TW200938633A - Vaccine - Google Patents

Abstract

The invention relates to a replication deficient simian adenoviral vector C7 encoding a protein comprising CS protein form P. falciparum or a fragment thereof, for example as shown in Seq ID No: 1 or Seq ID No: 3. The invention also relates to processes of preparing said viral vector and use of the viral vector in the treatment/prevention of malaria infection. Compositions, vaccines and kits comprising said viral vector are also described. In one aspect the invention employs a synthetic C7 viral vector. The C7 viral vector according to the invention may be co-administered or co-formulated with a malaria antigen such as RTS, S optionally in the presence of an adjuvant for example comprising 3D-MPL and/or a saponin such as QS21.

Description

200938633 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel malaria antigen derived from a sputum adenoviral vector, which specifically encodes a circumsporozoite protein derived from Plasmodium falciparum. The invention further relates to a method of preparing the viral vector and to the use of the viral vector for treating/preventing a malaria infection. [Prior Art]

Dysentery is the world's main health (four) problem, and more than 2 to 4 million people die from the disease each year. One of the most serious forms of the disease is caused by the protozoan parasite Plasmodium falciparum, which is the cause of most deaths due to malaria. The life cycle of Plasmodium falciparum is complex and requires two hosts. (Human and mosquito) can be completed. Human infection begins by infecting mosquito bites in the bloodstream to inoculate sporozoites. The sporozoites migrate to the liver and infect the liver cells there, where the sporozoites pass through cells outside the red blood cells. The internal phase differentiates into a merozoite phase, which can infect red blood cells (RBC) to begin circulating replication during the asexual blood phase. This is accomplished by the differentiation of many merozoites in RBC into sexually-producing gametophytic cells taken up by mosquitoes. This cycle, in which it develops in the midgut via a series of periods to produce sporozoites that migrate to the salivary glands. The sporozoite period of the protozoa has been identified as a potential target for malaria vaccines. It has not been shown, inoculation inactivated (irradiated) Spore vaccines can induce protection against experimental human malaria (Am. J, Trop. Med. Hyg 24: 297-402, 1975). However, based on this method, irradiation sporozoites are used. Both logically and logically 136387.doc 200938633 can produce malaria vaccine for the general population. The main surface protein of sporozoites is known as circumsporozoite protein (cs protein). It is believed that it is inoculated with sporozoites from mosquitoes. The movement from the initial position to the circulation (where it migrates to the liver) is related to movement and invasion. • The cs protein of Plasmodium is characterized by a central repeat domain (repeating region) with non-repetitive amine groups (7)-ends) And a carboxyl (C-terminal) fragment. To date, the most advanced clinical malaria vaccines are based on lipoprotein particles (also known as virus-like particles) called Φ, Φ. The granule contains a portion of the CS protein of Plasmodium falciparum, which substantially corresponds to 207-395 of the CS protein of Plasmodium falciparum (strain NF54 [3D7]) fused to the N-terminus of Skogen from Hepatitis B Amino acid. The S antigen may comprise a portion of preS2.

Rts, s particles are usually delivered together with a strong adjuvant. However, the cancer vaccine can be used as a recombinant adenovirus vector, for example, WO 2004/055187, which describes certain viral vectors including a specific glandular 5 (Ad5) and a gland 35 (Ad 35) vector encoding the CS protein (both of which) Derived from human adenosis Φ poison). Human adenovirus has more than 40 different serotypes, and its pathogenicity is different. & Ad5 is associated with mild respiratory infection in children.

Ad4 and Ad7 are associated with respiratory infections in adults and are believed to cause Ad4〇. Infant diarrhea. According to '^ is immune to adenovirus infection and will last for life. Pre-existing immunity to, inter alia, Ad5 and Ad35 is believed to result in neutralization of the human adenovirus-based / alpha adenopathy vector. Since the vector is prevented from entering the cells and the relevant antigen is produced in vivo, the therapeutic effect is lowered. 136387.doc 200938633 [Summary of the Invention] It is believed that 纟Invention II overcomes the pre-existing immune problem by providing a vaccine for preventing and/or treating dysentery, which comprises: a replication-deficient simian adenovirus vector C7 (also known as Pan) 7 or CV-33), which encodes a protein comprising a CS protein of Plasmodium falciparum or a fragment thereof, such as shown in Seq ID No: 1 or Seq ID No: 3.

BRIEF DESCRIPTION OF THE SEQUENCES Seq ID No: 1 Amino acid sequence of a protein/antigen derived from the CS protein of Plasmodium falciparum (herein referred to as Ade2 protein) Seq ID No: 2 Nucleic acid sequence encoding a protein of Seq ID No: 1. (herein referred to as Ade2 gene) Seq ID No: 3 Substituted amino acid sequence of protein/antigen derived from the CS protein of Plasmodium falciparum (herein referred to as Ade 1 protein) Seq ID No: 4 Encoding Seq ID No: 3 Nucleic acid sequence of the protein (herein referred to as Adel gene) Seq ID No: 5 Capsid protein sequence from chimpanzee gland 7 (seq ID No 17 from WO 03/046124) Seq ID No: 6 Amino group from chimpanzee gland 7 Acid sequence (seq ID No 20 from WO 03/046124) Seq ID No: 7 Amino acid sequence from the CS protein of M. falciparum Seq ID No: 8 Amino acid sequence from the CS protein of Plasmodium falciparum Seq ID No: 9 Amino acid sequence from the CS protein of Plasmodium falciparum Seq ID No: 10 Amino acid sequence from the CS protein of M. falciparum 136387.doc 200938633

Seq ID No: 11 Seq ID No: 12 Seq ID No: 13 Seq ID No: 14 Seq ID No: 1 5 Seq ID No: 16 Seq ID No: 1 7

Seq ID No: 18

Seq ID No: 19

Nucleotide sequence of CpG 1826 CpG 1758 nucleotide sequence CpG nucleotide sequence CpG 2006 nucleotide sequence CpG 1668 nucleotide sequence CpG 5456 nucleotide sequence display is selected into C7 adenovirus vector The nucleotide sequence of the alternative expression cassette of the Ade2 expression cassette shows that the nucleotide sequence of the Ade2 expression cassette cloned into the C7 adenoviral vector displays the complete nucleotide sequence of the synthetic recombinant vector C7-Ade2. The sequence and preparation of ❷C7 is described in WO 2003/046124. WO 2003/(Sequence ID No: 6 (pentagon sequence), 9 (nucleic acid sequence), 10 and 11 (hexon sequence) and 12 (fibrin) of M6124 are incorporated by reference. [ATCC VR-593] The characteristics and properties of any given adenoviral vector are generally unique, despite the hypothesis that vectors can be grouped and adenoviral vectors within a given family can have similar characteristics. This is particularly advantageous because it appears to be more stable than certain other known vectors (e.g., C6 also described in WO 2003/046124) after insertion of the gene encoding the protein. That is, C7 is considered less prone to reassembly. Of course' It is important that any adenoviral vector used in the vaccine is stable, as the pharmaceutical product needs to be fully characterized and shown to be stable and safe before being sold. 136387.doc 200938633 is available for sale. It is believed that the pre-existing immunity to C7 is extremely low, and therefore The risk is also low in the viral vector after the first administration to the patient. In addition, it is believed that C7 has one or more other properties that may make it particularly suitable for human administration and/or suitable for in vivo production. Immunology Reaction. In one aspect, the invention employs a synthetic C7 viral vector, which may be particularly suitable for obtaining regulatory approval for administration to humans. In one aspect, the last 12- of the dysentery antigen component of the CS protein is removed. 14 amino acids. In one aspect, the malaria antigen encoded by the adenoviral vector is modified to remove potential glycosylation sites, for example, the amino acid alanine can be substituted for serine, such as Seq ID No : 1 is shown at about position 379. In one aspect of the invention, the protein/antigen used comprises the following amino acids: NNGDNGREGKDEDKRDGNN [Seq ID No: 7] Depending on the case, the amino acid is 8 1 -99. In one aspect, the encoded protein/antigen comprises the following amino acids: AIGL [Seq ID No: 8] eg at the C-terminus. In one aspect, the invention employs a protein comprising the following amino acids:

PNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNVDPN

ANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANAN

PNANPNANPNANPNANPNANPN

[Seq ID No: 9] 136387.doc • 10- 200938633 In one aspect, the invention employs a protein comprising the following amino acids:

NANP NVDP NANP NVDP NANP NVDP NANP NANP NANP NANP

NANP NANP NANP NANP NANP NANP NANP NVDP NANP NANP

NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP

NANP NANP NANP NANP NANP NANP

[SeqlDMo: 10]. • In another aspect, the protein/antigen used comprises Seq ID No. 7 and/or

Seq ID No. 8 and/or Seq ID No 9 sequence. In another aspect, the protein/antigen used comprises Seq ID No. 7 and/or φ Seq ID No. 8 and/or Seq ID No 10 sequences. In one aspect, the encoded protein/antigen system Seq ID No: 1 or 3 °

The protein sequences shown in Seq ID No: 1 are novel and constitute an aspect of the invention. A polynucleotide encoding a protein sequence of Seq ID No: 1 also constitutes an aspect of the invention, particularly the polynucleotide sequence of Seq ID No: 2. This polynucleotide sequence (ID No: 2) has been codon optimized for expression in humans. The polynucleotide sequence encoding the protein of Seq ID No: 1 can be optimized by codon usage as needed. " The invention also extends to novel hybrid fusion proteins for the preparation of Seq ID No: 1 or vectors/plasmids/hosts for the preparation of viral vectors of the invention. When a protein needs to be prepared and isolated, the sequence encoding the protein can be inserted into a suitable host for synthesis using a suitable plasmid. An example of a suitable plasmid is for the 2 micron vector pRIT 15546 carrying the appropriate expression cassette. The plasmid will typically contain an intrinsic marker to aid in selection, such as a gene encoding antibiotic resistance or LEU2 136387.doc •11 - 200938633 or HIS auxotrophs. The host cell may be a prokaryotic or eukaryotic cell, but is preferably a yeast, such as a yeast (eg, Saccharomyces cerevbz'ae), such as DC5 in the ATCC database (Accession No. 20820) and named RIT DC5 cir (o) ) · Depositor: Smith Kline-RIT) and non-yeast yeast yeast. These include the genus Schizosaccharomyces (eg, S. cerevisiae, Kluyveromyces (^/i^veromyce·?) (eg Kluyveromyces cerevisiae m (A'/ifyveromyce·? /aciz) ···)), Pichia (Pz'c/π'α) (eg, P. sinensis (P/c/π'α pasiorb)), Hansenula (i/im> se «w/a) (eg Hansenula polymorpha (ugly p〇/less wc?rp/m)), Yarrowia (Γα""ονν/α) (eg Yarrowia lipolytica ( rarrovWa / φο / ;; ίί · <7 〇 and Schwangyotes such as Schwariniomyces occidentalis'f ° ° In one aspect, the present invention provides the vector of the present invention or Seq ID No 1 Use of a protein for the treatment or prevention of dysentery. In one aspect, the invention provides a pharmaceutical formulation comprising a viral vector of the invention and an excipient such as an isotonic carrier suitable for injection. Suitable excipients: It will be discussed in more detail below. In one embodiment, the formulation comprises: • an adenoviral vector of the invention, • a malaria antigen (eg, a lipoprotein particle, specifically an RTS) S) and • if necessary, include adjuvants such as saponin and/or 3D-MPL. When the vector encodes the Seq ID No: 1 sequence, the vector is particularly suitable for use of 136387.doc 200938633 with a protein called RTS, S The treatment regimen is that the protein encoded by the adenoviral vector should correspond as closely as possible to the "rt" component of RTS, S. It is believed that the carrier can be used in the scheme of using RTS, S. Effectively enhances the efficacy of RTS, S. The viral vectors described herein are suitable for use as a component of a malaria vaccine. The viral vectors of the invention may need to be used in combination with other components, including other antigens, to provide adequate protection against infection. The vector of the invention is at least suitable for use as a component of a vaccine or treatment regimen.

RTS, S can be prepared as described in 胥〇 93/10152 (e.g., from the Plasmodium falciparum NF54/3D7 strain). The nucleotide sequence of the RTS display cassette and the predicted translation product are provided in Figure 9 of WO 93/10152 (herein referred to as RTS*). In the context of this specification, an excipient refers to a component of a pharmaceutical formulation that does not itself have a therapeutic effect. The definition of excipients encompasses diluents or carriers. Suitable carriers include PBS, saline, and the like. This definition of excipient also encompasses adjuvants, since this effect is prevalent when the adjuvant may have an in vivo physiological effect and is not a unique therapeutic effect in the absence of a therapeutic component. Adjuvants. Specific adjuvants are selected from the group consisting of metal salts, oil-in-water emulsions, toluene-like receptor agonists (specifically, steroid receptor 2 agonists, classes) A purine receptor 3 agonist, a terpenoid receptor 4 agonist, a terpenoid receptor 7 agonist, a terpenoid receptor 8 agonist, and a terpenoid receptor 9 agonist), soap or a combination thereof. 136387.doc -13- 200938633 In one embodiment, the adjuvant is a terpenoid receptor (TLR) 4 ligand, such as, for example, a lipid A derivative (specifically, monophosphorus lipid A or more specifically 3 An agonist such as deazepine monophosphonium lipid A (3D-MPL). 3. Deaminyl monophosphonium lipid A is known from U.S. Patent No. 4,912,094 and U.S. Patent Application Serial No. 2,220,211 (Ribi) and is available from Ribi Immunochem, Montana, USA. 0 3D-MPL is a trademark of MPL®. Corixa sells and primarily promotes the CD4+ T cell response of the IFN-g (Thl) phenotype. It can be produced according to the method disclosed in the British Patent No. 2 220 211 A. Chemically, it is a mixture of 3_demethylated monophosphorus-grown lipid A and a 3, 4, 5 or 6 deuterated chain. Small particles 3D-MPL are typically used in the compositions of the invention. The small particle 3D-MPL has a particle size which allows it to be sterile filtered through a 〇22 μιη filter. These formulations are described in WO 94/2 1292. Synthetic derivatives of lipid oxime are known and are considered to be TLR 4 agonists including, but not limited to: OM174 (2-deoxy-6-0-[2-deoxy-2-[(R)-3-) Di-bristyloxytetrakis-ylamino]-4-0-linyl-β-D-glucopyranosyl]-2-[(R)-3-hydroxytetradecylamino] -α-D-«pyranosyl dihydrogen phosphate (WO 95/14026) ' OM 294 DP (3S,9R)-3_[(R)-dodecyldecyloxytetradecylamino ]-4-oxo-5-aza-9(R)-[(R)-3-ylaminotetrahydrofuranylamino] 癸-1,10-diol, 1,10-bis (phosphoric acid) Hydrogen esters) (WO 99/64301 and WO 00/0462), OM 197 MP-Ac DP (3S-, 9R)-3-[(R)-dodecyldecyloxytetraentylamino]- 4-oxo-5-aza-9-[(R)-3-carbyl-tetradecylamino] 136387.doc 200938633 癸-1,10-diol, 1-dihydrogen phosphate 10-( 6-Aminohexanoate) (WO 01/46127) ° Typically, when 3D-MPL is used, the antigen and 3D-MPL are delivered as an oil-in-water emulsion or as a plurality of oil-in-water emulsions. The inclusion of 3D-MPL is advantageous because of its stimulatory effect on the T-cell response of the effector. Other TLR4 ligand systems can be used, such as amino glucoside phosphate alkyl ester (AGP), for example, as disclosed in WO 9850399 or U.S. Patent No. 6,303,347 (also discloses a method for preparing AGP) or as US Patent No. 6764840 A pharmaceutically acceptable salt of AGP as disclosed in the number. Some AGP are TLR4 agonists and some are TLR4 antagonists. Both are believed to be used as adjuvants. Another immunostimulant that can be used in the present invention is Quil A and its derivatives. Quil A is a saponin preparation isolated from the South American tree species Quillai Sapowar/a Μσ/ζ·«α and was first introduced in 1974 by Dalsgaard et al. ("Saponin adjuvants", Archiv. fiir die gesamte Virusforschung > Volume 44, Springer Verlag, Berlin, pp. 243-254) illustrates adjuvant activity. Purified fragments of Quil A that retain adjuvant activity without the toxicity associated with Quil A (European Patent No. 0 362 278), such as QS7 and QS21 (also known as QA7 and QA21), have been isolated by HPLC. QS21 is a natural saponin derived from the bark of Quilla sinensis, which induces CD8+ cytotoxic T cells (CTL), Th1 cells, and significant IgG2a antibody responses. Specific formulations of QS21 have been described which further comprise steroids (WO 96/33739). The ratio of QS21 to steroid is typically from about 1:100 to 1:1 weight/weight. Excess steroids are typically present wherein the ratio of QS21 to steroid 136387.doc 15 200938633 is at least 1:2 w/w. Typically, for human administration, QS21 and steroids present in the vaccine range from about 1 Torr to about 1 Torr, for example from about 10 pg to about 50 gg per dose. Liposomal formulations usually contain a neutral lipid, such as phospholipid choline (which is a non-crystalline form at room temperature), such as egg yolk fat filling test, two oil-based fat-filled fat test, or birch Diliuryl fat filling test. Liposomes may also contain charged lipids which increase the stability of the liposome _QS21 structure of lipids composed of saturated lipids. In such cases, the amount of charged lipid is typically from 1 to 20% w/w, such as from 5 to 10%. The ratio of steroid to slag is 1-50% (mol/mol), for example 20-25%. These compositions may contain MPL (3-dedecylmonophosphonium lipid a, also known as 3D-MPL). A mixture of three types of de-indole-deuterated monophosphonium lipid A and a 4, 5 or 6 deuterated chain of 3D-MPL was obtained from British Patent No. 2,220, 21 (Ribi) and manufactured by Ribi Immunochem, Montana. Saponins may be in the form of micelles, mixed micelles (usually but not exclusively φ containing bile salts), or may be in the form of an ISCOM matrix (European Patent No. 〇ι 9942), when formulated with cholesterol and lipids It is in the form of a liposome or a phase. It is in the form of a gelatinous structure (such as a spiral-like or ring-like polymer complex or a lipid-layer/layer structure and a sheet), or in the form of an oil-in-water emulsion (for example, w〇• Said in 95/17210). Generally, saponins are provided in the form of liposome formulations, ISCOM or oil-in-water emulsions. Immunostimulatory nucleotides can also be used. Examples of nucleotides for use in adjuvants or vaccines of the invention include nucleotides containing CpG, which typically contain 136387.doc -16 - 200938633 having two or more by at least three, more preferably at least A dinucleotide CpG motif separated by six or more nucleotides. The CpG motif is a cytosine nucleotide followed by a guanine nucleotide. CpG nucleotides are usually deoxynucleotides. In one embodiment, the internucleotide linkage in the oligonucleotide is a phosphorodithioate, or more preferably a phosphorothioate linkage, but the scope of the invention encompasses phosphodiesters and other internucleotide linkages. . Also included within the scope of the invention are nucleotides having mixed internucleotide linkages. A method of preparing a phosphorothioate nucleotide or a dithiophosphorate is described in U.S. Patent No. 5,666,153, U.S. Patent No. 5,278,302, and WO 95/26204. Examples of oligonucleotides are as follows: TCC ATG ACG TTC CTG ACG TT (CpG 1826) [SeqlDNo: 11] TCT CCC AGC GTG CGC CAT (CpG 1758) [Seq ID No: 12] ACC GAT GAC GTC GCC GGT GAC GGC ACC ACG [SEQ ID No: 13] TCG TCG TTT TGT CGT TTT GTC GTT (CpG 2006) [Seq ID No: 14] TCC ATG ACG TTC CTG ATG CT (CpG 1668) [Seq ID No: 15] TCG ACG TTT TCG GCG CGC GCC G (CpG 5456), [Seq ID No: 16] These sequences may contain phosphorothioate-modified internucleotide linkages. An alternative CpG oligonucleotide may comprise one or more of the above sequences due to negligible deletion or addition of such oligonucleotides.

