer V, Druilhe P, Kajava A V, Corradin G (2007) Rapid identification of malaria vaccine candidates based on alpha-helical coiled coil protein motif. PLoS ONE, Issue 7, e645.

[0273] Wang Y, Wang G, Cai J P (2016) Identifying Novel B Cell Epitopes within Toxoplasma gondii GRA6. Korean J Parasitol. 54(4):431-437 (English. https://doi.org/10.3347/kjp.2016.54.4.431)

[0274] Watier H, Verwaerde C, Landau I, Werner E, Fontaine J, Capron A, Auriault C (1992). T-cell dependent immunity and thrombocytopenia in rats infected with Plasmodium chabaudi. Infect Immune, 60:136-142

[0275] Werner E B E, William W R Taylor, Holder A A. (1998) A Plasmodium chabaudi protein contains a repetitive region with a predicted spectrin-like structure. Mol Biochem Parasitol. 94:185-196.

Sequence CWU 1

1

2511939PRTPlasmodium chabaudi 1Met Ile Phe Asn Leu Lys Lys Ser Lys Lys Asn Glu Asp Gly Ser Asn1 5 10 15Lys Asp Ser Lys Lys Thr Asn Glu Thr Ser Gly Ile Glu Lys Lys Glu 20 25 30Lys Ser Asn Lys Trp Tyr Asn Lys Ile Val Asn Asn Ser Thr Lys Lys 35 40 45Asp Lys Asp Lys Asn Asn Asp Ser Ile Val Tyr Asp Asp Glu Ser Lys 50 55 60Val Gly Glu Asn Asp His His Met Lys Glu Tyr Glu Leu Glu Asp Gln65 70 75 80Leu Lys Glu Thr Leu Lys Ser Ile Thr Ala Leu Ser Ile Lys Val Lys 85 90 95Glu Tyr Glu Val Lys Ile Glu Glu Leu Glu Lys Glu Leu Lys Leu Glu 100 105 110Lys Glu Lys Gln Ile Asn Lys Glu Tyr Glu Lys Glu Leu Asn Glu Lys 115 120 125Ser Glu Phe Ile Lys Arg Gln Met Glu Leu Leu Lys Glu Lys Glu Leu 130 135 140Asn Ile Asn Leu Lys Glu Asn Lys Ile Asn Asn Lys Glu Ile Ile Thr145 150 155 160Leu Lys Arg Glu Glu Lys Leu Asn Asp Ile Glu Ser Glu Tyr Ile Glu 165 170 175Lys Asn Lys Glu Lys Glu Lys Leu Asn Tyr Glu Val Thr Asn Ile Lys 180 185 190Met Ser Leu Asp Lys Leu Thr Cys Glu Val Gln Glu Lys Lys Asp Asn 195 200 205Leu Glu Lys Ile Asn Lys Lys Val Ile Glu Lys Glu Asn Asn Leu Arg 210 215 220Glu Leu Lys Glu Phe Met Lys Glu Lys Asn Glu Ile Ile Glu Ser Leu225 230 235 240Asp Gly Thr Ile Asn Asp Lys Lys Asn Ala Tyr Glu Lys Leu Glu Ile 245 250 255Ser Phe Glu Glu Lys Arg Lys Met Ile Glu Met Leu Asp Ser Lys Leu 260 265 270Ile Glu Lys Glu Glu Asn Phe Ala Asn Lys Gln Ala Lys Leu Glu Lys 275 280 285Glu Asn Glu Ile Ile Ile Glu Lys Leu Lys Asp Ile Glu Ser Arg Glu 290 295 300Lys Asp Phe Lys Ser Lys Glu Glu Lys Phe Ala Ser Met Glu Asn Glu305 310 315 320Leu Asn Thr Leu Lys Ser Asp Leu Ser Lys Asn Ala Cys Gln Met Glu 325 330 335Val Tyr Lys Leu Glu Ile Lys Asp Leu Ser Gln Ser Leu Val Glu Lys 340 345 350Glu Arg Glu Ile Phe Glu Ile Lys Asn Glu Tyr Asp Asp Lys Ile Asn 355 360 365Asn Met Lys Glu Lys Leu Ser Ser Ile Asn Asp Lys Gly Ile Asp Asn 370 375 380Thr Val Leu His Ser Glu Glu Glu Lys Ile Asn Lys Leu Leu Lys Glu385 390 395 400Lys Glu Thr Glu Leu Asn Glu Ile His Lys Lys Tyr Asn Leu Glu Ile 405 410 415Glu Thr Ile Lys Asn Glu Leu Asn Glu Lys Glu Glu Glu Leu Glu Lys 420 425 430Asn Lys Lys Ala His Thr Val Glu Val Thr Asn Leu Thr Lys Glu Ile 435 440 445Lys Leu Leu Glu Lys Lys Thr Glu Asp Ala Lys Glu Gly His Lys Asn 450 455 460Glu Leu Asn Glu Leu Asn Asn Gln Leu Ser Lys Leu Asn Lys Glu Lys465 470 475 480Asp Asn Ile Lys Asn Glu Asn Thr Glu Leu Asn Asp Lys Ile Ser Ser 485 490 495Leu Asn Ser Glu Val Asn Ile Leu Asn Lys Asp Lys Gln Thr Leu Gly 500 505 510Asn Asp Ile Lys Thr Leu Asn Asp Leu Ile Asn Asn Leu Lys Asn Glu 515 520 525Ile Asn Thr Ser Asp Asn Lys Met Asn Lys Met Lys Glu Asp Leu Ala 530 535 540Met Leu Asn Glu Glu Met Glu Gly Lys Cys Val Val Ile Asp Glu Ile545 550 555 560Glu Lys Lys Tyr Lys Asn Glu Ile Phe Met Leu Glu Glu Lys Leu Lys 565 570 575Glu Lys Glu Asn Tyr Ala Asp Leu Asn Asp Glu Ile Ser Ile Leu Arg 580 585 590Asn Ser Ile Tyr Val Lys Glu Lys Glu Phe Ile Glu Met Lys Glu Phe 595 600 605Tyr Glu Asn Lys Ile Asn Leu Phe Asn Lys Asn Phe Glu Glu Lys Lys 610 615 620Asn Ile Tyr Glu Asn Glu Leu Asn Ser Leu Arg Leu Lys Tyr Asp Asn625 630 635 640Glu Gln Gly Leu Ile Lys Gln Ile Asp Glu Leu Asn Ile Gln Lys Leu 645 650 655Lys Thr Glu Glu Lys Tyr Leu Gln Leu Tyr Asn Asp Asn Met His Met 660 665 670Phe Arg Ser Ile Cys Thr Lys Ile Asp Met Pro Tyr Ser Glu Asn Ile 675 680 685Lys Gly Ser Asp Leu Val Asp Phe Val Thr Ala Tyr Ile Lys Arg Arg 690 695 700Asp Glu Ser Ser Ser Asp Ala Asn Pro Asp Thr Thr His Lys Glu Met705 710 715 720Val Ala Glu Leu Glu Lys Arg His Ala Ala Ile Val Ala Glu Leu Glu 725 730 735Glu Lys His Lys Glu Glu Ile Ala Lys Leu Gly Glu Gly His Lys Glu 740 745 750Val Val Leu Arg Leu Gly Glu Gln His Lys Glu Glu Thr Ile Ile Leu 755 760 765Glu Glu Lys His Lys Asp Val Val Thr Lys Leu Gly Glu Gln His Lys 770 775 780Glu Asn Ile Ile Lys Leu Glu Glu Glu His Lys Asp Val Val Thr Lys785 790 795 800Leu Gly Asp Gln Tyr Lys Glu Glu Ile Ala Lys Leu Lys Glu Glu His 805 810 815Ala Val Val Val Ala Glu Leu Glu Glu Lys His Lys Leu Gly Glu Gly 820 825 830His Lys Glu Met Val Asp Glu Leu Glu Lys Arg His Ala Asp Phe Val 835 840 845Glu Gly Leu Glu Glu Lys His Lys Ala Glu Thr Ala Lys Leu Glu Glu 850 855 860Gly His Lys Ser Glu Met Asn Glu Val Glu Lys Arg His Ala Asp Phe865 870 875 880Val Glu Gly Leu Glu Glu Lys His Lys Ala Glu Thr Ala Lys Leu Gly 885 890 895Glu Gly His Arg Glu Val Val Ala Gly Leu Glu Glu Lys His Lys Glu 900 905 910Val Val Ala Glu Leu Glu Glu Lys His Lys Glu Glu Ile Ala Lys Leu 915 920 925Glu Glu Gly His Lys Glu Val Met Ala Glu Leu Gly Glu Lys His Lys 930 935 940Glu Val Val Ala Gly Leu Glu Ala Lys His Asn Leu Glu Glu Gly His945 950 955 960Lys Glu Met Val Ala Glu Leu Glu Lys Arg His Ala Asp Leu Val Ala 965 970 975Val Leu Glu Glu Gln His Lys Ala Glu Ile Ile Lys Leu Gly Glu Glu 980 985 990His Lys Glu Val Val Ala Gly Ile Glu Glu Lys Tyr Lys Val Glu Ala 995 1000 1005Ile Lys Leu Ala Glu Glu His Lys Asp Val Val Thr Lys Leu Gly 1010 1015 1020Glu Gln His Lys Glu Glu Ile Ala Lys Leu Glu Asp Gly His Lys 1025 1030 1035Glu Val Val Asn Glu Val Glu Lys Lys Asn Ala Ser Leu Leu Asn 1040 1045 1050Met Leu Glu Glu Asn His Lys Asn Glu Met Ile Lys Leu Lys Glu 1055 1060 1065Glu His Lys Glu Ser Ala Ser Asp Leu Val Glu Lys Leu Tyr Gln 1070 1075 1080Lys Asp Glu Glu Val Lys Asn Ser Asn Asn Lys Ile Glu Glu Leu 1085 1090 1095Thr Asn Val Ile Lys Asp Leu Asn Asp Ser Ile Met Cys Tyr Lys 1100 1105 1110Lys Gln Ile Leu Glu Glu Val Glu Lys Arg Asn Glu Tyr Asn Glu 1115 1120 1125Glu Ile Asn Lys Leu Lys Ile Val Gln Asn Glu Met Lys Asp Met 1130 1135 1140Asn Asp Lys Lys Ile Leu Glu Lys Glu Asn Glu Ile Lys Lys Leu 1145 1150 