AU2007231854B2 - Methods and compositions for treating and preventing malaria (2) - Google Patents

Abstract

Abstract The present invention relates to vaccines for the treatment and prevention of malaria. In particular the invention provides immunogenic molecules comprising an amino acid sequence of an erythrocyte binding antigen (EBA) protein strain of Plasmodium falciparum wherein compositions comprising said antigens are capable of eliciting an immune response, thereby preventing invasion of Plasmodium parasites into erythrocytes.

Description

METHODS AND COMPOSITIONS FOR TREATING AND PREVENTING MALARIA (2) FIELD OF THE INVENTION The present invention relates to vaccines for the treatment and prevention of malaria. In particular the invention provides antigens capable of eliciting antibodies capable of preventing invasion of Plasmodium parasite into erythrocytes. BACKGROUND Human malaria is caused by infection with protozoan parasites of the genus Plasmodium. Four species are known to cause human disease: Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale and Plasmodium vivax. However, Plasmodium falciparum is responsible for the majority of severe disease and death. Recent estimates of the annual number of clinical malaria cases worldwide range from 214 to 397 million (World Health Organization. The world health report 2002: reducing risks, promoting healthy life. Geneva: World Health Organization, 2002; Breman et al (2004) American Journal of Tropical Medicine and Hygiene 71 Suppl 2:1-15.), although a higher estimate of 515 million (range 300 to 660 million) clinical cases of Plasmodium falciparum in 2002 has been proposed (Snow et al. (2004) American Journal of Tropical Medicine and Hygiene 71(Suppi 2):16-24). Annual mortality (nearly all from Plasmodium falciparum malaria) is thought to be around 1.1 million (World Health Organization. The world health report 2002: reducing risks, promoting healthy life. Geneva: World Health Organization, 2002; Breman et al (2004) American Journal of Tropical Medicine and Hygiene 71 Suppl 2:1-15.). Malaria also significantly increases the risk of childhood death from other causes (Snow et a. (2004) American Journal of Tropical Medicine and Hygiene 71 Suppl 2:16-24). Almost half of the world's population lives in areas where they are exposed to risk of malaria (Hay et al (2004) Lancet Infectious Diseases 4(6):327-36), and the increasing numbers of visitors to endemic areas are also at risk. Despite continued efforts to control malaria, it remains a major health problem in many regions of the world, and new ways to prevent andlor treat the disease are urgently needed. Early optimism for vaccines based on malarial proteins (so called subunit vaccines) has been tempered over the last two decades as the problems caused by allelic polymorphism and antigenic variation, original antigenic sin, and the difficulty of generating high levels of durable immunity emerged, and with the notable failures of 1 many promising subunit vaccines (such as SPf66) have led to calls for a change in approach towards a malaria vaccine. Consequently, this growing sense of frustration has lead to the pursuit of different approaches that focus on attenuated strains of malaria parasite or irradiated Plasmodium falciparum sporozoites (Hoffmann et al. (2002) J Infect Dis 185(8):1155-64). Similarly, both the limited success achieved to date with protein-based vaccines and the recognition that cell mediated immunity may be critical to protection against hepatic and perhaps blood stages of the parasite has led to a push for DNA and vectored vaccines, which generate relatively strong cell mediated immunity. To date DNA vaccines have demonstrated poor efficacy in humans with respect to antibody induction (Wang et al. (2001) PNAS 98: 10817-10822). To be effective, a malaria vaccine could prevent infection altogether or mitigate against severe disease and death in those who become. infected despite vaccination. Four stages of the malaria parasite's life cycle have been the targets of vaccine development efforts. The first two stages are often grouped as 'pre-erythrocytic stages' (i.e. before the parasite invades the human red blood cells): these are the sporozoites inoculated by the mosquito into the human bloodstream, and the parasites developing inside human liver cells (hepatocytes). The other two targets are the stage when the parasite is invading or growing in the red blood cells (the asexual stage); and the gametocyte stage, when the parasites emerge from red blood cells and fuse to form a zygote inside the mosquito vector (gametocyte, gamete, or sexual stage). Vaccines based on the pre-erythrocytic stages usually aim to completely prevent infection. For asexual, blood stage vaccines, because the level of