CpG oligonucleotides can be synthesized by any method known in the art (see, for example, European Patent No. 468520). For convenience, these nucleotides can be synthesized using an automated synthesizer. Examples of TLR 2 agonists include peptidoglycans or lipoproteins. °m β sits and rinses (eg, Imiquimod and Resimotte 136387.doc -17- 200938633 (Resiquimod)) are known TLR7 agonists. Single-stranded RNA is also known as a TLR agonist (TLR8 in humans and TLR7 in mice), while double-stranded RNA and poly-IC (commercially synthesized mimics of polyinosinic acid-polycytidine-viral RNA) are An example of a TLR3 agonist. 3D-MPL is an example of a TLR4 agonist, and an example of a CpG line TLR9 agonist. It can be used as an alternative or an additional immunostimulant. In one embodiment, the immunostimulatory agent is 3-dethiol monophosphonium lipid A (3D-MPL). In one aspect, the adjuvant comprises 3D-MPL. In one aspect, the adjuvant comprises QS21. In one aspect, the adjuvant comprises CpG. In one aspect, the adjuvant is formulated into an oil-in-water emulsion. In one aspect, the adjuvant is formulated into a liposome. Adjuvant combinations include 3D-MPL and QS21 (European Patent No. 0 671 948 B1) oil-in-water emulsions, or liposome formulations containing 3D-MPL and QS21, or 3D-MPL formulated with other carriers ( European Patent No. 689 454 B1). Other preferred adjuvant systems comprise a combination of 3D-MPL, QS21 and CpG oligonucleotides as described in U.S. Patent Nos. 6,558,670 and 6,544,518. Formulations Vaccine preparation is outlined in New Trends and Developments in Vaccines (Voller et al., ed., University Park Press, Baltimore, Maryland, U.S.A., 1978). For example, the encapsulation of liposomes is described by Fullerton in U.S. Patent No. 4,235,877. I36387.doc 18 200938633 The formulations of the invention are useful for both prophylactic and therapeutic purposes. Accordingly, the present invention provides a vaccine composition as described herein for use in medicine, for example, for the treatment and/or prevention of malaria. In one aspect, the invention provides a composition comprising a C7 adenoviral vector of the invention and a malaria antigen (eg, a novel antigen of RTS, S or Seq ID No: 1 or a virus-like particle thereof) and an excipient, Adjuvants are present as needed. 'Immunity in the context of the present specification is intended to mean the ability to elicit an immune response, wherein the response is specific to the malaria component of the relevant formulation. This reaction may require the presence of a suitable adjuvant and/or boost. For example, a booster containing a dose similar to or less than the initial dose may be required to achieve a suitable immunogenic response. The compositions/pharmaceutical formulations of the invention may also comprise a mixture of one or more other antigens, such as those derived from Plasmodium falciparum and/or P. vivax (WWx), for example, wherein the antigenic line is selected from DBP. , PvTRAP, PvMSP2, PvMSP4, PvMSP5, PvMSP6, PvMSP7, • PvMSP8, PvMSP9, PvAMAl and RBP or fragments thereof. In other examples, antigens derived from Plasmodium falciparum include PfEMP-1, Pfs 16 antigen, MSP-1, MSP-3, LSA-1, LSA-3, AMA-1, and TRAP. Other Plasmodium antigens include Plasmodium falciparum EBA, GLURP, RAP1, RAP2, clamp protein, Pf332, STARP, SALSA, PfEXP1, Pfs25, Pfs28, PFS27/25, Pfs48/45, Pfs230 and other Plasmodium genus Similarity. The invention also relates to the use of C7 encoding a malaria antigen, such as, for example, as described herein for the treatment and/or prevention of dysentery, or for the preparation of a medicament for use herein 136387.doc -19-200938633. The invention also encompasses a method of treatment comprising administering one or more aspects of the invention in a therapeutically effective amount. Optionally, the C7 viral vector of the present invention may be associated with a cancerous antigen (eg, an antigen of RTS, S or Seq ID No. 1), for example, in the presence of an adjuvant comprising 3D-MPL and/or saponin (eg, QS21). Co-invest or co-distribute together. The C7 vector can also be co-administered or co-administered with another different serotype and/or source of adenoviral vector 编码 (encoding the same or different antigens). The invention also extends to any of the aspects defined herein for use in a prime boost regimen, for example wherein a priming dose is administered at a time point (subsequently, for example, within 3 months), the reinforcement is for example At the end of the last priming dose, about 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks, further booster injections may be performed up to 1 year after the initial booster injection. Advantageously, one or more aspects of the invention (including the combination vaccine described above) stimulate specific body fluids (ie, antibody responses) and/or cellular immune responses (eg, CD8 + & / Φ or CD4+), such as antibody responses and CD 8 + and / or CD4 + reactions, especially CD8 + and antibody reactions. That is, it has a specific reaction to the cs protein and/or the 8 antigen (if necessary). · This type of balanced immune response may be needed to obtain so-called sterilization protection - to protect against malaria infection. Furthermore, the combined antibody response may be enhanced compared to antibody responses using only the adjuvanted regime scheme. In one embodiment, the invention provides for use as a prime or boost in a prime boost regimen, as a supplement to the regimen: I36387.doc • 20· 200938633 • C7 encoding the same or different malaria antigens An adenoviral vector; another viral vector, such as a human adenoviral vector (eg, Ad5 or Ad35) encoding a malaria antigen (eg, a CS protein of Plasmodium falciparum) or a serotype adenoviral vector (ie, non-C7); And/or • malaria antigens such as RTS, S, etc. and adjuvants comprising, for example, saponins and/or 3D_MPL.

The invention also provides any of the aspects described herein for the preparation of a medicament for the treatment and/or prevention of malaria infection. The amount of 3D-MPL used is generally small 'but the end-to-end vaccine formulation can range from 1-1000 Hg/dose (eg, υοο μ§/dose) and can be, for example, 1-100 pg/dose (eg 5 〇 or 25 pg / dose). The amount of CpG or immunostimulatory nucleotide in the adjuvant or vaccine of the invention is typically small, but the terminal vaccine formulation may be in the range of 1-1000 μΕ/dose (eg, 1-500 (four) dose) and may be For example, 11 bark / dose range. The amount of guanidine used in the adjuvant of the present invention may range from 1" to 1-5 〇 0 μ§ / dose, for example, a dose of (four), and especially within a dose of 1 - 100 Torr (e.g., or 25 (four) dose). Eight

Kg / dose, for example 40, 45, 5 〇, when administering protein, the dose can be, for example, 1-500 1〇-1〇〇μ§/dose, especially 20, 25, 30, 35 55 ' 60, 65, 70, 75 or 80 μβ/dose. Vpu, for example, when administering an adenovirus vector such as io6-io10 vpu 〇 dose can be, for example, 1〇3_1〇16 When using a combination, the amount of each component of the combination can correspond to a single 136387.doc -21 200938633 The dose when the component is given. The invention also extends to kits comprising the components used in the combinations of the invention. The invention further relates to a method of preparing an adenoviral vector of the invention and a formulation comprising the vector. The invention also relates to a method of preparing a protein of Seq ID No 1. In the context of this specification, the inclusion is to be understood as included. The invention extends to embodiments corresponding to the embodiments described herein that comprise certain elements but consist of or consist essentially of related elements. The discussion in the background section of this specification is provided for the purpose of bringing the invention in the context. It should not be considered as acknowledging that it is known and specific in the industry and that it is not a common general knowledge of its composition. The following examples are presented to illustrate the methods that can be used in the present invention. [Examples] Examples Example 1 | Synthetic gene lines were prepared by Medigenomix. This gene was cloned into the pCR2.1-TOPO-TA selection vector (Invitrogen, see Figure 1). The vector was visualized with /Voil and BamHI > and a recombinant shuttle plasmid vector (_Ade2) was generated. A map of the shuttle plasmid is shown in Figure 2. Description of the performance cassette and method for virus rescue The performance cassette contains the cytomegalovirus (CMV) early promoter and the first exon, an intron derived from the plasmid pCI (purchased from Promega), and the code of the heart. DNA and rabbit globin polyadenylation signals. The two sides of the complete box are the recognition sites for the restriction enzymes I-CeuI and ΡΙ-SceI. The 136387.doc -22· 200938633 performance cassette was excised from the shuttle plasmid using i_ceul and ΡΙ-SceI and as described (Roy et al., Hurn Gene)

Ther. (2004) 5: 519-530) was introduced into the pure plasmid strain of the E1 deletion genome of SAdV-24 (i.e., C7)-pC7 000 pkGFP to obtain the plasmid shown in Fig. 3. Recombinant adenovirus was rescued by linearization of plasmid molecule pure DNA by digestion with restriction enzyme PacI and transfection into HEK 293 cells. Adenoviruses are propagated, amplified and purified using standard techniques. The sequence of the performance cassette of the I-CeuI to Pl-Sce recognition site (Ade2) is shown in Seq ID No: 18. Example 2 Immunogenicity of C7-Adel and C7-Ade2 in C57B1/6 Mice Adenovirus was obtained by C7 black, one of the expression constructs Adel or Ade2, in a dose range (10el0, 10e9, 10e8 virions) One dose of C57B1/6 mice was immunized intramuscularly. As a positive control, some mice were immunized with human adenovirus 5 (at a dose of 10e9 and l〇e8) which expresses one of the constructs Ade 1 or Ade2. As a negative control, some mice were immunized with empty C7 and empty Ad5 viral vectors. Collecting and encapsulating peripheral blood on days 14, 28, 34, and 49 after immunization and using the sequence of interest (ie, the N-terminal region (N_end) or C-terminal region of the CS protein) (C-terminus) The 15 mer peptide pool was assayed for IL-2 and/or IFN-γ produced by Ag-specific CD4 and CD8 T cell responses by flow cytometry after overnight stimulation in vitro. As a negative control, some cells were also cultured overnight in the medium (unstimulated). The Ag-specific response is calculated by subtracting the average cytokine response produced by unstimulated cells from the average cytokine response produced by the stimulating cells. 136387.doc •23- 200938633 , '' σ fruit showed that both constructs induced c s _ specific CD4 and CD8 T cell responses under the above experimental conditions (Fig. 4-15). It should be noted that the c-terminal specific CD8 T cell response was only detected in mice immunized with an adenovirus carrying a Baxin 2 insert (Figs. 4 and 8). Specifically, the 〇-terminal specific CD8 T cell responses were similar in mice immunized with Ad7 Ade2 of lOelOvp or C10 Ade2 or 10e9vp (Fig. 8). In addition, the anti--08 antibody response was determined by performing elisa A 血清 on the serum collected on the 48th day after immunization. Specifically, the total Ig response against the R32LR polypeptide (i.e., it covers the middle portion of P. falciparum CSP) was measured (MeUens et al., Vaccine 2008). The results showed that a single immunization with C7 octaphylaxis or oral Ade2 induced a low degree of R32LR-specific antibody response. The intensity of this reaction correlates with the amount of viral particles used for immunization (dose range effect). Example 3 The immunogenicity of C7-Ade2 in CB6F1 mice Yin was expressed in a dose range (l〇elO, 10e9, 10e8 virus particles)

The C7 chimpanzee adenovirus of the Ade2 construct was immunized intramuscularly to CB6F1 mice (5 groups of mice/group). Peripheral blood was collected and pooled on days 21, 28, and 355 days after immunization, and was used to cover the sequence of interest (ie, the N-terminal region (N-terminal) or C-terminal region of the CS protein' ( C-terminal)) 15 mer peptide pool was measured by flow cytometry after in vitro stimulation of IL-2 by CS C-terminus and CS N-terminal specific CD4 and CD8 T cell responses. / or IFN-γ. As a negative control, some cells were also cultured overnight in culture medium (not stimulated). The average cytokine produced by stimulating cells from the peptide 136387.doc •24·200938633 The average cytokine response produced by unstimulated cells was subtracted to calculate the Ag-specific response. As a result, in the mouse strain, single immunization of l〇e9vP or 10el0vp of C7 Ade2 induced C-terminal and N-terminal specific CD4 and CD8 T cell responses (Fig. 17-20). Specifically, the average response intensity observed was the same, but was higher when using the 10e9 vp dose. The cs_specific CD8 T cell response is mainly N-terminal-specific, while the cs_specific cd4 τ cell response has the same probability of sputum-end and C-terminus of the CS protein. The cytokine distribution of CS-specific CD4 and CD8 T cell responses was also determined and was similar at all time points tested. The features shown on day 28 after immunization are shown in Figures 21-24 and are representative of other test time points. In short, the CS-specific CD8 T cell response mainly consists of CD8 T cells producing only IFNg (Figures 21 and 22). The CS-specific CD4 T cell response also contained CD4 T cells producing iFNg and, to a lesser extent, CD4 cells producing only IL2 or both IL2 and IFNg (Figures 23 and 24). 〇 Example 4 C7-Ade2 immunogenicity in CB6F1 mice when priming/boosting or 舆rtS, S/AS01B co-provisioning. C7 chimpanzee adenovirus expressing Ade2 construct at priming/enhancement • or Immunogenicity in CB6F1 mice when co-administered (combined) with RTS, S/AS01B (4 mice/group). AS01B is an adjuvant system containing 3D-MPL and QS21 formulated together with a liposome. The mice were immunized intramuscularly on Days, Days, and Day 28 as follows: 136387.doc -25· 200938633 dO dl4 d28 Group 1 A P P Group 2 P P A Group 3 P P P Group 4 C C r c

A=10e9 vp C7 Ade2 P=5 pg RTS, S/50 μΐ AS01B

C7 Ade2 + 5 RTS, S/50 μΐ AS01B of φ c=10el〇vp on the 21st day after the immunization (7d pll), the 35th day (7d pill), the 49th day (21d pill), the 63rd day (35d) Peripheral blood was collected and pooled on day 77 (49d pill) and after overnight stimulation in vitro with a 15 mer peptide pool covering the sequence of interest (CS N-terminus, CS C-terminus or HBs) Flow cytometry was used to measure IL-2 and/or IFN-7 produced by CS C-terminus, CS N-terminus and HBs-specific CD4 and CD8 T cell responses. As a negative control, some cells were also cultured overnight in the culture medium (unstimulated). The Ag-specific response was calculated by subtracting the average cytokine response produced by unstimulated cells from the average cytokine response produced by peptide-stimulated cells. The results showed that: -APP, PPA and CCC all induced N-terminal specific CD8 T cell responses. At the 7d pll time point, an N-terminal specific CD8 T cell response was observed in the CCC group, followed by the app group. At the later test time points (21d pill, 35d pill and 49d pill), the responses in the APP, PPA and CCC groups remained similar (Figure 25). 136387.doc -26· 200938633 - APP, PPA and CCC induced a C-terminal specific CD8 T cell response that persisted 49 days after the third immunization (Figure 26). The Ν-terminal specific CD4 T cell response was mainly detected in mice immunized with sputum or CCC, wherein the responses in the sputum group were of higher intensity (Fig. 27). • All groups exhibited a C-terminal specific CD4 Τ cell response. However, sputum and CCC induced a similarly higher degree of C-terminal specific CD4 Τ cell response and at all test time points the degree of response was higher than that of sputum and sputum induced by about 2-3 times (Fig. 28). ). - The immunized animals were more strongly reactive with HBs-specific CD4 and CD8 sputum cells than animals immunized with sputum, sputum or CCC (Figures 29 and 30). The -CCC treatment regimen is the only protocol that can simultaneously induce CS and HBs-specific CD4 and CD8 T cell responses. The cytokine distribution of CS- and HBs-specific CD4 and CD8 T cell responses was also determined and was similar at the time points tested. The cytokine distribution from the 21 d pill time point is shown below as a representative of all test time points (Figures 31-36). Briefly, the Ag-specific CD8 T cell response mainly involves the production of IFNg by CD8 T cells (Fig. 31-3 3). In contrast, the Ag-specific CD4 T cell response involves the production of IFNg, IFNg and IL-2 by CD4 T cells and, to a lesser extent, CD4 T cells producing IL-2 (Figures 34-36). Further, the Ag-specific antibody reaction was determined by performing ELISA on the serum collected on the 14th day and the 42nd day after the third immunization. Specifically, the anti-R32LR polypeptide (i.e., it covers the middle portion of Plasmodium falciparum CSP 136387.doc -27. 200938633) and the total Ig response against HBs (Mettens et al., Vaccine 2008) were measured. All immunization protocols elicited R32LR and HBs-specific antibody responses that persisted until the last test time point (i.e., day 42 after the third immunization) (Figures 37 and 38). Example 5 Co-regulation of C7-Ade2+RTS, S/AS01B immunogenicity in CB6F1 mice

In this experiment, the immunogenicity of chimpanzee adenovirus C7 Ade2 co-formulated (combined) with RTS, S/AS01B was compared. Specifically, the immune response elicited by 1, 2 or 3 injections of this combination in CB6F1 mice was compared (4 subgroups of mice/group). In addition, different intervals between the two injections of the combination (i.e., 14 and 21 days) were evaluated. Finally, the group immunized with A-P-P was used as a control for this experiment. The experimental design can be summarized as follows:

D0 d7 dl4 d28 group 1 C C group 2 C-C (interval 14 days) C C group 3 C-C (interval 21 days) C C group 4 C-C-C C c C group 5 A-P-P A P P

A=10e9 vp C7 Ade2 Ρ=5 μβ RTS, S/50 μΐ AS01B

C=10e9 νρC7 Ade2+5 pg RTS, S/50 μΐ AS01B Collected and pooled peripheral blood on days 35, 42, 48, 63 and 98 after immunization, and in the shelter The 15 mer peptide pool of the sequence of interest (ie, the N-terminal region (N-terminus) of the cs protein or HBs, the C-terminal region (C-terminus)) was 136387.doc • 28 - 200938633 after in vitro restimulation by overnight Flow cytometry was used to measure the ratio of cs c_end, cs N-end and HBs-specific CD4 and CD8 T cell responses and/or IFN-γ. As a negative control, some cells were also cultured overnight in the medium (unstimulated). The Ag-specific response is calculated by subtracting the average cytokine response produced by unstimulated cells from the average cytokine response produced by the peptide-stimulated cells. The results showed that simultaneous induction of Cs C_end, cs N-_end and HBs-specific CD4 and CD8 T cell responses under these experimental conditions required two immunizations using this combination. The interval between the two immunizations of this combination does not appear to significantly affect the extent of the detected Ag-specific T cell response. Mice immunized three times with this combination tend to have higher HBs-specific CD4 and CD8 T cell responses. The kinetics of the Ag-specific tau cell reaction is shown in Figure 39-44. The cytokine distribution of CS- and HBs-specific CD4 and CD8 T cell responses was also determined and was similar at all time points tested. The cytokine profile from day 42 of the study is shown in p below as a representative of all test time points (Figures 42-47). Briefly, the 'Ag-specific CD8 T cell response mainly consists of CD8 T cells producing IFNg (Figures 45-47). In contrast, Ag-specific CD4 T cell responses include CD4 T cells producing IFNg, IFNg and IL-2, and to a lesser extent CD4 T cells producing IL-2 (Figures 48-50). In addition, the Ag-specific antibody response was determined by performing an ELISA on the sera collected on days 56 and 99 of the study. Specifically, the anti-R32LR polypeptide (i.e., it covers the middle portion of the M. falciparum CSP) and the total Ig response against HBs (Mettens et al., Vaccine 2008) were measured. All immunization protocols elicited R32LR and HBs-specific antibody responses: in each group, 136387.doc -29- 200938633 These responses had similar intensities at the two time points tested. In addition, when the group immunized with the combination was compared, the group immunized with the combination of 3 doses had a higher response (Figs. 51 and 52). Example 6 Evaluation of the simultaneous initiation of both CS and HBs T cells and Ab reactions in CB6F1 mice. The need for each component of the combination (ie, C7_Ade2, RTS, S, and AS01B). In this experiment, the simultaneous induction of CS and HBs was evaluated. - The need for specific CD4 and CD8 T cell responses for each component of the combination (ie C7-Ade2, RTS, S and AS01B). In this experiment, 'CB6F1 mice (6-group mice/group) were immunized intramuscularly with the combination or its components as follows as follows (d day and day 14): d0 dl4 group 1 CC Group 2 PP group 3 RTS, S/buffer RTS, S/buffer group 4 RTS, S/A/buffer RTS, S/A/buffer group 5 AA group 6 A/AS01B A/AS01B group 7 RTS, S/C7 empty/AS01B RTS, S/C7 empty/AS01B group 8 RTS, S/C7 empty/buffer RTS, S/C7 empty/buffer where =

A=10e9 vp C7 Ade2 P=5 pg RTS, S/50 μΐ AS01B

C = 10e9 vp C7 Ade2+5 pg RTS, S/50 μΐ AS01B 136387.doc -30- 200938633 C7 empty = 10e9 vp C7 empty vector (no insert)