1155Asn Lys Lys Leu Ser Asn Tyr Lys Val Phe Glu Thr Lys Glu Asn 1160 1165 1170Thr Tyr Lys Asn Ser Glu Met Val Val Asn Glu Asn Lys Glu Arg 1175 1180 1185Ile Ile Val Asp Ser Val Cys Lys Glu Asn Ile Ser Glu Ser Asp 1190 1195 1200Val Glu Gly Lys Gly Gly Asn Leu Lys Met Thr Leu Ser Leu Lys 1205 1210 1215Lys Lys Glu Arg Asn Ile Phe Ser Ile Asn Asp Asn Lys Asn Glu 1220 1225 1230Ser Ser Glu Leu Val Asp Thr Ile Lys Ser Ala Tyr Ile Asn Lys 1235 1240 1245Ile Glu Met Tyr Lys Lys Glu Ile Glu Asp Asn Gly Lys Asn Ile 1250 1255 1260Glu Asp Leu Lys Asn Lys Ile Leu Asp Leu Ser Asn Glu Leu Ile 1265 1270 1275Asn Leu Glu Asn Met Lys Asn Val Leu Thr Asp Glu Asn Asn Asn 1280 1285 1290Leu Lys Lys Glu Ile Glu Ile Lys Asp Asn Lys Leu Asn Glu Lys 1295 1300 1305Glu Lys Asn Glu Asn Thr Glu Ile Leu Asn Leu Asn Asp Asp Ile 1310 1315 1320Ile Lys Leu Lys Lys Glu Ile Ser Glu Trp Lys Asp Glu Glu Glu 1325 1330 1335Lys Leu Thr Lys Glu Asn Ile Lys Leu Lys Asn Asp Ile Glu Gln 1340 1345 1350Ile Asn Lys Glu Tyr Lys Ile Lys Glu Glu Asn Leu Met Ile Lys 1355 1360 1365Phe Asn Glu Asn Ile Asn Glu Val Thr Ser Leu Lys Asn Gln Ile 1370 1375 1380Glu Ile Glu Lys Met Lys Leu Glu Glu Leu Asn Lys Asn Tyr Glu 1385 1390 1395Leu Leu Leu Ala Glu Lys Arg Glu Thr Asn Met Ser Ile Ser Asn 1400 1405 1410Asp Asp Asn Lys Ile Val Glu Asn Asn Ile Leu Glu Asp Thr Asp 1415 1420 1425Ser Lys Gln Asn Asn Leu Asn Lys Asn Val Glu Asp Lys Thr Gly 1430 1435 1440Asp Asp Ile Asn Cys Glu Lys Asn Asn Asp Gln Ala Lys Glu Ile 1445 1450 1455Ser Tyr Leu Lys Asp Glu Ile Lys Lys Ile Ser Met Leu Tyr Gly 1460 1465 1470Glu Glu Leu Asn Arg Lys Asn Ser Tyr Asp Glu Lys Val Lys Asn 1475 1480 1485Leu Thr Asn Glu Leu Lys Glu Leu Lys Ile Arg Asn Lys Lys Gly 1490 1495 1500Glu Glu Ala Ile Ala Glu Leu Asn Lys Leu Lys Asn Ile Lys Glu 1505 1510 1515Lys Asn Lys Ser Val Lys Gln Asn Asp Glu Ser Ser Ser Asn Asn 1520 1525 1530Ile Ile Thr Lys Asp Gly Asp Lys Thr Pro Glu Tyr Val Ser Asn 1535 1540 1545Asp Asp Lys Ile Gln Lys Asp Trp Lys Ala Asn Leu Val Leu Lys 1550 1555 1560Leu Lys Glu Lys Pro Asp Leu Trp Asp Asn Ile Asn Ser Leu Glu 1565 1570 1575Lys Glu Asn Phe Arg Val Met Ser Ile Val Lys Glu Asn Lys Asn 1580 1585 1590Val Gln Asn Asp Lys Ile Val Gly Ile Tyr Ser Tyr Phe Lys Lys 1595 1600 1605Cys Glu Lys Glu Leu Lys Asn Asp Met Leu Val Ile Cys Leu Val 1610 1615 1620Leu Lys Asp Ile Leu Ser Ile Leu Phe Leu Asn Asp Asn Phe Val 1625 1630 1635Asn Leu Phe Glu Lys Ile Asp Lys Ile Leu Trp Lys Gln Met Tyr 1640 1645 1650Ile Pro Thr Glu Ile Arg Ile Leu Phe Leu Arg Tyr Phe Ser Phe 1655 1660 1665Leu Asp Lys Leu Arg Asn Tyr Val Lys Cys Val Asn Glu Glu Tyr 1670 1675 1680Val Asn Asn Glu Arg Tyr Glu Tyr Ser Trp Ala Leu Phe Gln Thr 1685 1690 1695Tyr Leu Glu Thr Ala Ser Asn Leu Lys Lys Glu Met Ile Tyr Tyr 1700 1705 1710Val Leu Glu Lys Ala Glu Lys Asp Ser Cys Glu Asn Asn Ser Ser 1715 1720 1725Asn Phe Asp Lys Pro Lys Ile Thr Asp Ile Leu Asn Phe Ser Lys 1730 1735 1740Asp Ser Ile Arg Leu Lys Thr Ile Ala Gln Leu Arg Lys Glu Leu 1745 1750 1755Asn Phe Glu Arg Glu Ala Lys Asn Ile Leu Asn Tyr Asp Tyr Gln 1760 1765 1770Ile Ile Leu Asn Lys Tyr His Glu Cys Leu Arg Lys Leu Lys Ile 1775 1780 1785Val Lys Asn Met Ala Arg Glu Leu Asp Phe Asn Tyr Asn Val Ser 1790 1795 1800Ser Lys Phe Ser Ile Lys Lys Glu Leu Glu Met Cys Ser Asp Glu 1805 1810 1815Asn Asp Glu Phe Lys Tyr Asn Asn Ile Lys Asn Asn Glu Glu Lys 1820 1825 1830Asn Asp Thr Ile Lys Asp Pro Lys His Asn Asn Leu Ile Gln Lys 1835 1840 1845Ile Ile Asn Leu Gln Arg Asn Lys Lys Thr Glu Lys Lys Lys Asn 1850 1855 1860Asn Leu Val Asn Glu Ile Asn Thr Met Tyr Pro Gly Asp Thr Thr 1865 1870 1875Pro Lys Gly Lys Ile Phe Thr Thr Asn Asp Asn Ser Lys Gln Asn 1880 1885 1890Glu Ile Leu Lys Lys Lys Asp Asn Ile Asn Asn Asn Ile Thr His 1895 1900 1905Lys Asn Val Tyr Thr Gly Gln Val Lys Asn Ile Phe Asn Glu Pro 1910 1915 1920Val Glu Arg Lys Val Arg Ile Ser Phe Ile His Lys Ser Pro Phe 1925 1930 1935Asn21979PRTPlasmodium falciparum 2Met Val Phe Thr Phe Lys Asn Lys Lys Lys Lys Lys Glu Ala Ser Ser1 5 10 15Asp Lys Val Ser Lys Glu Ser Phe Asn Glu Glu Asp Asn Glu Asn Asn 20 25 30Glu Lys Arg Glu Lys Ser Asp Ser Trp Tyr Lys Lys Ile Ile Glu Thr 35 40 45Lys Gly Lys Ser Lys Thr Lys Tyr Lys Asn Asp Asn Ser Leu Asp Asp 50 55 60Asn Ile Asn Glu Asp Ile Ile Asn Asn Asn Asn Asn Asn Asn Asn Asp65 70 75 80Asn Asn Asn Asp Asn Asn Asn Asp Asn Asn Asn Asp Asn Asn Asn Asp 85 90 95Asn Asn Asn Asp Asn Asn Asn Glu Asn Asn Asn Asp Asn Asn Asn Phe 100 105 110Asn Asn Tyr Ser Asp Glu Ile Ser Lys Asn Ile Ile His Lys Asp Asn 115 120 125Glu Leu Glu Asn Gln Leu Lys Asp Thr Leu Lys Ser Ile Ser Ser Leu 130 135 140Ser Asn Lys Ile Val Asn Tyr Glu Ser Lys Ile Glu Glu Leu Glu Lys145 150 155 160Glu Leu Lys Glu Val Lys Asp Lys Asn Ile Asp Asn Asn Asp Tyr Glu 165 170 175Asn Lys Leu Lys Glu Lys Glu Asp Phe Val Lys Gln Lys Ile Asp Met 180 185 190Leu Asn Glu Lys Glu Asn Leu Leu Gln Glu Lys Glu Leu Asp Ile Asn 195 200 205Lys Arg Glu Lys Lys Ile Asn Glu Lys Glu Lys Asn Ile Ile Lys Lys 210 215 220Glu Glu Thr Phe His Asn Ile Glu Lys Glu Tyr Leu Glu Lys Asn Lys225 230 235 240Glu Arg Glu Thr Ile Ser Ile Glu Ile Ile Asp Ile Lys Lys His Leu 245 250 255Glu Lys Leu Lys Ile Glu Ile Lys Glu Lys Lys Glu Asp Leu Glu Asn 260 265 270Leu Asn Lys Lys Leu Leu Ser Lys Glu Asn Val Leu Lys Glu Leu Lys 275 280 285Gly Cys Val Lys Glu Lys Asn Glu Thr Ile Asn Ser Leu Asn Asp Asn 290 295 300Ile Ile Glu Lys Glu Lys Lys Tyr Lys Leu Leu Glu Tyr Glu Leu Glu305 310 315 320Glu Lys Asn Lys Gln Ile Asp Leu Leu Asn Lys Gln Glu Lys Glu Lys 325 330 335Glu Lys Glu Lys Glu Arg Glu Lys Glu Lys Glu Arg Glu Lys Glu Lys 340 345 350Glu Lys Glu Tyr Asp Thr Leu Ile Lys Glu Leu Lys Asp Glu Lys Ile 355 360 365Ser Ile Leu Glu Lys Val His Ser Ile Lys Val Arg Glu Met Asp Ile 370 375 380Glu Lys Arg Glu His Asn Phe Leu His Met Glu Asp Gln Leu Lys Asp385 390 395 400Leu Lys Asn Ser Phe Val Lys Asn Asn Asn Gln Leu Lys Val Tyr Lys 405 410 415Cys Glu Ile Lys Asn Leu Lys Thr Glu Leu Glu Lys Lys Glu Lys Glu 420 425 430Leu Lys Asp Ile Glu Asn Val Ser Lys Glu Glu Ile Asn Lys Leu Ile 435 440 445Asn Gln Leu Asn Glu Lys Glu Lys Gln Ile Leu Ala Phe Asn Lys Asn 450 455 460His Lys Glu Glu Ile His Gly Leu Lys Glu Glu Leu Lys Glu Ser Val465 470 475 480Lys Ile Thr Lys Ile Glu Thr Gln Glu Leu Gln Glu Met Val Asp Ile 485 490 495Lys Gln Lys Glu Leu Asp Gln Leu Gln Glu Lys Tyr Asn Ala Gln Ile 500 505 510Glu Ser Ile Ser Ile