parasitaernia is in general proportional to the severity of disease (Miller, et al. (1994) Science 264, 1878-1883), vaccines aim to reduce or eliminate (e.g. induce stertile immunity) the parasite load once a person has been infected. However, most adults in malaria-endemic settings are clinically immune (e.g. do not suffer symptoms associated with malaria), but have parasites at low density in their blood. Gametocyte vaccines aim towards preventing the parasite being transmitted to others through mosquitoes. Ideally, a vaccine effective at all these parasite stages is desirable (Richie and Saul, Nature. (2002) 415(6872):694-701). The SPf66 vaccine (Patorroyo et alt (1988) Nature 332:158-161) is a synthetic hybrid peptide polymer containing amino acid sequences derived from three Plasmodium falciparum asexual blood stage proteins (83, 55, and 35 kilodaltons; the 83 kD protein 2 corresponding to merozoite surface protein (MSP)-1) linked by repeat sequences from a protein found on the Plasmodium falciparum sporozoite surface (circumsporozoite protein). Therefore it is technically a multistage vaccine. SPf66 was one of the first types of vaccine to be tested in randomized controlled trials in endemic areas and is the vaccine that has undergone the most extensive field testing to date. While having marginal efficacy in four trials in South America (Valero et al. (1993) Lancet 341(8847):705-10. Valero et al. (1996) Lancet 348(9029):701-7; Sempertegui et al. (1994) Vaccine 12(4):337-42; Urdaneta et al. (1998) American Joumal of Tropical Medicine and Hygiene 58(3):378-85.), these trials suggested a slightly elevated incidence of Plasmodium vivax in the vaccine groups. The vaccine has also been demonstrated to be ineffective for reducing new malaria episodes, malaria prevalence, or serious outcomes (severe morbidity and mortality) in Africa (Alonso et al. Lancet 1994;344(8931):1175-81 and Alonso et al Vaccine 12(2):181-6); D'Alessandro et al. (1995) Lancet 346(8973):462-7.; Leach et al. (1995) Parasite Immunology 1995;17(8): 441-4.; Masinde et al. (1998) American Journal of Tropical Medicine and Hygiene 59(4):600-5; Acosta 1999 Tropical Medicine and International Health 1999;4(5):368-76) and Asia (Nosten et al. (1996) Lancet 348(9029):701-7.), and is consequently no longer being tested. Four types of pre-erythrocytic vaccines (CS-NANP; CS1 02; RTS,S; and ME-TRAP) have been trialed. The CS-NANP-based pre-erythrocytic vaccines were the first to be tested, beginning in the 1980s. The vaccines used in the first trials comprised three different formulations of the four amino acid B cell epitope NANP, which is present as multiple repeats in the circumsporozoite protein covering the surface of the sporozoites of Plasmodium falciparum. The number of NANP repeats in these vaccines varied from three to 19, and three different carrier proteins were used. The CS-NANP epitope alone appears to be ineffective in a vaccine, with no evidence for effectiveness of CS-NANP vaccines in three trials (Guiguemde et al. (1990) Bulletin de [a Societe de Pathologie Exotique 83(2):217-27; Brown et al. (1994) Vaccine 12(2):102-7; Sherwood et al. (1996) Vaccine 14(8):817-27). The CS102 vaccine is also based on the sporozoite CS protein, but it does not include the NANP epitope. It is a synthetic peptide consisting of a stretch of 102 amino acids containing T-cell epitopes from the C-terminal end of the molecule. All 14 participants in 3 this small trial of non-immune individuals had malaria infection as detectable by PCR (Genton et al. (2005) Acta Tropica Suppl 95:84). The RTS,S recombinant vaccine also includes the NANP epitope. It contains 19 NANP repeats plus the C terminus of the CS protein fused to hepatitis B surface antigen (HBsAg), expressed together with un-fused HBsAg in yeast. The resulting construct is formulated with the adjuvant ASO2/A. Thus the vaccine contains a large portion of the CS protein in addition to the NANP region, as well as the hepatitis B carrier. The RTS,S pre-erythrocytic vaccine has shown some modest efficacy, in particular with regard to prevention of severe malaria in children and duration of protection of 18 months (Kester et al. (2001) Journal of Infectious Diseases 2001;183(4):640-7.1; Bojang et al. (2001) Lancet 358(9297):1927-34; Alonso et al. (2005) Lancet 366(9502):2012 Alonso et al. (2005) Lancet 366(9502):2012-8), Bojang et al. (2005) Vaccine 23(32):4148-57). In four trials, it was effective in preventing a significant number of clinical malaria episodes, including good protection against severe malaria in children, with no serious adverse effects (Graves et al. (2006) Cochrane Database of Systematic Reviews 4: CD006199). The RTS,S vaccine has shown significant efficacy against both experimental challenge (in non-immunes) and