Title of Invention

A REPLICATION-DEFECTIVE RECOMBINANT ADENOVIRAL-BASED MALARIA VACCINES

Abstract

The present invention relates to novel vaccines against malaria infections, based on recombinant viral vectors, such as alphaviruses, adenoviruses or vaccinia viruses. The recombinant viral-based vaccines can be applied for immunization against different Plasmodium infections, such as infections by P.falciparum or P.yoelii. Novel codon-optimized circumsporozoite (CS) genes are disclosed. Preferably, replication-defective adenoviruses are used, derived of serotypes that encounter low titers of neutralizing antibodies. The invention therefore also relates to the use of different adenoviral serotypes that are administered to elicit a strong immune response, either in single vaccination setups, or in prime-boost set-ups in which compositions based on different serotypes can be applied.

Full Text

TITLE Recombinant viral-based malaria vaccines FIELD OF THE INVENTION The invention relates to the field of medicine. More in particular, the invention relates to the-'use of a recombinantly produced viral vector as a carrier of an antigenic determinant selected from a group of malaria pathogens for the development of a vaccine against malaria infections. BACKGROUND OF THE INVENTION Malaria currently represents one of the most prevalent infections in tropical and subtropical areas throughout the world. Per year, malaria infections lead to severe illnesses in hundreds of million individuals worldwide, while it kills 1 to 3 million people in developing and emerging countries every year. The widespread occurrence and elevated incidence of malaria are a consequence of the increasing numbers of drug-resistant parasites and insecticide-resistant parasite vectors. Other factors include environmental and climatic changes, civil disturbances and increased mobility of populations. Malaria is caused by the mosquito-borne hematoprotozoan parasites belonging to the genus Plasmodium. Four species of Plasmodium protozoa {P. falciparum, P.vivax, P.ovale and P.malariae) are responsible for the disease in man; many others cause disease in animalsf such as P.yoelii and P+berghei in mice. P. falciparum accounts for the majority of infections and is the most lethal type ("tropical corresponding occurring stage-specific antigens. Malaria parasites are transmitted -o man by several species of female Anopheles mosquitoes. Infected mosquitoes inject the *sporozoite' form of the malaria parasite into the mammalian bloodstream. Spcrozoites remain for few minutes in the circulation before invading hepatocytes. At this stage the parasite is locazed in the extra-cellular environment and is exposed co antibody attack, mainly directed to the circumsporczcite' (CS) protein, a major component of the spcrozoite surface. Once in the liver, the parasites replicate and develop into so-called ^schizonts'. These schizonts occur in a ratio of up to 20,000 per infected cell. During this 'intra-cellular stage of the parasite, main players of the host immune response are T-lymphocytes, especially CD8+ T-lymphocytes (Romero et al. 1998) . After about one week of liver infection, thousands of so-called ^merozoites' are released into the bloodstream and enter red blood cells, becoming targets of antibody-mediated immune response and T-cell secreted cytokines. After invading erythrocytes, the merozoites undergo several stages of replication and transform into so-called trophozoites' and into schizonts and merozoites, which can infect new red blood cells. This stage is associated with overt clinical disease. A limited amount of trophozoites may evolve into ^gametocytes', which is the parasite's sexual stage. When susceptible mosquitoes ingest erythrocytes, gametocytes are released from the erythrocytes, resulting in several male gametocytes and one female gametocyte. The fertilization of these gametes leads to zygote formation and subsequent transformation into ookinetes, then into oocysts, and finally into salivary gland sporozoites. Targeting antibodies against gametocyte stage-specific surface antigens can block this cycle within the mosquito mid gut. Such antibodies will not protect the mammalian host, but will reduce malaria transmission by decreasing the number of infected mosquitoes and their parasite load. Current approaches -o malaria vaccine development can be classified according to the different stages in which the parasite can exist, as described above. Three types of possible vaccines can be distinguished: - Pre-erythrocytic vaccines, which are directed against sporozoites and/or schizont-infected cells. These types of vaccines are mostly CS-based and should ideally confer sterile immunity, mediated by humoral and cellular immune response, preventing malaria infection. - Asexual blood stage vaccines, which are designed to minimize clinical severity. These vaccines should reduce morbidity and mortality and are meant to prevent the parasite from entering and/or developing in the erythrocytes. - Transmission-blocking vaccines, which are designed to hamper the parasite development in the mosquito host. This type of vaccine should favor the reduction of population-wide malaria infection rates. Next to these vaccines, the feasibility of developing malaria vaccines that target multiple stages of the parasite life cycle is being pursued in so-called multi-component and/or multi-stage vaccines. Currently no commercially available vaccine against malaria is available, although the development of vaccines against malaria has already been initiated more than 30 years ago: immunization of rodents, non-human primates and humans with radiation-attenuated sporozoites conferred protection against a subsequent challenge with sporozoites (Nussenzweig et al. 1967; Clyde et al. 1973). However, the lack of a feasible large-scale culture system for the production of sporozoites prevents the widespread application of such vaccines. To date the most promising vaccine candidates tested in humans have been based en a small number of sporozoite surface antigens. The CS protein is the only Ptfalciparum antigen demonstrated to consistently prevent malaria when used as the basis of active immunization in humans against mosquito-borne infection, albeit it at levels that is often insufficient. Theoretical analysis has indicated that the vaccine coverage as well as the vaccine efficiency should be above 85%, or otherwise mutants that are more virulent may escape (Gandon et al. 2001). One way of inducing an immune response in a mammal is by administering an infectious carrier, which harbors the antigenic determinant in its genome. One such carrier is a recombinant adenovirus, which has been replication-defective by removal of regions within the genome that are normally essential for replication, such as the El region. Examples of recombinant adenoviruses that comprise genes encoding antigens are known in the art (WO 96/39178), for instance HIV-derived antigenic components have been demonstrated to yield an immune response if delivered by recombinant adenoviruses (WO 01/02607; WO 02/22080). Also for malaria, recombinant adenovirus-based vaccines have been developed. These vectors express the entire CS protein of P.yoeliir which is a mouse-specific parasite and these vectors have been shown to be capable of inducing sterile immunity in mice, in response to a single immunizing dose (Brufia-Romero et al. 2001a) . Furthermore, a similar vaccine vector using CS from P.bergrhei was recently shewn to elicit long-lasting protection when used in a prime-boost regimen/ in combination with a recombinant vaccinia virus (Gilbert et al. 2002) in mice. It has been demonstrated that CD8+ T cells primarily mediate the adenovirus-induced protection. It is unlikely the P.yoelii- and P.berghei based adenoviral vectors would work well in humans, since the most dramatic malaria-related illnesses in humans are not caused by these two parasites. Moreover, it is preferred to have a vaccine which is potent enough to generate long-lasting protection after one round of vaccination, instead of multiple vaccination rounds using either naked DNA injections and/or vaccinia based vaccines as boosting or priming agents. Despite all efforts to generate a vaccine that induces an immune response against a malaria antigenic determinant and protects from illnesses caused by the malaria parasite, many vaccines do not fulfill all requirements as described above. Whereas some vaccines fail to give a protective efficiency of over 85% in vaccinated individuals, others perform poorly in areas such as production or delivery to the correct cells of the host immune system. DESCRIPTION OF THE FIGURES Figure 1 shows the newly synthesized clone 02-148 (pCR-script.Pf), which is based on a range of known Plasmodium falciparum genes, and which encodes the novel circumsporozoite protein (A) (SEQ ID NO:3) , plus the codon-optimized nucleic acid sequence (B) (SEQ ID NO:l) . SEQ ID NO:2 is the translated protein product translated from the Coding Sequence of SEQ ID N0:1 as generated by Patentln 3.1. SEQ ID NO:2 is identical to SEQ ID NO:3 in content. Figure 2 shows the amino acid sequence (A) (SEQ ID NO:6) and nucleic acid sequence (3) (SEQ ID NO:4) of synthetic clone named 02-559 (pf-aa-sub), which is the .circumsporozoite gene of the P. falciparum strain 3D7, lacking the C-terminal 14 amino acids. SEQ ID NO:5 is the translated protein product translated from the Coding Sequence of SEQ ID NO:4 as generated by Patentin 3.1. SEQ ID NO:5 is identical to SEQ ID NO:6 in content. Figure 3 shows the amino acid sequence (A) (SEQ ID NO:9) and nucleic acid sequence (B) (SEQ ID NO:7) of the codon-optimized circumsporozoite gene of P.yoelli. SEQ ID NO:8 is the translated protein product translated from the Coding Sequence of SEQ ID NO:7 as generated by Patentin 3.1. SEQ ID NO:8 is identical to SEQ ID NO:9 in content. Figure 4 shows the (A) cellular immune response and the (B) humoral immune response in mice upon immunization with Ad5- and Ad35-based vectors harboring the P.ycelii circumsporozoite gene, administered via two routes: intra muscular and subcutaneous in different doses. Figure 5 shows the inhibition in mice of a P.yoelii sporozoite challenge following immunization with Ad5- and Ad35-based vectors harboring the P.yoelli circumsporozoite gene, administered in different doses, depicted in percentage of inhibition (A), and in the presence of a parasite specific RNA molecules in the liver (B). Figure 6 shows the cellular immune response raised by immunization with an Ad5-based vector harboring the full length P.falciparum circusisporozoite gene, and two deletion mutants, administered in different doses. DESCRIPTION OF THE INVENTION The present invention relates to different kinds of replication-defective recombinant viral vectors comprising a heterologous nucleic acid encoding an antigenic determinant of several Plasmodium protozoa. Preferably it relates to viral vectors that comprise nucleic acids encoding the circumsporozoite (CS) protein of P. falciparum and P.yoelii. More preferably, said viral vector is an adenovirus, preferably based on a serotype that is efficient in delivering the gene of interest, that encounters low numbers of neutralizing antibodies in the host and that binds to the relevant immune cells in an efficient manner. In a preferred embodiment the CS protein is generated such that it will give rise to a potent immune response in mammals, preferably humans. In one aspect, the expression of the protein is elevated due to codon-optimization and thus altering the codon-usage such that it fits the host of interest. The novel CS proteins of the present invention are depicted in figure 1A (SEQ ID N0:3), 2A (SEQ ID N0:6) and 3A (SEQ ID N0:9), while the codon-optimized genes encoding said proteins are depicted in figure IB (SEQ ID N0:1), 2B (SEQ ID NO:4) and 3B (SEQ ID NO:7) respectively. The invention also relates to vaccine compositions comprising a replication-defective recombinant viral vector according to the invention, and a pharmaceutically acceptable carrier, further comprising preferably an adjuvant. Furthermore, the invention relates to the use of a vaccine composition according to the invention in the therapeutic, prophylactic or diagnostic treatment of malaria. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the use of recombinant viruses as carriers of certain specific antigenic determinants selected from a group of malaria antigens. It is the goal of the present invention to provide a solution to at least a part of the problems outlined above for existing vaccines against malaria. The present invention relates to a replication-defective recombinant viral vector comprising a heterologous nucleic acid enccding an antigenic determinant of Plasmodium falciparum. In a preferred embodiment s'aid viral vector is an adenovirus, an alphavirus or a vaccinia virus. In a more preferred embodiment said viral vector is an adenovirus, wherein said adenovirus is preferably derived from a serotype selected from the group consisting of: Ad5, Adll, Ad26, Ad34, Ad35, Ad48, Ad49 and Ad50. In one particular aspect of the invention the replication-defective recombinant viral vector according to the invention, comprises an antigenic determinant that is the circumsporozoite (CS) protein, or an immunogenic part thereof. Preferably, said heterologous nucleic acid is codon-optimized for elevated expression in a mammal, preferably a human. Codon-optimization is based on the required amino acid content, the general optimal codon usage in the mammal of interest and a number of provisions of aspects that should be avoided to ensure proper expression. Such aspects may be splice donor or -acceptor sites, stop codons, Chi-sites, poly(A) stretches, GC- and AT-rich sequences, internal TATA boxes, etcetera. In a preferred embodiment, the invention relates to a replication-defective recombinant viral vector according to the invention, wherein the adenine plus thymine content in said heterologous nucleic acid, as compared to the cytosine plus guanine content, is less than 87%, preferably less than 80%, more preferably less than 59% and most preferably equal to approximately 45%. The invention provides in one embodiment a replication-defective recombinant viral vector, wherein said circumsporozoite prccein is the circumsporozoite protein as depicted in figure 1A and in another embodiment a codon-optimized heterologous nucleic acid as depicted in figure IB. The proteins can be in a purified fcrm, but also expressed in vivo from nucleic acid delivery vehicles such as the recombinant viral vectors of the present invention. In a purified form, such proteins can be applied in other types of vaccines, wherein the protein is for instance enclosed in liposomes or other carriers used in the art. The nucleic acid can be cloned into other vectors than as disclosed herein, but also be applied as naked DNA in other vaccine-settings. In another embodiment, the- invention relates to a replication-defective recombinant viral vector according to the invention, wherein the circumsporozoite protein, or the immunogenic part thereof, is lacking a functional GPI anchor sequence. Apart from the use of new genes and proteins that can be applied for use in humans, the invention also discloses novel genes that may be used in humans as well as in other mammals. Therefore, the invention also relates to a replication-defective recombinant viral vector comprising a heterologous nucleic acid encoding the circumsporozoite protein of Plasmodium yoeliif wherein said nucleic acid is codon-optimized for elevated expression in a mammal. In a more preferred embodiment said viral vector is an adenovirus, an aiphavirus or a vaccinia virus, and it is even more preferred -o use a recombinant adenovirus, which is preferably selected from the group consisting of: Ado, Adll, Ad26, Ac34, Ad35, Ad48, Ad49 and Ad50. As in P. falciparum it is also for P.yoelii preferred to use a codon-optimized gene for proper expression in the host of interest. Therefore, in a preferred embodiment the adenine plus thymine content in said nucleic acid, as compared to the cytosine plus guanine content, is less than 87%, preferably less than 30%, more preferably less than 59% and most preferably equal to approximately 45%, The invention provides in one embodiment a replication-defective recombinant viral vector according to the invention, wherein said circumsporozoite protein is the circumsporozoite protein as depicted in figure 3A, while in another embodiment, a replication-defective recombinant viral vector is provided, wherein said nucleic acid is the nucleic acid as depicted in figure 3B. In a preferred aspect, the circumsporozoite protein, or the immunogenic part thereof, is lacking a functional GPI anchor sequence. The invention further relates to an isolated nucleic acid encoding a circumsporozoite protein of Plasmodium falciparum as depicted in figure IB, wherein said nucleic acid is codon-optimized, and to an isolated nucleic acid encoding a circumsporozoite protein of Plasmodium falciparum strain 3D7, as depicted in figure 2B, wherein said nucleic acid is codon-optimized. Such isolated nucleic acids can be applied in subcloning procedures for the generation of other types of viral-based vaccines, apart for the types as disclosed herein. Furthermore, such isolated nucleic acids can be used for naked DNA vaccines or in cloning procedures to generate vectors for in vitro production of the encoded protein, which, in itself can be further used for vaccination purposes and the like. The production can be in all kinds of systems, such as bacteria, yeasts or mammalian cells known in the art. In another embodiment of the present invention, an isolated nucleic acid encoding a circumsporozoite protein of Plasmodium yoelil as depicted in figure 3B is provided, wherein said nucleic acid is codon-optimized. Furthermore, a vaccine composition comprising a replication-defective recombinant viral vector according to the invention, and a pharmaceutically acceptable carrier is provided. Pharmaceutically acceptable carriers are well known in the art and used extensively in a wide range of therapeutic products. Preferably, carriers are applied that work well in vaccines. More preferred are vaccinas, further comprising an adjuvant. Adjuvants are known in the art to further increase the immune response to an applied antigenic determinant. The invention also relates to the use of a vaccine composition according to rhe invention in the therapeutic, prophylactic or diagnostic treatment of malaria. Another embodiment of the present invention relates to a method of treating a mammal for a malaria infection or preventing a malaria infection in a mammal, said method comprising (in either order, or simultaneously) the steps of administering a vaccine composition according to the invention, and administering a vaccine composition comprising at least one purified malaria-derived protein or peptide. The invention also relates to a method of treating a mammal for a malaria infection or preventing a malaria infection in a mammal, said method comprising (in either order, or simultaneously) the steps of administering a vaccine composition comprising a replication-defective recombinant viral vector comprising a malaria circumsporozoite anticren accordina to the invention; and administering a vaccine composition comprising a replication-defective recombinant viral vector comprising another antigen, such as LSA-1 or LSA-3 according to the invention. The advantages of the present invention are multifold. Next to the knowledge that recombinant viruses, such as recombinant adenoviruses can be produced to very high titers using cells that are considered safe, and that can grow in suspension to very high volumes, using medium that does not contain any animal- or human derived components, the present invention combines these features with a vector harboring the circumsporozoite gene of Plasmodium falciparum. P. falciparum is the parasite that causes tropical malaria. Moreover, the gene has been codon-optimized to give an expression level that is suitable for giving a proper immune response in humans. The present" invention provides a vaccine against malaria infections, making use of for instance adenoviruses that do not encounter high titers of neutralizing antibodies. Examples of such adenoviruses are serotype 11 and 35 (Adll and Ad35, see WO 00/70071 and WO 02/40665) . The nucleic acid content between the malaria-causing pathogen, such as P.falciparum and the host of interest, such as Homo sapiens is very different. The invention now provides a solution to some of the disadvantages of vaccines known in the art, such as expression levels that are too low to elicit a significant immune response in the host of interest, preferably humans. Recombinant viral vectors have been used in vaccine set-ups. This has been demonstrated for vaccinia-based vaccines and for adenovirus-based vaccines. Moreover, a platform based on alphaviruses is being developed for vaccines as well. In a preferred embodiment, the invention relates to the use of recombinant adenoviruses that are replication defective through removal of at least part of the SI region in the adenoviral genome, since the El region is required for replication-, transcription-, translation- and packaging processes of newly made adenoviruses. El deleted vectors are generally produced on cell lines that complement for the deleted El functions. Such cell lines and the use thereof for the production of recombinant viruses have been described extensively and are well known in the art. Preferably, PER.C63*1 cells, as represented by the cells deposited under ECACC no- 96022940 at the European Collection of Animal Cell Cultures (ECACC) at the Centre for Applied Microbiology and Research (CAMR, UK), are being used to prevent the production of replication competent adenoviruses (rca). In another preferred embodiment, cells are being applied that 3Upport the growth of recombinant adenoviruses other than those derived of adenovirus serotype 5 (Ad5) . Reference is made to publications WO 97/00326, WO 01/05945, WO 01/07571, WO 00/70071, WO 02/40665 and WO 99/55132, for methods and means to obtain rca-free adenoviral stocks for Ado as well as for other adenovirus serotypes. Adenoviral-based vectors that have been used in the art mainly involved the use of Ad5 vectors. However, as has been described (WO 00/03029, WO 02/24730, WO 00/70071, WO 02/40665 and in other reports in the art), administration of Ad5 and efficient delivery to the target cells of interest, responsible for sufficient