Glu Leu Ser Lys Lys Glu Lys Glu Tyr Asn Gln 515 520 525Tyr Lys Asn Thr Tyr Ile Glu Glu Ile Asn Asn Leu Asn Glu Lys Leu 530 535 540Glu Glu Thr Asn Lys Glu Tyr Thr Asn Leu Gln Asn Asn Tyr Thr Asn545 550 555 560Glu Ile Asn Met Leu Asn Asn Asp Ile His Met Leu Asn Gly Asn Ile 565 570 575Lys Thr Met Asn Thr Gln Ile Ser Thr Leu Lys Asn Asp Val His Leu 580 585 590Leu Asn Glu Gln Ile Asp Lys Leu Asn Asn Glu Lys Gly Thr Leu Asn 595 600 605Ser Lys Ile Ser Glu Leu Asn Val Gln Ile Met Asp Leu Lys Glu Glu 610 615 620Lys Asp Phe Leu Asn Asn Gln Ile Val Asp Leu Ser Asn Gln Ile Asp625 630 635 640Leu Leu Thr Arg Lys Met Glu Glu Lys Glu Asn Lys Met Leu Glu Gln 645 650 655Glu Asn Lys Tyr Lys Gln Glu Met Glu Leu Leu Arg Gly Asn Ile Lys 660 665 670Ser Ser Glu Asn Ile Leu Asn Asn Asp Glu Glu Val Cys Asp Leu Lys 675 680 685Arg Lys Leu Ser Leu Lys Glu Ser Glu Met Lys Met Met Lys Glu Glu 690 695 700His Asp Lys Lys Leu Ala Glu Leu Lys Asp Asp Cys Asp Val Arg Ile705 710 715 720Arg Glu Met Asn Glu Lys Asn Glu Asp Lys Ile Asn Met Leu Lys Glu 725 730 735Glu Tyr Glu Asp Lys Ile Asn Thr Leu Lys Glu Gln Asn Glu Asp Lys 740 745 750Ile Asn Thr Leu Lys Glu Gln Asn Glu Asp Lys Ile Asn Thr Leu Lys 755 760 765Glu Glu Tyr Glu His Lys Ile Asn Thr Met Lys Glu Glu Tyr Glu His 770 775 780Lys Ile Asn Thr Leu Asn Glu Gln Asn Glu His Lys Ile Asn Thr Leu785 790 795 800Asn Glu Gln Asn Glu His Lys Ile Asn Thr Met Lys Glu Glu Tyr Glu 805 810 815Asp Lys Met Asn Thr Leu Asn Glu Gln Asn Glu Asp Lys Met Asn Ser 820 825 830Leu Lys Glu Glu Tyr Glu Asn Lys Ile Asn Gln Ile Asn Ser Asn Asn 835 840 845Glu Ile Lys Ile Lys Asp Val Val Asn Glu Tyr Ile Glu Glu Val Asp 850 855 860Lys Leu Lys Val Thr Leu Asp Glu Lys Lys Lys Gln Phe Asp Lys Glu865 870 875 880Ile Asn Tyr Ala His Ile Lys Ala His Glu Lys Glu Gln Ile Leu Leu 885 890 895Thr Glu Met Glu Glu Leu Lys Cys Gln Arg Asp Asn Lys Tyr Ser Asp 900 905 910Leu Tyr Glu Lys Tyr Ile Lys Leu Ile Lys Ser Ile Cys Met Ile Ile 915 920 925Asn Ile Glu Cys Cys Asp Asp Ile Glu Asn Glu Asp Ile Ile Arg Arg 930 935 940Ile Glu Glu Tyr Ile Asn Asn Asn Lys Gly Leu Lys Lys Glu Val Glu945 950 955 960Glu Lys Glu His Lys Arg His Ser Ser Phe Asn Ile Leu Lys Ser Lys 965 970 975Glu Lys Phe Phe Lys Asn Ser Ile Glu Asp Lys Ser His Glu Leu Lys 980 985 990Lys Lys His Glu Lys Asp Leu Leu Ser Lys Asp Lys Glu Ile Glu Glu 995 1000 1005Lys Asn Lys Lys Ile Lys Glu Leu Asn Asn Asp Ile Lys Lys Leu 1010 1015 1020Gln Asp Glu Ile Leu Val Tyr Lys Lys Gln Ser Asn Ala Gln Gln 1025 1030 1035Val Asp His Lys Lys Lys Ser Trp Ile Leu Leu Lys Asp Lys Ser 1040 1045 1050Lys Glu Lys Ile Lys Asp Lys Glu Asn Gln Ile Asn Val Glu Lys 1055 1060 1065Asn Glu Glu Lys Asp Leu Lys Lys Lys Asp Asp Glu Ile Arg Ile 1070 1075 1080Leu Asn Glu Glu Leu Val Lys Tyr Lys Thr Ile Leu Tyr Asn Leu 1085 1090 1095Lys Lys Asp Pro Leu Leu Gln Asn Gln Asp Leu Leu Ser Lys Ile 1100 1105 1110Asp Ile Asn Ser Leu Thr Ile Asn Glu Gly Met Cys Val Asp Lys 1115 1120 1125Ile Glu Glu His Ile Leu Asp Tyr Asp Glu Glu Ile Asn Lys Ser 1130 1135 1140Arg Ser Asn Leu Phe Gln Leu Lys Asn Glu Ile Cys Ser Leu Thr 1145 1150 1155Thr Glu Val Met Glu Leu Asn Asn Lys Lys Asn Glu Leu Ile Glu 1160 1165 1170Glu Asn Asn Lys Leu Asn Leu Val Asp Gln Gly Lys Lys Lys Leu 1175 1180 1185Lys Lys Asp Val Glu Lys Gln Lys Lys Glu Ile Glu Lys Leu Asn 1190 1195 1200Lys Gln Leu Thr Lys Cys Asn Lys Gln Ile Asp Glu Leu Asn Glu 1205 1210 1215Glu Val Glu Lys Leu Asn Asn Glu Asn Ile Glu Leu Ile Thr Tyr 1220 1225 1230Ser Asn Asp Leu Asn Asn Lys Phe Asp Met Lys Glu Asn Asn Leu 1235 1240 1245Met Met Lys Leu Asp Glu Asn Glu Asp Asn Ile Lys Lys Met Lys 1250 1255 1260Ser Lys Ile Asp Asp Met Glu Lys Glu Ile Lys Tyr Arg Glu Asp 1265 1270 1275Glu Lys Lys Arg Asn Leu Asn Glu Ile Asn Asn Leu Lys Lys Lys 1280 1285 1290Asn Glu Asp Met Cys Ile Lys Tyr Asn Glu Met Asn Ile Lys Tyr 1295 1300 1305Gly Asp Ile Cys Val Lys Tyr Glu Glu Met Ser Leu Thr Tyr Lys 1310 1315 1320Glu Thr Ser Leu Lys Tyr Glu Gln Ile Lys Val Lys Tyr Asp Glu 1325 1330 1335Lys Cys Ser Gln Tyr Asp Glu Ile Arg Phe Gln Tyr Asp Glu Lys 1340 1345 1350Cys Phe Gln Tyr Asp Glu Ile Asn Lys Lys Tyr Gly Ala Leu Leu 1355 1360 1365Asn Ile Asn Ile Thr Asn Lys Met Val Asp Ser Lys Val Asp Arg 1370 1375 1380Asn Asn Asn Glu Ile Ile Ser Val Asp Asn Lys Val Glu Gly Ile 1385 1390 1395Ala Asn Tyr Leu Lys Gln Ile Phe Glu Leu Asn Glu Glu Ile Ile 1400 1405 1410Arg Leu Lys Gly Glu Ile Asn Lys Ile Ser Leu Leu Tyr Ser Asn 1415 1420 1425Glu Leu Asn Glu Lys Asn Ser Tyr Asp Ile Asn Met Lys His Ile 1430 1435 1440Gln Glu Gln Leu Leu Phe Leu Glu Lys Thr Asn Lys Glu Asn Glu 1445 1450 1455Glu Lys Ile Ile Asn Leu Thr Ser Gln Tyr Ser Asp Ala Tyr Lys 1460 1465 1470Lys Lys Ser Asp Glu Ser Lys Leu Cys Gly Ala Gln Phe Val Asp 1475 1480 1485Asp Val Asn Ile Tyr Gly Asn Ile Ser Asn Asn Asn Ile Arg Thr 1490 1495 1500Asn Glu Tyr Lys Tyr Glu Glu Met Phe Asp Thr Asn Ile Glu Glu 1505 1510 1515Lys Asn Gly Met His Leu Ser Lys Tyr Ile His Leu Leu Glu Glu 1520 1525 1530Asn Lys Phe Arg Cys Met Lys Ile Ile Tyr Glu Asn Glu Asn Ile 1535 1540 1545Lys Ser Ser Asn Lys Ile Ile Gly Leu Tyr Asn Tyr Ser Arg Tyr 1550 1555 1560Tyr Gly Leu Arg Glu Asp Leu Cys Lys Glu Glu Ile Val Pro Ser 1565 1570 1575Lys Ile Gly Asn Ile Ser Asn Lys Asn Glu Asn Asn Asn Lys Lys 1580 1585 1590Asn Asn Thr Cys Asp Gly Tyr Asp Glu Lys Val Thr Ile Val Leu 1595 1600 1605Cys Ile Ile Leu Asn Glu Ile Ile Lys Phe Leu Phe Leu Asn Asp 1610 1615 1620Glu Tyr Val Leu Leu Phe Glu Lys Ile His Lys Asn Val Trp Lys 1625 1630 1635Arg Met Tyr Ile Pro Glu Glu Ile Lys Phe Phe Ile Leu Lys Tyr 1640 1645 1650Ile Thr Leu Leu Asn Asn Leu Arg Asp Tyr Ile Ile Ser Val His 1655 1660 1665Asn Asn Met Lys Asn Glu Lys Tyr Asp Glu Cys Trp Phe Leu Phe 1670 1675 1680Gln His Tyr Phe Glu Arg Ser Ser Asp Val Arg Lys Glu Met Val 1685 1690 1695His Phe Leu Leu Glu Arg Lys Ser Gln Glu Asn Leu Ile Ser Phe 1700 1705 1710Lys Ser Lys Leu Lys Ser Lys Lys Glu Lys Ile Leu Thr Met Asp 1715 1720 1725Ile Leu Asn Phe Ser Lys