natural challenge (in participants living in endemic areas) with malaria. Although no evidence was found for efficacy of RTS,S against clinical malaria in adults in The Gambia in the first year of follow up, efficacy was observed in the second year after immunization, after a booster dose. However, there was no reduction in parasite densities (which positively associate with pathology). Nonetheless, in a recent study in Mozambique, the vaccine appeared to have efficacy in infants (Aponte et al. (2007) 370(9598) 1543-1551). The ME-TRAP pre-erythrocytic vaccine is a DNA vaccine that uses the prime boost approach to immunization. It uses a malaria DNA sequence known as ME (multiple epitope)-TRAP (thrombospondin-related protein). The ME string contains 15 T-cell epitopes, 14 of which stimulate CD8 T-cells and the other of which stimulates CD4 T cells, plus two B-cell epitopes from six pre-erythrocytic antigens of Plasmodium falciparum. It also contains two non-malarial CD4 T-cell epitopes and is fused in frame to the TRAP sequence. This sequence is given first as DNA (two doses) followed by one dose of the same DNA sequence in the viral vector MVA (modified vaccinia virus Ankara). There was no evidence for effectiveness of ME-TRAP vaccine in preventing 4 new infections or clinical malaria episodes, and the vaccine did not reduce the density of parasites or increase mean packed cell volume (a measure of anaemia) in semi-immune adult males (Moorthy et al. (2004) Nature 363(9403):150-6). The first blood-stage vaccine to be tested in challenge trials is Combination B, which is a mixture of three recombinant asexual blood-stage antigens: parts of two merozoite surface proteins (MSP-1 and MSP-2) together with a part of the ring-infected erythrocyte surface antigen (RESA), which is found on the inner surface of the infected red cell membrane. The MSP-1 antigen is a 175 amino acid fragment of the relatively conserved blocks 3 and 4 of the Ki parasite line; it also includes a T-cell epitope from the Plasmodium falciparum circumsporozoite (CS) protein as part of the MSP1 fusion protein. The MSP2 protein includes the nearly complete sequence from one allelic form (3D7) of the polymorphic MSP-2 protein. The RESA antigen consists of 70% of the native protein from the C-terminal end of the molecule. A small efficacy trial of Combination B in non-immune adults with experimental challenge showed no effect (Lawrence (2000) Vaccine 18(18):1925-31). In the single natural-challenge efficacy trial of in semi-immune children (Genton (2002) Journal of Infectious Diseases 185(6):820 7), no effect on clinical malaria infections was detected. In this trial, significant efficacy (measure by reduction in parasite density) was only observable in the group who were not pretreated with sulfadoxine-pyrimethamine. Also, in these children there was a reduction in the proportion of children with medium and high parasitaemia levels. Vaccinees in the Genton et al. (2002) trial had a lower incidence and prevalence of parasites with the 3D7 type of MSP2 (the type included in the vaccine) than the placebo group, and a higher incidence of malaria episodes were associated with the FC27 type of MSP2, suggesting specific immunity. Importantly, there was no statistically significant change in prevalence of parasitemia, nor was there evidence for an effect of combination B against episodes of clinical malaria in either the group pretreated with the antimalarial or the group with no antimalarial, in fact the results for these subgroups tended in the opposite direction. Furrthermore, the relative role of the three vaccine constituents cannot be assessed when based on the trials that have been carried out to date. In addition to the asexual-stage components of Combination B, many other potential asexual stage vaccines have been under preclinical evaluation, such as regions of apical 5 membrane antigen 1 (AMA1), the merozoite surface proteins MSPl, MSP2, MSP3, MSP4, and MSP5,: glutamate-rich protein (GLURP), rhoptry associated protein-2 (RAP2), EBA-175, EBP2, MAEBL, and DBP, and Plasmodium falciparum (erythrocyte membrane protein-1 (PfEMP1). Importantly however, a recent examination of the vaccine candidate still under consideration (Moran et al. (2007) The Malaria Product Pipeline, The George Institute for International Health, September 2007) has shown that many preclinical vaccine projects are inactive; in particular vaccine projects using the F1 domain of EBA-175 (e.g. by ICGEB), EBA-140 (also known as BAEBL), and RAP-2 are inactive. The inactivity of these projects highlights that much work is needed to find blood stage antigens that will afford a protective immune response. There are many problems faced in the selection of antigens for malaria vaccine development, including