immunogenic responses, is hampered by the presence of high titres of neutralizing antibodies circulating in the bloodstream if a subject previously encountered an Ad5 infection. It has been investigated what serotypes are better suited for therapeutic use, and it turned out that a limited number of serotypes encountered neutralizing antibodies in only a small percentage of individuals in the human population. These experiments have been described in WO 00/70071. Therefore, in a preferred embodiments the invention relates to the use of adenovirus serotype 11, 26, 34, 35, 48 and 50, and more preferably to Adll and Ad35, since these serotypes encountered no neutralizing antibodies in the vast majority of tested samples. Apart from avoiding the presence of neutralizing antibodies directed against certain serotypes, ir might also be beneficial to target the replication-deficient recombinant viral vectors to a certain subset of cells involved in the immune response. Such cells are for instance dendritic cells. It was found that certain adenovirus serotypes, such as Adl6, Ad35 and Ad50, carry capsid proteins that specifically bind to certain receptors present on dendritic cells (WO 02/24730) . Ad5 is a serotype that is mainly homing to the liver, which -~ may be a disadvantage if sufficient numbers of viral particles should infect cells of the immune system. It was found that at least in in vitro experiments some of the serotypes, different from Ad5 could infect dendritic cells multi-fold better than Ad5, suggesting that also in vivo the delivery to such cells is more efficient. It still remains to be seen whether this in vitro to in vivo translation holds up, and if serotypes other than Ad5 will give rise to the required protection level. It is also part of the invention to provide the serotypes of choice, as far as neutralizing antibodies are concerned, with capsid proteins, such as the fiber or a part thereof from a serotype that is able to selectively recognize dendritic cells. It must be noted here that in the published documents WO 00/03029, WO 02/24730, WO 00/70071 and WO 02/40665, Ad50 was mistakenly named Ad51. The Ad51 serotype that was referred to in the mentioned publications is the same as serotype Ad50 in a publication by De Jong et al. (1999), wherein it was denoted as a B-group adenovirus. For the sake of clarity, Ad50 as used herein, is the 3-group Ad50 serotype as mentioned by De Jong et al. (1999). It is now known that a first administration with a specific adenoviral serotype elicits the production of neutralizing antibodies in the host against that specific vector. Thus, it is desirable to use in a subsequent setting (a follow-up boost or in the administration of another, non-related vaccine) a composition based on a different adenovirus serotype, which is not neutralized by antibodies raised in the first administration. Therefore, the invention further relates to methods for vaccinating mammalian individuals in which a priming vaccine composition comprises a replication-defective recombinant adenovirus of a first serotype, while in a boosting vaccine composition a replication-defective recombinant adenovirus of a second serotype are used. Prime/boost settings have been described in more detail in international patent applications PCT/NL02/00671 and PCT/EP03/50748 (not published) ; these applications relate to the use of a recombinant adenovirus vector of a first serotype for the preparation of a medicament for the treatment or prevention of a disease in a human or animal treated with a recombinant adenovirus vector of a second serotype, wherein said first serotype is different from said second serotype, and wherein said first serotype is selected from the group consisting of: Adll, Ad26, Ad34, Ad35, Ad46 and Ad49, and wherein said second serotype is preferably adenovirus serotype 5. Thus, it relates to the use of different adenoviral serotypes that encounter low pre-existing immunities in subjects that are to be treated. Preferred examples of such serotypes are the recombinant mentioned, wherein Ad5 is not excluded for individuals that have never experienced an Ad5 infection. The settings described and claimed in the applications mentioned above relate to the use of adenoviral vectors carrying transgenes such as those from measles, or gag from HIV (for treatment of humans) or SIV (for treatment and studies in monkeys). One non-limiting example of a prime-boost set-up towards Malaria is a setting in which, next to different adenovirus serotypes, also different antigenic determinants may be used. One non-limiting example of an antigen different from CS is the Liver Specific Antigen 1 (LSA-1, Kurtis et al. 2001). Such set-up3 are at least for one reason useful, namely that the CS antigen is expressed mainly during the blood-stage of the parasite, while its expression goes down in the liver-stage. For LSA-1, this situation is more or less the opposite; it is expressed to low levels during the blood-stage, but is highly expressed during the liver-stage. Although one could use both antigens in subsequent administrations, it may also be used at the same time to provide protection against the parasite at the blood-stage as well as at the liver-stage. In a further embodiment of the present invention both antigens may be delivered by one adenovirus serotype (either cloned together in the same vector, or separately in separate vectors of the same serotype). In another embodiment both antigens are delivered by different serotypes that may be delivered at the same time or separately in time, for instance in a prime-boost setting. The vaccines of the present invention may also be used in settings in which prime-boosts are being used in combination with naked DNA or other delivery means, unrelated to the replication-defective viral vectors of the present invention, such as purified proteins or peptides. Examples of such proteins that may be used in prime-boosts (Ad/protein; protein/Ad; protein/Ad/Ad; Ad/prctein/Ad; Ad/Ad/protein, etc) are CS, IiSA-1, LSA-3, MSP-1, MSP-119, MSP-142 (see below), or the hepatitis B particles-containing and CS-derived vaccine composition known as RTS,S {see Gordon et al. (1995; US 6,306,625 and WO 93/10152). Although the invention is exemplified herein with the use of adenoviruses, it is to be understood that the invention is by no means intended to be limited to adenoviruses but also relates to the use of other recombinant viruses as delivery vehicles. Examples of viruses that can also be used for administering the antigenic determinants of the present invention are poxviruses (vaccinia viruses, such as MVA) and flaviviruses such as alphaviruses. Non-limiting examples of alphaviruses that may be applied for delivering the immunogenic Plasmodium components of the present invention are: Ndumu virus, Buggy Creek virus, Highland J. virus, Fort Morgan virus, Babanki virus, Kyzylagach virus, Una virus, Aura virus, Whataroa virus, Bebaru virus, South African Arbovirus No. 86, Mayaro virus, Sagiyama virus, Getah virus, Ross River virus, Barmah Forest virus, Chikungunya virus, O'nyong-nyong virus, Western Equine Encephalitis virus (WEE), Middelburg virus, Everglades virus, Eastern Encephalitis virus (EEE), Mucambo virus and Pixuna virus. Preferably, when an alphavirus is the virus of choice, Semliki Forest Virus, Sindbis virus or Venezuelan Equine Encephalitis virus are applied. A sequence is 'derived' as used herein if a nucleic acid can be obtained through direct cloning from wild- type sequences obtained from wild-type viruses, while they can for instance also he obtained through ?CR by using different pieces of DNA as a template, Thi3 means also that such sequences may be in the wild-type form as well as in altered form. Another option for reaching the same result is through combining synthetic DNA. It is to be understood that ^derived' does net exclusively mean a direct cloning of the wild type DNA. A person skilled in the art will also be aware of the possibilities of molecular biology to obtain mutant forms of a certain piece of nucleic acid. The terms Afunctional part, derivative and/or analogue thereof are to be understood as equivalents of the nucleic acid they are related to. A person skilled in the art will appreciate the fact that certain deletions, swaps, (point) mutations, additions, etcetera may still result in a nucleic acid that has a similar function as the original nucleic acid. It is therefore to be understood that such alterations that do not significantly alter the functionality of the nucleic acids are within the scope of the present invention. If a certain adenoviral vector is derived from a certain adenoviral serotype of choice, it is also to be understood that the final product may be obtained through indirect ways, such as direct cloning and synthesizing certain pieces of genomic DNA, using methodology known in the art. Certain deletions, mutations and other alterations of the genomic content that do not alter the specific aspects of the invention are still considered to be part of the invention. Examples of such alterations are for instance deletions in the viral backbone to enable the cloning of larger pieces of heterologous nucleic acids. Examples of such mutations are for instance E3 deletions or deletions and/or alterations in the regions coding for the E2 and/or E4 proteins of adenovirus. Such chances applied to the adenoviral backbone are known in the art and often applied, since space is a limiting factor for adenovirus to be packaged; this is a major reason to delete certain parts of the adenoviral genome. Other reasons for altering the E2, E3 and/or E4 regions of the genome may be related to stability or integrity of the adenoviral vector, as for instance described in international patent applications PCT/NL02/00280, PCT/EP03/50125, PCT/NL02/00281, PCT/EPQ3/50126 (non published) . These applications relate amongst others to the use of an E4orf6 gene from a serotype from one subgroup in the backbone of an adenovirus from another subgroup, to ensure compatibility between the E4orf6 activity and the E1B-55K activity during replication and packaging in a packaging cell line. They further relate to the use of a proper functioning pIX promoter for obtaining higher pIX expression levels and a more stable recombinant adenoviral vector. 1 Replication defective' as used herein means that the viral vectors do not replicate in non-complementing cells. In complementing cells, the functions required for replication, and thus production of the viral vector, are provided by the complementing cell. The replication defective viral vectors of the present invention do not harbor all elements enabling replication in a host cell other than a complementing cell. Heterologous' as used herein in conjunction with nucleic acids means that the nucleic acid is not found in wild type versions of the viral vectors in which the heterologous nucleic acid is cloned. For instance in the case of adenoviruses, the heterologous nucleic acid that is cloned in the replication defective adenoviral vector, is not an adenoviral nucleic acid. Antigenic de-erminar.t' as used herein means any antigen derived from a pathogenic source that elicits an immune response in a host towards which the determinant is delivered (administered) . Examples of antigenic determinants of Plasmodium that can be delivered by using the replication defective recombinant viruses of the present invention are the circumsporozoite protein, the SE36 polypeptide, the merezoite surface protein 119 kDa C-terminal polypeptide (MS?