RTS, S = 5 gg RTS, S

AS01B=GSK Patented Adjuvant System IB Buffer=AS0 IB Buffer (No Immunostimulant) Peripheral blood was collected and pooled on days I, 28, 70, 91 and 112 after immunization, and Flow cytometry after overnight stimulation in vitro with a 15 mer peptide pool covering the sequence of interest (ie, the N-terminal region (N-terminus) or C-terminal region (C-terminus) of the cs protein or HBs) The instrument measures the IL c and/or IFN-γ produced by the CS c_ terminus, the CS N-terminus, and the HBs-specific CD4 and CD8 T cell responses. As a negative control, some cells were also cultured overnight in the medium (unstimulated). The Ag-specific response is calculated by subtracting the average cytokine response produced by unstimulated cells from the average cytokine response produced by the peptide-stimulated cells. In addition, the Ag-specific antibody response was determined by performing an ELISA on the serum collected on days 42 and 84 of the study. Specifically, the anti-R32LR polypeptide (i.e., it covers the middle portion of P. falciparum CSP) and the total Ig response against HBs (Mettens et al., Vaccine 2008) were measured. The results showed that simultaneous induction of both CS (N-terminal and C-terminal) CD4 and CD8 T cell responses (Fig. 53-5 8) and R32LR and HBs antibody responses required each component of the combination (Figures 65 and 66). The general cytokine profiles of CS- and HBs-specific CD4 and CD8 T cell responses were also determined at each time point of the study and are shown in Figures 59-64. Briefly, the 'Ag-specific CD8 T cell response mainly consists of CD8 T cells producing IFNg (Fig. 59-6 1). In contrast, Ag-specific CD4 T fine 136387.doc -31 - 200938633 cellular responses include CD4 T cells producing IFNg, IFNg and IL-2, and to a lesser extent CD4 T cells producing lL-2 (Fig. 62 -64). Example 7 Immunogenicity of synthetic C7 Ade2 in CB6F1 mice A synthetic C7 chimpanzee adenovirus expressing the Ade2 construct was prepared and compared in immunogenicity in mice with the immunogenicity of the original C7 Ade2. In this experiment, CB 6F1 mice (6-group mice/group) were immunized with 10e9 vp of the original C7 Ade2 or its synthetic counterpart. Peripheral blood was collected and pooled on days 21, 28, and 35 after immunization, and included in the sequence of interest (ie, the N-terminal region (N-terminal) of the CS protein, and the c-terminal region (C-terminus). The 15 mer peptide pool was assayed for IL-2 and/or IFN-γ produced by CS C-terminus and CS N-terminal CD4 and CD8 T cell responses by flow cytometry after overnight stimulation in vitro. As a negative control, some cells were also cultured overnight in the medium (unstimulated). The Ag-specific response was calculated by subtracting the average cytokine response produced by unstimulated cells from the average cytokine response produced by the peptide-stimulated cells. The results showed that both C7 adenoviruses elicited similar levels of N-terminal and c-terminal specific CD4 and CD8 T cell responses. Specifically, regardless of the viral vector (primary or synthetic) used, the Ag-specific CD8 T cell response was predominantly N-terminally specific (Figures 67 and 68). N-terminal and C-terminal specific CD4 T cell responses have similar strength regardless of the viral vector used (Figures 69 and 7). The cytokine distribution of CS-specific CD4 and CD8 T cell responses was also determined and is shown in Figures 71-74. Briefly, the Ag-specific CD8 butyl cell response mainly consisted of CD8 T cells producing iFNg (Fig. 71 and 72). In contrast, 136387.doc 32-200938633, Ag-specific CD4 T cell responses include CD4 T cells producing IFNg, IFNg and IL-2, and to a lesser extent CD4 T cells producing IL-2 (Figure 73-74). ). Amino acid sequence of SEQ ID NO 1 MMRKLAILSVSSFLFVEALFQEYQCYGSSSNTRVLNELNYDNAGTNLYNE 50 LEMNYYGKQENWYSLKKNSRSLGENDDGNNNNGDNGREGKDEDKRDGNNE 100 DNEKLRKPKHKKLKQPADGNPDPNANPNVDPNANPNVDPNANPNVDPNAN 150 PNAN PNAN PNAN PNANPNAN PNAN PNAN PNAN PNAN PNAN PNVDPNAN PN 200 AN PNAN PNANPNAN PNANPNAN PNAN PNAN PNAN PNAN PNAN PNAN PNAN 250 PNANPNANPNANPNANPNKNNQGNGQGHNMPNDPNRNVDENANANSAVKN 300 NNNEEPSDKHIKEYLNKIQNSLSTEWSPCSVTCGNGIQVRIKPGSANKPK 350 DELDYANDIEKKICKMEKCSSVFNVVNSAIGL 382 SEQ ID NO 2 nucleosides Acid sequence

ATGATGAGAAAACTTGCCATCCTCAGCGTCAGCTCTTTCCTGTTCGTGGA 50 GGCCCTCTTCCAGGAGTATCAGTGCTACGGAAGCAGCAGCAATACAAGGG 100 TCCTGAACGAGCTCAACTATGACAACGCTGGAACGAACCTGTATAACGAG 150 CTGGAGATGAACTACTATGGCAAGCAGGAGAACTGGTATAGCCTGAAGAA 200 GAACAGCCGGTCCCTGGGCGAGAACGACGACGGCAACAACAACAACGGCG 250 ACAACGGCAGGGAGGGCAAAGATGAGGACAAGAGGGACGGGAACAACGAG 300 GATAACGAGAAGCTGCGGAAGCCCAAGCACAAGAAACTCAAGCAGCCCGC 350 CGACGGGAACCCGGACCCCAATGCAAATCCCAACGTCGACCCAAACGCAA 400 ACCCTAACGTGGACCCCAACGCCAATCCCAACGTCGATCCTAATGCCAAT 450 CCAAATGCCAACCCTAACGCAAATCCTAATGCAAACCCCAACGCCAATCC 500 TAACGCCAACCCAAATGCCAACCCAAACGCTAACCCCAACGCTAACCCAA 550 ATGCAAATCCCAATGCTAACCCAAACGTGGACCCTAACGCTAACCCCAAC 600 GCAAACCCTAACGCCAATCCTAACGCAAACCCCAATGCAAACCCAAACGC 650 AAATCCCAACGCTAACCCTAACGCAAACCCCAACGCCAACCCTAATGCCA 700 ACCCCAATGCTAACCCCAACGCCAATCCAAACGCAAATCCAAACGCCAAC 750 CCAAATGCAAACCCCAACGCTAATCCCAACGCCAACCCAAACGCCAATCC 800 TAACAAGAACAATCAGGGCAACGGGCAGGGCCATAACATGCCGAACGACC 850 CTAATCGGAATGTGGACGAGAACGCCAACGCCAACAGCGCCGTGAAGAAC 900 AACAACAACGA GGAGCCCTCCGACAAGCACATCAAGGAATACCTGAACAA 950 GATCCAGAACAGTCTGAGCACCGAGTGGTCCCCCTGCTCCGTGACCTGCG 1000 GCAACGGCATCCAGGTGAGGATCAAGCCCGGCTCCGCCAACAAGCCCAAG 1050 GACGACCTGGACTACGCCAACGACATCGAGAAGAAGATCTGCAAGATGGA 1100 GAAATGCAGCTCTGTGTTCAACGTCGTGAACTCCGCCATCGGCCTGTGA 1149

Seq ID NO 3 -33- 136387.doc 200938633 MMRKLAILSVSSFLFVEALFQEYQCYGSSSNTRVLNELNYDNAGTNLYNE 50 LEMNYYGKQENWYSLKKNSRSLGENDDGNNNNGDNGREGKDEDKRDGNNE 100 DNEKLRKPKHKKLKQPADGNPDPNANPNVDPNANPNVDPNANPNVDPNAN 150 PNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNVDPNANPN 200 ΑΝΡΝΑΝΡΝΑΝΡΝΑΝΡΝΑΝΡΝΑΝΡΝΑΝΡΝΑΝΡΝΑΝΡΝΑΝΡΝΑΝΡΝΑΝΡΝΆΝ 250 PNANPNANPNANKNNQGNGQGHNMPNDPNRNVDENANANSAVKNNNNEEP 300 SDKHIKEYLNKIQNSLSTEWSPCSVTCGNGIQVRIKPGSANKPKDELDYA 350 NDIEKKICKMEKCSSVFNVVNS 372

Seq ID NO 4

Atgatgaggaaactggccatcctgagcgtgagcagcttcctgttcgtgga 50 Ggccctgtttcaggagtaccagtgctacggcagcagcagcaacacccggg 100 Tgctgaacgagctgaactacgacaacgccggcaccaacctgtacaacgag 150 Ctggagatgaactactacggcaagcaggagaactggtacagcctgaagaa 200 Gaacagccggtctctgggcgagaacgacgacggcaacaacaacaacggcg 250 Acaacggccgggagggcaaggacgaggacaagcgggacggcaacaacgag 300 Gacaacgagaagctgcggaagcccaagcacaagaaacttaagcagcccgc 350 Cgacggcaaccccgaccccaacgccaaccccaacgtggaccccaacgcca 400 Atcctaatgtcgaccccaatgccaatccgaacgttgatcccaatgcgaat 450 Cctaacgctaaccccaatgccaacccaaatgccaatccaaatgcaaatcc 500 Caacgccaatccaaacgcaaaccctaatgctaatccaaacgctaatecta 550 Atgccaatcccaatgctaacccaaacgtcgatcctaacgcaaatccgaac 600 Gctaaccccaacgcaaatcccaacgctaacccgaacgcaaaccctaacgc 650 Caatccgaatgccaacccaaacgccaacccgaacgctaatccgaatgcta 700 Acccgaatgctaatcctaacgcaaacccaaatgcaaaccccaatgcaaac 750 Ccgaacgccaatcccaacgccaatoctaatgccaacaagaacaatcaggg 800 Caacggccagggccacaacatgcccaacgaccccaaccggaacgtggacg 850 Agaacgccaacgccaacagcgccgtgaagaacaacaacaacgaggagccc 900 Agcgacaagca Catcaaggagtacctgaacaagatccagaacagcctgag 950 Caccgagtggagcccctgcagcgtgacctgcggcaacggcattcaggtgc 1000 Ggatcaagcccggcagcgccaacaagcccaaggacgagctggactacgcc 1050 Aatgacatcgagaagaagatctgcaagatggagaagtgcagcagcgtgtt 1100 Caacgtggtgaactcctga 1119

Seq ID NO. 5 Chimpanzee gland 7 (seq ID No 17 from WO 03/046124)

Ala Pro Lys Gly Ala Pro Asn Thr Cys Gin Trp Thr Tyr Lys Ala Gly 1 5 10 15

Asp Thr Asp Thr Glu Lys Thr Tyr Thr Tyr Gly Asn Ala Pro Val Gin 20 25 30

Gly lie Ser He Thr Lys Asp Gly lie Gin Leu Gly Thr Asp Ser Asp 35 A0 45

Gly Gin Ala lie Tyr Ala Asp Glu Thr Tyr Gin Pro Giu Pro Gin Val 50 55 60

Gly Asp Ala Glu Trp His Asp lie Thr Gly Thr Asp Glu Lys Tyr Gly 65 70 75 60

Gly Arg Ala Leu Lys Pro Asp Thr Lys Met Lys Pro Cys Tyr Gly Ser 85 90 95 -34- 136387.doc 200938633

Phe Ala Lys Pro Thr Asn Lys Glu Gly Gly Gin Ala Asn Val Lys Thr 100 105 HO Glu Thr Gly GXy Thr Lys Glu Tyr Asp lie Asp Met Ala Phe Phe Asp 115 120 125 Asn Arg Ser Ala Ala Ala Ala Gly Leu Ala Pro Glu Lie Val Leu Tyr 130 135 140 Thr Glu Asn Val Asp Leu Glu Thr Pro Asp Thr His lie Val Tyr Lys 145 a50 155 160 Ala Gly Thr Asp Asp Ser Ser Ser Ser Tie Asn Leu Gly GXn Gin Ser 165 170 175 Met Pro Asn Arg Pro Asn Tyr Tie Gly Phe Arg Asp Asn Phe lie Gly 180 185 190 Leu Met Tyr Tyr Asn Ser Thr Gly Asn Met Gly Val Leu Ala Gly Gin 195 200 205 Ala Ser Gin Leu Asn Ala Val Val Asp Leu Gin Asp Arg Asn Thr Glu 210 215 220 Leu Ser Tyr Gin Leu Leu Leu Asp Ser Leu Gly Asp Arg Thr Arg Tyr 225 230 235 240 Phe Ser Met Trp Asn Gin Ala Val Asp Ser Tyr Asp Pro Asp Val Arg 245 250 255 lie lie Glu Asn His Gly Val Glu Asp Glu Leu Pro Asn Tyr Cys Phe 260 265 270 Pro Leu Asp Ala Val Gly Arg Thr Asp Thr Tyr Gin Gly lie Lys Ala 275 280 285 Asn Gly Asp Asn Gin Thr Thr Trp Thr Lys Asp Asp Thr Val Asn Asp 290 295 300 Ala A Sn Glu Leu Gly Lys Gly Asn Pro Phe 305 310

Seq ID NO. 6 Chimpanzee gland 7 (seq ID No 20 from WO 03/046124) Thr Leu Trp Thr Thr Ala Asp Pro Ser Pro Asn Cys Lys lie Tyr Ser 1 5 10 15 Glu Lys Asp Ala Lys Leu Thr Leu Cys Leu Thr Lys Cys Gly Ser Gin 20 25 30 lie Leu Gly Thr Val Thr Val Leu Ala Val Asn Asn Gly Ser Leu Asn 35 40 45 Pro lie Thr Asn Thr Val Ser Thr Ala Leu Val Ser Leu Lys Phe Asp 50 55 60 Ala Ser Gly Val Leu Leu Ser Ser Ser Thr Leu Asp Lys Glu Tyr Trp 65 70 75 80 Asn Phe Arg Lys Gly Asp Val Thr Pro Ala Glu Pro Tyr Thr Asn Ala 85 90 95 lie Gly Phe Met Pro Asn He Lys Ala Tyr Pro Ly$ Asn Thr Ser Ala 100 105 110 Ala Ser Lys Ser His lie Val Ser Gin VaX Tyr Leu Asn Gly Asp Glu 115 120 125 Ala Lys Pro Leu Met Leu lie lie Thr Phe Asn Glu Thr Glu Asp Ala 130 135 140 Thr Cys Thr Tyr Ser lie Thr Phe Gin Trp Lys Trp Asp Ser Thr Lys 145 150 155 160 Tyr Thr Gly Glu Thr Leu Ala Thr Ser Ser Phe Thr Phe Ser Tyr lie 165 17〇175 Ala Gin Glu

NNGDNGREGKDEDKRDGNN

[Seq ID No: 7]

AIGL

[Seq ID No: 8] 136387.doc 35- 200938633

PNANPNANPNANPNANPNANPNANPNANPNANPNANPNANFNANPNVDPN

ANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANAN

PNANPNANPNANPNANPNANPN fSeq ID No: 9]

NANP NVDP NANP NVDP NANP NVDP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP NANP

NANP NANP NANP NANP NANP NANP 1J 1J 1J 5 0 12 3 4 5 6 [Seq ID No TCC ATG ACG TTC CTG ACG TT (CpG 1826) [Seq ID No TCT CCC AGC GTG CGC CAT (CpG 1758) [Seq ID No ACC GAT GAC GTC GCC GGT GAC GGC ACC ACG [Seq ID No TCG TCG TTT TGT CGT TTT GTC GTT (CpG 2006) [Seq ID No TCC ATG ACG TTC CTG ATG CT (CpG 1668) [Seq ID No TCG ACG TTT TCG GCG CGC GCC G (CpG 5456), [Seq ID No ❹

Seq ID NO: 17

Sequence of the performance cassette of the protein of Seq ID No. 3. The protein coding region is underlined.

TAACTATAACGGTCCTAAGGTAGCGAAAGCTCAGATCGGCTGACCGCCCAACGACCC

CCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTT

CCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCA

AGTGTATCATATGCCAAGTCCGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGC

CTGGCATTATGCCCAGTACATGACCTTACGGGACTTTCCTACTTGGCAGTACATCTA

CGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACACCAATGGGCG

TGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGG

GAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAATAACCCCGC

CCCGTTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGC

TCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCA

TAGAAGACACCGGGACCGATCCAGCCTCCGCGGCCGGGAACGGTGCATTGGAACGCG

GATTCCCCGTGCCAAGAGTGCGGCCAGCTTTATTGCGGTAGTTTATCACAGTTAAAT

TGCTAACGCAGTCAGTGCTTCTGACACAACAGTCTCGAACTTAAGCTGCAGAAGTTG

GTCGTGAGGCACTGGGCAGGTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCA

ATAGAAACTGGGCTTGTCGAGACAGAGAAGACTCTTGCGTTTCTGATAGGCACCTAT

TGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGTTCAA ttacagctcttaaggctagagtggccgcaccatgatgaggaaactggccatcctgag

CGTGAGCAGCTTCCTGTTCGTGGAGGCCCTGTTTCAGGAGTACCAGTGCTftCGGCAG

CftGCAGCAACACCCGGGTGCTGAACGAGCTGAACTACGACftACGCCGGCACCAftCCT

GTACAACGAGCTGGAGftTGAACTACTACGGCAAGCAGGAGAACTGGTACAGCCTGftA

GAAGAACAGCCGGTCTCTGGGCGAGAACGACGftCGGCAACAACAACAACGGCGfiCAA

CGGCCGGGAGGGCAAGGACGAGGACAAGCGGGACGGCAACAACGAGGACAACGAGAA

GCTGCGGAAGCCCAAGCACAAGAAACTTAAGCAGCCCGCCGACGGCAACCCCGftCCC

CAACGCCAACCCCAACGTGGACCCCAACGCCAATCCTAATGTCGACCCCAATGCCAA

TCCGAACGTTGATCCCftATGCGAATCCTAACGCTAACCCCAATGCCAACCCAAATGC

CAATCCAAATGCAAATCCCAACGCCAATCCAAACGCAAACCCTAATGCTAATCCAAA

CGCTAATCCTAATGCCftATCCCAATGCTAACCCAAACGTCGATCCTAACGCAAATCC

GAACGCTAACCCCAACGCAAATCCCAACGCTAACCCGAACGCAAACCCTAACGCCAA

TCCGAATGCCftACCCAAACGCCAACCCGAACGCTAATCCGAATGCTAACCCGAATGC

TAATCCTAACGCAAACCCAAATGCAAACCCCAATGCAAACCCGAACGCCAATCCCAA -36- 136387.doc 200938633

CGCCAATCCTAftTGCCAACRAGAACRATCAGGGCAACGGCCAGGGCCACAACATGCC

CAACGftCCCCAACCGGAACGTGGACGAGAACGCCAACGCCAACAGCGCCGTGAAGAA CAACAACAACGAGGAGCCCAGCGACAAGCACATCAAGGAGTACCTGAACAAGATCCft

GftACAGCCTGAGCACCGAGTGGAGCCCCTGCAGCGTGACCTGCGGCAACGGCATTCA

GGTGCGGATCAAGCCCGGCAGCGCCAACAAGCCCAAGGACGAGCTGGACTACGCCAA

TGACftTCGAGAAGAAGftTCTGCAAGATGGftGAAGTGCAGCAGCGTGTTCAACGTGGT

GAACTCCTGAGGATCCGATCTTTTTCCCTCTGCCAARAATTATGGGGACATCATGAA gccccttgagcatctgacttctggctaataaaggaaatttattttcattgcaatagt gtgttggaattttttgtgtctctcactcggaagcgatctgaattcatctatgtcggg

TGCGGAGAAAGAGGTAATGAAATGGCA

Seq ID NO: 18

The sequence of the Ade2 performance cassette is as follows. The protein coding region is underlined.

TAACTATAACGGTCCTAAGGTAGCGAAAGCTCAGATCGGCTGACCGCCCAACGACCC

CCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTT CCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCft

AGTGTATCATATGCCAAGTCCGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGC

CTGGCATTATGCCCAGTACATGACCTTACGGGACTTTCCTACTTGGCAGTACATCTA

CGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACACCAATGGGCG

TGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGG

GAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAATAACCCCGC

CCCGTTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGC

TCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCA

TAGAAGACACCGGGACCGATCCAGCCTCCGCGGCCGGGAACGGTGCATTGGAACGCG

GATTCCCCGTGCCAAGAGTGCGGCCAGCTTTATTGCGGTftGTTTATCACAGTTAAAT

TGCTAACGCAGTCAGTGCTTCTGACACAACAGTCTCGAACTTAAGCTGCAGAAGTTG

GTCGTGAGGCACTGGGCAGGTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCA

ATAGAAACTGGGCTTGTCGAGACAGAGAAGACTCTTGCGTTTCTGATAGGCACCTAT

TGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGTTCAA

TTACAGCTCTTAAGGCTAGAGTGGCCGCftCCATGATGAGAAAACTTGCCATCCTCAG

CGTCAGCTCTTTCCTGTTCGTGGAGGCCCTCTTCCAGGAGTATCAGTGCTACGGAAG

CAGCAGCAATACAAGGGTCCTGAACGAGCTCAACTftTGACAACGCTGGAACGAACCT

GTATAACGftGCTGGAGATGAACTACTATGGCRAGCAGGftGJ^ACTGGTATftGCCTGAA

GAAGAACAGCCGGTCCCTGGGCGAGAACGACGACGGCflACAACftACAACGGCGACAA

CGGCAGGGAGGGCAAAGATGAGGftCAAGAGGGACGGGAACAACGAGGATftACGAGAA

GCTGCGGAAGCCCAAGCACftAGftAACTCAAGCftGCCCGCCGACGGGAACCCGGACCC

CAATGCAAATCCCAACGTCGACCCAAACGCAAACCCTAACGTGGACCCCAACGCCAA

TCCCAACGTCGATCCTAATGCCAATCCAAATGCCAACCCTAACGCAAATCCTAATGC

AftACCCCAACGCCAATCCTAACGCCAACCCARATGCCAACCCARACGCTAACCCCAA

CGCTAACCCAAATGCAAATCCCAftTGCTAACCCAAACGTGGACCCTAACGCTAACCC

CAACGCAAACCCTAACGCCAATCCTAACGCAAftCCCCAATGCAAACCCAAACGCAAA

TCCCAACGCTAACCCTAACGCAAACCCCAftCGCCARCCCTAATGCCAACCCCftATGC

TAACCCCAACGCCAATCCAAACGCAAATCCAAACGCCAACCCAAATGCAAACCCCAA

CGCTAATCCCAftCGCCAACCCAAACGCCAATCCTftACAAGAACAATCAGGGCAACGG

GCAGGGCCATAACATGCCGAACGACCCTAACCGGAATGTGGACGAGAACGCCAACGC

CAACAGCGCCGTGAAGAACAACAACAACGAGGAGCCCTCCGACftAGCACftTCAAGGA

ATACCTGAACAAGftTCCAGAACAGTCTGAGCACCGAGTGGTCCCCCTGCTCCGTGAC

CTGCGGCRACGGCATCCAGGTGAGGATCAAGCCCGGCTCCGCCAACAAGCCCAAGGA 37- 136387.doc 200938633

CGAGCTGGACTACGCCAACGACATCGAGAAGAAGATCTGCAAGATGGAGAAATGCAG ctctgtgttcaacgtcgtgaactccgccatcggcctgtgaggatccgatctttttcc

CTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTA

ATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACT

CGGAAGCGATCTGAATTCATCTATGTCGGGTGCGGAGAAAGAGGTAATGAAATGGCA

T [Simple diagram of the diagram] Figure 1 shows the plasmid map of pCR2.1-Ade2. Figure 2 shows the plasmid map of pShuttle6-Ade2. Figure 3 shows the plasmid map of pC7000-CMV Ade2. Figure 4-7 shows the borrowing of C57B1/6 mice. Comparison of CS-specific T cell responses induced by C7 Adel and C7 Ade2. Figure 8-11 shows a comparison between CS-specific T cell responses induced by C7 Ade2 and Ad5 Ade2 in C57B1/6 mice. Figures 12-15 show a comparison between CS-specific T cell responses induced by C7 Adel and Ad5 Adel in C57B1/6 mice. Figure 16 shows the anti-CS antibody response as determined by ELISA in C57B 1/6 mice. Figures 17 and 18 show the kinetics of CS-specific CD8 T cell responses induced by C7-Ade2 in CB6F1 mice. Figures 19 and 20 show the kinetics of CS-specific CD4 T cell responses induced by C7-Ade2 in CB6F1 mice. Figures 21 and 22 show cytokine profiles of CS-specific CD8 T cell responses induced by C7-Ade2 in CB6F1 mice. Figures 23 and 24 show cytokine profiles of CS-specific CD4 T cell responses induced by C7-Ade2 in CB6F1 mice. Figures 25 and 26 show CS-specific CD8 T cell responses induced by co-provisioning of C7-Ade2 in CB6F1 mice during priming/boosting 136387.doc •38-200938633 or with RTS, S/AS01B dynamics. Figures 27 and 28 show the kinetics of CS-specific CD4 T cell responses induced by C7-Ade2 in priming/boosting or co-provisioning with RTS, S/AS01B in CB6F1 mice. Figure 29 shows the kinetics of HBs-specific CD8 T cell responses induced by C7-Ade2 in priming/boosting or co-provisioning with RTS, S/AS01B in CB6F1 mice. Figure 30 shows the kinetics of HBs-specific CD4 T cell responses induced by C7-Ade2 in priming/boosting or co-administered with RTS, S/AS01B in CB6F1 mice. Figures 31 and 32 show cytokine profiles of CS-specific CD8 T cell responses induced by C7-Ade2 in priming/boosting or co-administered with RTS, S/AS01B in CB6F1 mice. Figure 33 shows the cytokine profile of HBs-specific CD8 T cell responses induced by C7-Ade2 in priming/boosting or co-administered with RTS, S/AS01B in CB6F1 mice. Figures 34 and 35 show cytokine profiles of CS-specific CD4 T cell responses induced by C7-Ade2 in priming/boosting or co-administered with RTS, S/AS01B in CB6F1 mice. Figure 3 6 shows the cytokine profile of HBs-specific CD4 T cell responses induced by C7-Ade2 in priming/boosting or co-administered with RTS, S/AS01B in CB6F1 mice. Figures 3 and 38 show antibody responses induced by €7-eight (162 in priming/boosting 136387.doc-39-200938633 or in combination with RTS, S/AS01B) in €86 cadres 1 mouse Figure 3 9-41 shows the kinetics of CS- and HBs-specific CD8 T cell responses induced by C7-Ade2+ RTS, S/AS01B co-conditioning in CB6F1 mice. Figure 42-44 shows in CB6F1 Kinetics of CS- and HBs-specific CD4 T cell responses induced by co-provisioning of C7-Ade2+ RTS, S/AS01B in mice. Figures 45-47 show C7-Ade2+ RTS in mice, S/AS01B co-regulates the cytokine distribution of CS- and HBs-specific CD8 T cell responses induced. Figure 48-50 shows induction in CB6F1 mice by C7-Ade2+RTS, S/AS01B co-provisioning Cytokine distribution of CS- and HBs-specific CD4 T cell responses. Figures 51 and 52 show the antibody responses elicited by the co-administered C7-Ade2+ RTS, S/AS01B in CB6F1 mice. The kinetics of CS- and HBs-specific CD8 T cell responses induced by C7-Ade2, RTS, S and AS01B responses in CB6F1 mice are shown. Figures 56-58 are shown in CB6F1 mice by C7- Ade2, RTS Kinetics of CS- and HBs-specific CD4 T cell responses induced by S and AS01B reactions. Figures 59-61 show CS- and induced by C7-Ade2, RTS, S and AS01B reactions in CB6F1 mice. Cytokine distribution of HBs-specific CD8 T cell responses. 136387.doc -40- 200938633 Figure 62-64 shows CS- and HBs-induced by C7-Ade2, RTS, S and AS01B reactions in CB6F1 mice. Cytokine distribution of specific CD4 T cell responses. Figures 65 and 66 show antibody responses induced by C7-Ade2, RTS, S and AS01B reactions in CB6F1 mice. Figures 67 and 68 show borrowing in CB6F1 mice. Kinetics of CS-specific CD8 T cell responses induced by the synthesis of C7 Ade2. Figures 69 and 70 show the kinetics of CS-specific CD4 T cell responses induced by synthesis of C7 Ade2 in CB6FL. Figures 71 and 72 show cytokine profiles of CS-specific CD8 T cell responses induced by synthesis of C7 Ade2 in CB6F1 mice. Figures 73 and 74 show CS induced by synthesis of C7 Ade2 in CB6F1 mice. - Cytokine distribution of specific CD4 T cell responses.

136387.doc -41 - 200938633 <120><130> Sequence Listing Belgian GlaxoSmithKline Blue Biopharmaceutical Company Vaccine VB62729 <140> 097147198 <141> 2008-12-04 <150> US60/992802 <151> 2007-12-06 <160> 19 <170> Patentln version 3.5 <210> 1 <211> 382 <212> PRT <213> Artificial sequence <220><223> Ade2 protein amino acid sequence <400> 1

Met Met Arg Ly$ Leu Ala lie Leu Set Val Ser Ser Phe Leu Phe Val 15 10 15

Glu Ala Leu Phe Gin GLu Tyc Gin Cys Tyr Gly Ser Ser Ser Asn Thr 20 25 30

Arg Val Leu Asr> Glu Leu Asn Tyr Asp Asn Ala GLy Thr Asn Leu Tyr 35 40 45

Asn Glu Leu Glu Met Asn Tyr Tyr Gly Lys Gin Glu Asn Trp Tyr Ser 50 60

Leu Lys Lys Asn Ser Arg Ser Leu Gly Glu Asn Asp Asp Gly Asn Asa 65 70 75 80

Asn Asn Gly Asp Asn Gly Arg Gla Gly Lys Aap Glu Asp Lys Arg Asp 85 90 95

Giy A5n Asn Glu A$p Asn Glu Lys Ueu Arg Lys Pro Lys His Lys Lys 100 105 110

Leu Uys Gin Pro Ala Asp GXy Asn Pro Asp Pro Asn Ala Asn Pro Asn 115 120 125

Val Asp Pro Asn Ala Asn Pro Asn val Asp Pro Asn Ala Asn Pro Asn 230 135 140

Val Asp Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn 145 150 Ibh i6〇

Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn 165 Π0 175 136387.doc 200938633

Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn 180 185« 190

Vai Asp Pro Asn Ala Asn Pro Asn AXa Asn Pro Asn Ala Asn Ho Asn 195 200 205

Ala Asn Pro Asn Ala Asn Pro Asn AXa Asn Pro Asn Ala Asn Pro Asn 210 215 220

Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn 225 230 235 240

Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn 245 250 255 A丄a Asn Pro Asn Ala Asn Pro Asn Ala Asn Pjro Asn Lys Asn Asn Gin * 260 265 270 ❹

Gly Asn Gly Gin Gly His Asm Met Pro Asn Asp Pro Asn Arg Asn Val 275 280 285

Asp Glu Asn AXa Asn Ala Asn ser Ala Val Lys Asn Asn Asn Asn Glu 290 295» 300

Glu Pro S&r Asp Lys His lie Lys Glu Tyc Asn Lys He Gin Asr\ 305 310 315 320

Ser Leu Ser Thr Glu Trp Ser Pro Cys Ser Val Thr Cys Gly Asn Gly 325 330 335 lie Gin Val Arg lie Lys Pro Gly Ser Ala Asn Lys Pro Lys Asp Glu 340 345 350

Leu Asp Tyr Ala Asn Asp He Glu Lys Lys lie Cys Lys Met Glu Lys 355 360 365

Cys Ser Ser Val Phe Asn Val Val Asn Ser Ala lie Gly Leu 370 375 3Θ0 <210> 2 <211> 1149 <212> DNA <213>Artificial Sequence <220><2υ> Ade2 Nucleic Acid Sequence<;400> 2 60 120 atgatgagaa aacttgccat cctcagcgtc agctctttcc tgttcgtgga ggccctcttc caggagtatc agtgctacgg aa9cagcagc aatacaaggg tcctgaacga gctcaactat qacaacgctg gaacgaacct gtata^cgag ctggagatga actactatgg caagcaggag -2- 136387.doc 180 200938633

aactggtata dacaac99G9 gataacgaga ccggacccca gccaatccca gcaaacccca gctaacccaa gcaaacccta gctaacccta gccaatccaa gccaacccaa ccgaacgacc aacaacaacg agtctgagca atcaagcccg aagaagatct ggcctgtga qcctgaagaa dcaacggcag agctgcggaa atgcaaatcc acgtcgatcc acgccaatcc atgcaaatcc acgccaatcc acgcaaaccc acgcaaatcc acgccaatcc ctaatcggaa aggagccctc ccgagtggtc gctccgccaa gcaagatgga gaacagcc9g ggagggcaaa gcccaagcac cadcgtcgac tadtgccaat taacqccaac caatgctaac taacgcaaac caacgccaac aaacgccaac taacaagaac tgtggacgag cgacaagcac cccctgctcc caagcccaag gaaatgcagc tccctgggcg gatgaggaca aagaddctca ccaaac9caa ccaaat9cca ccaddtgcca ccaaacgtgg cccaatgcaa cctaatgcca ccaaatgcaa aatcagggca aacgccaacg atcaaggaat gtgacctgcg gacgagctgg tctgtgttca agaacgacga agagggacgg agcagcccgc accctaacgt accctaacgc acccaaacgc accctaacgc acccaaacgc accccaatgc accccaacgc acgggcaggg ccaacagcgc acct ^ aacaa gcaacggcac actacgccaa acgtcgtqaa cggcaacaac gaacaacgag cgacgggaac ggaccccaac aaatcctaat taaccccaac taaccccaac aaatcccaac taaccccaac taatcccaac Ccataacatg cgtgaagaac gatccagaac ccaggtgagg cgacatcgag ctccqccatc 240 300 360 420 480 540 600 660 720 780 640 900 960 1020 1080 1140 1149 ❹ <210> 3 <211> 372 C212> PRT c213>Artificial sequence<220><223> Adel Amino acid sequence of protein <40Q> 3 Met Met Arg Lys Leu ftla lie Leu S«r val Ser S«r Ph order teu Phe val 15 10 15

Glu Ala

Leu Phe Gin Giu Tyr Gin Cys Tyr Gly Ser Ser Ser Asn Thr 20 25 30

Arg Val

Leu Asn Glu Leu Asn Tyr Asp Asn Ala Gly Thr Asn I*eu Tyr 35 40 45

Asn Glu Leu Glu 50

Met Asn Tyr Tyr Gly Lys Gin GXu Asn Trp Tyr Ser 55 60

Leu Lys Lys Asn Ser Arg Ser Leu Giy Glu Asn Asp Asp Giy Asn Asn 65 70 75 e〇

Asn Asn Gly Asp Asn Gly Arg Glu Gly Lys Asp Glu Asp Lys Arg Asp 65 90 55 136387.doc 200938633

Gly Asn Asn Glu Asp Asn Glu Lys Leu Arg Lys Pro Lys His Ly$ Lys 1 (8) IQb 110

Leu Lys Gin Pro Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn 115 120 12b

Val Asp Pro Asn Ala Asn Pro Asn Val Asp Pro Asn Ala Asn Pro Asn 230 135 HO

Val Asp Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn 145 350 】55 160

Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn pro Asn Ala Asn Pro Asn 165 1,0 175

Ala Asn Pro Asn AU Asn Pro Asn Ala Asn Pro Α3Π Ala Asn Pro Asn - 180 185 190 e

Val Asp Pro Asn Ala Asn Pro Asn Ala Asn pro Asn Ala Asn Pro Asn 195 200 205

Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn 210 215 220

Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asa Pro Asn 225 230 235 240

Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn pro Asn Ala Asn Pro Asn 2Ab 250 2bb

Ala Asn Pro Asn Ala Asn Lys Asn Asn Gin Gly A$n Gly Gin Gly His 260 265 27〇

Asn Met Pro Asn Asp Pf〇 Asn Arg Asn Val Asp Glu Asn Ala Asn Ala 275 280 285

Asn Ser Ala Val Lys Asn Asn Asn Asn Glu Glu Pro Ser Asp Lys His 290 295 300 lie Lys GXu Tyr Leu Asn Lys lie Gin Asn Ser Leu Ser Thr Glu Trp 305 310 315 320

Ser Pro Cys Ser Val Thr Cys Gly Asn Gly He Gin Val Arg He Lys 325 330 335

Pro Gly Ser Ala Asn L<ys Pro Lys Asp Glu Leu Asp Tyr Ala Α3Π Asp 340 345 350

Xla Glu Lys Lys He Cys Lys Met Glu Lys Cys Ser Ser val Phe Asn 355 360 365 -4 136387.doc

200938633

Val Val Asn Ser 370 <210> 4 <211> 1119 <212> DNA <213>Artificial sequence<220><223> Adel nucleic acid sequence <400> 4 atgatgagga aactggccat cctgagcgtg agcagcttcc tgttcgtgga ggccctgttt caggagtacc agtgctacgg cagcagcagc aacacccggg tgctgaacga gctgaactac gacaacgccg gcaccaacct gtacaacgag ctggagatga actactacgg caagcaggag aactggtaca gcctgaagaa gaacagccgg tctctgggcg agaacgacga cggcaacaac aacaacggcg acaacggccg ggagggcaag gacgaggeca agcgggacgg caacaacgag gacaacgaga a < gctgcggaa gcccaagcac aagaaactca agcagcccgc cgacggcaac cccgacccca acgccaaccc caacgtggdc cccaacgcca atcctaatgt cgaccccaat gccaatccga acgttgatcc caatgcgaat cctaacgcta accccaatgc caacccaaat gccaatccaa atgcaaatcc caacgccaat ccaadcgcaa accctaatgc taatccdaac gctaatccta atgccaatcc Caatgctaac ccaaacgtcg atcctaacgc aaatccgaac gctaacccca acgcaaatcc caacgctaac ccgaacgcaa accctaacgc caatccgadt gccaacccaa acgccaaccc gaacgctaat ccgaatgcta acecgaatgc taatcctaac gcaaacccaa atgcaaaccc caatgcaadc ccgaacgcca atcccaacgc caa tcctaat gccaacaaga acaatcaggg caacggccag ggccacaaca tgcccaacga ccccaaccgg aacgtggacg agaacgccaa cgccaacagic gccgtgaaga acaacaacaa cgaggagccc agcgacaagc acatcaagga gtacctgaac aagatccaga acagcctgag caccgagtgg agcccctgca gcgtgacctg cggcaacggc attcaggtgc ggatcaagcc cggcagcgcc aacaagccca aggacgaoct ^ gactacgcc aatgacatcg agaagaagat ctgcaagatg g ^ gaagtgca ^ cagc ^ tgtt caacgtggtg aactcctga < 210 > 5 < 211 > 314

<212> PRT <213> chimpanzee adenovirus pan7 <400> 5

Ala Pro Lys Gly Ala Pro Asn Thr Cys Gin Trp Thr Tyr Lys Ala Gly 1 5 10 15 60 120 180 240 300 360 A2Q 480 540 600 660 720 780 840 900 960 1020 1080 1119

Gly Asn Ala

Pro val Gin 30

Asp Thr Asp Thr Glu 20

Lys Thr Tyr Thr Tyr 2S 136387.doc 200938633

Gly lie Ser lie Thr Lys Asp Gly lie Gin Leu Gly Thr Asp Ser Asp 35 40 45

Giy Gin Ala He Tyr Ala Asp Glu Thr Tyj: Gin Pro Giu pro Gin val 50 55 60

Gly Asp Ala Glu Trp His Asp 113⁄4 Thr Gly Thr Asp Glu Lys Tyr Gly 65 70 75 8〇

Gly Arg Ala Leu tys Pro Asp Thx Lys Met ϊ-ys Pro Cys Tyr Gly Ser 8S 90 95

Phe Ala Lys Pro Thr Asn Lys Glu Gly Gly Gin Ala Asn Val Lys Thr , 100 105 Π0

Glu Thr Gly Gly Thr Lys Glu Tyr Asp lie Asp Met Ala Phe Phe Asp - 115 120 125 β

Asn Arg Ser Ala Ala Ala Ala Gly Leu Ala Pro Glu He Val Leu Tyr 130 135 WO

Thr Glu Asn val Asp X, eu Glu Thr Pro Asp Thr His He Val Tyr Lys 145 150 155 160

Ala Gly Thr Asp Asp Ser Ser Ser Ser lie Asn teu Gly Gin Gin Ser 165 170 175

Met pro Asn Arg Pro Asn Tyr lie Gly Phe Arg Asp Asn Phe lie Gly 180 185 190

Leu Met Tyr Tyr Asn Ser Thr Gly Asn Met Gly Val Leu Ala Gly Gin 195 200 205

Aia Ser Gi/> Leu Asn Ala Val Val Asp Leu Gin Asp Arg Asn Thr Glu 210 215 220

Leu ser Tyr Gin Leu L«u Leu Asp Ser Leu Gly Asp Arg Thr Arg Tyr 225 230 235 240

Phe $er Met Trp Asn Gin Ala Val Asp Ser Tyr Asp Pro Asp Val Arg 245 250 255 Πβ Ue Glu Asn His Gly val Glu Asp Glu Leu Pro Asn Tyr Cys Phe 260 265 270

Pro l^u Asp Ala Val Gly Arq THr Asp Thr Tyr Gin Gly lie Lys Ala 275 2Θ0 285

Asn Cly Asp Asn Gin Thr Thr Trp Thr Lys Asp Asp Thr Val A$n Asp 290 295 300 -6 136387.doc 200938633

Ala A$n Glu Leu Gly Lys Gly Asn Pro Phe 305 310 <210> 6 <212> 179

<212> PRT <213> chimpanzee adenovirus pan7 <_> 6

The Leu Trp Thr Thr ALa Asp Pro Ser Pro Asn Cys i.ys tie Tyr Ser 15 10 15

Glu Lys Asp Ala Lys Leu Thr hen Cya Leu Thr Lys Cys Gly ser Gin 20 2b 30 lie Leu Gly Thr Val Thr Val Leu Ala Vai Asn Asn Gly Ser Leu Asn 35 40 45

Pro lie Thr Asn Thr Val Ser Thr Ala Leu Val Ser Leu Lys Phe Asp 50 55 60

Ala Ser Giy Val Leu l>eu Sex Ser Thr Leu Asp Lys Glu Tyr Trp ¢5 7〇 lb 80 A«n Phe Arg Ly3 Gly Asp Val Thr Pro Ala Glu Pro Tyx Thr Asn Ala 85 90 95

He Gly Phe Met Pro Asn He Lys Ala Tyr Pro Lys Asn Thr Ser Ala 100 105 110

Ala Ser Lys Ser His Tie Val Ser Gin Val Tyr Leu Asn Giy Asp Glu 115 120 125

Ala Lys Pro Leu Met Leu He He Thr Phe Asn Glu Thr Glu Asp ALa 130 135 340

Thr Cys Thr Tyr Ser lie Thr Phe Gin Trp Lys Trp Asp Ser Thr Lys 145 150 155 160

Tyr Thr Gly Glu Thr Leu Ala Thr Ser Ser Phe Thr Phe $er Tyr lie 165 l^〇 175

Ala Gin Glu <210> 7 <211> 19

<212> PRT <2I3> Plasmodium falciparum <400> 7

Asn Asn Qly Asp Asn Gly Arg Glu GLy Lys Asp Glu Asp Lys Arg Asp ! ^ 10 15 136387.doc 200938633

Gly Asn Asn <210> 8 <211> 4 <212> PRT <213>Artificial sequence <220><223> Amino acid sequence derived from the M. falciparum CS protein <400>

Ala lie Gly Ley <210> 9 <2U> 122 <212> PRT <213> Artificial sequence

❷ <22〇><223> Amino acid sequence derived from Plasmodium falciparum CS protein <400>

Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn 1 5 10 13⁄4

Pro A$n Ala Asn Pro Asn Ala Asn Pro As^i Ala Asn Pro Asn Ala Asn 20 2b 30

Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Val Asp 35 AO Μ

Pro Asn Ala Asn Pro Asn Ala Asn Pro hsn Ala Asn Pro ftsn Ala Asn 50 55 60

Pro Asn Ma Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn 65 70 75 80

Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Bb 90 95

Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn loo 105 no

Pro Asn Ala ftsn Pro Asn Ala Asn Pro Asn 115 120 <210>l〇<211><212> PRT <213>Artificial Sequence 136387.doc <220> 200938633 <223> Derived from Plasmodium Amino acid sequence of insect CS protein <400> 10