Glu His Met Gln Leu Lys Thr Ile Ala 1730 1735 1740His Leu Arg Lys Glu Ile Asn Tyr Glu Lys Leu Ser Lys Asp Thr 1745 1750 1755Leu Asn Arg Asp Tyr Asn Leu Leu Leu Tyr Lys Tyr Gln Glu Cys 1760 1765 1770Val Ser Lys Leu Lys Arg Val Lys Asn Leu Met Lys Glu Ile Asn 1775 1780 1785Gln Asn Val Phe Ile Glu Lys Tyr Asp Asp Ile Ser Lys Glu Leu 1790 1795 1800Asp Asn Phe Ser Asp Gly Tyr Asn Glu Gln Asn Glu Gln His Val 1805 1810 1815Met Asp Pro Ile Leu Leu Asn Asn Asn Lys Asn Lys Asn Asn Lys 1820 1825 1830Leu Ile Thr Glu His Asn Asn Pro Ile Ile Asn Arg Leu Thr Asn 1835 1840 1845Phe Thr Gln Asn Arg Asp Ser Lys Tyr Lys Asn Lys Ile Met Asp 1850 1855 1860Asp Val Lys Gln Arg Lys Ile Asn Ser Thr Met Asn Asn Thr Asn 1865 1870 1875Lys Asn Gly Ile Asn Ile Ile Tyr Asn His Tyr Glu Asn Leu Asn 1880 1885 1890Lys Pro Asn Tyr Asn Asp Asn Ile Asn Arg Leu Asn Ser Tyr His 1895 1900 1905Gln Asn Ile His Ile Ala Asn Ser Ile His Pro Asn Arg Asn Gln 1910 1915 1920Asn Lys Ser Phe Leu Thr Asn Gln Ala Asn Ser Thr Tyr Ser Val 1925 1930 1935Met Lys Asn Tyr Ile Asn Ser Asp Lys Pro Asn Leu Asn Gly Lys 1940 1945 1950Lys Ser Val Arg Asn Ile Phe Asn Glu Ile Val Asp Glu Asn Val 1955 1960 1965Asn Lys Thr Phe Val His Lys Ser Val Phe Phe 1970 197531867PRTPlasmodium vivax 3Met Val Phe Lys Phe Lys Lys Lys Lys Lys Glu Glu Ser Ser Asp Lys1 5 10 15Leu Ser Lys Gln Ser Gln Asn Asp Glu Gly Asn Ala Asn Glu Glu Ala 20 25 30Glu Lys Lys Asp His Lys Ser Asn Ser Trp Tyr Lys Lys Ile Ile Asp 35 40 45Asn Ala Ile Ile Thr Lys Ser Lys His Asp Asp Lys Glu Glu Gln Glu 50 55 60Glu Glu Lys Asn Gly Glu Gly Asn Asp Ser Arg Ala Met Glu Arg Asn65 70 75 80Lys Asp Tyr Gln Leu Glu Glu Gln Leu Lys Glu Thr Leu Arg Ser Ile 85 90 95Thr Ser Leu Ser Thr Lys Ile Val Asn Tyr Glu Thr Lys Ile Glu Asp 100 105 110Leu Glu Lys Glu Leu Lys Met Glu Lys Asp Lys Gln Val Asp Lys Ala 115 120 125Tyr Glu Lys Glu Leu Lys Glu Lys Glu Asn Phe Ile Lys Gln Lys Ile 130 135 140Gly Met Leu Asn Glu Lys Glu Asn Leu Leu Asn Glu Lys Glu Leu Asp145 150 155 160Ile Asn Met Arg Glu Glu Lys Ile Asn Asp Arg Glu Met Phe Ile Ser 165 170 175Lys Lys Glu Asp Lys Leu Asn Asp Met Gln Glu Gln Tyr Leu Glu Lys 180 185 190Asn Lys Glu Lys Glu Lys Leu His Phe Glu Ile Ala Asp Ile Lys Ile 195 200 205Ser Leu Glu Lys Leu Lys Tyr Glu Val Lys Asp Lys Lys Asp Cys Leu 210 215 220Glu Asn Val Ser Asn Lys Val Ile Leu Lys Glu Asn Thr Leu Arg Glu225 230 235 240Leu Lys Glu Phe Ile Arg Glu Lys Asn Glu Met Ile Glu Ser Leu Asn 245 250 255Glu Lys Ile Thr Glu Lys Glu Lys Ile Tyr Glu Gln Leu Gly Lys Asp 260 265 270Val Glu Glu Lys Arg Lys Ile Ile Glu Leu Leu Asp Met Lys Ala Asn 275 280 285Glu Lys Glu Lys Tyr Phe Glu Glu Lys Ile Lys Glu Leu Glu Lys Glu 290 295 300Gln Asn Ala Leu Leu Gln Lys Leu Asn Asn Val Lys Met Arg Glu Lys305 310 315 320Glu Val Glu Thr Arg Glu Asn Asp Phe Leu His Met Glu Asp Glu Leu 325 330 335Asn Asp Leu Arg Ser Ser Phe Ser Lys Asn Asp Cys Gln Leu Lys Ile 340 345 350Tyr Lys Leu Glu Ile Lys Asp Leu Ser Ser Ala Leu Val Glu Lys Glu 355 360 365Arg Glu Ile Leu Asp Leu Lys Asn Thr Tyr Asp Gly Glu Ile Cys Ser 370 375 380Leu Lys Asp Gln Ile Lys Glu Lys Glu Lys Glu Ile Ala Lys Gly Ser385 390 395 400Ser Ser Gly Gly Asp Val Gly Ala Gln Asp Glu Pro Ala Ser Glu Val 405 410 415Glu Ser Glu Glu Lys Ala Asp Pro Lys Glu Glu Gly Val Glu Asn Ser 420 425 430Leu Thr Asp Leu Leu Lys Met Lys Glu Arg Glu Leu His Glu Met Lys 435 440 445Glu Lys Tyr Ala Lys Glu Ile Asp Thr Leu Asn Ser Glu Leu Asn Glu 450 455 460Lys Lys Lys Glu Phe Val Glu Ala Lys Asn Ser His Ile Asn Gln Ile465 470 475 480Asn Asn Leu Asn Asp Glu Ile Glu Glu Ser Glu Ser Lys Met Ala Glu 485 490 495Leu Lys Ser Gly Tyr Glu Met Glu Ile Lys Lys Leu Arg Ser Glu Ile 500 505 510Asn Ala Val His Glu Glu Lys Tyr Leu Leu Ser Asn Glu Lys Gln Thr 515 520 525Leu Ser Gly Glu Ile Asp Lys Leu Asn Glu Glu Lys Lys Ser Leu Ala 530 535 540Ser Glu Lys Glu Glu Leu His Asn Lys Ile Thr Thr Leu Asn Ser Glu545 550 555 560Ile Gly Thr Leu His Val Glu Lys Gln Ala Leu Thr Gly Glu Ile Asn 565 570 575Thr Leu Asn Asp Leu Ile His Thr Leu Lys Asn Glu Ile Ser Ser Ser 580 585 590Asp Asn Leu Ile Ser Lys Leu Lys Glu Gln Met Asn Ala Ile Asn Glu 595 600 605Glu Lys Glu Gly Lys Glu Lys Leu Ile Thr Glu Ile Glu Asn Asn Tyr 610 615 620Lys Asn Glu Ile Asn Ala Leu Lys Glu Lys Leu Lys Asp Thr Asp Asn625 630 635 640Gln Val Ser Ile Ser Ile Arg Glu Glu Met Asp His Leu Lys Cys Val 645 650 655Leu Gly Glu Thr Glu Lys Glu Asn Lys Gln Met Lys Glu Asp Tyr His 660 665 670Lys Lys Ile Lys Gln Tyr Asp Glu Glu Leu Leu Ser Lys Gln Gln Tyr 675 680 685Phe Glu Glu Glu Leu Asn Asn Ile Arg Ile Lys Ser His Glu Lys Glu 690 695 700Gln Ile Leu Ile Leu Lys Asn Asp Glu Leu Lys Glu Ser Lys Leu Lys705 710 715 720Thr Glu Glu Lys Tyr Leu Lys Leu Tyr Asp Asp Lys Met Ser Leu Leu 725 730 735Arg Asn Met Cys Ser Lys Val Gly Leu Pro Tyr Ser Asp Glu Val Ser 740 745 750Val Glu Glu Leu Leu Glu Arg Val Gly Asn Tyr Val Ser Gly Met Gly 755 760 765Glu Pro Gly Gly Ala Ala His Arg Gly Glu Gln Ser Glu Glu Pro His 770 775 780Glu Gly Gln Ser Ile Val Glu Glu Thr Asn Glu Pro Leu Leu Ser Ala785 790 795 800Gln Thr Ala Asp Asn Ala Asn Ser Leu Glu Asp Lys Thr Thr Leu Gln 805 810 815Ala Leu Gln Lys Glu Leu Glu Ser Val Gln Glu Glu Tyr Arg Glu Glu 820 825 830Val Ala Lys Met Lys Ser Tyr Leu Ala Met Lys Glu Lys Thr Ile Glu 835 840 845Glu Ser Asn His Thr Ile Ala Glu Leu Thr Gly Lys Ile Asn Ser Leu 850 855 860Asn Asp Thr Ile Ser Phe Phe Lys Val Asn His Ser Glu Glu Lys Ile865 870 875 880Asn Ser Tyr Met Asp Glu Ile Asn Ser Leu Ser Leu Thr Leu Ser Glu 885 890 895Leu Lys Ala Asn Asn Glu Gln Glu Gln Leu Glu Asn Arg Asn Glu Ile 900 905 910Ala Arg Leu Ser Glu Glu Leu Ser Gly Tyr Lys Arg Arg Ala Asp Glu 915 920 925Gln Cys Arg Lys Arg Ser Ser Glu Lys Glu Arg Ser Glu Ser Lys Arg 930 935 940Gly Asp Thr Arg Gly Asp Ser Glu Lys Glu Gln Ile Ser Glu Ser Asp945 950 955 960Val Glu Gly Gly Gly Asn Leu Lys Ser Phe Leu His Phe Pro Leu Arg 965 970 975Lys Ile Lys Gly Lys Lys Arg Lys Ala Ser Lys Thr Glu Lys Glu Ile 980 985