-119), MSP-1, MSP-142, Liver Stage Antigen 1 or 3 (LSA-1 or -3), or a fragment of any of the aforementioned. In a preferred aspect the invention relates to the circumsporozoite (CS) protein from P. falciparum. ^Codon-optimized' as used herein means that the nucleic acid content has been altered to reach sufficiently high expression levels of the protein of interest in a host of interest to which the gene encoding said protein is delivered. Sufficiently high expression levels in thi3 context means .that the protein levels should be high enough to elicit an immune response in the host in order to give protection to a malaria-inducing parasite that may enter the treated host before or after treatment. It is known in the art that some vaccines give an immune response in humans, through which approximately 60% of the vaccinated individuals is protected against illnesses induced by subsequent challenges with the pathogen (e.g., sporozoites). Therefore the expression levels are considered to be sufficient if 60% or more of the treated individuals is protected against subsequent infections. It is believed that with the combinations of adenoviral aspects that can be applied and the choice of antigen as disclosed herein, such percentages may be reached. Preferably, 85% of the individuals are protected, while it is most preferred to have protection to a subsequent challenge in more than 90% of -he vaccinated hosts. The nucleic acids disclosed in the present invention are codon-optimized for expression in humans. According to Narum et al. (2001), the content of adenine plus thymine (A-T) in DNA of Homo sapiens is approximately 59%/ as compared to the percentage cytcsine plus guanine (C+G). The adenine plus thymine content in P. falciparum is approximately 80%. The adenine plus thymine content in the CS gene of P.falciparum is approximately 87%. To obtain sufficient protection it is believed to be necessary to improve production levels in the host. One way to achieve this is to optimize codon usage by altering the nucleic acid content of the' antigenic determinant in the viral-based vector, without altering the amino acid sequence thereof. For this, the -replication-defective recombinant viral vectors according to the invention have an adenine plus thymine content in the heterologous nucleic acids of the present invention of less than 87%, preferably less than 80%r and more preferably less than or equal to approximately 59%. Based on codon-usage in human and the amino acid content of the CS genes of P. falciparum and yoelii, the percentages of the codon-optimized genes were even lower, reaching approximately 45% for the amino acid content as disclosed by the present invention. Therefore, as far as the CS genes are concerned it is preferred to have an adenine plus thymine content of approximately 45%. It is to be understood, that if another species than humans is to be treated, which may have a different adenine plus thymine concentration (less or more than 59%), and/or a different codon usage, that the genes encoding the CS proteins of the present invention may be adjusted to fit the required content and give rise to suitable expression levels for that particular host. Of course, it cannot be excluded either, that slight changes in content may result in slight expression level changes in different geographical areas around the world. It is also to be understood that slight changes in the number of repeats included in the amino acid sequence of .the proteins, that percentages may differ accordingly. All these adjusted contents are part of the present invention. EXAMPLES Example 1. Assembly of the Plasmodium falciparum circumsporozoite synthetic gene. Comparative studies conducted with DNA vaccines based on native and codon-cptimized genes encoding merozoites proteins of P. falciparum have indicated a direct correlation with expression levels and immunogenicity (Narum et al. 2001) . A new sequence of the gene encoding the Plasmodium falciparum circumsporozoite {CS) protein was designed. Studies on populations of malaria parasites obtained from widely separated geographical regions have revealed the presence of CS sequence polymorphism. The new P. falciparum CS sequence was assembled by alignment of the different available protein sequences present in the GeneBank database (listed in Table I). First, all the different sequences were placed in order of subgroups based on global location or by lab-strain where the isolates originated. All CS complete or partial sequences were used in order to identify variation between the different geographical areas and identified lab-strains. The final amino acid consensus sequence determined was thoroughly examined. The inventors of the present invention subsequently adjusted this consensus sequence and to have a new CS gene synthesized (Fig. 1) , The novel amino acid sequence is shown in Fig. 1A. The new CS protein harbors the aspects listed below (from N-terminus to C-terminus): The N-terminal signal sequence, which would direct the protein to the endoplasmic reticulum, is left unchanged. The HLA binding peptide amino acid (31-40) , as well as region 1 (predominant B-cell epitope) are conserved, therefore these sequences are left unchanged. A number of repeats: there are 14-41 NAN? (SEQ ID NO:10) repeats in the different isolates and 4 NVDP (SEQ ID NO: 11) repeats. It was chosen to incorporate 27 NANP repeats, a cluster of 3 NVDP repeats and one separate NVD? repeat. The ENANANNAVXN (SEQ ID NO:12) sequence directly downstream of the repeats mentioned above, was found to be reasonably conserved between strains. The Th2R region and the immunodominant CDS epitope (Lockyer et al. 1989; Zevering et al. 1994) : a single consensus sequence that differs in some respects from that of the known, and frequently used lab-strain 3D7 sequence was determined. This sequence is sometimes referred to as the ^universal epitope' in literature (Nardin et al. 2001). The region 2, overlapping with the Th2R region, remained conserved. The TH3R region, which is considered to be a less important CD8 epitope, is used in the form of a consensus sequence, since only point mutations were found. The C-terminal 28 amino acids, which constitute a GPI signal anchor sequence, that is inefficient in mammalian cells (Moran and Caras, 1994), and not hydrophobic by itself to serve as a stable membrane anchor. The gene was constructed such that the whole sequence can be removed, but also leaving open the possibility of remaining present. This allows a comparison of the antigenicity of adenovirus vectors carrying a full length CS versus those: expressing the protein deleted in the GPI signal anchor sequence. In fact it has been described that removal of the GPI signal sequence from a CS DNA vaccine enhanced induction on immune response against malaria infection in rodents (Scheiblhofer et al. 2001). - Substitution S to A at position 373: this amino acid substitution was introduced to eliminate a potential glycosylation site recognized by mammalian cells- Since the malaria parasite residue usage (37% A and T) is significantly different from that of the Homo sapiens, the gene encoding the newly designed CS protein was codon-optimized in order to improve its expression in mammalian cells, taking care of the following aspects to avoid cis-acting sequences: no premature poly (A) sites and internal TATA boxes should be present; Chi-sites, ribosomal entry sites and AT-rich sequence clusters should be avoided; no (cryptic) splice acceptor and -donor sites should be present; repetitive sequence stretches should be avoided as much as possible; and GC-rich sequences should also be avoided. The final codon-optimized gene is shown in Fig. IB, The newly designed CS consensus sequence was synthesized and cloned into pCR-script (Stratagene) by GeneArt (Regensburg, Germany), using methodology known to persons skilled in the art of synthetic DNA generation, giving rise to a clone named 02-143 (pCR-scripr.Pf) (SEQ ID NO:l). Next to this synthetic clone, another syr.-hetic gene was generated/ wherein a number of mutations were introduced in the 3' end, zo obtain an amino acid sequence that is identical to the P. falciparum CS protein of the 3D7 strain, which is deleted in the last 14 amino acids (Fig. 2) . This gene was also codon-optimized using the same provisions as described above and subsequently synthesized and cloned into pCR-script (Stratagene) by GeneArt. The clone was named 02-659 (pf-aa-sub) (SEQ ID NO:4). Example 2. Codon-optioizatxon of the circumsporozoite gene of the rodent-specific malaria parasite Plasmodium yoelii. Malaria species that have been adapted to robust rodent models, such as P.berghei and P.yoelii, have been powerful tools for identification and testing of malaria candidate vaccines. Since infectivity of P.yoelii sporozoites resembles that of P. falciparum, it was decided to make use of the P.yoelii model for exemplification of the capability of Ad35 vectors carrying codon-optimize CS proteins to provide sterile immunity and therefore protection against malaria infection. The P.yoelii CS gene, encoding for residues 1-356 as previously described (Rodrigues et al, 1997), was codon-optimized using the same provisions as described above and synthesized by GeneArt (GmbH-Regensburg, Germany) . The sequence of the codon-optimized P.yoelii CS gene (plasmid 02-149) is depicted in Fig, 3. Example 3. Generation of recombinant adenoviral vectors based on Ad5. RCA-free recombinant adenoviruses can be generated very efficiently using adapter plasmids, such as pA&Apt, and adenovirus plasmid backbones, such as pWE/Ad.Aflll-rlTRsp. Methods and tools have been described extensively elsewhere (WO 97/00326, WO 99/55132, WO 99/64582, WO 00/70071, WO 00/03029). Generally, the adapter plasmid containing the transgene of interest in the desired expression cassette is digested with suitable enzymes to free the recombinant adenovirus sequences from the plasmid vector backbone. Similarly, the adenoviral complementation plasmid pWE/Ad.Aflll-rlTRsp is digested with suitable enzymes to free the adenovirus sequences from the vector plasmid DNA. The cloning of the gene encoding the CS protein from P.yoelii parasite into pIPspAdaptl was performed as follows. Plasmid 02-149 (GeneArt, see above) containing . the codon optimized CS gene was digested with Hindlll and BamHI restriction enzymes. The 1.1 Kb fragment corresponding to the P.yoelii CS gene was isolated from agarose gel and ligated to Hindlll and BamHI-digested pIPspAdaptl vector (described in WO 99/64582) . The resulting plasmid was named pAdapt. CS. Pyoel and contains the CS gene under the transcriptional control of full length human immediate-early (IS) cytomegalovirus (CMV) promoter and a downstream SV40 poly (A) signal. The cloning of the gene encoding the full length CS protein from P. falciparum parasite into pIPspAdaptl was performed as follows. Plasmid 02-148 pCR-script.Pf (see above) containing the codon optimized CS gene was digested with Hindlll and BamHI restriction enzymes. The 1.2 kb fragment corresponding to the CS gene was