antigenic variation, antigen polymorphism, and original antigenic sin, and further problems such as MHC-limited non-responsiveness to malarial antigens, inhibition of antigen presentation, and the influence of maternal antibodies on the development of the immune system in infants. Many blood stage vaccine candidates, such as MSP-1, MSP-2, MSP-3 and AMA-1, have substantial polymorphisms that may have an impact on both immunogenicity and protective effects, and in the case of MSP-1, and MSP-2, immune responses to particular allelic forms has been observed in vaccine trials (and also for MSP-3 and AMA-1 in mice). Molecular epidemiological studies can guide antigen selection and vaccine design as well as provide information that is needed to measure and interpret population responses to vaccines, both during efficacy trials and after introduction of vaccines Into the population. They also may provide insight into the selective forces acting on antigen genes and potential implications of allele specific immunity. Consequently the different allelic forms would need to be included in any vaccine to counter the affect of antigenic polymorphism at immunogenic residues. The cyclical recrudescences of malaria parasites in humans is thought to be due to the selective pressure placed upon parasitized red cells by antibodies to variant antigens, such as PfEMP1. Plasmodium falciparum possesses about 50 variant copies of PfEMP1 which are expressed clonally such that only one is expressed at a time, and the development of antibodies against the expanding clonal type then reduce this clone from the affected individual, and subsequently a different variant, not recognized by 6 antibodies, emerges and cycling continues. This antigenic variation also poses a problem for vaccines containing clonally expressed antigens, and immunization studies with recombinant conserved CD36-binding portion of PfEMP1 failed to confer protection in Aotus monkeys (Makobongo et al. (2006) JID 193:731-740. A third problem confounding malaria vaccine initiatives is original antigenic sin; a phenomenon in which individuals tend to make antibodies only to epitopes expressed on antigenic types to which they have been exposed (or cross-reactive antigens), even in subsequent infections carrying additional, highly immunogenic epitopes (Good, et al. (1993) Parasite Immunol. 15, 187-193. Taylor et al. (1996) Int. Immunol. 8, 905-915, Riley, (1996) Parasitology 112, S39-S51 (1996)) It has also been proposed that immunity to malaria relies on maintaining high levels of immune effector cells, rather than in the generation of effectors from resting memory cells (Struck and Riley (2004) Immunological Reviews 201: 268-290). Consequently, the time taken to generate sufficient levels of effector cells may be crucial in determining whether a protective memory response can be mounted to prevent disease. Also, malaria parasites may interfere directly with memory responses by interfering with antigen presentation by dendritic cells (Urban et al. (1999) Nature 400:73-77, Urban et al.(2001) PNAS 98:8750-8755), and premature apoptosis of memory cells (Toure-Balde et al.(1996) Infection and Immunity- 64: 744-750, Balde et al. (2000) Parasite Immunology 22:307-318). Furthermore, it has been demonstrated that antibodies to particular malarial antigens (such as MSP-1) may inhibit the activity of malaria-protective antibodies (Holder et al (1999) Parassitologica 41:409-14), and that there may be MHC-limited non responsiveness to malarial antigens (Tian et al (1996) J Immunol 157:1176-1183, Stanisic et -al. (2003) Infection and Immunity 71: 5700-5713). Maternally derived antibodies have also been shown to interfere with the development of antibody responses in infants, and has been implicated for malaria in mice (Hirunpetcharat and Good (1998) PNAS 95:1715-1720), consequently these problems need to be addressed for vaccination of children against malaria. As will be apparent from the foregoing review of the prior art, there remained significant problems to be overcome in the design of an efficacious vaccine against malaria. It is an 7 aspect of the present invention to overcome or ameliorate a problem of the prior art by providing antigens capable of eliciting antibodies that can treat or prevent malaria. A reference herein to a patent document or other matter which is given as prior art is not to be taken as an admission that that document or matter was known or that the information it contains was part of the common general knowledge as at the priority date of any of the claims. SUMMARY OF THE INVENTION The present invention provides an immunogenic molecule comprising a contiguous amino acid sequence of an erythrocyte binding antigen (EBA) protein of a strain of Plasmodium falciparum, wherein