Asn Ala A$n Pro Asn V is 1 ^sp Pro Asn Ala Asn Pro Asn Val Asp Pro 1 5 10 15

Asn Ala Asn Pro Asn Val Asp Pro Asn Ala Asn Pro Asn Ala Asn Pro 20 25 30

Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Aia Asn Pro 35 45

Asn Ala Asn Pro Asn Ala Asn Pro Asn Aid Asn Pro Asn AJa Asn Pro 50 5b 60

Asn Ala Asn Pro Asn Val Asp Pro Asn Ala Asn Pro Asn Ala Asn Pro 65 70 75 80

Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 85 90 95

Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro loo 105 no

Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 115 120 125

Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 130 135 140

<21〇> 11 <2\l> 20 <212> DNA <213> Artificial sequence <220><223> CpG nucleotides <Ί00> Ηtccatgacgt tcctgacgtt <210><211> 18 <212> DNA <213> Artificial sequence <220><223> CpG nucleotides <4Q0> 12 tctcccagcg tgcgccat <210> 13 <211> 30 <212> DNA <213> Artificial sequence 20 136387.doc 18 200938633 <22〇><223> CpG oligonucleotide <400> 13 accgatgacg tcgccggtga cggcaccacg 30 <210> 14 <2U> 24 <212&gt ;〇m <213>Artificial sequence<220><223> CpG nucleotides <400> 14 tcgtcgtttt gtcgttttgx; cgtt 24

<210> 15 <211> 20 <212> DNA <213> Artificial sequence <220><223> CpG nucleotides <400> X5 tccatgacgt tcctgatgct 20 <210> 16 <211> 22 <212> DNA <213>Artificial sequence<220><223> CpG nucleotides <400> 16 tcgacgtttt cggcgcgcgc eg 22

<210> 17 <2ll> 2250 <212> DNA <213>Artificial sequence<220><223> Adel performance box <400> 17 taactataac ggtcctaagg tagegaaage tcaqatcqgc tgaccgccca acgacccccg 60 cccattgacg tcaataatga cgtatgttcc catagtaacg ccaataggga ctttccattg 120 acgtcaatgg gtggagtatt tacggtaaac tgcccacttg gcagtacatc aagtgtatca i $ 〇tatgecaagt ccgcccccta ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc 2A0 ccagtacatg accttacggg actttcctac ttggcagtac atetaegtat tagteatege 3〇〇taCtaccatg gtgatgcggt tttggcagta caccaatggg cgtggatagc g ^ cttgactc 360 acggggattt ccaagtctcc accccattga cgtcaatgqg agtttgtttt ggcaccaaad 々20 tcaacgggac cttccaaaat gtcgtaataa ccccgccccg ctgacgcdaa tgggcgqtag 430 136387.doc -10' 540 540

200938633 gcgtgtacgg tgggaggtcc atdtaa9cag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt ttgacctcca tdgaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg gaacgcggat tccccgtgcc aagagtgcgg ccagctttat tgcggtagtt tatcacagtt; aaattgctaa cgcagtcagt gctcccgaca caacagtctc gaacttaagc tgcagaagtc ggccgtgagg cactgggcag gtaagtatca aggttacaag acaggtttaa ggagaccaac agaaactggq cttgtcgaga cagagaagac tcttgcgttt ctgataggca cctattggtc ttactgacat ccactttgcc tttctctcca caggtgtcca ctcccagttc aattacagct cttaaggcta gagtggccgc accatgatga ggaaactggc catcctgagc gtgagcagct tcctgttcgt ggaggccctg tttcaggagt accagtgcta cggcagcagc agcaacaccc gggtgctgaa cgagccgaac tacgacaacg ccggcaccaa cctgtacaac gagctgqaga tgaactacta C9gcaagcag gagaactggt acagcctgaa gaagaacagc cggtctctgg gcgagaacga cgacggcaac aacaacaacg gcgacaacgg ccgggagggc aaggacgagg acaagcggga cggcaacaac gaggacaacg agaagctgcg gaagcccaag cacaagaaac ttaagcagcc cgqcgacggc aaccccgdcc ccaacgccaa ccccaacgtg gaccccaacg ccaatcctaa tgtcgacccc aacgccaatc cgaacgtt ga tcccaatgcg aatcctaacg ctaaccccaa tgccaaccca aatgccaatc caaatgcaaa tcccaacgcc aatccaaacg caaaccctaa tgctaatcca ctaatgccaa aacgctaatc agaacaacaa caacgaggag cccagcgaca tcccaatgct aacccaaacg tcgatcctaa cgcaaatccg aacgctaaco ccaacgcaaa tcccaacgct aacccgaacg caaaccctaa cgccaatccg aatgccaacc caaacgccaa cccgaacgct aatccgaatg ctaacccgaa tgctaatcct aacgcaaacc caaatgcaaa ccccaatgca aacccgaacg ccaatcccaa cgccaatcct aatgccaaca agaacaatca 99gcaacggc cagggccaca acatgcccaa cgaccccaac cggaacgtgg ac9agaacgc caacgccaac agcgccgtga agcacatcaa ggagtacctg aacaagatcc agaacagccc gagcaccgag tggagcccct gcagcgtgac ctgcggcaac ggcattcagg tgcggatcaa gcccggcagc gccaacaaqc ccaaggacga gctggactac gccaatgaca tcgagaagaa gatctgcaag atggagaagt gcagcagcgt gttcaacgtg gtgaactcct gaggatccga tctttctccc tctgccaaaa attatgggga catcatgaaq ccccttgagc atctgacttc tg ^ ctaataa aggaaattta ttttcattgc aatagtgtgt tggaattttt tgtgtctctc actcggaagc gatctgaatt catctatgtc gggtgcggag aaagaggtaa tgaaatggca < 210 > 18 < 211 > 2281 <212≫ DNA <21ϋ> artificial sequence 136387.doc -11 · 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 lbOO 1560 1620 1680 1740 1300 I860 1920 1980 2040 2100 2160 2220 2250 <220> 60 60

200938633 < U3 > Ade2 expression cassette < 400 > 18 taactataac ggtcctaagg tagcgaaagc tcagatcggc tgaccgccca acgacccccg cccattgacg tcaataatga cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt tacggtaaac tgcccacttg gcagtacacc «agtgtatca tatgccaagt ccgcccccta ttgacgtcaa tgacggtaaa tggcccgcct gqcattatgc ccagtacatg acctcacggg actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt tttggcagta caccaatggg cgt ^ gatagc g ^ tttgactc acggggattt ccaagtctcc accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgg9 ^ c tttccaaaat gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tqggaggtct atataaqcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattq gaacgcggat tccccgtgcc aagagtgcgg ccagctttat tgcggtagtt tatcacagtt aaattgctaa cgcagtcagt gcttctgaca caacagtctc gaacttaagc tgcagaagtt ggtcgtgagg cactgggcag gtaagtatca aggttacaag acaggtttaa ggagaccaat Agaaactggg cttgtcgaga cagagaagac tcttgcgttt ctgataggca cctattggtc tta ctgacat ccacttt9〇c tttctctgca caggtgtcca ctcccagttc aattacagct cttaaggcta gagtggccgc accatgatga gaaaacttgc catcctcagc gtcagctctt tcctgttcgt ggaggccctc ttccaggagt atcagtgcta cggaagcagc agcaatdcaa gggtcctgaa cgagctcaac tatgacaacg ctggaacgaa cctgtataac gaqctggaga tgaactacta Cggcaagcag gagaaccggt atagcctgaa gaagaacagc cggtccctgg gcgagaacga cgacggcaac aacaacaacg gcgacaac9g cagggagggc aaageitgagg acaagaggga cgggaacaac gaggataacg agaagctgcg gaagcccaag cacaagddac tcaagcagcc cgccgacggg aacccggacc ccaatgcaaa tcccaacgtc gacccaadcg caaaccccaa cgtggacccc aacgccaatc ccaacgtcga tcctaatgcc aatccaastg ccaaccccaa cgcaaatcct aatgcaaacc ccaacgccaa tcctaacgcc aacccaaatq ccaacccaaa cgctaacccc aacgctaacc caaatgcaaa tcccaatgct aacccaaacg tggaccctaa cgctaacccc aacgcaaacc ctaacgccaa tcctaacgca adccccaatg cdaacccaaa cgcaaatccc aacgctaacc ctaacgcaaa ccccaacgcc aaccctaatg ccaaccccaa tgctaacccc aacgcceatc cadacgcaaa tccaaacgcc aacccaaatg caaaccccaa cgctaatccc aacgccaacc caaacgccaa tcctaacaag aacaatcagg gcaacgggca gggccataac atgccgaacg accctaaccg 9aatgtggac gagaacgcca acgccaacag cgccgcgasg adcaacaaca acgaggagcc ctccgacaag cacatcaagg aatdcctgaa caagatccag aacagtctqa gcaccgagtg gtccccccgc tccgtgaccC gcggcaacgg catccaggtg dggatcaagc ccggctccgc 136387.doc -12 · 120 iao 240 300 360 420 480 bAO 600 660 720 780 B40 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 200938633 caacaaqccc ggagaaaCgc tctttttccc tggctaataa actcggaagc t aaggacgagc agctctgtgt tctgccaaaa aggaaattta gatccgaatt tggactacgc tcaacgtcgt attatgggga ttctcattgc catctatgtc caacgacatc gaactccgcc catcatgaag aatagtgtgt gggtgcggag atcggcctgt ccccttgagc tggaattttt aaagaggtaa tctgcaagat gdggatccga atctgacttc tgtgtctctc tgaaatgqca 2040 2100 2160 2220 2280 2281

<210> 19 <211> 3839Θ <212> DNA <213> Artificial sequence <220><223> Synthesis of recombinant vector C7_Ade2. ≪ 400 > 19 catcatcaat aatatacctc aaacttttgg tgcgcgttaa tatgcaaatg agctgtttga atttggggdg ggaggaaggt gattggccqa gagacgggcg accgttaggg gcggggcggg tgacgtttt9 dtgacgtggc c9tga99〇gg agccggtttq caagttctcg tgggaaaagt gacgtcaaac g ^ ggtgt ^ gt ttgaacacgg aaatactcaa ttttcccgcg ccctctgaca ggaaatgagg tqtttctggg cggatgcaag tgaaaacggg ccattttcgc gcgaaaactg aatgaggaag tgaaaatctg agtaatttcg cgtttatggc agggaggagt atttgccgag ggccgagtag actttgaccg attacgtggg ggtttcgatt accgtatttt tcacctaaat ttccgcgtac ggtgtcaaag tccggtgttt ttacatcatt tccccgaaaa gtgccacctg acgtaactat aacggtccta aggtagc ^ aa agccca ^ atc 99〇cgaccgc ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa tgggtg ^ agt atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac dtgsccttac gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc atggtgatgc ggttttggca Gtacaccaat gggcgtggat agcggtttqa ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgc tt tggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc aaatgggcgg taggcgtgta cggtgggagg tctatacaag cagagctcgt ttagtgaacc gtcagatcgc ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc gatccaqcct ccgcggccgg gaacggtgca ttggaacgcg gattccccgt gccaagagtci cggccagctt tattgcggta gtttatcaca gttaaattgc taacgcagtc agtgcttctg acacaacagt ctcgaactta agctqcdgaa gttggtcgtg aggcactggg caggtaagta tcaaggttac aagacaggtc taaggagacc datagaaact gggcttgtcg agacdgagaa gactcttgcg tttctgatag gcacccattg gtcttactga catccacttt gcctttctcc ccacaggtgt 136387 .doc 60 120 180 240 300 360 420 480 540 eoo ¢60 720 7S0 840 900 960 1020 1080 1140 1200 1260 1320 1-380 •13· 200938633

ccactcccag tgccatcctc ctacggaagc gaacctgtdt gaagaagaac cggcagggag gcggaagccc aaatcccaac cgdncctaat caatcctaac aaatcccaat caatcctaac aaaccccfiac aaatccaaac caatcctaac tcggaatgtg gccctccgac gtggtccccc cgccaacaag gatggagaaa cgatcttttt ttctggctaa ctcactcgga gcattatggg tgtgacctcg caatgtgcac tgtgaaggtg catgaatgtg ctgcgadcgc cctgcgaccc agaatctgac tgdctaaaat gggaggggta gaatgtgatg ttca ^ ttaca agcgtcagct a9cagcadta adcga9ct99 agccggtccc ggcaaagacg aagcdcaaga gtcgacccaa gccaatccaa gccaacccaa gctaacccaa gcaaacccca gccaacccta gccaacccda aagaacaatc gacgagaacg aagcacatca tgctccgtga cccaaggacg tgcagctctq ccctctgcca taaaggaaat agcgatctga tattatgggt cacccccgca ctggggtccc ctgctggaqc gagctgtgga ggaggcaagc gatcatttgg ta ^ fagtgagt ctgtgttttc ttcagccctt ggatccacgg gctcttaagg ctttcctgtt caagggtcct a ^ dtgaacta tgggcgagda aggacaagag aactcaagca acgcaaaccc atgccaaccc at ^ ccaaccc acgtggaccc atgcaaaccc atgccaaccc atgcaaaccc agggcadcgg ccdacgccaa diggaatacct cctgcggcaa aqctggacta tgttcaacgt aaaattatgg ttattttcat attcatc tat ctgcaccadt agacatggcc gccgaggcat ccgatgccat aaattctgag acgccagqct tgttgtcctg agtgtttggg ctcftgtgttg atctgacggg tggacggccg ctagagtggc cgtggaggcc gaacgagctc ctatggcaag cgacgacggc ggacg ^ gaac tgcccgccgac taacgtggac taacgcaaat aaacgctaac taacgctaac daacgcaaat caatgctaac caacgctaac gcagggccat cagcgccgtg gaacaagatc cggcatccag cgccaacgac cgtqaactcc ggaca tcatg tgcaatagtg gtcgggtgcg gaatcggcca cgagttcgag gttcatgccc gtccagagtg atatgatgaa tcagcccgtg caacgggacg ggaggtggag cagcagcatg gcgtctcccc gcccgtgcag cgcaccatga ctcttccagg aactatgaca caggagaact aacaacaaca aacgaggata gqgaacccg ^ cccaacgcca cctaatgcaa cccaacgcta cccaacgcaa cccaacgcta cccaacgcca cccaacgcca aacatqccga dagaacaaca cagaacagtc gtgaggatca atcgagaaga gccatcggcc aagccccttg tgttggaatt ga ^ jaaagagg gatatgctgg cacaacgtca taccagtgca agcctgacgg tccaagacca tgtgtggaqg gagttcggct ggcttgtatg agcggaagcg tcctgggcgg cccgcgaact tgagaaaact agtatcagtg acgctggaac ggtatagcct acqqcgacaa acgagaagct accccaatgc atcccaacgt accccaacgc acccaaatgc accctaacgc ac cctaacgc atccaaacgc acccaaacgc acgaccctaa acaacgagga tgagcaccga agcccggctc agatctgcaa tqtgaggatc agcatctgac ttttgtgtct taatgaaatg ccaccgtgca tgacccgatg acatgcaatt gggtgtttga ggtgccgggc tgacgga99d ccagcgggga aggggcagaa cctcctttga gagtgcgtca ctccaaccct 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 28Θ0 2940 3000 3060 3120 3280 3240 3300 3360 3420 -14- 136387.doc 200938633

gacctacgcg cgccgccagc caactcgact ggcccagctc gcaggcggag aataaacgga cgcgcggtag gacccggtag gaggtagctc gcaggggcgc cagccccttg gatgagatgc ggggttcatg atgcaacttg ttccatqcac gtttcggggg aatgaatttg gtagttgccc cacctgcggg caggttccgg cggctgcagg ctcgttcatc gccccccagc ggccatgg ^ c gatgtgccct cgggagtagg cgcagggtcc cttgcgaggg tgcgcgtcgg cccttggcgc agggccftaga ctggcgcaga acgaggtttc ccccgctggg accctgagct gccgtgcgcg tccaccaata gaggccctga acgcgggccg gacggttgtt gccctggacc aggtgggctt cattgcaggg agggcgtggt gtgtaggtgt atcttggcct ttgtgcagga gaag99aagg tcatccanga tcggacacat gggcggaggg tcgcagatct 9cgatgaaaa agcdgctggg tggtagttga atctcgcgca gagagga9ct attttggaga agggcatctc gcaccaggcg gcgtcagcgt tgcgcttcag ccaggtagca ggagcttacc gctcgggggc cggtctcgca ctccgtgctt tgacaaagag cctcgtccgt gaatggccct atcccgccag cccagcgcct cggttgccac gattttaaca accggtctcg ggatgttgag cctcgtgctc gctgcacgat tgacgaacct ggatcttgag ccaccagcac cgtgaadgaa tgatggcgat cgtagttgtg tgcccgactg gcatctccca aaecggtttc acttgccgca 999agagaca catgcatgtt cttgcagcg a gggtctgttg gatccagcag atgggcgtcc ggtctccgtc gctcatccgg attgagcatg tttggaagtg gaggaagacg ctccacgagc cttgatgcgt gctgtccgtg ggacgcagct gggcgccggc cctgaacgag gggcgagctg ggtgaaaacc cagagtcttg atcattgagc gtacatgggc gggggcggtg gtccttgagg gttgagctgg attggcgatg ggtgtatccg tttggagacg gggcccgtgg gtcctgggtg ggggacgaag ggccttgagc cggggcgggg gccggtgggg gctgcc9tcc ctcgcgcacg ggcgaagttt caagagttcc acctcctcgt agcgaggcca acggtgaagg ctggtcgaga agttcgtagt tgtccgcaga gactcggggg caqgtgaggt ttcttacctc tccccgtaga gccgccgcag tact ^ cagct gagaagctgc acccagcagg aaataaaaaa aatctttatt acccggtgga atgagcccqt ttgtaaatca aggagactga gagggatgca ttcccgccca gtgcacttg9 cccttgtgac gcggcggcct agctcgtcat qtgccctcqa tcggaggggg gagatgagct ccgtagatga tcgcggag9a agttccgcca ttc ^ gcg9ct agacggtccc ttcgcqggtt gggtccggtc ggtgcgcgcc accgctcccg tgagcgcctc cgggacagag cgtaggcgtc cgggccggtt tggtctccat ccgactttac ctgctgcttc ctctggtggc tgctgctgat tggctcagct tgadtcaata tgatttttcg ttttttccag cccgggggt; g cccagtcata tggccacgqg tgcgggggga gatcccg ccg ggaatttgtc cgcccaggtt gggcaaagac aggccatttt tcccgggggc ggatcatgtc gggccgaaag ccccgatgac d ggggccac ggaggcgctc tgagcccgtc agagctcggt ggggcgactg cttccagggt gggctgggcg 9t〇9gcgccc ggccgcgtgg gagggacttg cgcgccgcag ggggtcaaaa gagctcgtgt gggccggtcc 3480 3540 3600 3660 3720 37SO 3840 39D0 3960 4020 4080 4140 4200 4260 4320 4380 AAAO 4500 4560 4620 4680 4740 4Θ00 4860 4920 4980 5040 5100 5160 5220 528Q 5340 5400 5^60 •15· 136387.doc

200938633 tcgagcgggg tgccgcggtc ctcgtcgtag aggaaccccg cccactccga gacgaaggcc cgggtccagg ccagcacgaa ggaggccacg tgggag ^ ggt agcggtcgtt gtccaccagc gggtccacct tctccagggt atgcaagcac atgtccccct cgtccacatc caggaaggtg attggcttgt aagtgtaggc cacgtgaccg ggggtcccgg ccgggggcfgt ataaaagggg gcgqgcccct gctcgtcctc actgtcttcc ggatcgctgt ccaggagcgc cagctgttgg ggtaggtatt ccctctcgaa ggctggcata acctc ^ gcac tcaggttgtc agtttctaga aacgaggagg atttgatatt gacggtgccg ttggagacgc ctttcatgag cccctcgtcc atcrtggtcag aetaagacgat ctttttgttg ccgagcttgg tggcgaagga gccgtagagg gcgttggaga ggagcttggc gatggagcgc atggtctggt tcttttcctt gtcggcgcgc tccttggcgg cgatgttgag ctgcacgtac tcgcgcgcca cgcacttcca ttcggggaag acgqtggtga gctcgtcggg cacgattctg acccgccagc cgcggttgtg cagggtgatg aggtccacgc tggtggccac ctcgccgcgc aggggctcgt tggtccagca gaggcgcccg cccttgcgcg agcagaaggg gggc & qcggg tccagcatgd gctcgtcggg ggggtcggcg tccacggtqa agatgccggg cagaagctcg gggtcgaagt agctgatgca ggtgtccaga tcgtccagcg ccgcttgcca qtcgcgcacq gccagcgcgc gctcqtaggg gtgc cccagg gcatggggtg cgtgagc ^ cg gaggcgtaca tgccgcagat gtcgtagacg tagaggggct cctcgaggac gccgatgtag gtggggtagc agcgcccccc gcggatgccg gcgcgcacgt agtcgtacag ctcgtgcgag ggcgcgagga gccccgtgcc gaggttggag cgttqcggct tttcggcgcg gtagacgatc tggcggaaga tggcgtggga gttggaggag atggtgggcc tctggaagat gttgaagtgg gcgtggggca ggccgaccga gtccctgatg aagtgggcgt aggagtcctq cagcttggcg acgagctcqg cggtgacgag gacgtccagg gcgcagtagt cgagggtctc ttggatgatg tcgtacttga gctggccott ctgcttccac agctcgcggt tgagaaggaa ctcttcgcgg tccttccagt actcttcgag ggggaacccg tcctgatcgg cacggtaaga gcccaccatg tagaactggt tgacggcctt gtaggcgcag cagcccttct ccaeggggag ggcgtaa9〇t tgtgcggcct tgcgcaggga ggtgtgggcg agggcgaagg tgtcgcgcac catgaccttg aggaaccggt gcttgaagtc ga ^ gtcgtcg cagccgccct gctcccagag ctggaagtcc gtgcgcttct tgtaggcggg gttgggcaaa gcgaaagtaa catcgttgaa gaggatcttg cccgcgcggg gcacgaagtc gcgagtgatg cggaaaggct ggggcacctc qgcccggttg ttgatgacct gg ^ cgqcgag gacgatctcg tcgaagccgt tgatgtt ^ tq cccgacgatq tagagttcca cgaatcgcgg gcggccctta Acgtggggca g cttcttgag ctcgtcgtag gtgagctcgg cggggtcgct gagcccgtgc tgctcgaggg cccagtcggc gacgtggggg ttggcgctga ggaaggaagt ccagagatcc ac9gccaggg cggtctgcaa gcggtcccgg tactgacgga actgctggcc cacggccatt ttttcggggg tgacgcagta gaaggtgcgg gggtcgccgt gccagcggtc ccacttgagc 136387.doc -16- 5 ^ 20 5560 5640 5700 5760 5820 5880 5940 6000 6120 6,180,624,063,006,360 6〇eo ^ 6 20 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 70S0 7140 7200 7260 7320 7380 7440 7500