isolated from agarose gel and ligated to Hindlll and BamHI-digested pIPspAdaptl vector. The resulting plasmid was named pAdapt.CS.Pfalc and contains the CS gene under the transcriptional control of full length husian immediate-early (IE) cytomegalovirus (CMV) promoter and the downstream SV40 poly(A) signal. The cloning of the gene encoding the CS 2. falciparum protein minus the GPI anchor sequence, thus with the deletion of the last 23 amino acids, intc pIPspAdaptl was performed as follows. A 1.1 kb PCR fragment was amplified using plasmid 02-143 as template, with the primers Forw.Falc (5'-CCA AGC TTG CCA CCA TGA TGA 5G-3') (SEQ ID NO:13) and Rev.Falc.CS-28 (5'-CCG GAT CCT CAG CAG "ATC TTC TTC TCG-3') (SEQ ID NO:14). Primers were synthesized by Invitrogen. For the PCR, the enzyme Pwo DEA polymerase (Inno-train Diagnostic) was used, while the following program was applied: 1 cycle of 5 min at 94°C, 1 min at 50°C, 2 min 30 sec at 72°C; 5 cycles of 1 min at 94°C, 1 min at 50°C, 2 min 50 sec at 72°C; 20 cycles of 1 min at 94°C, 1 min at 54°C, 2 min 50 sec at 72°C; and 1 cycle of 1 min at 94°C, 1 min at 54°C, followed by 10 min at 72°C. The amplified PCR product was digested with the restriction enzymes Hindll and BaraHI and then cloned into pIPspAdaptl which was also digested with Hindlll and BamHI. Th"e resulting plasmid was designated pAdapt.CS.Pfalc(-28) and contains the CS gene under the transcriptional control of full length human immediate-early (IE) cytomegalovirus (CMV) promoter and the downstream SV40 poly(A) signal. The cloning of the gene encoding the CS ?. falciparum protein minus the GPI anchor, thus with the deletion of the last 14 amino acids, into pIPspAdaptl was performed as follows. A 1.1 to PCR fragment was amplified using plasmid 02-148 as template, with the primers Forw.Falc (SEQ ID NO:13) and Rev.Falc.CS-14 (5'-CCG GAT CCT CAG CTG TTC ACC ACG TTG-3') (SEQ ID N0:15). Primers were synthesized by Invitrogen. For the PCR, the enzyme Pwo DNA polymerase (Inno-train Diagnostic) was used, while the following program was applied: 1 cycle of 5 min at 94°C, 1 min ac 50°C, 2 min 30 sec at 72°C; 5 cycles of 1 min at 94°C, 1 min at 50°C, 2 min 50 sec at ;72°C; 20 cycles of 1 min at 94°C, 1 min at 54°C, 2 min 50 sec at 72°C; and 1 cycle of 1 min at 94°C, 1 min at 54°C, followed by 10 min at 72°C. The amplified ?CR product was digested with the restriction enzymes Hindlll and 3amHI and then cloned into pIPspAdaptl also digested with HindiXI and 3amHl. The resulting plasmid was designated . pAdapt.CS.Pfalc(-14) and contains the CS gene under the transcriptional control of full length human immediate-early (IE) cytomegalovirus (CMV) promoter and the downstream SV40 poly(A) signal. The cloning of the gene encoding the CS P. falciparum protein minus the GPI anchor, displaying a C-terminal sequence as in the 3D7 strain, into pIPspAdaptl is performed as follows. Plasmid 02-659 pf-aa-sub (see above) containing the codon-optimized CS.gene is digested with Hindlll and Bamfil restriction enzymes. The 1.1 kb fragment corresponding to the CS gene is ligated to Hindlll and BamHI-digested pIPspAdaptl vector. The resulting plasmid is designated pAdapt.CS.Pfalc (pf-aa-sub) and contains the CS gene under the transcriptional control of full length human immediate-early (IE) cytomegalovirus (CMV) promoter and the downstream SV40 poly(A) signal. The generation of the recombinant virus named Ad5AE3.CS.Pyoel was performed as follows. pAdapt.CS.Pyoel was digested by Pad restriction enzyme to release the left-end portion of the Ad genome. Plasmid pWE/Ad.Aflll-rIITRsp containing the regaining right-end part of the Ad genome has a deletion of 1878 op in the 23 region (xbal deletion). This construct was also digested with Pad. pAdapt.CS.Pyoel was separately transfected with Pad digested pWE.Ad.Aflll-rlTRsp into PER-E1355K producer cells (cells have been described in WO 02/40665) using lipofectamine transfecticn reagent (Invitrogen) using methods known in the art and as described in WO 00/70071. Homologous recombination between overlapping sequences led to generation of the recombinant virus named Ad5AE3.CS. Pyoel. It is to be understtod that Ad5-based vectors can also be produced on PER.C6'm cells, which cells are represented by the cells deposited under ECACC no. 96022940 (see above) . The adenoviral vector, in crude lysates, resulting from this transfection were plaque purified using methods known to persons skilled in the art. Single plaques were analyzed for the presence of'the CS transgene and amplified for large-scale production in triple-layer flasks (3x175 cmVflask) . Upon simplification cells are harvested at full CPE and the virus is purified by a two-step Cesium Chloride (CsCl) purification procedure as routinely done by those skilled in the art and generally as described in WO 02/40665. The generation of the recombinant virus named Ad5AE3.CS.Pfalc was performed as follows. pAdapt.CS.Pfalc was digested by Pad restriction enzyme to release the left-end portion of the Ad genome. Plasmid pWE/Ad.Aflll-rlTRsp containing the remaining right-end part of the Ad genome has a deletion of 1878 bp in the E3 region (Xbal deletion). This construct was also digested with Pad. pAdapt.CS.Pfalc was transfected with Pad digested pWE.Ad.Aflll-rlTRsp into PER-E1B55K producer cells using lipofectamine transfection reagent. Homologous recombination between overlapping sequences led to generation of the recombinant virus named Ad5AE3.CS.Pfalc. The adenoviral vector, in crude lysates, resulting from this transfection was plaque purified using methods known "to persons skilled in the art. Single plaques were analyzed for the presence of the CS transgene and amplified for large-scale production in triple-layer flasks (3x175 cm2/flask;. Cells were harvested at full CPE and the virus was purified by a two-step CsCl purification procedure as routinely done by those skilled in the art and generally as described in WO 02/4*06(55. The generation of the recombinant viruses named Ad5AE3.CS.Pfaic(-28) and Ad5AE3.CS.pfalc(-14) was performed as follows. pAdapt.CS.Pfalc(-28) and pAdapt.CS.Pfalc(-14) were separately digested by Pad restriction enzyme to release the left-end portion of the Ad genome. Plasmid pWE/Ad.Aflll-rlTRsp containing the remaining right-end part of the Ad genome has a deletion of 1878 bp in the E3 region (Xbal deletion). This construct was also digested with Pad. pAdapt.CS.Pfalc(-28) and pAdapt.CS.Pfalc(-14) were separately transfected with Pad digested pWE.Ad.Aflll-rlTRsp into PER-E1B55K producer cells using lipofectamine transfection reagent. Homologous recombination between overlapping sequences led to generation of recombinant viruses named respectively Ad5AE3.CS.Pfalc(-28) and Ad5AE3.CS.Pfalc (-14). Adenoviral vectors in crude lysates resulting from these transfections are plaque purified using methods known to persons skilled in the art. Single plaques are analyzed for the presence of the CS transgene and amplified for large-scale production in triple-layer flasks (3x175 cmVflask) . Cells are harvested at full CPE and the virus is purified by a two-step C5Cl purification procedure as routinely done by those skilled in the art and generally as described in WO 02/40665. The generation of the recombinant virus named Ad5AE3.CS.Pfalc(pf-aa-sub) is performed as fellows. pAdapt.CS.Pfalc(pf-aa-sub) is digested by Pad restriction enzyme to release the left-end portion of the Ad genome. Plasmid pWE/Ad.Aflll-rlTRsp containing the remaining right-end part of the Ad genome is also digested with Pad. pAdapt.CS.Pfalc(pf-aa-sub) is transfected with Pad digested pWE.Ad.AflII-rITRspAE3 into PER.C6m or PZR-E1B55K producer cells using lipofectamine transfection reagent, or by other means such as electroporation or ether transfection methods known to persons skilled in the art. Homologous recombination between overlapping sequences leads to generation of the recombinant virus named Ad5AE3.C5.Pfale (pf-aa-sub). The adenoviral vector, in crude lysates, resulting from this transfection is plaque purified using methods known to persons skilled in the art. Single plaques are analyzed for the presence of the CS transgene and amplified for large-scale production in triple-layer flasks (3x175 cmVflask) . Cells are harvested at full CPE and the virus is purified by a two-step CsCl purification procedure as routinely done by those skilled in the art and generally as described in WO 02/40665. Next to these procedures, generation of the control recombinant adenovirus named Ad5AE3. empty was carried out as described above, using as adapter the plasmid pAdapt, lacking a transgene. Example 4. Generation of recombinant adenoviral vaccine vectors based on Ad35. A first 101 bp PCR fragment containing the Ad5 pIX promoter (nucleotides 1509-1610) was generated with the primers SV40for (5'-CAA XGT ATC TTA TCA TGT CTA G-3') (SEQ ID NO: 16) and pIX5Rmfe (5'-CTC TCT CAA. TTG CAG ATA CAA AAC TAC ATA AGA CC-3') (SEQ ID NO:17) . The reaction was done with Pwo DNA polymerase according to manufacturers instructions but with 3% DMSO in the final mix. pAdApt was used as a template. The program was set as follows: 2 min at 94 °C; 30 cycles of: 30 sec at 94°C, 30 sec at 52°C and 30 sec at 72°C; followed by 8 min at 72°C. The resulting PCR fragment contains the 3' end of the SV40 poly (A) signal from pAdApt and the Ad5-pIX promotor region as present in Genbank Accession number M73260 from nucleotide 3511 to nucleotide 3586 and an Mfel site at the 3' end. A second PCR fragment was generated as described above but with primers pIX35Fmfe (5'-CTC TCT CAA TTG TCT GTC TTG CAG CTG TCA TG-3') (SEQ ID NO: 18) and 35R4 (for reference to the sequence of the 35R4 primer, see WO 00/70071) . pAdApt35IPl (described in WO 00/70071) was used as a template, the annealing was set at 58 °C for 30 sec and the elongation of the PCR program was set at 72 °C for 90 sec. This PCR procedure amplifies Ad35 sequences from nucleotide 3467 to nucleotide 4669 (sequence numbering as in WO 00/70071) and adds an Mfel site to the 5' end. Both PCR fragments were digested with Mfel and purified using the Qiagen PCR purification kit (Qiagen). Approximate equimolar amounts of the two fragments were used in a ligation reaction. Following an incubation of two hours with ligase enzyme in the correct buffers, at room temperature, the mixture was loaded on an agarose gel and the DNA fragments of 1.4 kb length were isolated with the Geneclean II kit (BIO101, Inc) . The purified DNA was used in a PCR amplification reaction with primers SV40for and 35R4. The PCR was done as described above with an annealing temperature of 52 °C and an elongation time of 90 sec. The resulting product was isolated from gel- using the Qiagen gel extraction kit and digested with Agel and BgIII. The resulting-0.86 kb fragment containing the complete 100 nucleotide pIX promoter form Ad5, the Mfel site and the pIX ORF (fragment Mfel-Agel, including the ATG start site) from Ad35, but without a poly (A) sequence, was isolated from gel using the Geneclean II kit. RCA-free recombinant adenoviruses based on Ad35 can be generated very efficiently using adapter piasmids, such as pAdApt535 (described below) and adenovirus plasmid backbones, such as pWE/Ad35.pIX-rITRA£3 (described in WO 02/40665) . To generate pAdApt535, pAdApt35.Luc (described