990Gln Thr Glu Leu Arg Arg Asn Glu Pro Glu Asn Glu Gln Ser Glu Lys 995 1000 1005Asn Glu Lys Ala Pro Arg Gly Asp Ser Leu Glu Val Asp Gln Tyr 1010 1015 1020Lys Lys Glu Leu Glu Glu Lys Ala Lys Ile Ile Glu Asp Leu Lys 1025 1030 1035Asp Lys Ile Cys Thr Leu Thr Asn Glu Val Met Asp Leu Lys Asn 1040 1045 1050Leu Lys Asn Glu Leu Ala Glu Arg Asp Ser Ser Leu Ala Lys Ala 1055 1060 1065Gly Glu Glu Ala Glu Arg Gln Arg Glu Gln Leu Asp Thr Leu Ser 1070 1075 1080Ala Gln Leu Gly Gly Ala Asn Gly Glu Val Glu Arg Leu Ser Glu 1085 1090 1095Glu Val Glu Arg Leu Asn Glu Glu Val Glu Lys Leu Lys Glu Gly 1100 1105 1110Glu Ala Gln Ser Trp Gly Glu Ala Glu Lys Trp Lys Gly Glu Ala 1115 1120 1125Glu Lys Trp Lys Glu Asp Ala Ala Lys Trp Glu Ala Asp Thr Val 1130 1135 1140Lys Leu Lys Glu Asp Ala Ala Lys Trp Glu Ser Asp Ala Val Lys 1145 1150 1155Trp Glu Ser Asp Ala Glu Thr Trp Arg Lys Glu Ala Glu Glu Leu 1160 1165 1170Arg Ser Ser Ala Asn Gln Leu Asn Glu Glu Leu Cys Ser Lys Glu 1175 1180 1185Asn Asn Tyr Val Leu Lys Leu Asn Glu Asn Val Gly Val Ile Gln 1190 1195 1200Lys Met Lys Asp Ser Ile Asp Ala Arg Glu Lys Glu Lys Glu Asn 1205 1210 1215Tyr Val Arg Glu Ile Asn Asp Leu Arg Asn Glu Leu Glu Gly Leu 1220 1225 1230Lys Leu Lys His Asp Ala Leu Ser Glu Thr Tyr Lys Gln Leu Glu 1235 1240 1245Gly Lys Ser Ser Pro Pro Ser Gly Asp Asp Pro Pro Gly Gly Asp 1250 1255 1260Asn Tyr Thr Ser Glu Gly Glu Asn Lys Leu Ser Ile Pro Asn Glu 1265 1270 1275Asn Cys Glu Met Asp Gln Ala Glu Glu Ala Asn Ala Asn Pro Gly 1280 1285 1290Val Pro Lys Ser Glu Ile Ala Thr Glu Gly Gly Val Ser Ser Leu 1295 1300 1305Ala Val Asn Asp Tyr Ile Ser Glu Ile Ala His Leu Lys Glu Glu 1310 1315 1320Ile Asn Arg Leu Thr Leu Leu Tyr Ser Asn Glu Leu Asn Glu Lys 1325 1330 1335Asn Ser Ser Asp Ile Arg Thr Lys Glu Leu Leu Ser Gln Leu Lys 1340 1345 1350Glu Leu Glu Val Arg Asp Lys Glu Asn Glu Glu Lys Ile Ala Ala 1355 1360 1365Leu Ser Lys Met Asn Glu Lys Met Lys Ala Lys Asn Glu Lys Leu 1370 1375 1380Lys Ser Gly Lys Trp Leu Ser Arg Lys Asp His Ala Pro Asn Glu 1385 1390 1395Glu Val Asp Ile Ala Gly Glu Glu Arg Lys Lys Lys Glu Lys Glu 1400 1405 1410Lys Val Pro His Pro Asp Val Lys Glu Glu Ser Leu Ser Ser Glu 1415 1420 1425His Val Asn Thr Leu Glu Gly Asn Thr Tyr Arg Val Met Arg Ile 1430 1435 1440Val Asp Glu Ser Ser Pro Ala Gly Gly Gly Gln Ile Ile Gly Ser 1445 1450 1455Tyr Leu Tyr Thr Lys Lys Val Glu Asp Leu His Ala Val Asn Gly 1460 1465 1470Ala Asn Val Ala Asp Ala Gln Leu Ala Glu Lys Asn Ala Ile Thr 1475 1480 1485Val Val Cys Leu Ile Leu Ser Glu Ile Leu Ser Leu Leu Phe Leu 1490 1495 1500Asn Asp Gln Phe Val Asn Ala Phe Glu Arg Ile Asn Lys Ser Leu 1505 1510 1515Trp Lys Leu Met Tyr Met Pro Glu Glu Ile Lys Ala Leu Leu Leu 1520 1525 1530Arg Tyr Phe Ser Phe Met Ser Lys Leu Arg Asp Tyr Ala Lys Glu 1535 1540 1545Val His Gly Arg Val Glu Asn Glu Arg Tyr Glu Asp Ser Gln Arg 1550 1555 1560Gln Asp Asn Gln Arg Tyr Asp Asp Ser Trp Leu Leu Phe Gln Asn 1565 1570 1575Tyr Leu Glu Thr Ser Ser Ser Ile Lys Arg Asp Leu Val Cys Phe 1580 1585 1590Ile Leu Glu Glu Lys Glu Asn Glu Leu Ala Glu Leu Gly Glu His 1595 1600 1605Tyr Gly Gly Gly Met Arg Lys Gly Glu Glu Val Ile Gly Gly Val 1610 1615 1620Arg Gly Val Arg Gly Gly Lys Ile Ala Asp Ile Ile Asn Leu Ser 1625 1630 1635Lys Asp Glu Met Arg Leu Lys Thr Ile Ala Gln Leu Arg Arg Asp 1640 1645 1650Leu Asp Phe Glu Lys Lys Ser Lys Thr Leu Leu Ser Arg Asp Tyr 1655 1660 1665Gln Leu Leu Leu Tyr Lys Tyr Gln Glu Cys Val Arg Lys Leu Lys 1670 1675 1680Arg Val Lys Asn Met Ile Arg Gln Leu Asn Leu Asn Asp His Ser 1685 1690 1695Asn Arg Gly Ser Phe Ala Leu Asn Arg Glu Leu Asp Arg Cys Ser 1700 1705 1710Glu Val Ser Asn Glu Arg Gly Phe Asn Glu Glu Gly Gly Asp Glu 1715 1720 1725Asp Ser His Gly Asn Tyr Lys Asn Cys Ile Leu Gln Asp Asn Asn 1730 1735 1740Asn Asn Ser Ser Val Asn Asn Tyr Asn Ser Ser Asn Thr Lys Leu 1745 1750 1755Glu Ser Arg Glu Asn Val Leu Ile Lys Asp Leu Ile Asn Leu Arg 1760 1765 1770Arg Ala Gln Lys Val Lys Gly Asn Asn Leu Ile His Trp Gly Arg 1775 1780 1785Pro Ser Met Met Met Gly Gly Arg Cys His Gln Asp Ala Ser His 1790 1795 1800Val Val Arg Ala Met Val Asn Gly Pro Lys Ile Ser Ser Gln Asn 1805 1810 1815Ile Phe Ala His Met Asn Arg Leu Ser Asn Ala Pro Lys Ile Ser 1820 1825 1830Asp His Leu Asp Asp Met Lys Lys Met Lys Asn Ile Phe Asn Glu 1835 1840 1845Phe Val Glu Thr Arg Gly Asp Val Thr Phe Val His Arg Ser Pro 1850 1855 1860Phe Cys Glu Thr 186545940DNAPlasmodium falciparum 4atggtattca cgttcaaaaa taagaaaaag aaaaaagaag ctagttcaga taaagtaagc 60aaagaatcat ttaatgagga agataatgaa aataatgaaa agagggaaaa aagcgattca 120tggtataaaa aaataataga aactaaagga aaaagtaaaa ctaaatataa aaatgataat 180tccttagatg ataatattaa tgaggacata ataaataata ataataataa taataatgat 240aataataatg ataacaataa tgataataat aatgataata ataatgataa taataatgat 300aataataatg agaataataa tgataataat aattttaata attatagcga tgaaatatca 360aaaaatatta tacataaaga caatgagcta gaaaaccagc ttaaggatac attaaagtcc 420attagttcgt tgtcgaataa aattgtgaat tacgaaagta aaattgaaga attagaaaaa 480gaattaaaag aagtaaagga taagaatatt gataataatg attatgaaaa taaattaaaa 540gaaaaagaag attttgttaa acaaaaaatt gatatgctaa atgaaaaaga aaatctttta 600caagaaaaag aattagatat taataaaaga gaaaagaaaa ttaatgaaaa agaaaagaat 660ataataaaaa aggaagaaac atttcataat atagaaaaag agtatttaga aaaaaataaa 720gaaagagaaa cgatttctat agaaattata gatattaaaa aacatctaga aaaactaaaa 780atagaaataa aagaaaaaaa agaagattta gaaaatttaa ataaaaaatt gttatcaaaa 840gaaaatgtac taaaagaatt aaaaggatgt gttaaggaaa aaaatgaaac cattaattca 900ttgaatgata atattattga aaaagaaaaa aaatataaat tattagaata tgagttggaa 960gaaaaaaata aacaaattga tttattaaac aaacaagaaa aagaaaagga aaaggagaag 1020gaaagggaaa aggagaagga aagggaaaag gaaaaagaaa aggaatatga tacattaatc 1080aaagaattaa aagatgaaaa gatttccatt ttagaaaaag ttcattccat taaagtaaga 1140gaaatggata ttgaaaaaag agaacataat ttccttcata tggaagatca attaaaagat 1200ttaaaaaata gttttgtaaa gaataataat caattaaaag tatataaatg tgaaataaag 1260aatcttaaaa ccgaattaga aaaaaaagaa aaagaattaa aagatataga aaatgtatct 1320aaagaagaaa taaataaatt aataaaccaa ttaaatgaaa aggagaaaca aattcttgcg 1380tttaataaaa atcataaaga agaaattcat ggattgaaag aagaattaaa agaatctgtg 1440aaaataacca aaatagaaac acaagagtta caagaaatgg tagacatcaa acaaaaagag 1500ttagaccaat tgcaggaaaa atataacgca caaatagaaa gtataagcat cgaattaagt 1560aaaaaagaga aggaatataa tcaatataaa aatacttata tagaagaaat aaataattta 1620aatgaaaaat tagaagaaac taataaagaa tatacgaatt tacaaaataa ttatacaaat 1680gaaataaata tgttaaataa tgatatacat atgttaaatg gcaatataaa aaccatgaat 1740acacaaataa gtactttaaa aaatgatgta catttgttaa atgaacaaat agataaatta 1800aataatgaaa agggtacatt aaatagtaaa attagtgaat tgaatgttca aattatggat 1860ttaaaagagg aaaaagattt cttaaataat caaattgtag atttaagtaa tcaaattgat 1920ttgttaacaa gaaaaatgga agagaaggaa aataaaatgt tggaacagga gaataagtat 1980aaacaagaga tggaactctt aagggggaat ataaaaagtt ctgagaatat tttaaacaat 2040gacgaagagg tgtgtgattt aaaaaggaaa ttaagtttga aggaaagtga aatgaaaatg 2100atgaaggagg aacatgataa gaagttggct gagttgaaag atgattgtga tgtgaggata 2160cgggagatga atgaaaagaa tgaagataaa attaatatgt taaaggaaga atatgaagat 2220aaaattaata cgttgaagga acaaaatgaa gataaaatta atacgttaaa ggaacaaaat 2280gaagataaaa ttaatacatt gaaagaagag tatgaacata aaattaatac gatgaaggaa 2340gaatatgaac ataaaattaa tacgttgaat gaacaaaatg aacataaaat taatacgttg 2400aatgaacaaa atgaacataa aattaatacg atgaaggaag aatatgaaga taaaatgaac 2460acgttgaatg aacaaaatga agataaaatg aattcgttga aggaagagta tgaaaataag 2520ataaatcaaa ttaatagtaa taatgaaata aaaataaaag atgtagtgaa tgaatatatt 2580gaagaagtgg acaaattaaa agttactttg gatgaaaaaa aaaaacaatt tgataaagaa 2640ataaattacg cacatatcaa agctcatgaa aaggagcaaa tattattaac agaaatggaa 2700gaattaaaat gtcagaggga taataaatat tcagatttat atgagaaata tattaaacta 2760ataaaaagta tttgtatgat aattaacatt gaatgttgtg atgatataga aaatgaagat 2820attataagaa gaattgaaga atatataaat aataacaaag gcttgaaaaa agaagtagaa 2880gaaaaagaac ataaaagaca ttcctccttt aatattttaa aaagtaaaga aaagtttttt 2940aaaaatagca