200938633 tggagggcga ggtcgtgggc gagctcgacg agcggcgggt ccccggagag tttcatgacc agcatgaagg ggacgagctg cttgccgaag gaccccatcc aggtgtaggt ttccacatcg taggtgagga agagcctttc ggtgcgagga tgcgagccga tggggaagaa ctggatctcc tgccaccagt tggaggaatg gccgttgatg tgatggaagt agaaatgccg dcggcgcgcc gagcactcgt gcttgtgttt atacaagcgt ccgcagtgcc cgcaac ^ ctg cacgggatgc acgtgctgca cgagctgtac ctgggttcct ttgacgagga atttcagtgg gcagtggagc gctggcggct gcatctggtg ctgtactacg tcctggccat cggcgtggcc atcgtctgcc tcgatggtgg tcatgctgac gagcccgcgc gggaggcagg tccagacttc ggctcggacg ggtcggagag cgaggacgag ggcgcgcaqg ccggagctgt ccagggtcct gagacgctgc ggagtcaggt cagtgggcag cggcggcgcg cggttgactt gcaggagctt ttccagggcg cgcgggaggt ccagatggta cttgatctcc acggcgccgt tggtggcgac gtccacggct tgcagggtcc cgtgcccctg gggcgccacc accgtgcccc gtttcttctt gggcgctgct tccatgccgg tcagaagcgg cggcgaggac gcgcgccggg cggcaggggc ggctcgggac ccggaggcag gggcggcagg ggcacgtcgg cgccgc9cgc gggcagqttc cggtactgcg cccggageag actggcgtga gcgacgacgc gacggttgac gccctggatc tgacgcctct gggtgaaggc cacgggaccc gtgagtttga acctgaaaga gagttcgaca gaatcaatct cggtatcgtt gacggcggcc tgccgcagga tctcttgcac gtcgcccgag ttgtcctggt aggcgatctc ggtcatgaac tgctcgatct cctcctcctq aaggtctccg cggccggcgc gctcgacggt ggccgcgagq tcgttggaga tgcggcccat gagctgcgag adggcgttca tgccggcctc gttccagacg cggctgtaga ccacggctcc gtcggg ^ tcg cgcgcgcgca tgaccacctg ggcgaggttg agctcgacgt ggcgcgtgaa gaccgcgtag ttgcagaggc gctggtagag gtagttgagc gtggtggcga tgtgctcggt. gacgaagaag tacatgatcc agcggcggag cgqcatctcg ctgacgtcgc ccagggcttc caagcgctcc atggccccgt: agaagtccac ggcgaagttg aaaaactggg agttgcgcqc cgagacggtc aactcctcct ccagaaciacg gatgagctca gcgatggtgg cgcgcacctc gcgctcgaag gccccggggg gctcctcttc ttccatctct tcctcctcca ctaacatctc tcctacttcc tcctcaggag gcggcggcgg gggaggggcc ctgcgtcgcc ggcggcgcac gggcagacgg tcgatgaagc gctcgatggt ctccccqcgc cggcgacgca tggtctcggt gacggcgcgc ccgtcctcgc ggggccgcag cgtgaagacg ccgccgc ^ ca tctccaggtg gccgccggqg gggtctccgt tgggcaggga gagggcgctg acgatgcatc ttatcaattg gcccgtaggg actccgcgca aggacct gag cgtctcgaga tccac ^ 99at cc ^ aaaaccg ctgaaegaag gcttcgagcc agtcgcagtc gcaaggtagg ctgagcccgg tttcttgttc tccggggatt tcgggaggcg ggcgggcgat gctgctggtg atgaagttqA agtaggcggt cctqaqBcqq cggatggtqg cgaggagcac caggtccttg ggcccggctt gctggatgcg cagacggccg gccatgcccc 136387.doc • 17 · 7560 7620 7680 7740 7600 7360 7 $ 20 7980 8040 8100 8160 8220 8280 8340 8400 8460 8520 Θ580 8640 8700 8760 8320 83Θ0 9940 9000 9060 9220 9180 9240 9300 9360 9420 9460 9540 200938633

aggcgtggtc ctgacacctg gcgaggtcct tgtagtagtc ctgcatgagc cgctccacgg 9600 gcacctcctc ctcgcccgcg cggcc9tgca cgcgcgtgag cccgaacccg cgctggggct 9660 ggacgagcgc caggtcggcg acgacgcgct cggcgaggat ggcctgctgt atctgggtga 9720 gggtggtctg gaagtcgtcg aagtcgacga agcggtggta ggctccggtq ttgatggtat 9780 aggagcagtt ggccatgacg gaccagttga cggtccggtg gccgggtcgc acgagctcgt 9640 ggtacttgag gcgcgagtag gcgcgcgtgt cgaagatgta gtcgttgcag gtgcgcacga 9900 ggtactggta tccgacgagg aagtgcggcg gcggctggcg gtaga ^ cggc catcgctcgg 9960 tggcggggqc gcogggcgcg aggtcctcga gcatgaqgcg gtggtagccg tagatgtacc 10020 tqgacatcca ggtgatgccq gcggcggtgg tggaggcgcg cqggaactcg cggacgcggt 10080 tccagatgtt gcgcagcggc aggaagtagt tcatggtggc cgcggtctgg cccgtga ^ gc 10H0 gcgcgcagtc gtggatgctc tagacatacg ggcaaaaacg aaagcggtca gcggctcgac 10200 tccgtggcct 9ga ^ gctaa9 c ^ aacgggtt qggctgcgcg tgtaccccgg ttcgaatctc 10260 gaatcaggct ggagccgcaci ctaacgtggt actggcactc ccgtctcgac ccaagcctgc 10320 taacgaaacc Tcc^ggatac gqaggcgggt cgttttttgg ccttggtcgc tgg tcatgaa 10380 aaactagtaa gcgc ^ aaag cgaccgcccg cgatggctcg ctgccgtagt ctggagddag 104-) 0 aatcgccagg gttgcgttgc ggtgtgcccc ggttcgagcc tcagcgctcg gcgccggccg 10500 gattccgcgg ctadcgtggg cgtggctqcc ccgtcgtttc caagacccct tagccagccg 10560 acttctccag ttacgga ^ cg agcccctctt tttcttgtgt ttttqccaga tgcatcccgt 10620 actgcggcag atgcgccccc accctccacc tcaaccgccc ctdcc ^ ccgc agcagcagca 10680 acagccggcg cttctgcccc cgccccagca gcagccdgcc actaccgcgg cggccgccgt 10740 gagcggagcc ggcgttcagc atgacctggc cttggaagag ggcgaggggc tg ^ cgcggct 10800 gggggcgtcg tcgccggagc ggcacccgcg cgtgcagatg aaaagggacq ctcgcgaggc 10860 ctacgtgccc aagcagaacc tgttcagagd caggagcggc gaggagcccg aggagatgcg 10920 cgcctcccgc ttccacgcgg ggcgggagct gcggc ^ cggc ctggaccgaa agcgggtgct 10980 gagggacgag gatCCCgagg cggacgagct gacggggatc agccccgcgc gcgcgcacgt llOAQ ggccgcggcc aacctggtca cggcgtacga gcagaccgtg a accounted gcaacttcca 11100 Aaaatccttc aacaaccacg tgcgcacgct gatcgcgcgc gdggdggtga ccctgggcct 11160 gatgcacctg tggcfacctgc tggaggccat cgtgcaga ac cccacgagca agccgctgac 11220 ggcgcagctg tttctggtgg tgcagcacag tcgggdcaac gagacgttca gggaggcgct 11280 gctgaatdtc accgagcccg agggccgctg gctcctggac ctggtgaaca ttctgcagag Π340 catcgtggtg caggagcgcg ggctgccgct gtccgagaag ctggcggcta tcaacttctc 11400 ggtgctgagc ctggqcaagt actacgctag gaagaectac aagaccccgt acgtgcccat 11460 agdcadggag gtgaagatcg acgggtttta catgcgcacg accctgaaag tgctgaccct 11520 gagcgacgat ctgggggtgt dccgcadcga cdggatgcac cgcgcggtga gcgccagccg 11580 136387.doc - 18- 200938633

ccggcgcgag cgggaccgag ccgggccttg ggagggcgag ccaccgcctc tcctcggacg gaagccttta ccctcgcgct aacaaggcca gcccgctaca gaggcggtgt ctgaacgcct aacttcatca tcggggccgg caggctttca acggtgtcga acggacagcg gaggccatcg cgcgcgctgg aaccggtcgc cgctacgtgc gc ^ ctcgaca atcaataagc aacgcc ^ tct atgcccgacc cgccccgcca tccggtcgcg cccttttcgc ctgggcgagg cccaataacg gagcacaggg gacaggcagc gacttgggtg ctgatqtaag ctgagcgacc ggggagagct gaagctgccg tacctggaag ctgatcccgc attggaccca gacagcagcc cgaaccccac tccgcggcga acagcaccaa cgcagcgcga tcctgagcac gcgcgctgcg actacttctt agaacttgca gcctgctgac gcagcgtgag g ^ caggcgca gccaggag < 3a agaagatccc agcagagcgt tgaccgcgcg tgatggacta tgaacccgca ccaacgacgg ccaccgtgtg cgggtgctgc tg & acagcgt agga ^ tacct ggatagagag acgagccccg ggggtctggt ggagtggtgg aatctgaaaa aggagctgat actttgacat gcggttcccc actgatggcg gatgcgggcg ggccatgcaa tcaggccaac gcacgagaag cgaggccggg cgtqcagacg gcggttccac gcagcccgcc gctgatqgtg ccagaccagt gggactgtgg gccgaactcg ccgcqactcg cgtggacgaq cccgggcaac gccccagtac Ggggctgttc caacatggag ct tgcatcgg ctggctcccg gttcctgtgfg gaagaeagag cgcggcggtg gcgcagcagc gaacgactcc cctggtqgac a ^ ctagcagc gtgggacgat tggtaacccg aataaaaaac gcacagcctg gggcgcggac ctacgtggag cgaccgtatt gcgctgcaga cgcatcatgg cggctctcgg gtgctggcca ctggtgtaca aacctggacc cgcgagtcga aacgtgcccc gccgaggtgc cgccagggcc ggcgtgcagg cgcctgctgc tacctgggct cagacctacc ctggaggcca gcgctgagca ctgat ^ cagg cccagcacgt gcggccgcca ccgcccgggt gacgacgtgg ggcgg99dcc cccgaggccg gagctgggtc ttgttgaggc aagatgagcc agcgcaggca gaggatcccg ttcgctcact ggtactcacc cagcgggccc ctgcgctggc gaggtggacg tttgctagat gccagccgtc cgctgacgac ccatcctgga tcgtgaacgc acgcgccgct gcstggtgac acctgggctc ggggccagga cccagagcga tgcagacc ^ t ccccggtcgg tgctgctggt acctgcttaa dggagatcdc ccctgaactt ccgaggagga agggggccac dcgctcgcaa tgaactcgga tctacacggg acugcagcgt ggcggccgtc ccagcccctt ggctgacgcg ccgagc9c < ga gctggaagac cccgtagacg ccgacgacag tgcgcccccg aaggccatgg tgaccggggc agcccagccg atgaggagga gcagcaacag cggcattaac ccgcaatccc ggccgtggtg gctggtggag ggagcgcgtq cgacgtgcgc catggtg gcg ggactacacc ggt9taccag gaacctgagc ggaccgcgcg ggcgcccttc cctgtaccgc ccacgtgagc cctgctgacc gcgcatcctg gcccagcgcc ccgcccgttc ctactttacc cgagtacgac gttctcgccg ctcggcgctg cccgagcctg gccgcgcctg gaagaacttc gtacgcgcac ccagcgacac c ^ gcgtgttg tatcgggcgc cgaccagcgt 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 124Θ0 12540 12600 12660 12 * 720 12780 12840 12900 12960 13020 13090 13140 13200 13260 13320 13380 13440 13500 13560 13620 -19- 136387.doc 200938633

❹ gcgttcttct ctgttqtttg ccctcgtacg agagcgtgat gcgccttacg tgcccccgcg tcggagctgg cacccttgta gacatcgcct cgctgaacta aacaacgatt tcacccccac cggtggggcg gccagctgaa atgtacagca acaagttcaa gcggtggatg agaattatga gagctgcccg agggcaactt atcgacaact acttggcggt aagttcgaca cgcgcaactt ggcgtgtaca ccaacgaggc 9acttcaccg agagcccfcct gagggcttcc agatcctgta gtcgaagcct atgagaaaag accgcctcta ccgaggtgcg gctgaaaccg aaagtdagac tacaacgtgc tcgcggacaa tacggcgacc ccgagaaggg tgcggcgtgg agcaagtcta cgctccacgc gtcaagttag tccaagagcC tcttcaacga ctcacgcacg tcttcaaccg accattacca ccgtcagtga cgcagcagta tccggggagt ccctacgtct ac ^ aggccct taadaaatgt ccattctcat agcaagatgt acggaggcgc cacttccgcg ctccctgggg gacgtgatcg accaggtggt tccaccgtgg acgccgtcat aagagccg9c ggcggcgcat cgagccttgc tgcgcagggc tagtagtatg atgag9cgc9 gca ^ fcaggcg gtggcggc ^ g gtacctggcg cctacggagg cgataccecc cggttgtacc ccdgaacgac cacagcaact ggaggccagc acccagacca aaccatcatg cacaccaaca ggcgcgggtg atggtctcgc tggtagtcag gacgagctga ctcggtgacc atgaccatcg ggggcgtcag aacggggtgc ccgg ctggqc tgggaccccg cttccacccc gacatcgccc cagcaacctg ctgggcatcc cgaggacctg gaggggggcd caaggaggag gccgccgcag gggcgataat tttgctagcg agtcatccag ccggtggaga gaaaaacacc gcctaccgca cgtgcgctcc tggacqctgc ctggtcgctg cccgacatga caactacccg gtggtgggcg gcaggccgtc tactcgcagc ctcccccgag aaccagatcc aaacgttcct gctctcacag ccagcgcgtg accgtcactg gggcgtagtc gcgccgcgcg ctcgcccagt aataacaccg tcgccaacgc tccacgcaac cgccctcaag ggccqcgtgc ggccgacgcg cgcaactaca cgacagcgtg gtggccgatg cgcccggcgg caccggagca caggcgcacg ggacgcaggg tgtacccgga gggtcctcct cgatgcagcc cccgctggag ggcggaacag cattcgttac Cggtggacaa caagtcggcg tcctgaccac cgtggtgcag tca ^ ctttga cgagcgctcg tgcccaacgt gaacgagttc gcaagacccc caatggggtc cttacgagtg ggtggagttt atccgatgaa caacgccatc tggagagcga catcggcgtg tcfaccgagct ggtgatgccg tgctgcccgg ctgcggcgtg gcaagcggca gcccttccag acatccccgc gctcttggat cggcgaccgc agccgtgacc ccgcggcagt ggccgaggcg aggacagcda ggacaggagc gctggtacct g ^ cctacaac tcaccacctc ggacgtcacc tacaagaccc ggtcaccttc ccgagctcct gcccgtctac agccgcgcgc ct tcacctcg tcgtccgccc gcccgcgccc atcacgggac cctgccgctg acgccdgacg ccgcacctgc tcctctcgag ccgcaccttc gttggggcct gcgcgcgccc acccccftgcg cgtgcgcggg gctcgc ^ cac caccgtcgac cgcccgccgc cgcgcccgcc cgcgccggta cgcccgcgcc cccccgccat gcgcqcggcg ccatgctcag ggcggccaga 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 1040 14400 1 ^ 60 14520 145B0 14640 14700 24 760 14820 14880 14940 15000 15060 15120 15180 15240 15300 15360 15420 15480 15540 15600 15660 • 20- 136387.doc

❷ 200938633 cgcgcggcct ccggcagcag cagcgccqgc aggacccgca gacgcgcggc cacggcggcg gcggcggcca tcgccagcat gtcccgcccg cggcgcggca acgtgtactg ggtgcgcgac gccgccaccg gtgtgcgcgt gcccgtgcgc acccgccccc ctcgcacttg aagat9〇tga cctcgcgatg ttgatgtgtc ccagcggcga ggaggatgtc caagcgcaaa cacaaggaag agatgctcca ggtcatcgcg cctgagatct acggccccgc ggtgaaggag gaaagaaacjc cccgcaaact gaagcgggtc aaaaaggaca aaaaggaaga ggaagatgtg gacggactgg tgqagtttgt gcgcgagttc gccccccggc ggcgcgtgca gtggcgcggg cggaaagtga aaccggtgct gcggcccggc accacggtgg tcttcacgcc cggcgagcgt tccggctccg cctccaagcg ctcctacgac gaggtgtacg gggacgagga catcctcgag caggcggtcg agcgtctggg cgagtttgct tacggcaacfc gcagccgccc cgcgcccttq aaagaggagg cggtgtccat cccgctggac cacggcaacc ccacgccgag cctgaagccg gtgaccctgc agcaggtgct gccgagcgcg gcgccgcgcc ggggcttcaa gcgcgagggc ggcgaggatc tgtacccgac catgcagctg atggtgccca agcgccagaa gctggaggac gtgctggagc acatgaaggt ggaccccgag qtgcaqcccg aggtcaaggt gcggcccatc aagcaggtgg ccccgggcct gggcgtgcag accgtggaca tcaagatccc cacggagccc atg gaaacgc agaccgagcc cgtgaagccc agcaccagca ccatggaggt gcagacggat ccctggatgc cggcgccggc ttccdccdct cgccgaagac sentence caagtacg sentence 〇9cggccaqc ctgctgatgc ccaactacgc gctgcatcct tccatcaccc ccacgccggg ctaccgcggc acgcgcttct accgcggcta caccagcagc cgccgcaaga ccaccacccg ccgccgccgt cgtcgcaccc gccgcagcag caccqcgact tccgccgccg ccctggtgcg gagagtgtac cgcagcgggc gcgagcctct gaccctgccg cgcgcgcgct accacccgag catcgccatt taactctgcc gtcgcctcct acttgcagat catqccgcct ccgcgtcccc attacgggct accgaggaag aaagccgcgc cgtagaaggc tgacgg atggccctca ^ gaa cgggctgcgt cgccatcacc accggcggcg gcgcgccatc agcaagcggt tggggggagg cttcctgccc gcgctgaccc ccdtcatcgc cgcggcgatc ggggcgatcc ccggcatagc ttccgtggcg gtgcaggcct ctcagcgcca ctgagacaca gcttggaaaa tttgtaatad aaaaatggac tgacgctcct ggtcctgtga tgtgtgtttt tagatggaag acatcaattt ttcgtccctg gcaccgcgac acggcacgcg gccgtttatg ggcacctgga gcgacatcgg caacagccaa ctgaacgggg gcgccttcaa ttggagcagc ctctggagcg ggcttaagaa tttcg ^ gtcc acgctcaaaa cctatggcaa caaggcgtgg aacdgcagc and cagggcaggc gctgagggaa aagct gaadg agcagaactt ccagcagaag gtqgtcgdtg gcctggcctc gggcatcasc ggggtggtgg acctggccaa ccaggccgtg cagaaacaga tcaacagccg cctggac9〇g 9tcccgcccg cggggtccgt ggagatgccc caggtggagg aggagctgcc tcccctggac dagcgcggcg acaagcgacc gcgtcccgac gcggaggaga 〇9Ctgctgac gcacacggac gagccgcccc 136387.doc • 21 · 15720 15780 15040 15900 15960 16020 16080 U140 16200 16260 16320 16380 16440 16500 16620 16680 16740 16500 16860 16920 16900 17040 11100 Π160 Π220 17280 17340 17400 17460 17520 17580 17640 17700 200938633