ir. WO 00/70071) was digested with Bglll and Agel and the resulting 5.8 kb vector was isolated from gel. Thi3 fragment was ligated with the isolated 0.86 kb 3glII-AgeI fragment containing the Ad5-Ad35 chimeric pIX promoter described above, to result in a plasmid named pAdApt535.Luc, which was subsequently digested with Bglll and Apal. The resulting 1,2 kb insert was purified over gel. pAcApt35IPl was digested with Bglll and Apal and the 3.6-kb vector fragment was isolated over gel. Ligation of the 1.2 kb Bglll-Apal insert from pAdApt535.Luc and the 3.6 kb Bglll-Apal digested vector resulted in pAdApt535. The cloning of the gene encoding the CS protein from P.yoelii parasite into pAdapt535 was performed as follows. Plasmid 02-149 containing the codon optimized P.yoelii CS gene (see above) was digested with the restriction enzymes Hindlll and BamHI. The 1.1 kb fragment corresponding to the CS gene was isolated over agarose gel and ligated to the HindIII and BamHI digested pAdap-535 vector. The resulting plasmid was ramed pAdapt535-CS.Pyoel and contains the CS gene under the transcriptional control of the full length human CMV promoter and the downstream SV40 poly(A) signal. The cloning of the gene encoding the full length CS protein from P. falciparum parasite into pAdap-535 was performed as follows. Plasmid 02-148 (pCR-script.Pf) containing the codon optimized CS gene of P. falciparum was digested with the restriction enzymes Hindlll and BamHI. The 1.2 kb fragment corresponding to the CS gene was isolated over agarose gel and ligated to the Hindlll and BamHI digested pAdapt535 vector. The resulting plasmid was named pAdapt535-CS.Pfalc and contains the CS gene under the transcriptional control of the full length human CMV promoter and the downstream SV40 poly (A) signal. The cloning of the gene encoding the CS P. falciparum protein minus the GPI anchor sequence, thus with the deletion of the last 28 amino acids, into pAdapt535 is performed as follows. The 1.1 kb PCR fragment obtained as described above using primers Forw.Falc and Rev.Falc.CS-28, is digested with the restriction enzymes Hindlll and BamHI and then cloned into pAdapt535 vector also digested with Hindlll and BamHI. The resulting plasmid is designated pAdapt535.CS.Pfalc(-28) and contains the CS gene under the transcriptional control of the full length human CMV promoter and the downstream SV40 poly (A) signal. The cloning of the gene encoding the CS P. falciparum protein minus the GPI anchor sequence, now with the deletion of the last 14 amino acids, into pAdapt535 is performed as follows. The 1.1 kb PCR fragment obtained as described above using primers Forw.Falc and Rev.Falc.CS-14, is digested with the restriction enzymes Hindlll and BamHI and then cloned into pAdapt535 vector also digested with Hindlll and BamEI. The resulting plasmid is . * designated pAdapt335.CS.2falc(-14) and contains the CS gene under the transcriptional control of the full length human CMV promoter and the downstream SV40 poly (A) signal. The cloning of the ger.e encoding the CS ?. falciparum protein minus the G?I anchor sequence, displaying a C-terminus sequence as in the 3D7 strain, into pAdaptS35 is performed as follows. Plasmid'02-659 pf-aa-sub (see above) containing the codon optimized CS gene is digested with Hindlll and 3amEI restriction enzymes. The 1.1 kb fragment corresponding to the CS gene is liga-ed to Hindlll and BamHI digested pAdapt535 vector. The resulting plasmid is designated pAdapt535.CS.Pfalc (pf-aa-sub) and contains the CS gene under the transcriptional control of the full length human CMV promoter and the downstream SV40 poly(A) signal. The generation of the recombinant virus named Ad35AE3.CS.Pyoel was performed as follows. pAdapt535.CS.Pyoel was digested by Pad restriction enzyme to release the left-end portion of the Ad genome. Plasmid pWE.Ad35.pIX-rITRAE3, containing the remaining right-end part of the Ad genome with a deletion of 2673 bp in the S3 region is digested with Notl. pAdapt535.CS.Pyoel was transfected with Notl digested pWE.Ad35.pIX-rITRAZ3 into PER-E1B55K producer cells using lipofectamine transfection reagent. The generation of the cell line PER-E1B55K has been described in detail in WO 02/40665. In short, this publication describes that PER.C6™ cells were stably transfected with Seal linearised pIG35-55K DNA, carrying the E1B-53K gene of adenovirus serotype 35, after which a selection procedure with G418 yielded in 196 picked colonies. Further culturing of a limited number of well growing colonies resulted in stable cell lines that upon numerous subcultures stably expressed the Ad35 E1B-55K gene and supported the growth of recombinant Ad35 viruses, while the original PER.C634 cell were very inefficient in supporting this. Homologous recombination between overlapping sequences led to generation of the recombinant virus named Ad35AE3.CS.Pyoel. The adenoviral vector, in crude lysa-es, resulting from thi3 transfection was plaque purified using methods known to persons skilled in the art. Single plaques were analyzed for the presence of the CS transgene and amplified for large-scale production in triple-layer flasks (3x175 air/flask) . Upon amplification cells were harvested at full CPE and the virus was purified by a two-step CsCl purification procedure as routinely done by those skilled in the art and generally as described in WO 02/40665. The generation of the recombinant virus named Ad35A33.CS.Pfalc was performed as follows. pAdapt535.CS.Pfalc was digested by Pad restriction enzyme to release the left-end portion of the Ad genome. Plasmid pWE.Ad35.pIX-rITRAE3, containing the remaining right-end part of the Ad genome with a deletion of 2673 bp in the S3 region was digested with Notl. pAdapt535.CS,Pfalc was transfected with Notl digested pWE.Ad35.pIX-rITRAE3 into PER-E1B55K producer cells using lipofectamine transfection reagent. Homologous recombination between overlapping sequences led to generation of the recombinant virus named Ad35AE3.CS.Pfalc. The adenoviral vector, in crude lysates, resulting from this trans feet ion was plaque purified using methods known to persons skilled in the art. Single plaques were analyzed for the presence of the CS transgene and amplified for large-scale production in triple-layer flasks (3x175 cmVflask) . Upon amplification cells were harvested at full CPE and the virus was purified by a two-step CsCl purification procedure as routinely done by those skilled in the art and generally as described in WO 02/40665. The generation of the recombinant viruses named Ad35AE3.CS.Pfalc(-28) and Ad35AE3,CS.Pfalc(-14) is performed as follows. pAdapt535.CS.Pfalc(-2 8) and pAdapt535.CS.Pfalc(-14) were separately diges-ed by Pad restriction enzyme to release the left-end portion of the Ad genome. Plasmid pWE.Ad35.pIX-rITRAE3 containing the remaining right-end part of the Ad genome is digested with Kotl. pAdapt535.CS.Pfalc(-28) and pAdapt535.CS.Pfalc(-14) are separately transfected with NotI digested pWE.Ad35.pIX-rITRAE3 into PER-E1B55K producer. Homologous recombination between overlapping sequences leads to generation of recombinant viruses named respectively Ad35AE3.CS,Pfalc(-28) and Ad35AE3.CS.Pfalc(-14). Adenoviral vectors in crude lysates resulting from these transfections are plaque purified using methods known to persons skilled in the art. Single plaques are analyzed for the presence of the CS transgene and amplified for large-scale production in triple-layer flasks (3x175 cmVflask) . Cells are harvested at full CPE and the virus is purified by a two-step CsCl purification procedure as routinely done by those skilled in the art and generally as described in WO 02/40665. The generation of the recombinant virus named Ad35AE3.CS.Pfalc(pf-aa-sub) is performed as follows. pAdapt535.CS.Pfalc(pf-aa-sub) i3 digested by Pad restriction enzyme to release the left-end portion of the Ad genome. Plasmid pWE.Ad35.pIX-rITRAE3 containing the remaining right-end part of the Ad genome is digested with Notl. pAdapt535.CS.?falc(pf-aa-sub) is transfected with Notl digested pWE.Ad35.pIX-rITRAE3 into PER-E1355X producer cells using lipofectamine transfection reagent: (Invitrogen) using methods known in the art and as described in WO 00/70071 or by electroporation or other transfection methods known to those skilled in the art. Homologous recombination between overlapping sequences leads to generation of the recombinant virus named Ad35AE3.CS.Pfalc(pf-aa-sub). The adenoviral vector, in crude lysates, resulting from this transfection is plaque purified using methods known to persons skilled in the art. Single plaques are analyzed for the presence of the CS transgene and amplified for large-scale production in triple-layer flasks (3x175 cm2/flask) . Cells are harvested at full CPE and the virus is purified by a two-step CsCl purification procedure as routinely done by those skilled in the art and generally as described in WO 02/40665. Example 5. Inducing protection against P.yoelii malaria infection using recombinant adenoviral-based vaccines in vivo. Adenovirus serotype 5 (Ad5)-based vectors genetically engineered to express the CS antigen of the rodent malaria P.yoelii have been shown capable to induce complete protection against P.yoelii infection (Rodrigues et al. 1997) . A side-by-side comparison between Ad5 and Ad35 vectors carrying the codon-optimized P.yoelii CS gene was designed to investigate the immune response that is induced, and to investigate their ability in raising protection against P.yoelii parasite infection in mice. The study enrolled 3alb/C mice that were immunized by intra-muscular or subcutaneous injection of 10a-1010 viral particles (vp) of Ad5AE3~ or Ad35AE3-based viral vectors (33 described above) carrying either the P&oel±i CS gene (Ad5AE3-CS.Pyoel and Ad35AE3-CS.Pyoel) or no transgene (Ad5AE3-empty and Ad35AE3-empty) . Figure 4 shows the results of the experiments wherein the administration route was compared using both vectors. The number of IFN-y-secreting cells in a population of 106 splenocytes was determined (Fig. 4A) as well as the antibody titers in the serum (Fig. 43) . The experiments were performed on mice that were sacrificed two weeks after injection with the recombinant adenoviruses. Each of the bars represents the average of 5 mice. If mice were not sacrificed they were used for a challenge with live sporozoites, after which the rate of protection was determined (Fig. 5A and B) . Each of these bars represents the average of 5 mice. The experiments on humoral and cellular immune responses are performed with immunological assays well known to persons skilled in the art and as described for instance by Bruiia-Romero et al. (2001a) . The immunization, challenge and read out are scheduled in Table II and III. Antibodies titers against sporozoites can be determined by an indirect immunofluorescence assay or with an ELISA. Figure 4B shows the results as calculated with an ELISA. Cellular immune responses were determined by ex-vivo ELISPOT assay measuring the relative number of CS-specific, IFN-y-secreting, CD8+ and CD4+ T cells. Protection against malaria infection was monitored by determining the levels of parasite inhibition in the livers of immunized mice through reverse transcriptase PCR quantification of P.yoelii ribosomal RNA copies. . The immunization with Ad5- and