tagaagataa aagtcatgaa ttaaaaaaaa aacatgaaaa agatttatta 3000tcaaaagata aagaaattga agaaaagaat aaaaaaataa aagaactgaa taatgatata 3060aaaaagttac aagatgaaat attagtatat aaaaaacaaa gtaatgcaca acaagtagat 3120cataaaaaga aaagttggat tcttcttaaa gataaatcta aagagaaaat aaaagataaa 3180gaaaatcaaa taaatgtaga aaaaaatgaa gaaaaggatt taaaaaaaaa agatgatgaa 3240ataagaattt taaatgaaga acttgtaaaa tataaaacaa ttttatataa tttaaaaaaa 3300gatccattat tacaaaatca agatttatta tcaaaaattg acataaattc tttaacaata 3360aatgaaggaa tgtgtgtaga taaaatagaa gagcacattt tggattatga tgaagaaata 3420aataaaagca gatctaattt gtttcaacta aaaaatgaaa tatgttcttt aacaactgag 3480gttatggaac ttaataataa gaaaaatgaa ttaattgaag aaaataataa attaaattta 3540gtagatcaag gaaagaagaa attaaaaaag gatgtggaaa aacaaaaaaa agaaatagag 3600aaattaaata aacaattaac aaaatgtaat aaacaaatag atgaattaaa tgaagaagtg 3660gaaaaattaa ataatgaaaa tattgaatta attacatatt caaatgattt aaataacaaa 3720tttgatatga aagaaaataa tcttatgatg aaattagatg aaaatgaaga taatataaag 3780aaaatgaaaa gtaaaattga tgatatggaa aaagaaataa aatatagaga agatgaaaaa 3840aaaagaaatt taaatgaaat taataattta aagaaaaaga atgaagatat gtgtattaaa 3900tataatgaaa tgaatattaa gtatggagat atttgtgtaa aatatgaaga aatgtctctt 3960acgtataaag aaacatctct taaatatgag caaattaaag tgaaatatga tgaaaagtgt 4020tctcaatatg acgaaatacg ttttcaatat gatgagaaat gttttcaata tgatgagata 4080aataagaaat atggtgcttt attaaatata aatattacta ataaaatggt tgattcaaaa 4140gtggatagaa ataataatga aataatttca gtagataata aagtagaagg aattgcgaat 4200tatttaaaac aaatatttga attaaatgaa gagatcatac gattaaaagg agaaataaat 4260aaaattagct tattatatag taatgaatta aatgagaaaa atagttatga tataaacatg 4320aaacatatac aagaacaatt actttttttg gaaaagacaa ataaagaaaa tgaagaaaaa 4380ataattaatt tgactagcca atattctgat gcatacaaga agaagagtga tgaatctaaa 4440ttatgtggtg cacagtttgt tgatgatgtt aatatatatg gaaatatatc aaataataat 4500ataagaacaa atgaatataa atatgaagag atgtttgata cgaatataga agagaagaat 4560ggtatgcatt tatctaagta tattcatcta ttagaagaaa ataaatttcg atgtatgaaa 4620ataatttatg aaaatgaaaa tataaaaagt agtaataaaa taattggatt gtataattat 4680tcaaggtatt atgggttaag agaagatttg tgtaaagaag aaatcgttcc ttcaaaaata 4740ggaaatatat ctaataaaaa tgaaaataat aataagaaga acaacacttg tgatggttat 4800gatgagaagg ttacaatagt tttatgcatt atattaaatg aaataataaa atttttattt 4860ttaaatgacg aatatgtatt attatttgaa aagattcata aaaatgtttg gaaacgaatg 4920tatatcccag aagaaataaa attttttatc ctaaaatata ttacgctgtt aaataacttg 4980agagattata taataagtgt acataataat atgaaaaatg agaaatatga tgaatgttgg 5040tttttatttc aacattattt tgaaagatcg agtgatgtaa gaaaagagat ggttcatttc 5100ttattagaaa gaaagagtca agaaaattta atatctttta aaagtaaatt aaaaagtaaa 5160aaagaaaaaa tattaacaat ggacatattg aattttagta aagaacatat gcaattaaaa 5220accatagctc atctaagaaa agaaataaat tatgaaaaac tttctaagga taccttaaat 5280agagattata atttattatt atataaatat caagaatgtg taagtaaatt aaaaagggta 5340aaaaatttaa tgaaagaaat aaatcaaaat gtatttatag aaaaatatga tgatataagt 5400aaagaattag ataatttttc agatggatat aatgaacaaa atgaacaaca tgtaatggat 5460cctattttat taaataataa taaaaacaaa aataacaaat tgataactga acataataat 5520cctataatta ataggctaac taattttaca caaaacagag attcaaaata taaaaataaa 5580ataatggatg atgtaaaaca aagaaaaata aatagtacaa tgaataatac aaataaaaat 5640ggtattaata ttatatataa tcattatgaa aatttaaata aaccaaacta taatgataat 5700ataaatagat taaattcata tcatcaaaat atacatattg ctaattcaat tcatcctaat 5760agaaatcaaa ataaaagttt tcttacgaat caagcaaata gtacatatag tgttatgaaa 5820aattatataa attcagataa accaaattta aatggaaaaa agagtgtaag aaatattttt 5880aatgaaattg tcgatgaaaa tgtaaataaa acgtttgttc ataaaagtgt atttttttaa 594055604DNAPlasmodium vivax 5atggtattca aatttaagaa gaaaaagaag gaagaaagct cggacaagtt aagcaagcaa 60tcgcaaaacg atgaaggaaa tgccaatgag gaggcagaaa aaaaagacca caagagtaac 120tcctggtaca agaaaataat cgacaatgca attataacga agagcaagca tgacgataag 180gaggagcagg aggaggagaa aaatggcgaa ggaaatgaca gcagggcgat ggaaagaaat 240aaagattatc aattggaaga gcaactgaag gaaaccctaa ggtcaatcac gtccttgtca 300accaaaattg tgaattacga aacgaagatt gaagatttgg agaaagagtt aaaaatggaa 360aaagataaac aagtggataa ggcatacgaa aaggagttga aggagaagga gaattttatt 420aaacaaaaaa ttggcatgct aaatgagaag gaaaatctgc taaatgagaa ggagctggac 480ataaatatga gagaagaaaa aattaatgac agagaaatgt tcatttcgaa aaaggaagac 540aaactgaatg acatgcagga gcagtacttg gaaaaaaata aagaaaaaga aaaactccat 600tttgaaattg cagatattaa gatttcctta gaaaagctaa agtacgaagt taaagataaa 660aaggactgcc tagaaaatgt cagcaataag gtaattttga aggaaaatac tctgagggag 720ttaaaagaat ttataaggga aaaaaacgaa atgatagaat cgcttaacga gaagataaca 780gagaaggaga aaatatatga gcagttaggg aaggacgtgg aggagaagag aaagatcatc 840gaattgctag acatgaaggc aaatgaaaag gaaaaatatt tcgaagaaaa aattaaagag 900ttagaaaaag aacaaaatgc gcttctgcaa aagttaaata atgttaagat gagggagaag 960gaagttgaga cgagggaaaa tgacttcctg cacatggagg acgagctgaa tgatcttcgc 1020agtagcttct cgaagaatga ttgtcagcta aagatctaca aattggaaat aaaagatttg 1080agcagcgccc ttgtggagaa ggagagagaa atattggact tgaaaaatac ctacgacggg 1140gaaatctgct cattaaagga tcagataaag gaaaaggaaa aggaaatcgc caaaggtagt 1200tcctccggtg gtgacgtggg tgcacaagat gagccagcta gcgaagttga aagtgaagaa 1260aaggcggacc ccaaagagga aggtgtggag aacagcttga ccgatttgct caaaatgaag 1320gaaagagagc tgcacgaaat gaaggaaaaa tacgcaaagg aaatagacac actgaatagc 1380gagctgaatg agaaaaagaa agaattcgtg gaggcaaaaa atagccacat caaccagata 1440aacaacctaa atgatgaaat tgaggagagc gaaagcaaaa tggcagaact gaaaagtggc 1500tacgaaatgg agatcaaaaa actgcgcagc gaaattaatg cagtgcacga ggagaagtac 1560ctcttgagca acgaaaaaca aacactcagt ggagagatag acaagctgaa tgaagagaag 1620aagtccctgg ccagcgagaa ggaggagcta cataacaaaa taaccacgtt gaacagcgaa 1680attgggacgt tacatgtgga gaaacaggca ctcactggag aaataaacac cttaaacgat 1740ctgattcaca ccctgaagaa tgaaatcagc tcgtcggata acctgattag caaattgaaa 1800gagcaaatga acgccatcaa cgaagaaaag gaaggaaagg aaaaactcat cacagagata 1860gaaaataatt ataaaaatga aataaacgcg ctgaaggaaa aattaaaaga cacggacaat 1920caagtgagca taagtattag ggaagagatg gaccacctca aatgcgtcct tggcgaaacg 1980gaaaaggaaa acaaacagat gaaggaggac taccacaaaa agataaaaca gtatgatgaa 2040gaattgctat cgaagcagca atattttgaa gaagaattaa ataacatacg catcaaatcg 2100cacgaaaagg aacaaatttt gattttaaaa aatgacgagt tgaaggagtc gaagctaaag 2160acggaggaga agtacctcaa gctgtacgat gacaaaatga gtctcctcag gaatatgtgc 2220tccaaagtgg ggctccccta cagcgatgaa gtttcggtgg aggagcttct cgagcgggtg 2280ggcaactacg taagtgggat gggtgaaccg gggggtgcgg cacacagggg ggagcaaagt 2340gaggagccgc atgaggggca gtcgattgtg gaggagacga atgaacccct tttgagcgcc 2400caaacggccg acaatgctaa tagcctagag gacaagacaa ccctacaggc gctacagaaa 2460gaactggaaa gtgtgcaaga agagtacaga gaagaggtag ccaaaatgaa gagctatttg 2520gcgatgaagg aaaaaacgat agaggagtcg aaccacacaa tcgccgagtt gaccggaaag 2580ataaacagcc tgaatgatac catttcgttt tttaaggtta accactctga ggagaaaatt 2640aattcctata tggacgaaat taacagcttg agcttgacgc ttagcgagct gaaggctaat 2700aatgaacagg agcagttgga gaatcgaaac gaaattgcca ggctgtcgga agagctcagc 2760gggtataagc ggcgtgctga tgagcaatgt agaaagagga gcagcgagaa ggagagaagc 2820gagtccaaga ggggagacac aagaggtgac tccgagaagg aacaaatctc cgagtcggac 2880gtggaagggg ggggcaattt aaaatccttt ttacactttc cccttcgaaa aataaaaggg 2940aaaaaaagaa aggcctctaa aactgagaag gaaatacaaa cggagcttag gagaaacgag 3000ccagagaatg aacagagtga gaaaaatgag aaggcgccta gaggagacag cctggaggtg 3060gaccagtaca aaaaggaatt ggaggaaaag gcgaagatta ttgaggactt gaaggacaaa 3120atatgcaccc tgacgaatga ggttatggat ttgaagaatt tgaagaacga gctggctgag 3180cgggatagca gcttggcgaa ggcgggcgag gaggcggaaa ggcaaagaga gcagttggac 3240acgctgagcg cccaactggg gggtgcaaac ggagaggtgg agagactcag cgaagaggtg 3300gagaggctca acgaagaggt ggagaagctg aaggagggag aggcacaatc gtggggggaa 3360gcggagaagt ggaaagggga agcagagaag tggaaagaag acgcagcgaa gtgggaagcg 3420gacacagtga aattgaaaga ggacgcagcg aaatgggaat cggacgcagt gaagtgggaa 3480tcggacgccg agacgtggag gaaagaagcg gaggaactga gaagcagcgc gaatcaattg 3540aacgaagaat tatgctcgaa ggaaaataac tacgtgttga agctgaacga aaatgtggga 3600gttatacaaa aaatgaagga ctcaattgat gcacgtgaaa aggagaagga gaattacgtt