cgtacgag9a ccggggtgct cttcccgccc cccgaggccg tgcagagtqt ctgtgtgtat gatggccacc ttcggagtac tctggggaac cagccagcgg cadagtgcgc ctttgacatc ctacaacagc tgatactgat tacaaaggat aacttatcaa tgaaaaatat ttttgccaag taccaaagad cctagcccca tattgtatac catgcccaac caacagcact ggacttgcag cagaaccagg cattsttgae tgtgggtdga gaccaaagat ggagatcaac cctgcccgac ctacgattac cggggcgcgc cgcgggcctq ccaggtgccc ggcggtgaaa gaaacccagc ctccacagtg cccccaggcg gaagcgccgc atgtatgtcc ccatcgatgc ctgagtccgg dagtttagga ctgacgctgc tacacgctgg cgcggcgtgc ctggctccca acagaaaaaa qgtattcaac ccagagcctc ggaggcagag cctaccaata tatgacattg gaaattgttt aaggcdggta agacccaact qgcaatatgq gacacfaaacd tatttcagta aatcacggtg actgatactt gatactgtta atccagqcca atgaacggcc tggtcgctgg cgataccgcc caadagtttt ctgggtctgc agcagcagcc gctaagcccc aactggcaga cgctgctatt 9〇cgaccaga tgccccagtg gtctggtgca accccacggt gcttcgtgcc ccgtgggcga tggatcgggg agggagcgcc cctatacaca ttggaactga aagtgggtga ctctteagcc aagaaggagg acatggcatt tgtatactga cagatgacdg acattggctt gtgtact tcctacaagt ggc ccgaactgtc tgtggaatca tggaggatga accagggaat atgatgctaa acctgtggcg acacgccggc gcgtggtggc accccatgga ccatgctcct tcgccatcaa ccaccacgcg agcccgcgac tgccgccggt gcactctgaa aaaagacact aggaggaaga ggcgtacatg gttcgcccgc ggcgcccacg cgtggaccgc caaccgcgtg gcccagcttc caacacttgc tggaaatgca cagcgatqqt tgctgaatgg tgacaccaaa ccaggcaaat cttcgataat gaatqtggat cagagacaac tggacaggcc ctaccaqctc qgcggtggac acttcccaac taaggccaat tgaattgggc gaacttcctc caacatcacg gccctcgctg caacgtcaac gggcaacggg gagcctcctg gcccgtggcg cctggacttg ggccgtcgcg cagcatcgtg tagctcttct gtagcgctca ggcgcgtcgc cacdtcgccg gccacagaca cacgatgt < | a gaggacaaca ctggacatgg aaaccctact cagtggacat cctgtgcaag caggcdatct catgdcatca atgaagcctt gtgaaaaccg cgaagtgcag ctggaaactc atcaatttgg tttatcggtc tcccagctga ttgcttgact agttatgacc tattgcttcc ggtgataatc aagggcaatc tacgcgaacg ctgcccacca gtggacgcct cccttcaacc cgctacgtgc ctcctgcccg octetggcca cctccgcctg tcgcgcgccc ggtctgggag aettgettgt cgagttgcaa gacaggacgc cctacttcag ccaccgaccg cctactcgta ccagcaccta cc ggcaccgc ataaagctgg gcattagcat atgcagaccfa ctggtactga gctatggttc aaacaggcgg ctgccgccgg cagacaccca gtcagcagtc tgatgtacta atgctgtggt ctctgggtga ccgatgtgcg ccctggatgc a ^ accacctg ctttcgccat tggcgctgta acaccaacac acatcaacat accaccgcad ccttccacat ggtcctacac 17760 1782Q 17880 17940 18000 18060 18120 m $ o 18240 18300 18360 18420 18480 18540 18600 18660 18720 18780 10840 18900 18960 19020 19080 19140 19200 19260 19320 19380 19A4Q 19500 19560 19620 19680 15740 • 22· 136387.doc 200938633

ctacgagtgg aacttccgca aggac ^ tcaa catgatcctg cagagctccc tcggca ^ cga 19800 cctgcgcacg gacggggcct ccatcgcctt caccagcatc aacctctacg ccaccttctt 19860 cccc ^ tggcg cacaacaccg cctccacgct cgaqgccatg ctgcgcaacg acaccaacga 19920 ccagtccttc adcgactacc tctcggcggc caacacgccc taccccatcc cggccaacgc 19980 caccaacgtg cccatctcca tcccctcgcg caactgggcc gccttccgcg gctggtcctt 20040 cacgcgcctc aagacccgcg agacgccctc gctcggctcc gggttcgacc cctacttcgt 20100 ctactcgggc tccatcccct acctcgacgg caccttctac ctcaaccaca ccttcaagaa 20160 ggtctccatc accttcgacc cctccgtcag ctggcccggc aacgaccgcc tcctgacgcc 20220 caacgagttc gaaatcaaqc gcaccgtcga cggagagggg tacaacgtgg cccagtgcaa 20280 catgaccaag gactggttcc tqgtccagat gctggcccac cacaacatcg gctaccaggg 20340 cttctacgtg cccgagggct acaaggaccg catgtactcc ttcttccgca acttccagcc 20400 catgagccgc caggtcgtgg acgaggtcaa ctacaaggac taccaggccg tcaccctggc 20460 ctaccagcac aacaactcgg gcttcgtcgg ctacctcgcg cccaccatgc gccagggcca 20520 gccctacccc gccaactacc cctacccgct Catcggcaag agcgccg tcg ccagcgtcac 20580 ccagaaddag ttcctctgcg accgggtcat gtggcgcatc cccttctcca gcaacttcat 20640 gtccatgggc gcgctcaccg acctcggcca gaacatgctc tacgccaact ccgcccacgc 20700 gctagacatg aatttcgaag tcgaccccat ggatgagtcc acccttctct atgttgtctt 20760 cgaagtcttc gacgtcgtcc gagtgcacca gccccaccgc ggcgtcatcg aggccgtcta 20820 cctgcgcacg cccttctcgg ccggcaacgc caccacctaa gcctcttgct tcttgcaaga 20880 tgacggcctg cgcgggctcc ggcgagcagg agctcagggc catcctccgc gacctgggct 20940 gcgggccctg cttcctgggc acctccgaca agcgcttccc gggattcatg gccccgcaca 21000 agctggcctg cgccatcgtc aacacggccg gccgcgagac cgqgqgcg ^ g cactggctgg 21060 ccttcgcctg gaacccgcgc tcccacacct gctacctctt cgaccccttc gggttctcgg 21120 acgagcgcct caagcagatc taccagttcg agtacgaggg cctgctgcgt cgcagcgccc 2Π80 tggccaccga ggaccgctgc gtcaccctgg daaaqtccac ccagaccgtg cagggtccgc 21240 gctcggccgc ctgcgggctc ttctgctgca tgttcctgca cgccttcgtg cactggcccg 21300 accgccccat ggacaagaac cccaccacga acttgctgac gggggtgccc aacggcatgc 21360 tccagtcgcc ccaggtggaa cccaccc tgc gccqcaacca ggaggcgctc taccgctccc 21420 tcaacgccca ctccgcctac tttcgctccc accgcgcgcg catcgagadg gccaccgcct 21480 tcgaccgcat gaatcaagac atgtadtccg gtgtgtgtat gtgaatgctt tattcatcat 21540 aataaacagc acatgtttac gccaccttct ctgaggctct gactttattt agaadtcgaa 21600 ggggttctgc cggctctcgg catggcccgc gggcagggat acgttgcgga actggtactt 21660 gggcagccac ttgaactcgg ggatcagcag cttcggcacg gggaggtcgg ggaacgagtc 21720 gctccacagc ttgcgcgtga gttgcaqggc gcccagcagg tcgggcgcgg agatcttgaa 21780 136387.doc -twenty three-

200938633 atcgcagttg ggacccgcgt tctgcgcgcg agagttacgg tacacggggt tgcagcactg gadcdccdtc agggccgggt gcttcacgct cgccagcacc gtcgcgtcgg tgatgccctc cacgtccaga tcctcggcgt tggccatccc gaaggggigtc atcttgcagg tctgccgccc catgctgggc acgcagccgg gcttgtggtt gcaatiogcag tgcdggggga tcagcatcat ctgggcctgc tcggagctca tgcccgggta catggccttc atgaaagcct ccagctggcg gaaggcctgc tgcgccttgc cgccctcggt gaagaagacc ccgcaggact tgctagagaa ctggttggtg gcgcagccag cgtcgtgcac gcagcagcgc gcgtcgttgt tggccagctg caccacgctg cgcccccagc ggttctgggt gatcttggcc cggtcggggt tctccttcag cgcgcgctgc ccgttctcgc tcgccacatc catctcgatc gtgtgctcct tctggatcat cacggtcccg tgcaggcacc gcagcttgcc ctcggcctcg gtgcacccgt 9cagccacag cgcgca ^ ccg gtgctctccc agttcttgtg gqcgatctgg ^ agtgcgagt gcacgaagcc ctgcaggaag cggcccatca tcgtgqtcag ggtcttgttg ctggtgaagg tcagcggaat gccgcggtgc tcctcgttca catacaggtg gcagatacgg cggtacacct cgccctgctc gggcatcagc tqgaaggcgg acttcaggtc gctctccacg cggtaccggc ccatcagcag cgtcatcaot tccatgccct tctcccaggc cqaaacgatc ggcaqigctca gggggccc tt caccgttgtc accttagtcg ccgccqccga agtcaggggg tcgttctcgt ccagggtctc aaacactcgc ttgccgtcct tctcggtgat gcgcacgggg ggaaagctg ^ agcccacggc cgccagctcc tcctcggcct gcctttcgtc ctcgctgtcc tggctgatgt ctt ^ caaagg cacatgcttg gtcttgcggg gtttcttttt gcigcg ^ caga ggcggcggcg gagacgtgct gggcgagcgc gagttctcgc tcaccacgac tatttcttct ccttggccgt cgtccgagac cacgcggcgg taggcatgcc tcttctgggg cagaggcgga ggcgacgggc tctcgcggtt cggcgggcgg cCggcagagc cccttccgcg ttcg9gggtg cgctcctggc ggcqctgctc tgactgactt cctccgcggc cggccattgt gttctcctag ggagcaagca tggagactca gccatcgtcg ccaacatcgc catctgcccc cgccgccgcc gacgagaacc agcagcagca gadtgaaacic ttaaccgccc cgccgcccag ccccacctcc gacgccgcag ccccagacat gcaagagatg gaggaatcca tcgagattga cctgggctac gtgacgcccg c9gagcacgd ggaggagctg gcagcgcgct tttcagcccc ggaagagaac caccaagagc agccagagca ggaagcagag agcgagcaga accaggctgg gctcgaqcat ggcgactacc tgagcggggc agaggacgtg ctcatcaagc atctggcccg ccaatgcatc atcgtcaagg acgcgctgct cgaccgcgcc gaggtgcccc tcagcgtggc ggagctcagc cgcgcctacg agcgcaacct cttct cgccg cgcgtgcccc ccaagcgcca gcccaacggc acctgcgagc ccaacccgcg cctcaacttc tacccggtct tcgcggtgcc cgaggccctg gccacctacc acctcttttt caagaaccaa aggatccccg tctcctgccg cgccaaccgc acccgcgccg acgccctgct caacctgggc cccggcgccc gcctacctga tatcgcctcc ttggaagagg ttcccasgat 136387.doc • 24- 21840 21900 21960 22020 22080 22140 22200 22260 22320 22380 22440 22500 22560 22620 22680 22740 22800 22860 22920 22980 23040 23100 23160 23220 23290 23340 23400 23460 23520 23580 23640 23700 23760 23820 200938633

cttcgagggt ctgggcagcg ggagcatgag caccacagcq cctcaagcgc acggtcgagc ggtcatgagc gccgtcatgg ggagatgcag gaccccgaga ggcgcgctgg ctgggagcga gatggccgtg gtcctggtga ggagaccctg cgcaaggtcg ccaggcctgc aagatctcca gcacgagaac cgcctggggc cgactacatc cgcgactgcg cgtgtggcag cagtgcctgg gaacctcaag gccctgtgga cctcatcttc cccgagcgcc ccaaagcatg ttgcaaaact cacctgctcc gcgctgccct gctctggagc cactgctacc gatcgaggac gtcagcggcg gccgcaccgc tccctggcct cttcgagttg caaggccccg gacctcggcc cacttgcgca ctacgaggac caatcccagc ggccatcctg gcccaattgc gggccacggg gtctacttgg ggatgccccg aggaagcagc tggaggaaga ctgggagagc ctcaggcaga ggag ^ acagc cagaggaaga agcagccgcc gcacggatac catctccgct acgagaccgg gcgcttcccg acaagtcctg gcgggggcac acatctcctt cacccggcgc tcttgcatta ctaccgtcac cccagcagca gcagcagcag acgagactcg ggccgcgaac ccctggtgga gttggaaggc tgacccactt cgcctacccg aicc ^ ggtgct catcaagcgc gctcggacga gggcaagccc gtagcacccc ccagagcctg ccqtggagct ggagtgtctg aggagaacct gcactacctc acgtggagct gaccaacctg agaacgtgct gcacaccacc tct ^ ccCgta cctctgccac aggagcaga a cccgadagag ccgggttcga cgagcgcacc tgcggctgac gctgcgcaac ttcgctcttt catcctcgaa cggacttcgt gccgctgacc tgctgcgcct ggccaactac agggcctgct cgagtgccac gcaaccccca gccgccgagc gcgagggcaa ggggggtctg agttcgtgcc cgaggactac cgcccaaggc cgagctgtcg a ^ gccatcca gaaatcccgc acccccagac cggagaggag aagaagctga aagtggagct agtcaggcag aggaggagga ctgcaagaca gtctggagga gccagaccgt cgtcctcggc ccgggtcggg gtcgcggcgg aaccccacca cccagaccgg aaaaacgcca tcgtctcctg tacctgctct tccaccgcgg ctccacagcc cctactactg cagaaaacca gcggcagcaq gctctgcaag 9ddgc99aga gacaacgcgc gcctggcggt gcgctcaacc tgccccccaa gcctcgcccc tctcggagga gtggtcagcg acgagcagct gaagagcggc gcaagctcat cgccgcttct tcgccgacgc ttcagacacg ggttcgtgcg gtctcctaca tgggcatcct ctgcgcgggg aggcccgccg acctggqaga cgggcatggg ctctgcaagc tcctgcagaa accgcc ^ cgg acctggccga gggctgcccg actttatgag cgctccgqga tcctgcccgc gccccccgcc ctggcctacc actcggacgt tgccgctgca acctctgcac gagacccaga tcatcggcac aaactcaccc cggggctgtg catcccttcg agatcaggtt gcctgcgtca tcacccaggg caa9aatttc tgctgada ttccgcgagt aa ctcaacccca gcttccccca gccgccgccg ccggaggatt gatggaagac tgggacagca ggaagacgag gtggaggagg ggaggaggsg daagcaagca ccgggcccac agtagatqgg taagaaggag cgqcagggat cttgcaagcc tgcgggggca ggtgaacttc ccccgcaaca tttccaagaa gaggcagaaa ctagaaaatc cacagcggcg 23880 23940 24000 24060 24120 24190 24240 24300 24360 2 Correcting 20 24480 24b40 24600 24660 24720 24780 24840 24900 24960 25020 25080 25140 25200 25260 25320 25380 25440 255. 0 25560 25620 25740 25800 25860 -25- 136387.doc 200938633

gcaggtggac atctttccca gtcaagaacc caacttcagc cttaaagagt gcgcccttcg accagcccca ggctcagtgc agatactcct attggcccgc gagacgccca ccctgtgtcg cacagctcaa aactcgccgg gttcgtcctc ctccctcggt tcccgaactt gcgcggctga ct〇9ggdtct cccacgqagt gccagcgtcc tctgcaacca aaagccgaga ttcttcaccg acctggctgt ctgctgagcg caacccttcc ctgatcccga caccgtcgcg ccaacctctg gttgcgggtg gtgctgtgtt tggcggtggt atccccgctt tgaggatcgc ccctctatgc gttctctgcg gcactctcga agcccgcgcc cccgaccatc gatgggcctg cgggcccgcg agaacagtca cgccccggtg ggccgaagtc tcaccgcccc cgacgaggtg atcggggaga gcagccccgc ctacttcaac cgacgccatc cctagctcgq cgccgagttt gcggatcgtc gatcctggcc ccccggcctg tcagcgacta ggaacgagac tccagggctc gccctgccaa tccccgggac ataccacagc acctttcctc ggatttacta ggcttttggc gctggtttaa gctttcgatt gcatttcaat 99cgaacgag catcttccag ctcgctcacc ggacgc〇9dg cgcccacaca atcatgagca gccgccggcg atgatctcac gcgatcaccg taccaggaas cagctgacta gctcagggta gtgagctctt tcttccttca tcgggtggca cccttctccg agcgagtcgg

Cttcgacacc gcctactttg gtcgaaggqg gagcgcgagc catgaaagtc ctccggactt ccjagctccag tccgatcgcc ccttactttt ctatcagtgc gtcgctcccc tgggtctaat cggcccctgg tctctgctac gaaatgggga gtggqactgg cccgacaaat ccggcgcaga cagagtcggg cgcagttqtc gctctcttca cggaaaaagg aagagattcc ccgcccagga gggtgaatga ccacgccccg ttccccagcc actcaggtgt taaagcggct cgctgggtct cgcctcgtca tcggcactct gcccccccgg tggacggcta tggaccactg agctgcccga gtctcgactc aag ^ acagac tttqttgtct ccgcgcgtcc ctccagtgta gttgtcaacc tccacccgca gtctcgggac ^ ctaccaaca accactaccg gagqtggta ^ ctatacctcc agatcaccct gcggcgcggc gccagctgag cccgggagct ggcaagagca tgtatcacaa acaagtactg cgggaattac cacgcctt ^ c ctactccacc catccgcgcc ccatcacctt cacgaccgta ccagctggcc ggtgatccga gcgacctgac ggccgtcctg ccagttcgtg ccactacccg cgattgaatg ccgccgcttc ggagcaccct ccacctgctt ccttctgacc gctgtgtact ctgctatcaa agccccacaa actgcgacaa gaagcaagct cctgccatca accaaactdc gaggtgagct ggttaatagc cttgctgttc agtgagctgc tgtagtgaag ttttcagccc gaggaaccgg ggdactgada gagcgaagac cgcgctcact gtcaccacct atgtggagc t cgcatgaact caccgaaacc aatccgcgta ctacttccgc ggcggcgccg ggcdgaggca ggagtcttcc dctttggaga ^ aggagttca gacgagttca tcccatggtg cgctgcttcg ca99gccc9g cggatcttca ctgtactgca gagtataata ccagtccctg gaaqtacctc cgacggagtc ccagctcttc caccttccac ccaccaacgc ccgaggtcqa gctaggccta gtacttdgtg ggtgtgctgg ^ agadggccq gatggcaatc 25920 2S980 26040 2S100 26160 26220 20280 26340 26400 26460 26520 26S80 26640 26700 26760 26B20 26880 26940 2 ^000 27060 27120 27180 27240 27300 27360 27420 27480 27540 27600 27660 27720 27780 27Θ40 27900 -26· 136387.doc 200938633 ❹

ggtgcgcggt acaagactcg ccgtctctgt cgcacatgtg aggagaacat tcgtgtgcct aaaaacagcc tttgctttta tatttacact gcattgttat aaatgagagc cactagagac ttatcaagtt acctgttacc aaataqcacc cattattgtt cttctgctac ttaatttttt tctatgcaat aggtccagca agdactttgc caatggcact ccctggagat tccaccgccc ag ^ agcagag cgatcagcgg agtcatdatc atcagaccca gctctagttt accatttatg ctaaaatacc tgtaatggag ggccagagtt actgtcatca gctgdtcaag gaacaatacc ccccggtgcc cgacacggtc cgtggtcttc gagcattcac ataacacgtt tttgccagtc ggcactaatc tttaatgadt attactctca tatgtaggta tctgtgtctg actataca ^ c agcattcaac 9〇t9tagtgg agaaacjcaca agaaccatga tctgacaatg aaaggtatgc aatgqtcaaa gacttagtat gatgccgaca accaccacaa ttggccttcc tgtccggggc atctgcatgt ctgctgaacc tttgttcttt aaggtgagaa atctagatgg ttaacctcac tcactagaaa gaaatgagac tgcggatggg ctcgcgtccg gacggctccc atgtggatga tccatcgctt atgctcatcg ttttcacaca tcattgccgt acacattgaa cagatgtacc tcaagtttca tgtattatgg aacccaccac tcactaccaa ccaccccacc tgtgcatgtt gactgaacga agatcctagg aggacgttac tttcgtggta aaggcaaaac tgctcaatgt atatgat ttt ctactcatac aggttcacgg tgctcgtcag tcatttttgc tctatgttta gattggcatt tgccactcta gtggaaagac cattactaat taatgggtat tgccaccacc aatgcgagaa tgtggcagcc cgcgcaccgt gcaagcagta acagcgtgtg ctattcgccc cctttttcag cattcatgga aggtccagaa tactgaactc atgtggatct adctacagca gcctagaatg tggctttctt ca ^ tgaggaa gatcatcgcc caagctggaa ccttttagtt tgtcgttgtc ttgttggttc ctcaaattct cacgaaagca ttacaaagtg cacacacaca agattccttt cggcattgtc ttgctgctat attttttcca gtttttagtg gtgggcatca atttgcgatt gccacccaag gaatcccata acacagatgc catga9ddtc cggggacccc gaataatact cgatatgtgg cacggcgcta cagaaataat accatggcct atgagtaatg aaagccacag tgtggaaaca gacttaaccc ggcatttcgg accacaacca gccatgcctc attcccagat ttgtgcatgg cactcactaa ttttctatca ggatcaaacc ggaactgacg aaaatctcta tatgctggca gaagtggtcg gaacaaacac gctgtcasta ggtgtgcttt agaaggcctt gagccatgaa ctgggttttt gtggtcaaaa ggaatgtcac atcagaatgg acatgtttat ccactacaca gagtacaata gagtggtaca ttcatttttg ccccccacga atcaccgcta gccgaaaaag ctgttaaatt agaaaattac aagtttcatg acaacaaaaa taattaacat acatgg aatt caaaaactac aagtgqctga ccatgattgg tgtactatgc gtgttgaatt ttacctctgc acacactaaa agcaacagac attatcaatg gttacacctg accccactac cagaggcagc cccctacacc cgggattagc accgacdaaa ggcagtcagc gaaaaatctt tgtcagctg9 tgtgtataca taggtttaag ctatgacgtc cagttctacc 27960 28020 28080 28140 28200 26260 28320 28380 28440 28500 28560 28620 26680 28740 28800 28860 28920 28980 29040 29100 29160 29220 29280 29340 2 ^ 400 29460 29520 29580 29640 29700 29760 29820 29880 29940 -27- 136387.doc 200938633