Ad35-based vectors was performed as follows. Aliquots of recombinant adenoviruses that were stored at -70°C were:gradually thawed on ice and diluted to 100 ul in the desired concentration in PBS with 1% heat-inactivated Normal Mouse Serum. Subsequently the samples were sonicated for 5 sec. Sub-cutaneous administration was performed at both sides of the tail base with a volume of 50 ul at each side. Intra muscular administration was performed in both thighs with a volume of 50 ul at each thigh. The Indirect Immunofluorescence Assay (IFA) is performed according to Brufta-Romero et al. (2001a) . First, infected mosquitoes are generated by initially having a native mouse infected with an infected mosquito by having the mouse bitten at three different sites. Blood is removed from the mouse after 8 days when parasitemia is 4-8% and diluted to 1%. Then, other naive mice are injected i.p. with the diluted blood sample. After 3 days the blood is taken which serves as a blood meal for starved mosquitoes. These are fed for 2 days. After 14 days P.yoelii sporozoites are isolated from the blood-fed mosquitoes by anaesthetizing infected mosquitoes on ice and subsecruently saturating them in 70% ethanol. Then, the mosquitoes are transferred to PBS pH 7.4 and the salivary glands are dissected. These are subsequently grinded on ice and the sporozoites are separated from the debris by centrifugation. Using this method, approximately 35,000 P.yoelii sporozoites can be obtained from 1 mosquito. Thenf glass-slides in a 12-multi-well plate are coated with approximately 10,000 P.yoelii sporozoites each in Dulbecco's Modified Eagle's Medium (DMEM) plus 10% Fetal Bovine Serum by air-dryir.g. A range of dilutions of sera of the vaccinated mice (in a volume of 10 ul in PBS plus 5% FBS) is subsequently incubated with the air-dried sporozoites for 30 min at room temperature in a mois-ures environment. Then, the slides are aspirated, washed twice with PBS .and 10 ul cf a 30-fold diluted FITC conjugated Goat-anti-Mcuse antibody (Kirkegaard & Perry Laboratories, US.-., catalogue no. 02-18-06) is added and incubated for 30 min at rocm temperature. Wells were again aspirated and washed twice. For counterstaining, a solution of 100 ug/ml Ethidium Bromide is incubated for 10 min, after which the aspiration step is repeated and the wells are washed with water. Slides are mounted using permount containing phenylenediamine/anti fade. The anti-sporozoize antibody titers are determined as the highest serum dilution producing fluorescence. For the determination of antibody titers, one can also use an ELISA. For this, ELISA plates (Immulon II, Dynatech) were coated with 2 ug/ml antigen in PBS by adding 100 μl per well of this solution and leaving it overnight at 4°C. The antigen that was used is a 3x6 amino acid repeat of the P.yoelii CS protein: QGPGAPQGPGAPQGPGAP (SEQ ID NO:19). The plates were subsequently washed three times with washing buffer (Ix PBS, 0.05% Tween), and 200 ul blocking buffer (10% FCS in washing solution) was added per well. Plates were incubated for 1-2 h at room temperature. Then, plates were washed three times again with washing buffer including 5% FCS. Dilutions of the sera were made as follows: 50 μl washing buffer plus 5% FCS was added to wells 2-12. Then 100 ul washing buffer plus 5% FCS is added to the first well and 1:2 serial dilutions are made by transferring 50 ul from well 1 to 2, then from 2 to 3, etc. Plates are incubated for 1 h at room temperature. Then the plates are washed three times wish washing buffer and 100 ul of a 1:2000 diluted percxidase-labeled Goat anti-Mouse IgG (anti Heavy and Light chain, human absorbed, Kirkegaard & Perry Laboratories, catalogue no. 074-1806) is added per well and incubated. Then, plates are washed with washing buffer three times and once with PBS and then 100 ul A3TS substrate solution (A3TS 1-Component, Kirkegaard & Perry Laboratories, catalogue number 50-66-18) is added to each well. The reaction is terminated by the addition of 50 ul 1% SDS, and plates are read at 405 nm in an ELISA reader. The ELISPOT assay to determine the relative number of CS-specific IFN-f-secreting, CD8+ and CD4+ T cells in the spleen, and the reverse transcriptase PCR and realtime PCR to quantify the amount of parasi-e specific RNA present in the liver of the challenged mice were all performed as described by Bruiia-Romero et al. (2001a and 2001b) except for the fact that the number of cycles in the real-time PCR was 45. While attenuation P.yoelii infection in Ad5AE3-CS.Pyoel vaccine recipients is predicted (Rodrigues et al. 1997), vaccination with Ad35AE3-CS.Pycel is expected to be superior or at least equally effective. Figure 4A shows that with an administration of 109 and 1010 viral particles per mouse the Ad35-based vector is at least as effective in inducing a cellular immune response as the Ado-based vector, if not superior. It can be concluded that with this set-up that there is no dramatic difference in cellular response as indicated by the number of IFN-y-secreting cells after intra muscular and subcutaneous delivery. Figure 43 shows the antibody titers in the same experiment and performed on the same sera using the indirect immuno-flucrescence experiment outlined above. If compared to the results shown in Figure 4A it is clear that at a dose of 103 viral particles, the Ad35 based vector induces a significant cellular immune response but does not give rise to very high titers of anti-sporozoite antibodies. Again, there is not a significant difference between the two routes of administration. Animals that received different doses of Ad5- and Ad35-based vectors expressing the codon-cptimized P.yoelii CS antigen, were subsequently challenged i.v. with 105 sporozoites purified "as'described above. The results of these experiments are shown in Figure 5A and B. The percentage of inhibition was calculated as compared to naive mice that were not immunized. Mice that were immunized received s.c. 109 or 1010 viral particles (vp) and were challenged after 14 days with the sporozoites and then sacrificed after 48 h. Negative controls were empty vectors without antigen and non-immunized mice. Clearly, a high percentage of inhibition is obtained when using the Ad5-based vector as well as with the Ad35-based vector, applying the two doses, while no protection was found in the negative controls (Fig. 5A) . Importantly, only a low number of parasite-specific 18S ribosomal RNA's could be determined in the liver of the immunized mice, while the mice that received no adenoviral vector or empty vectors contained large numbers of these RNA's (Fig, 5B) . This strongly indicates that the Ad35-based vector, like the Ad5-based vector can give rise to significant protection against the malaria parasite, even after a single round of immunization. Ixample 6. Inducing immunity against P. falciparum malaria infection using recombinant adenoviral-baaed vaccines in iVO. A side-by-aide comparison between Adenovirus serotype 5 (Ad5) and Adenovirus serotype 35 (Ad35) rectors is designed to investigate the ability to induce lumoral and cellular immune responses against the CS antigen of the P. falciparum parasite in mice. In addition, immunogenicities of Adenovirus vectors containing full length and GPI minus CS are compared. This study enrolls B10.BR mice. Animals are immunized by intra-muscular injection of 109-1010 vp of Ad5AE3 or Ad35AE3 viral vectors carrying either the full length CS gene (Ad5AE3-CS,Pfalc and Ad35A£3-CS.Pfalc) or the GPI-anchor sequence minus CS gene (Ad5AE3-CS.Pfalc. (-28)/ (-14) and Ad35AE3-CS.Pfalc. (-28)/(-14) or no transgene (Ad5AE3-empty and Ad35AE3-empty) . At two weeks- and six to eight weeks post-vaccination, cellular and humoral responses are monitored with immunological assays well known to persons skilled in the art as described above. The immunization, challenge and read out is scheduled in Table IV and V. Immunogenicity of the Ad35-based vectors is expected to be superior or at least comparable to the immunogenicity triggered by Ad5-based vectors. Figure 6 shows the results that were obtained by using the Ad5~ based vector containing the full length gene encoding the P. falciparum CS protein, the gene encoding the protein with the 14 amino acid deletion and the gene encoding the protein with the 28 amino acid deletion. The results indicate that all three (Ad5-based) vectors are able to induce a cellular immune response as measured by the number of CS-specific IFN-y-secreting cells in a population of splenocyties, determined by the ex-v±vo 3LISP0T assay described above, and generally as in Bruna-Romero et al- (2001a). Example 7. Inducing a long-lasting protection against P.yoelii malaria infection by prime-boost regimens with different adenovirus serotype-based vaccines. Recombinant Adenovirus serotype 5 expressing a CS antigen of P.yoelii was shown to elicit protection when used in prime-boost regimen in combination with a recombinant vaccinia virus carrying the same antigen (Brufla-Romero et al. 2001a). An experiment to investigate the capability of prime/boost regimens based on adenovirus vectors carrying codon-optimized CS and derived from two different serotypes to induce long-lasting protection against the P. yoelii CS antigen was designed. This study enrolls Salb/C mice distributed in experimental groups of 12 mice each. Animals are .immunized by intra-muscular injection of an optimal dose of Ad5AE3 or Ad35AE3 viral vectors carrying either the P.yoelii CS gene (Ad5AE3-CS.Pyoel and Ad35AE3-CS.Pyoel) or no transgene (Ad5AE3-empty and Ad35AE3-empty) . One group of animals is primed at week 0 with Ad5AE3-CS-Pyoel and boosted at week 8 with Ad35∆E3-CS.Pyoel. Another group of mice is primed at week 0 with Ad35AE3-CS,Pyoel and boosted at week 8 with Ad5AE3-CS.Pyoel. Other groups of mice are primed at week 0 with Ad35∆E3-CS.Pyoel or Ad5AE3-CS.Pyoel and boosted at week 8 with the same vector. Finally, a control group of mice is primed at week 0 with Ad5AE3-empty and boosted at week 8 with Ad35∆E3-empty. At week 2 post-boost, 6 mice of each group are sacrificed to allow evaluation and characterization of humoral and cellular immune responses with immunological assays well kr.own -o persons skilled in the art, the remaining 6 mice from each group are challenged with live sporozoites. The immunization, challenge and read out are scheduled in Table VI. Protection against malaria infection will be monitored and measured using assays well known to people skilled in the art as described above. Vaccine regimens based on Ac35 alone or Ad5/Ad35 combinations are expected to be superior or at least comparable in efficacy as compared to regimens based solely on Ad5. Example 8. Inducing a long-lasting immunity against P. falciparum malaria infection by prime-boost regimens with different adenovirus serotype-based vaccines. An experiment to investigate the ability of prime/boost regimens based en adenovirus vectors derived from two different serotypes to induce long-lasting immunity against the P.falciparum CS antigen was designed. The study enrolls 310.BR mice distributed in experimental groups of 24 mice each. Animals are immunized by intra-muscular injection of an optimal dose of adenoviral vectors carrying either the full length CS gene (Ad5AE3-CS.Pfalc and Ad35AE3-CS.Pfalc) or the GPI- anchor sequence minus CS gene {Ad5AE3-CS.Pfalc(-28)/(-14) and Ad35AE3-CS.Pfalc(-28)/(-14)) or no transgene (Ad5AE3- empty and Ad35AE3-erapty) • One group of animals is primed at week 0 with Ad5AE3-CS.Pfalc or Ad5AE3-.CS.Pfalc(-28) / (- 14) and boosted at week 8 with Ad35AE3-CS.Pfalc or Ad35AE3-CS.?falc(-28)/(-14). Another group of mice is primed at week 0 with Ad35AE3-CS.Pfalc or Ad35AE3- CS.Pfalc(-28)/(-14) and boosted at week 8 with Ad5AE3- CS.Pfalc or Ad5AE3-CS.Pfalc(-28) / (-14) . Another group of mice is primed at week 0 with Ad35AE3-CS.Pfalc or d35∆E3-CS.Pfalc(-23)/(-14) and boosted at week 8 with :he same vector. Finally, a control group of .