when administered to a subject the molecule is capable of inducing an invasion-inhibitory immune response to the strain. The EBA protein may be EBA175, EBA140, or EBA181. The contiguous amino acid sequence comprises about 5, 8, 10, 20, 50 or 100 or more amino acids. The contiguous amino acid sequence may be found in the region between the F2 domain and the transmembrane domain of the EBA protein. The contiguous amino acid sequence may be found in the region from about residue 746 to about residue 1339 of the EBA protein. In one form of the immunogenic molecule the EBA is EBA140. In one form the contiguous amino acid sequence is found in the region between the F2 domain and the transmembrane domain of EBA140, or in the region from about residue 746 to about residue 1045 of EBA140. In another form of the immunogenic molecule the EBA is EBA175. In one form of the immunogenic molecule the contiguous amino acid sequence is found in the region between the F2 domain and the transmembrane domain of EBA175. The contiguous amino acid sequence may be found in the region from about residue 761 to about residue 1271 of EBA175. In another form of the invention the EBA is EBA181. In one form of the invention the 8 contiguous amino acid sequence may be found in the region between the F2 domain and the transmembrane domain of EBA181. In another form of the immunogenic molecule the contiguous amino acid sequence is found in the region from about residue 755 to about residue 1339 of EBA181. Another aspect of the present invention provides a composition comprising an immunogenic molecule as described herein and a pharmaceutically acceptable excipient and optionally a vaccine adjuvant. Yet a further aspect of the present invention provides a composition comprising a contiguous amino acid sequence of an invasion ligand of a strain of Plasmodium falciparum involved in sialic-acid-dependant invasion of red cells further comprising a contiguous amino acid sequence of an invasion ligand of a strain of Plasmodium falciparum involved in sialic-acid-independent invasion of red cells wherein when administered to a subject the composition is capable of inducing an invasion-inhibitory immune response to the strain. The composition may comprise an immunogenic molecule comprising a contiguous amino acid sequence of a reticulocyte-binding protein homologue (Rh) protein of the strain of Plasmodium falciparum, wherein when administered to a subject the Rh protein is capable of inducing an invasion-inhibitory immune response to the strain. The Rh may be Rh1, Rh2a, Rh2b or Rh4. In one form of the composition the Rh is Rh2b. In another form of the immunogenic molecule the contiguous amino acid sequence is found in the region between about 31 amino acids N-terminal of the Prodom PD006364 homology region to about the transmembrane domain of Rh2b. In one form of the composition the contiguous amino acid sequence is found in the region from about residue 2027 to 3115 of Rh2b, or the region from about residue 2027 to about residue 2533 of Rh2b, or the region from about residue 2098 to about residue 2597 of Rh2b, or the region from about residue 2616 to about residue 3115 of Rh2b. In one form of the composition the Rh is Rh2a. In one form of the composition the 9 contiguous amino acid sequence is found in the region between about 31 amino acids N-terminal of the Prodom PD006364 homology region to about the transmembrane domain of Rh2a. In one form of the invention the contiguous amino acid sequence is found in the region from about residue 2027 to 3115 of Rh2a, or the region from about residue 2027 to about residue 2533 of Rh2a, or the region from about residue 2098 to about residue 2597 of Rh2a, or the region from about residue 2616 to about residue 3115 of Rh2a. In one form of the composition the Rh is Rh1. In one form of the composition the contiguous amino acid sequence is found in the region between about residue 1 to about the transmembrane domain of Rhi, or the region from about residue 1 to about residue 2897 of Rhi. In one form of the composition the Rh is Rh4. In another form of the composition the contiguous amino acid sequence is found in the region from about the MTH1187/YkoF like superfamily domain to about the transmembrane domain of Rh4. In a further form of the composition the contiguous amino acid sequence is found in the region from about residue 1160 to about residue 1370 of Rh4. The contiguous amino acid sequence may comprise about 5, 8, 10, 20, 50 or 100 or more amino acids. The strain of Plasmodium falciparum may be a wild type strain. In another aspect the present invention provides a method of treating or preventing a condition caused by or associated with infection by Plasmodium falciparum comprising administering to a subject in need