3660cgcgagataa acgatttgag aaacgaactc gaagggttga aattgaagca tgatgcgttg 3720agtgagacgt ataagcagtt ggaggggaag agcagccccc ccagtggaga tgacccccct 3780ggtggagata actacaccag tgagggagag aataaattaa gcatcccaaa tgagaattgc 3840gaaatggacc aagcggagga agcgaatgcc aacccaggtg ttcccaagag cgaaattgcc 3900accgaggggg gtgtctcctc attggcagtg aacgattaca taagcgaaat agcgcacctg 3960aaggaagaaa taaacagact aaccctactg tatagcaacg aactgaacga aaaaaacagc 4020tctgatatta ggaccaaaga gctgctgagc cagttgaagg aactcgaagt gagggataaa 4080gaaaatgagg aaaagattgc tgcgctgagc aaaatgaatg agaaaatgaa agcgaaaaat 4140gaaaagctga aatcggggaa gtggttatct aggaaggacc acgcgccgaa tgaagaggta 4200gatatcgcag gggaggagcg taagaagaag gagaaggaga aagtgcctca cccggatgtg 4260aaagaggaga gtctgtcttc agagcatgtg aacacactgg aaggaaacac ctaccgcgtg 4320atgagaatag ttgatgaaag tagccccgcg ggaggaggcc aaataatagg gtcctacttg 4380tacaccaaaa aggtggaaga tttacacgca gtaaatggag caaatgtggc agatgcacag 4440ctggctgaga aaaacgcaat cacagttgtg tgtctaattc taagcgaaat cttaagcctc 4500ctatttttga acgatcaatt tgttaacgcc tttgaacgga taaacaaaag tctgtggaag 4560cttatgtaca tgcctgaaga gattaaagcg ctgcttctga ggtatttttc ctttatgagt 4620aagctcaggg attatgccaa ggaggtgcac gggagggtgg aaaatgagag gtatgaagac 4680agccaaaggc aggacaacca acggtacgac gattcgtggt tactttttca aaactatttg 4740gagacgtcga gtagtatcaa gagggacctg gtgtgcttca ttttggaaga gaaggaaaat 4800gaactagccg agctgggcga gcactatggt ggtggaatga gaaagggaga ggaagtaatc 4860gggggagtac gcggagtgcg cgggggaaaa atcgccgaca tcataaacct ttcaaaggac 4920gaaatgagat tgaagaccat agcacagtta agaagagacc tagattttga aaagaaatcg 4980aaaacattgc taagcaggga ttatcagttg ttactttata agtaccagga atgcgtgagg 5040aagctaaaga gggtaaaaaa tatgataagg cagctaaatc tgaacgacca ttcaaataga 5100ggcagtttcg ccttaaacag ggagctggac aggtgttccg aagtgagcaa cgagcgaggt 5160tttaacgagg aggggggtga tgaagattcg cacggaaatt acaaaaactg cattctgcaa 5220gacaataata ataatagcag tgtaaataac tataatagta gtaacaccaa attggagagt 5280cgggaaaatg ttctaatcaa ggacctaatc aatttgagga gggcgcaaaa ggtgaaggga 5340aataatttga tccactgggg ccgtcccagc atgatgatgg ggggcaggtg tcaccaagac 5400gcttcccatg tggtaagggc gatggtaaat ggacccaaaa taagcagcca gaatatcttc 5460gcacacatga acaggctgag caatgcgccc aaaattagcg accacttgga tgacatgaaa 5520aaaatgaaaa atatttttaa cgaatttgtt gaaaccagag gggacgttac gtttgtgcac 5580aggagtccct tctgcgaaac gtga 56046600PRTPlasmodium falciparum 6Met Val Phe Thr Phe Lys Asn Lys Lys Lys Lys Lys Glu Ala Ser Ser1 5 10 15Asp Lys Val Ser Lys Glu Ser Phe Asn Glu Glu Asp Asn Glu Asn Asn 20 25 30Glu Lys Arg Glu Lys Ser Asp Ser Trp Tyr Lys Lys Ile Ile Glu Thr 35 40 45Lys Gly Lys Ser Lys Thr Lys Tyr Lys Asn Asp Asn Ser Leu Asp Asp 50 55 60Asn Ile Asn Glu Asp Ile Ile Asn Asn Asn Asn Asn Asn Asn Asn Asp65 70 75 80Asn Asn Asn Asp Asn Asn Asn Asp Asn Asn Asn Asp Asn Asn Asn Asp 85 90 95Asn Asn Asn Asp Asn Asn Asn Glu Asn Asn Asn Asp Asn Asn Asn Phe 100 105 110Asn Asn Tyr Ser Asp Glu Ile Ser Lys Asn Ile Ile His Lys Asp Asn 115 120 125Glu Leu Glu Asn Gln Leu Lys Asp Thr Leu Lys Ser Ile Ser Ser Leu 130 135 140Ser Asn Lys Ile Val Asn Tyr Glu Ser Lys Ile Glu Glu Leu Glu Lys145 150 155 160Glu Leu Lys Glu Val Lys Asp Lys Asn Ile Asp Asn Asn Asp Tyr Glu 165 170 175Asn Lys Leu Lys Glu Lys Glu Asp Phe Val Lys Gln Lys Ile Asp Met 180 185 190Leu Asn Glu Lys Glu Asn Leu Leu Gln Glu Lys Glu Leu Asp Ile Asn 195 200 205Lys Arg Glu Lys Lys Ile Asn Glu Lys Glu Lys Asn Ile Ile Lys Lys 210 215 220Glu Glu Thr Phe His Asn Ile Glu Lys Glu Tyr Leu Glu Lys Asn Lys225 230 235 240Glu Arg Glu Thr Ile Ser Ile Glu Ile Ile Asp Ile Lys Lys His Leu 245 250 255Glu Lys Leu Lys Ile Glu Ile Lys Glu Lys Lys Glu Asp Leu Glu Asn 260 265 270Leu Asn Lys Lys Leu Leu Ser Lys Glu Asn Val Leu Lys Glu Leu Lys 275 280 285Gly Cys Val Lys Glu Lys Asn Glu Thr Ile Asn Ser Leu Asn Asp Asn 290 295 300Ile Ile Glu Lys Glu Lys Lys Tyr Lys Leu Leu Glu Tyr Glu Leu Glu305 310 315 320Glu Lys Asn Lys Gln Ile Asp Leu Leu Asn Lys Gln Glu Lys Glu Lys 325 330 335Glu Lys Glu Lys Glu Arg Glu Lys Glu Lys Glu Arg Glu Lys Glu Lys 340 345 350Glu Lys Glu Tyr Asp Thr Leu Ile Lys Glu Leu Lys Asp Glu Lys Ile 355 360 365Ser Ile Leu Glu Lys Val His Ser Ile Lys Val Arg Glu Met Asp Ile 370 375 380Glu Lys Arg Glu His Asn Phe Leu His Met Glu Asp Gln Leu Lys Asp385 390 395 400Leu Lys Asn Ser Phe Val Lys Asn Asn Asn Gln Leu Lys Val Tyr Lys 405 410 415Cys Glu Ile Lys Asn Leu Lys Thr Glu Leu Glu Lys Lys Glu Lys Glu 420 425 430Leu Lys Asp Ile Glu Asn Val Ser Lys Glu Glu Ile Asn Lys Leu Ile 435 440 445Asn Gln Leu Asn Glu Lys Glu Lys Gln Ile Leu Ala Phe Asn Lys Asn 450 455 460His Lys Glu Glu Ile His Gly Leu Lys Glu Glu Leu Lys Glu Ser Val465 470 475 480Lys Ile Thr Lys Ile Glu Thr Gln Glu Leu Gln Glu Met Val Asp Ile 485 490 495Lys Gln Lys Glu Leu Asp Gln Leu Gln Glu Lys Tyr Asn Ala Gln Ile 500 505 510Glu Ser Ile Ser Ile Glu Leu Ser Lys Lys Glu Lys Glu Tyr Asn Gln 515 520 525Tyr Lys Asn Thr Tyr Ile Glu Glu Ile Asn Asn Leu Asn Glu Lys Leu 530 535 540Glu Glu Thr Asn Lys Glu Tyr Thr Asn Leu Gln Asn Asn Tyr Thr Asn545 550 555 560Glu Ile Asn Met Leu Asn Asn Asp Ile His Met Leu Asn Gly Asn Ile 565 570 575Lys Thr Met Asn Thr Gln Ile Ser Thr Leu Lys Asn Asp Val His Leu 580 585 590Leu Asn Glu Gln Ile Asp Lys Leu 595 600726PRTPlasmodium falciparum 7Lys Gln Glu Lys Glu Lys Glu Lys Glu Lys Glu Arg Glu Lys Glu Lys1 5 10 15Glu Arg Glu Lys Glu Lys Glu Lys Glu Tyr 20 25828PRTPlasmodium falciparum 8Lys Asn Leu Lys Thr Glu Leu Glu Lys Lys Glu Lys Glu Leu Lys Asp1 5 10 15Ile Glu Asn Val Ser Lys Glu Glu Ile Asn Lys Leu 20 25941PRTPlasmodium falciparum 9Ser Lys Lys Glu Lys Glu Tyr Asn Gln Tyr Lys Asn Thr Tyr Ile Glu1 5 10 15Glu Ile Asn Asn Leu Asn Glu Lys Leu Glu Glu Thr Asn Lys Glu Tyr 20 25 30Thr Asn Leu Gln Asn Asn Tyr Thr Asn 35 401029PRTPlasmodium falciparum 10Lys Glu Glu Tyr Glu Asp Lys Met Asn Thr Leu Asn Glu Gln Asn Glu1 5 10 15Asp Lys Met Asn Ser Leu Lys Glu Glu Tyr Glu Asn Lys 20 251144PRTPlasmodium falciparum 11Lys Gly Leu Lys Lys Glu Val Glu Glu Lys Glu His Lys Arg His Ser1 5 10 15Ser Phe Asn Ile Leu Lys Ser Lys Glu Lys Phe Phe Lys Asn Ser Ile 20 25 30Glu Asp Lys Ser His Glu Leu Lys Lys Lys His Glu 35 401230PRTPlasmodium falciparum 12Lys Asp Lys Ser Lys Glu Lys Ile Lys Asp Lys Glu Asn Gln Ile Asn1 5 10 15Val Glu Lys Asn Glu Glu Lys Asp Leu Lys Lys Lys Asp Asp 20 25 301329PRTPlasmodium falciparum 13Glu Asp Glu Lys Lys Arg Asn Leu Asn Glu Ile Asn Asn Leu Lys Lys1 5 10 15Lys Asn Glu Asp Met Cys Ile Lys Tyr Asn Glu Met Asn 20 251428PRTPlasmodium falciparum 14Lys Thr Asn Lys Glu Asn Glu Glu Lys Ile Ile Asn Leu Thr Ser Gln1 5 10 15Tyr Ser Asp Ala Tyr Lys Lys Lys Ser Asp Glu Ser 20 251525PRTPlasmodium falciparum 15Ser Asn Asn Asn Ile Arg Thr Asn Glu Tyr Lys Tyr Glu Glu Met Phe1 5 10 15Asp Thr Asn Ile Glu Glu Lys Asn Gly 20 251625PRTPlasmodium falciparum 16Gly Asn Ile Ser Asn Lys Asn Glu Asn Asn Asn Lys Lys Asn Asn Thr1 5 10 15Cys Asp Gly Tyr Asp Glu Lys Val Thr 20 251745PRTPlasmodium falciparum 17Ile Lys Thr Met Asn Thr Gln Ile Ser Thr Leu Lys Asn Asp Val His1 5 10 15Leu Leu Asn Glu Gln Asp Lys Leu Asn Asn Glu Lys Gly Thr Leu Asn 20 25 30Ser Lys Ile Ser Glu Leu Asn Val Gln Ile Met Asp Leu 35 40 451825PRTPlasmodium falciparum 18Leu Leu Ser Lys Asp Lys Glu Ile Glu Glu Lys Asn Lys Lys Ile Lys1 5 10 15Glu Leu Asn Asn Asp Ile Lys Lys Leu 20 251949PRTPlasmodium falciparum 19Ile Cys Ser Leu Thr Thr Glu Val Met Glu Leu Asn Asn Lys Lys Asn1 5 10 15Glu Leu Ile Glu Glu Asn Asn Lys Leu Asn Leu Val Asp Gln Gly Lys 20 25 30Lys Lys Leu Lys Lys Asp Val Glu Lys Gln Lys Lys Glu Ile Glu Lys 35 40 45Leu2077PRTPlasmodium falciparum 20Val Asp Lys Ile Glu Glu His Ile Leu Asp Tyr Asp Glu Glu Ile Asn1 5 10 15Lys Ser Arg Ser Asn Leu Phe Gln Leu Lys Asn Glu Ile Cys Ser Leu 20 25 30Thr Thr Glu Val Met Glu Leu Asn Asn Lys Lys Asn Glu Leu Ile Glu 35 40 45Glu Asn Asn Lys Leu Asn Leu Val Asp Gln Gly Lys Lys Lys Leu Lys 50 55 60Lys Asp Val Glu Lys Gln Lys Lys Glu Ile Glu Lys Leu65 70 752125PRTPlasmodium falciparum 21Leu Asp Glu Asn Glu Asp Asn Ile Lys Lys Met Lys Ser Lys Ile Asp1 5 10 15Asp Met Glu Lys Glu Ile Lys Tyr Arg 20 252225PRTPlasmodium falciparum 22Leu Asp Glu Asn Glu Asp Asn Ile Lys Lys Met Lys Ser Lys Ile Asp1 5 10 15Asp Met Glu Lys Glu Ile Lys Tyr Arg 20 252327PRTPlasmodium falciparum 23Thr Ile Ser Ser Leu Ser Asn Lys Ile Val Asn Tyr Glu Ser Lys Ile1 5 10 15Glu Glu Leu Glu Lys Glu Leu Lys Glu Val Lys 20 252425PRTPlasmodium falciparum 24Ile Ile Asp Ile Lys Lys His Leu Glu Lys Leu Lys Ile Glu Ile Lys1 5 10 15Glu Lys Lys Glu Asp Leu Glu Asn Leu 20 252538PRTPlasmodium falciparum 25Ile Lys Thr Met Asn Thr Gln Ile Ser Thr Leu Lys Asn Asp Val His1 5 10 15Leu Leu Asn Glu Gln Asp Lys Leu Asn Asn Glu Lys Gly Thr Leu Asn 20 25 30Ser Lys Ile Ser Glu Leu 35