-nice is primed at week 0 with Ad5AE3-empty and boosted at week B with Ad35AE3-empty. At week 2 and 5 or 10 or 15 post-boost, 6 mice are sacrificed at each time point and cellular and humeral responses are monitored with immunological assays well known to persons skilled in the art and as described above. The immunization, challenge and read out are scheduled in Table VII, Vaccine regimens based en Ad35 alone or Ad5/Ad35 combinations are expected to be superior or at least comparable in efficacy as compared to regimens based solely on Ad5. Example 9, Inducing an immune response against: the P. falciparum CS antigen by prime/boost regimens using different Adenovirus serotype-based vaccines in non-human primates. An example of an experiment useful to investigate the capability of prime/boost regimens based en adenovirus vectors derived from two.different serotypes to elicit immunity against the P. falciparum CS antigen in non-human primates is described. Moreover, the effect of two different routes of vaccine administration, intramuscular and intra-dermal, is evaluated. Rhesus monkeys are vaccinated with adenoviral vectors carrying either the full-length CS gene (Ad5AE3-CS.Pfalc or Ad35A33-CS.Pfalc) or the GPI-anchor sequence minus CS gene (Ad5∆E3-CS.Pfalc(pf-aa-sub) or Ad35AE3-CS.Pfale(pf-aa-sub)). Prime/boost regimens (Ad5 followed by Ad35 or Ad35 followed by Ad.5) are compared to generally applied prime/boost regimens (Ad5 followed by Ad5 or Ad35 followed by Ad35) . Humoral and cellular immune responses are monitored using immunological assays well known to persons skilled in the art. Serum of immunized monkeys is tested by ELISA assay to determine the nature and magnitude of ~he antibody response against the repeat region of CS. Cellular immune response is measured by ELISPOT assay to determine the amount of antigen-specific IFN-y secreting cells. Table I. Names ar.d Genbar.k database entry numbers of the ?.falciparum circumspcrczoite amino acid sequences used to generate the final consensus sequence. REFER3NCES Bruna-Romero 0, Gonzalez-Aseguinoiaza G, Hafalia JCR, et al. (2001a) Complete, long-lasting protection against malaria of mice primed and boosted with two distinct viral vectors expressing the same plasmcdial antigen. Proc Natl Acad Sci USA 98:11491-11496 Bruna-Romero 0, Hafalia JC, Gonzalez-Aseguinolaza G, sano G, Tsjui M, Zavala F. (2001b) Detection of malaria liver-stages in mice infected through the bite of a single Anopheles mosquito using a highly sensitive real-time PCR. lat J Parasitol 31:1499-1502 Clyde DF, Most H, McCarthy VC, Vanderberg JP. (1973) Immunization of men against sporozoite-induced falciparum malaria. Am J Med Sci 266:169-177 De Jong JC, Wermenbol AG, Verweij-Uijterwaal MW, Slaterus RW, Wertheim-Van Dilien P, Van Doornum GJ, Khoo SH, Hierholzer JC. (1999) Adenoviruses from human immunodeficiency virus-infected individuals, including two strains that represent new candidate serotypes Ad50 and Ad51 of species 31 and D, respectively. J Clin Microbiol 37:3940-3945 Gandon S, Mackinnon MJ, Nee 3, Read AF. (2001) Imperfect vaccines and the evolution of pathogen virulence. Nature 414:751-756 Gilbert SCf Schneider J, Hannan CM, et al. (2002) Enhanced CD8 T cell immunogenicity and protective efficacy in a mouse malaria model using a recombinant adenoviral vaccine in heterologous prime-boost immunisation regimes. Vaccine 20:1039-1045 Gordon DM, McGovern TW, Krzych U, Cohen JC, Schneider I, LaChance R, Heppner DG, Yuan G, Hollingdale M, Slaoui M et al. (1995) Safety, immunogenicity, and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein-hepatitis B surface antigen subunit vaccine. J Infect Dis 171:1576-1585 Kurtis JD, Hollingdale MR, Luty AJF, Lanar DE, Krzych U and Duffy PE (2001) Pre-erythrocytic immunity to Plasmodium falciparum: the case for an LSA-1 vaccine. Trends in Parasitology 17:219-223 Lockyer MJ, Marsh K, Newbold CI. (1989) Wild isolates of Plasmodium falciparum show extensive polymorphism in T cell epitopes of the circumsporozoite protein. Mol Biochem Parasitol 37:275-280 Moran P and Caras IW. (1994) Requirements fcr glycosylphosphatidylinositol attachment are similar hut not identical in mammalian cells and parasitic protozoa. J Cell Biol 125:333-343 Nardin EH, Calvo-Calle JM, Oliveira GA, et al. £2001) A totally synthetic polyoxime malaria vaccine containing Plasmodium falciparum B cell and universal T cell epitopes elicits immune responses in volunteers of diverse HLA types. J Immunol 166:481-489 Narum DL, Kumar S, Rogers WO, et al. (2001) Codon optimization of gene fragments encoding Plasmodium falciparum merzcite proteins enhances DNA vaccine protein expression and immunogenicity in mice. Infect and Immun 69:7250-7253 Nussenzweig RS, Vanderberg J, Most H, Orton C- (1967) Protective immunity produced by the injection of X-irradiated sporozoites of Plasmodium berghei. Nature 216:160-162 Romero-P, Marayar.ski JL, Corradin G, et al. (1989) Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria. Nature 341:323-326 Rodrigues EG, Zavala F, Eichinger D, et al. (1997) Single immunizing dose of recombinant adenovirus efficiently induces CD8+ T cell-mediated protective immunity against malaria. J Immunol 158:1268-1274 Scheiblhofer S, Chen D, Weiss R, et al. (2001) Removal of the circumsporozoite protein (CSP) glycosylphosphatidylinositol signal sequence from a CSP DNA vaccine enhances induction of CSP-specific Th2 type immune responses and improves protection against malaria infection. Eur J Immunol 31:692-698 Zevering Y, Khambconruang C, Good MF. (1994) Effect of polymorphism of sporozoite antigens on T-cell activation. Res Immunol 145:469-476 1. A replication-defective recombinant adenovirus derived from a serotype selected from the group consisting of: Adll, Ad26, Ad34, Ad35, Ad48, Ad49 and Ad50, wherein said recombinant adenovirus comprises a heterologous nucleic acid encoding an antigenic determinant of Plasmodium falciparum. 2. A replication-defective recombinant adenovirus according to claim 1, wherein said antigenic determinan is the circumsporozoite protein,- or an immunogenic part thereof. 3. A replication-defective recombinant adenovirus according to claim 1 or 2, wherein said heterologous nucleic acid is codon-optimized for elevated expression in a mammal. 4. A replication-defective recombinant adenovirus according to claim 3, wherein said mammal is a human. 5. A replication-defective recombinant adenovirus according to claim 3 or 4, wherein the adenine plus thymine content in said heterologous nucleic acid, as compared to the cytosine plus guanine content, is less than 87% preferably less than 80%, more preferably less than 59% and most preferably equal to approximately 45% 6. A replication-defective recombinant adenovirus according to claim 2, wherein said circumsporozcite protein is the circumsporozoite protein as depicted.in figure 1A (SEQ ID N0:3). 1. A replication-defective recombinant adenovirus according to claim 3, wherein said codon-optimized heterologous nucleic acid is the nucleic acid as depicted in figure IB (SEQ ID NO:l) . 8. A replication-defective recombinant adenovirus according to any one of claims 2 to 7, wherein the circumsporozoite protein, or the immunogenic part thereof, is lacking a functional GPI anchor sequence. 9. A replication-defective recombinant adenovirus derived from a serotype selected from the group consisting of; Adll, Ad26, Ad34, Ad35, Ad48, Ad49 and Ad50, wherein said recombinant adenovirus comprises a heterologous nucleic acid encoding the circumsporozoite protein of Plasmodium yoelii, and wherein said nucleic acid is codon-optimized for elevated expression in a mammal• 10. A replication-defective recombinant adenovirus according to claim 9, wherein the adenine plus thymine content in said nucleic acid, as compared to the cytosine plus guanine content, is less than 87%, preferably less V preferably equal to approximately 45%. 11. A replication-defective recombinant adenovirus according to claim 9, wherein said circumsporozoite protein is the circumsporozoite protein as depicted in figure 3A (SEQ ID NO:9). 12. A replication-defective recombinant adenovirus according to claim 9, wherein said nucleic acid is the nucleic acid as depicted in figure 3B (SEQ ID NO: 7). 13. A replication-defective recombinant adenovirus according to any one of claims 9 to 12, wherein the circumsporozoite protein, or the immunogenic part thereof, is lacking a functional GPI anchor sequence. 14. A replication-defective recombinant adenovirus according to claim 1, wherein said antigenic determinant is selected from the group consisting of: LSA-1, LSA-3, MSP-1, MSP-119 and MSP-142, or combinations thereof. 15. A replication-defective recombinant adenovirus according to any one of claims 1 to 14, wherein said adenovirus further comprises a gene encoding a liver specific antigen for Plasmodium falciparum as antigenic determinant, or an immunogenic part thereof. 16. A replication-defective recombinant adenovirus antigen is LSA-1. 17. An isolated nucleic acid encoding a circumsporozoite protein of Plasmodium falciparum as depicted in' figure 1A (SEQ ID NO: 3), wherein said nucleic acid is codon-optimized. 18. An isolated nucleic acid encoding a circumsporozoite protein of Plasmodium falciparum strain- 3D7, as depicted in figure 2A (SEQ ID NO: 6), wherein said nucleic acid is codon-opt imiz ed. 19. An isolated nucleic acid encoding a circumsporozoite protein of Plasmodium yoelii as depicted in figure 3A (SEQ ID NO:9), wherein said nucleic acid is codon- optimized, 20. An isolated nucleic acid comprising the sequence of SEQ ID NO:l, SEQ ID NO: 4 or SEQ ID NO: 7. 21. A vaccine composition comprising a replication-defective recombinant adenovirus according to any one of claims 1 to 16, and a pharmaceutically acceptable carrier. 22. A vaccine composition according to claim 21, further comprising an adjuvant. or preventing a malaria infection in-a mammal, said method comprising (in either order, or simultaneously) the steps of: administering a vaccine composition according to claim 21 or 22, and administering a vaccine composition comprising at least one purified malariarderived protein or peptide. 24. Method of treating a mammal for a malaria infection or preventing a malaria infection in a mammal, said method comprising (in either order, or simultaneously) the steps of: administering a vaccine composition comprising a replication-defective recombinant adenovirus according to any one of claims 1 to 13; and - administering a vaccine composition comprising a replication-defective recombinant adenovirus according to any one of claims 14 to 16.

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