thereof an effective amount of a composition as disclosed herein. A further aspect provides use of a composition as described herein in the manufacture of a medicament for the treatment or prevention of a condition caused by or associated with infection by Plasmodium falciparum. A further aspect of the present invention provides a method of screening for the presence of a Plasmodium falciparum invasion-inhibitory antibody directed against an 10 erythrocyte binding antigen (EBA) of a strain of Plasmodium falciparum in a subject, comprising obtaining a biological sample from the subject and identifying the presence or absence of an antibody capable of binding to an immunogenic molecule as described herein. A further aspect of the present invention provides a method of screening for the presence of a Plasmodium falciparum invasion-inhibitory antibody directed against a reticulocyte-binding homologue protein (Rh) of a strain of Plasmodium falciparum in a subject, comprising obtaining a biological sample from the subject and identifying the presence or absence of an antibody capable of binding to an immunogenic molecule as described herein. The method may further comprise identifying the presence of a Plasmodium falciparum invasion-inhibitory antibody directed against an erythrocyte binding antigen (EBA) of a strain of Plasmodium falciparum in a subject comprising identifying the presence or absence of an antibody capable of binding to an immunogenic molecule as described herein. Throughout the description and the claims of this specification the word "comprise" and variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps. BRIEF DESCRIPTION OF THE FIGURES Figure 1. Inhibition of different Plasmodium falciparum lines by serum antibodies from malaria exposed Kenyan children and adults. Results shown were selected to demonstrate representative examples of the inhibitory activities observed. Values are expressed as a percentage of invasion using non exposed donors. All samples were tested in duplicate; values represent mean ± range. A) Inhibition of W2mef-wt compared to W2mefAEBA175 cultured with normal or neuraminidase-treated erythrocytes. B) Inhibition of W2mef-wt compared to W2mef SelNm cultured with normal or neuraminidase-treated erythrocytes. C) Inhibition of 3D7 wt compared to 3D7AEBA175 cultured with normal or neuraminidase-treated erythrocytes. Numbers on the X-axis are study codes for individual serum samples. Norm, cultured with normal erythrocytes. Neur, cultured with neuraminidase-treated erythrocytes. 11 Figure 2. Differential inhibition of W2mef Plasmodium falciparum lines by serum antibodies from malaria-exposed Kenyan children and adults. Results show the proportion of sera (n=80) that differentially inhibited the two parasite lines tested for each comparison shown. Grey bars show the proportion of samples that inhibited the parental wild-type parasite line more than the W2mefAEBA175 line or W2mefselNm line (type-A response). Black bars show the proportion of samples that inhibited the W2mefAEBA175 line or W2mefselNm line more than the corresponding parental line (type-B response). The proportion with differential inhibitory activity is shown for all samples and separately by age groups (S5, 6-14, and >14 years of age). A, B) W2mef-wt compared to W2mefAEBA175 cultured with normal (A) or neuraminidase treated (B) erythrocytes. C, D) W2mef-wt compared to W2mefSelNm cultured with normal (C) or neuraminidase-treated (D) erythrocytes. W2mef-wt was cultured with normal erythrocytes in all assays. Differences between the age groups were not statistically significant. Figure 3. Differential inhibition of 3D7 Plasmodium falciparum lines by serum antibodies from malaria-exposed Kenyan children and adults. Results show the proportion of sera (n=80) that differentially inhibited the two parasite lines tested for each comparison shown. Grey bars show the proportion of samples that inhibited parental 3D7 (3D7-wt) more than 3D7AEBA175 (type-A response). Black bars show the proportion of samples that inhibited 3D7AEBA175 more than the parental 3D7 (type-B response). The proportion with differential inhibitory activity is shown for all samples and separately by age groups (55, 6-14, and >14 years of age). Comparisons are shown with 3D7AEBA175 cultured with normal (A) or neuraminidase-treated (B) erythrocytes. 