Claims

1-23. (canceled)

24. A vaccine V comprising: (A) at least one isolated polypeptide strand P comprising or consisting of at least nine consecutive amino acid moieties of SEQ ID NO: 2, of SEQ ID NO: 3 or of SEQ ID NOs: 2 and 3, or a polynucleotide strand encoding for said polypeptide strand P; and (B) at least one pharmaceutically acceptable carrier or excipient.

25. The vaccine V of claim 24, wherein the isolated polypeptide strand P is obtained from heterologous expression.

26. The vaccine V of claim 24, wherein the isolated polypeptide strand P is obtained from heterologous expression in bacterial or eukaryotic cells.

27. The vaccine V of claim 24, wherein the at least one isolated polypeptide strand P comprises or consists of at least nine consecutive amino acid moieties of a sequence having at least 80% sequence homology to a peptide sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

28. The vaccine V of claim 24, wherein said vaccine V comprises an adjuvant supporting immunologic stimulation.

29. The vaccine V of claim 24, wherein said vaccine V comprises at least one adjuvant supporting immunologic stimulation selected from the group consisting of alum and an immunostimulatory peptide.

30. The vaccine V of claim 24, wherein the at least one isolated polypeptide strand P consists of or comprises a peptide strand having at least 80% sequence homology to sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression.

31. The vaccine V of claim 24, wherein the at least one isolated polypeptide strand P consists of or comprises a peptide strand having a sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression.

32. The vaccine V of claim 24, wherein the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising or consisting of a fraction of SEQ ID NO: 2 truncated by at least 100 amino acid moieties in length and comprising at least two peptide sequences selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

33. The vaccine V of claim 24 wherein the at least one isolated polypeptide strand P is a truncated version of SEQ ID NO: 2 comprising or consisting of a fraction of SEQ ID NO: 2 truncated by at least 100 amino acid moieties in length and comprising all of the peptide sequences SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

34. The vaccine V of claim 24, wherein said vaccine V comprises or consists of: (A) at least one isolated polypeptide strand P comprising or consisting of a peptide strand having at least 80% sequence homology to a sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression; and (B) at least one adjuvant supporting immunologic stimulation and optionally one or more further pharmaceutically acceptable carriers.

35. The vaccine V of claim 24, wherein said vaccine V comprises or consists of: (A) at least one isolated polypeptide strand P comprising or consisting of a peptide strand of sequence SEQ ID NO: 2 or SEQ ID NO: 3 obtained from heterologous expression; and (B) at least one adjuvant supporting immunologic stimulation selected from the group consisting of alum and an immunostimulatory peptide, and optionally one or more further pharmaceutically acceptable carriers.

36. The vaccine V of claim 24, wherein the polynucleotide strand encoding for said polypeptide strand P is double or single stranded DNA or double or single stranded RNA, or an analogue of double or single stranded DNA or double or single stranded RNA.

37. The vaccine V of claim 24, wherein the polynucleotide strand encoding for said polypeptide strand P is a plasmid.

38. A method for preventing malaria in a patient, wherein the patient is administered with a sufficient amount of a vaccine V of claim 24.

39. A method for preparing an antibody AB binding to Plasmodium falciparum or Plasmodium vivax comprising the following steps: (i) providing: (a) a vaccine V according to claim 24, and (b) an organism O suitible for generating antibodies; (ii) administering the organism O with the vaccine V; (iii) waiting until the subjected organism of step (ii) shows an immune response against the antigens of the vaccine V; (iv) obtaining antibody-generating cells C of the organism O of step (iii); (v) optionally hybridizing the antibody-generating cells of step (iv) with myeloma cells obtaining immortalized antibody-generating cells C1; (vi) optionally isolating the nucleotide encoding for the antibody AB of interest and transfer it to another antibody-generating cell type C2 suitible for expressing the antibody AB; (vii) cultivating the antibody-generating cells C, C1 or C2 of any of steps (iv) to (vi) under conditions enabling the production of the antibody AB; and (viii) isolating the antibody AB from step (vii).

40. An antibody or antibody fragment AB binding a polypeptide strand P SEQ ID NO: 2 or SEQ ID NO: 3 or a polynucleotide strand encoding for said polypeptide strand P with a dissociation constant of not more than 1000 nM.

41. An antibody or antibody fragment AB binding a polypeptide strand P SEQ ID NO: 2 or SEQ ID NO: 3 or a polynucleotide strand encoding for said polypeptide strand P with a dissociation constant of not more than 1000 nM, wherein said antibody or antibody fragment AB is obtained from a method of claim 39.

42. The antibody or antibody fragment AB of claim 40, wherein said antibody or antibody fragment AB is a monoclonal humanized antibody.

43. The antibody or antibody fragment AB of claim 40, wherein said antibody or antibody fragment AB bears a binding affinity to a polypeptide strand P of SEQ ID NO: 2 or SEQ ID NO: 3 of a dissociation constant of not more than 100 nM, not more than 50 nM, not more than 20 nM, not more than 10 nM, or not more than 5 nM.

44. A method for treating or preventing malaria in a patient, wherein the patient is administered with a sufficient amount of an antibody or antibody fragment AB of claim 40.

45. A method for diagnosing malaria in a patient, wherein the patient is administered with a sufficient amount of an antibody or antibody fragment AB of claim 40.

46. A method for staining Plasmodium falciparum or Plasmodium vivax in vitro, said method comprising the steps of: (i) providing (a) an optionally fixed sample S containing Plasmodium falciparum or Plasmodium vivax, and (b) an optionally stained antibody or antibody fragment AB according to claim 40; (ii) contacting the sample S with the optionally stained antibody or antibody fragment AB; (iii) optionally contacting the treated sample of step (ii) with a second antibody or antibody fragment AB2 which is stained and selectively binds to the antibody or antibody fragment AB.