❷ actactacca acagcagcaa caacctagta agccacacca tctacaccaa caaactgagg atcctggccg ccggcctaca aggaatcttc gatcactatt cagtccagac ctgctgctgt tgtgcgcatc gctcaggctc ctcccccgcc aaattccaag aqictggacca atttacccct cctgacacac cadtacatgc agttacttca ccttctcctg ccagcagcag gaaaggcatc ccatcqcctc caaccccatc cgactccccc ccccatgaac ataasaaata aaaaataaag acaccacctc tcctccacac ctatcagatg cgatgcagac tgcaadccac agccaagtag caactactag cagctacctc tcagtcccgc acagcggcac tgttgctcta agcccatcgt cttatctgcc tgtattgggc agcatagtct gcctacctgc ctctgataag ccgtcgaccc tcttctcttt aaccctggaa tgaccattgg gctttgactt caccacagca ccatattaga atctaaccgg gacatggacg gagagagccg ttctgcctgq tcctacgagc gtcatcaccc gactgcgtcc caaccacccc atcatttgat aatcacttac actcccctct gctgaagggg tccaaaaagc aacgcaccga acagacaacc tgcagcgcct gaccaatgag cagtgccttc tactactccc gcaatggcag ctacatcttc tatcgggcag tacagtatgg tcctccaagt ccttcgcctc gcctgcttat gccaccaccc catgcgggct ccggtccccc attcctcaaa gatcgtgaac tggttggaac acctcaggca ctatgaggcc cggagatgac gccgcgcctc tcaag gagct tgaaacaggc tcctgcagca agcagtcggg acactctgat cttatccagt ttgaddtddd ttgaaatctg tcccagctct atgtcaaatt gcgtccgggt cc9tgccctt actacdtcaa cagccccagg ca9actactg tctagcaccg accccagctc atcaccctgc tgccgccgca ccggagccgc tgattgaact ctgtgccacc ctacgtgctc caccttcttc ccagtaccgc ctgctacttc actcagtccc tgctaccgcc attctggcct tcqccaqaqq cacgcactac gagccacagc tgacccactg ggagcagcga gcaggacggc caagdtctcc gcgccagaag cgataccaag caagaccctc gaaataaata gatacaatca ataccagatc ggtactgcag cctcctgtcc ggatgatgac catcaacccc ctcagcatat ctttggcttt aatttttgtc ccaatctctc ttctccccac tcattgtgat ttcccaacgc ttcaggtgga acgattccta ctcgctctgg tttgccttca cagttcateg gaccagcgag tcqcgcttct ccgaagaggt aaaaatcaga gcaccctcat cgctctatct caccaccaca gacccatgct gccaacaaca ctcgcccaac atagccatcc tacgaggtca ttcacctgcc gggtqcatcc tgcggcctcc tcatattgat tattgatgat tctgt ccacg accccggcgg ctcaatcttc ttcgaccccg cccttcgtct gaccaccact gaaagctgca cactgtcgag ctcgctttcc tcccctgaag cgggttggtc gcaccgcaaa agggggtcta gacaattctt tggccaacgc tcacctgcat act ggatctt tggcgcggct gctgttagtg ccgcaaatgc catgcttccc ctcctttgtg cccgcctgaa gcctaggcca ccccgctatt acgtcaacga ttcgcattcg accagtgcaa ccccgaccga tggtcggagt actgctcctg gcgaccccct gacgattcaa ttgagtttta ttttctgcca gctgcaaact attttatctt tctaccccta cttcagatgg 30000 30060 30120 30180 30240 30300 30360 30420 30430 30540 30600 30660 30720 30780 30840 30900 30960 31020 31080 31140 31200 31260 31320 31380 31440 31500 33560 31620 31680 31740 31800 31860 31920 31980 -28 - 136387.doc 200938633

dttccaagag gaacggggaa catctccaac ccttaacatg accgttaaac tttaggactg tgaaaaa99a acttagtatc caacataagc cdgaggattg tcaagttaaa caaagacfcfat atactctgaa 999tactgtg dagcactgca attagacaae taatgct ^ ta aaaaagccat gattattact gaaatgggat ctacatcgcc tctgtctatg tcaacagttt caccaccctc tttggtctcc gaaaccctcc ggtggtcggg gcgaacggga tccgtcaagc gccctcagca tcgctgcagt ctccagccga aggtdaacca atgtggcggt aa ^ cccctgg atcaccctca acggccacca gatacccctc atattaadat agtggtggca aatattaaaa aactgcaaaa tgqcctaaag gdatttggaa tt99gtactg gataaactta aaagatgcca actgtattgg ctcgtctccc gaatattgga ggttttatgc attgtcagtc tttaatgaaa agtactaagt caagaatgaa gaaaaaactc tacaggattc tccccccgca acgttccac ^ gggcactccc atcacggtta tcggccggtg tgctgctcag tcagtcgtct acgtgcaaca aactcatcgc agtggcgctc tcaccdcctc gggtgctgtc agctgggaga aggccgccgc tttataccaa caaccattct ctgctcttgc ttaacctagc gaggggtcac gtdtaagatt ccactagtac 9〇cttacctt cattatggac aactcacact ca9tgaataa tca ^ gtccga acttcdgaaa ctaacataad aagtttatct ctgaggatcjc acacaggtga cactgtatcc tgaagcacaa gagca gttat cagccctgaa cagtttcaga gcatctgcac tctggaagaa gtgtcgcatc ggggtccggg ggtgcggcgg caggaccacc gggaaggatg cctccagaac ccggtaccac cctgcgactg gggggtggac ccctctcagt agatggaaaa gaacacatts agtacagttg cagtggtcca tgtcactacc t ^ aaggtaat agagactgat tgacagtaca caca < 5ccqac ttgcttgaca tggaagtctc tgc ^ agtgga gggagatgtt ggcctatcct caatg ^ ggat aacttgcacc aacacttgct caccctgcat aataaaataa ttttcctcca ca ^ ctgaatg gcgagccagt ctcacagctc gcagaagaqc aggccccgca cccagggact gcgcagcagc aggttgttca ctacccacgt acgctgccca atcaccctct gctgaccccg ctcgactcct ttttccaaca ttatccttac gctgtagctt gcctctccac ttaacagttg tcaggagdtg ggcatagctg gtcacagatg ggcgccattg ccctcgccaa aagtgtggaa aacccaatca gttctgctdd acacctgctg aaaddcacat gaggccaaac tacagtatca accagctcct gccaaccctt agttcaagtg ccctcccagg ccattggtga ctcgggtcgg aaca9ct < ja9 ggcggtggga gcagtcgctg ccctcagcat gcatgcggat acagtccata ggccgtcgta cgtacatgat ggttgaacat tcaccaccaa cgggaadact acaccatttc aagtctctcc atggatcagg tcacttttga atgcaagtcg caattgaaag Caaacattgg catacccaat ttgcttg gaa attgcaaaat gtcaaattct caaacacagt gcagctccac agccctatac ccgcagcctc cactgatgct ctcttcaatg tcaccttctc cccaccccac ttttattgat acatggaata tggacatgct tcagggagat g-att ^ tcctc atcatagtcc ccgccgccgc gacgcccacg ctcgctcagg gttcaacacg ccagatcctc ctccttgggc gcagccccgg 32040 32100 32160 32220 32290 32340 32400 32460 32520 32580 32640 32700 327 ^ 0 32820 32880 32940 33000 33060 33120 33180 33240 33300 33360 33420 33-380 33540 33600 33660 33720 33780 33840 33900 33960 34020 136387.doc -29· 200938633

atgatcctgc ggaaccacag gggtcccggc aatggcdatg aacaagtcta tgttggcaca tcctcggggg tcaaaaccat gcagaacagci gcaaccctcg ggcagcaccg ggtgatcctc aaqggggccg gccgatacgg atgatgcagt tgctttc ^ ga gcacaccgat cgccggcggc cagccactct ctcagaccgc atgcctgata gctctgatca gcaattttgt tgggtttcgg cttttaatcc aaacggtctc gcccccgctg cgttggtgga ttccacggtg gcttccagca agcgggaggg ttctctaatt attttcattt ttccagcctt catgataaa ^ agctcgcgca tccaagatat tctgcccctg ctgccgcgat ccctaagccc ccgaaatttt tagccatagg aaccgaagtc ctccccagtg gacccggcga tatcttccag tcaacaaaag aaaaatcctc atgcaagcgg tgcgttccag cattaaacca tgctagcctg gccacggggt ctccggcgcg gagagacgtt cccggtggcc ttgqcgtccg cgagtgaaaa ctcaagtcca gcaaagcgat atgtaattac tcccctcctg aiiagcctcag cgtccatagc aaggctgagc tctaacctgt gacgtaaagg ccaaagtcta g ^ ccagcacc gccccgcccg gaggacccac cgctcgtacc gcacaggcat atgctcatgc atcccagggc acggggaact cacataactt acattgtgca caccagagaa gcgcgggtct gtgatggcgg gacgcggctq cattttcgta cttgctgta ^ ggtcccggcg cttggaacgc gcagcagatc tagggcctca catcgaccac cgt99aatgg t9acggc9 g9 ggagggaaga ggagcacttc aaaatgaagg aaataacagc caggtcaaag aagcctccac gcgcacatcc cctcaatcat catgttacac gaatgattcg aactdgttcc gagcgccctc caccggcatt gttcacctgc agcagattga ctccctcagc aacaactgta accaccagga ataagattag agcattgcca aatgcaagac ataact9gac agaaaatcac caggtgcacg tttagagcct catggttagt tagctgatct gcgaacaggC gggtaaatgg accctcgtaa aaattgtcgc ggcgtgaatg attcgacaag aaagcgcccq aggaagcaac gccatgcgga tgaagcacaa cacaggcagc gaagcccccg ttaccga ^ ca gcagcacdca ccacccgctc tctgctcaat aaaatacccg ccaaataatc ccatgcagcg aagagacccc cgtggatcat ctgggagctg atctcttca ^ cactctcagc cttgcaggac agcgaacccc tggacagggt atcgcaatca cggtctcctc acagcgtggt atcgtgttcg cgaccgtgtc cagaacctgg tccgggcgct tcggtgttga aattgtdaaa ggagtgatga agatcccatc; gccagaccca gccagatgat acacigaagaa ccatgattaa tcgcggagat gqcacctctc gtgatdcggt tct〇9agatg agaaacaaga caatagcgaa tcctgcacca tccccagata tgaggtaaat ccaagccagc cttaagcaca ccctcataat caagcggaat atcaaaatct agtactcttt catatcctct ggcaagccac agtacagata tgctataagc atgctggcta ccaggcaact c tcaagaaaa cgggaacaac gatgaagtaa gtaaaaaaca aaaaataadd ttctctccag caccaggc ^ g tatgattgaa aaccatcaca atgaatacac ccccggaaca aaqgcdccac aatgctcagc aatcctca99 tgcgtacaaa atccctccag atacacatac acaggcgc ^ d gagtcagaga atatagccca gatctacact acacacgccc agcacacgcc 34090 34140 34200 34260 34 320 34380 3AAA0 34500 34560 34620 346Θ0 34740 34800 34860 3 ^ 920 34980 35040 35100 35160 35220 35280 35340 35400 35460 35520 35590 35640 35700 35760 35Θ20 35880 359^0 36000 36060 -30- 136387.doc 200938633

cag ^ aaccgg catttccggg aaaacgtcac tccccaaatt ttgatgatga taccgcatca ctgc99C9ag gataacgcag gccgcgttgc cgctcaagtc ggaagctccc tttctccctt gtgtaggtcg tgcgccttat ctggcaqcag ttcttgaagt ctgctgaagc accgctggta tctcaagaag cgttaaqgga tdaaaatgaa caatgcttda gcctgactcc gctgcaatga ccagccggaa attaattgtt gttgccattg tccggttccc agctccttcg gttatggcag actggtgagt tgcccggcgt attggaaaac tcgatgtaac tgacacactc ttcccacgct ccgccccgcc caaacagctc tcctaattaa ggcgctcttc cggtatcagc gaaagaacat tggcgttttt agaggtggcg tcgtgcgctc cgggaagcgt ttcgctccaa ccggtaacta ccactggtaa ggtggcctaa cagttacctt gcggtggttt atcctttgat ttttggtcat gttttaaatc tcagtgaggc ccgtcgtgta taccgcgag ^ gggccgagcg gccgggaagc gtgcaggc ^ t aacgatcaag gtcctccgat cactgcataa actcaaccaa caacacggga gttcttcggq ccactcgtgc aaaaaadtac acgtcatcg9 cctaacggtc atttgcatat catgcggtgt cgcttcctcg tcactcaaag gtgagcaaaa ccataggctc aaacccgaca tcctgttccg ggcgctttct gctgggctgt tcgtcttgag caggattagc ctacggctac cggaaaaaga ttttgtttqc cttttctacg gagattatca aatctaaagt acctatctca gataactacg cccacgctca cagadgtggt tagagtaagt cgtggtgtca 9cgagtcaca cgttgtcaga ttctcttact gtcattctga taataccgcq gcgaaaaccc acccaactga gcgcacttcc aattcgactt gcccgtctct taacgcgcac gaaataccgc ctcactgact gcggtaatac ggccagcaaa cgcccccctg ggactataaa accctgccgc catagctcac gtgcacgaac tccaacccgg agagcgaggt actagaagga qttggtagct aagcagcaga 99Qtctgacg aaaaggacct atatatgagt gcgatctgtq atacgggagg ccggctccag cctgcdactt agttcgccag cgctcgtcqt tgatccccca agtaagttgg gtcatgccat gaatagtgta ccacatagca tcaaggatct tcttcagcat tcaaacgccc tcaaattccg cggccaatca cadaagtttg acagatgcgt cgctgcgctc ggttatccac aggccaggdd acgagcatca qataccaqqc ttaccggata gctgtaggta cccccgttca taagacacga atgtaggcgg cagtatttgg cttgatccgg ttacgcgcag ctcagtg ^ aa tcacctagat aaacttggtc tatttcgttc gcttaccatc atttatcagc tatccgcctc ttaacagttt ttggt ^ tggc tgtcgtgcaa ccgcagtgtt ccgtaagdtg tgcggcgacc gaaccttaaa taccgctgtt cttttacttt aaactgccgt tcgaccgtta ccttcctccc aggtatatta aaggagadaa ggtcgttcgg agaatcaqgg ccgtaae accounted for ag caaaaatqgd gcttccccct cctgtccgcc tctcagt tcg gcccgaccgc cttatcgcca tgctacagag tatctgcgct caaacaaacc aaaaaaagga cgaaaactca ccttttaaat tgacagttac oitccatagtt tggccccagt aataaaccag catccagtct gcgcaacgtt ttcattcegc daaagcggtt atcactcetg cttttctgtg gagttgctct agtgctcatc ga ^ acccagt caccagcgtt 36120 361§0 36240 36300 36360 36420 36480 36540 36600 36660 36720 36790 36840 36900 36960 37020 37000 37140 37200 3 * 7260 37320 3,738,037 to 0 37500 37560 37620 37740 37800 37860 37920 37930 38040 38100 • 31 - 136387.doc 200938633 tctgggtgag caaaaacagg aaggcaaaat gccgcaaaaa agggaataag ggcgacacgg aaatgttgaa tactcatact cttccttttt caatattatt gaagcattta tgtctcatga gcggatacat atttgaatgt atttagaaea ataaacaaat cgcdcatttc cccgaaaagt gccacctgac gtctaagaaa ccattattat acctataaaa ataggcgtat cacgaggccc tttcgtcttc aagaatttta tcaqggttat aggggttccg catgacatta Attacccc 38160 38220 38280 38340 38398

32- 136387.doc

Claims (1)

200938633 X. Patent application scope - - replication-deficient sputum adenovirus Plasmodium μ r 7 1 2 3 4 is a protein containing a sub-segment. The protein encoded therein contains the protozoan (hu/a/u>ar_) iCs protein ..., steep 2. The virus of the request 1 is N〇: 7 sequence. The protein package 3. The virus of the request 1 or claim 2 is planted in the hip, wherein the 3 Seq ij) No: 8 sequence is encoded. A viral vector having Seq 4, such as claim 1 or 2, wherein the IDN〇:1 sequence is encoded. White 5. The viral vector of claimant or claim 2, wherein the encoded protein has a sequence of Seq ID No: 3. 6. A composition comprising the excipients of claims 1 to 5 and an excipient. A vaccine composition for treating or preventing malaria, comprising the viral vector of any one of claims 1 to 5 and an adjuvant. 2. The vaccine composition of claim 7, which further comprises a protein. 3. The vaccine composition of claim 8, wherein the protein is RST, S. A vaccine composition comprising (1) a replication-defective sputum adenoviral vector 匸7 encoding a protein comprising a CS protein of P. falciparum or a fragment thereof, (2) a dysentery antigen, and (3) an adjuvant. . 11. The vaccine composition of claim 10, wherein the protein encoded by the adenoviral vector C7 has a sequence of Seq ID No: 1. 12. The vaccine composition of any one of the preceding claims, wherein the dysentery antigen is RST, S. The vaccine composition of any one of claims 7 to 3, wherein the vaccine composition of any one of claims 7 to 3, wherein The adjuvant contains a special. 15. The vaccine composition of claim 4, wherein the saponin is qS2i. 16. The vaccine composition of any one of claims 7 to 3 wherein the adjuvant comprises '3D-MPL and QS21. The vaccine composition of any one of claims 7 to 11, wherein the formulation is provided as an oil-in-water emulsion. The vaccine composition of any one of claims 7 to 11, wherein the vaccine is a liposome formulation. 19. The vaccine composition of claim 1 comprising (丨) a replication-deficient adenoviral vector C7 encoding a CS protein comprising Plasmodium falciparum, a protein having a sequence of Seq ID No: 1, (2) The malaria antigens rtS, S, and (3) contain adjuvants for 3D-MPL and QS21. ❿ 20. A kit comprising (1) a replication-deficient adenoviral vector C7 encoding a protein comprising a CS protein of P. falciparum or a fragment thereof, (2) a malaria-antigen, and (3) an adjuvant. . • 21. The set of claim 20 wherein the protein encoded by the adenoviral vector has a sequence of Seq ID No: 1. 22. The kit of claim 20 or 21, wherein the malaria antigen system is rst, s. 23. The kit of claim 20 or 21, wherein the adjuvant comprises 3D_MpL. 24. The kit of claim 20 or 21 which comprises the adjuvant comprising a saponin. 25. The kit of claim 24 wherein the saponin is QS2i. 136387.doc 200938633 26. If the claim 2 constitutes a set of A1, wherein the adjuvant comprises a set of 3D-MPL and QS21 〇3 seeking 2G or 21, wherein the formulation is in oil-in-water The lotion is provided. A method of preparing a viral vector according to any one of item 15, which comprises the steps of: ❿ a·proliferating the vector on a suitable cell line, and b. recovering the vector. 29. A method of preparing a composition as claimed in claim 6 or a method according to any one of claims 7 to 19, which comprises a request item! The step of mixing the viral carrier of 5 with at least one excipient/carrier. 30. If the request is to go to any of the main malaria in 5. And a carrier for use in the treatment or prevention of the virus vector according to any one of claims 5 to 5, which is carried out in a (Pr丨me) boosting scheme, and is primed, such as a request item to 5 Medium: Γ treatment or prevention of cancer. Preparation of a medicament for the treatment or prevention of dysentery. 胄. It is used for 33. A use of the composition of claim 6 for the preparation of a medicament for the prevention or prevention of malaria. The use of a virus according to any one of claims 7 to (4) for the preparation of a medicament for treating or preventing cancer, which uses 136387.doc