3D7-wt was cultured with normal erythrocytes in all assays. Differences between the age groups were not statistically significant. Figure 4. The effect of serum antibodies from Kenyan donors on erythrocyte invasion by different Plasmodium falciparum lines. Results represent the mean from testing 80 Kenyan serum antibody samples; error bars 12 represent 95% confidence intervals. Values are expressed relative to control samples from non-exposed donors. Samples were not tested for inhibition of 3D7-wt or W2mef-wt invasion into neuraminidase-treated erythrocytes (NT, not tested). Numbers on the X axis are study codes for individual serum samples. Norm, invasion into normal erythrocytes. Neur, invasion into neuraminidase-treated erythrocyte. Figure 5. Differential inhibition of 3D7-wt and 3D7AEBA175 by serum antibodies. A selection of individual samples is shown that inhibit 3D7-wt to a greater extent than 3D7AEBA175. This suggests the presence of inhibitory antibodies against EBA175. Values are expressed as a percentage of invasion using non-exposed donors. All samples were tested in duplicate; values represent mean ± range. Figure 6. Age-associated acquisition of antibodies to recombinant EBA and Rh proteins measured by ELISA. Results (n=150) are grouped by age and show mean ± SEM absorbance expressed relative to the levels for adults (>14 years). P<0.001 for comparisons between age groups for all antigens. Donors were residents of a malaria endemic region of Kenya (Kilifi District). The relative absorbance using sera from non-exposed donors (n=10) is also shown (Contr). Figure 7. Recombinant Rh4 binds the surface of erythrocytes A. Schematic representation of Plasmodium falciparum Rh4 and recombinant Rh4 proteins. Rh4 is a two exon gene with a transmembrane domain (green) at the C terminal end. Amino acids 28-766 and amino acids 853-1163 of Rh4 are fused to a hexa-histidine tag (orange) to generate Rh4e and Rh4 42 respectively. Diagram is not drawn to scale. B. Purification of Rh4as. Rh4aa was purified using Ni-NTA agarose beads and eluted with 250 mM imidazole buffer. Lane 1 and 2 are expression levels of purified RH4 8 obtained from two separate bacteria clones. C. Rh4M8 binds to the surface of erythrocytes. The PBS lane represents the control lane in which proteins were eluted in a binding assay performed in the presence of PBS with no fusion protein. Eluted RH4 88 is detected using a penta-histidine antibody upon binding to erythrocytes, spun through 13 oil and also upon washing the bound erythrocytes with PBS. D. Rh4 42 does not bind the surface of erythrocytes. No detection of Rh4 4 2 could be observed in the erythrocyte binding assay using a penta-histidine antibody. Figure 8. Age-associated acquisition of antibodies to Rh2 measured by ELISA Results (n=150) are grouped by age and show mean ± SEM absorbance expressed relative to the levels for adults (>14 years). P<0.001 for comparisons between age groups for both antigens. Donors were residents of a malaria endemic region of Kenya (Kilifi District). The relative absorbance using sera from non-exposed donors (n=10) is also shown (Melbourne). Antibodies to both amino acids 2098 to 2597 of Rh2 and 2616 to 3115 of Rh2 were detected and acquired in an age-dependent manner. Figure 9. Antibodies to Rh2 are associated with protection from malaria among a cohort of 206 children in Madang Province, Papua New Guinea Graphs are Kaplan Meier survival curves. The cumulative proportion (Y-axis) of individuals with symptomatic Plasmodium falciparum malaria over time (X-axis) is plotted. Children were classified into three groups on the basis of their antibody response to Rh2: 0 = highest tercile of responders (i.e. these children had the highest antibody levels; 1 = middle tercile of responders; and 2= lowest tercile of responders (i.e. these children had the lowest levels of antibodies). A. Children with the highest level of antibodies to PfRh2-A9 (amino acids 2098 to 2597 of Rh2) had the lowest risk of malaria (p<0.01). B. Children with the highest level of antibodies to PfRh2-A11 (amino acids 2616 to 3115 of Rh2) had the lowest risk of malaria (p<0.01). Figure 10. Antibodies to EBA are associated with protection from malaria Graphs are Kaplan Meier survival curves. The cumulative proportion (Y-axis) of individuals with symptomatic Plasmodium falciparum malaria over time (x-axis) is plotted. 14 A. Antibodies to EBA proteins (EBA175, EBA140, and EBA181) by ELISA were associated with reduced risk of clinical malaria. Children were classified into three groups (high, medium, low) on the basis of their antibody response to all three EBAs. Highest responders show lowest risk of malaria, indicating that the breadth and level of antibodies is associated with protection (P<0.01). B, C. D. Children were classified as having high (red) or low (blue) antibody levels and plotted against time to first clinical episode. Those with high antibody levels had a significantly lower risk of malaria (P<0.01). Figure 11. Differential inhibition of 3D7-wt and 3D7AEBA140 by serum antibodies. A selection of individual samples is shown that inhibit 3D7-wt to a greater extent than 3D7AEBA140. This suggests the presence of inhibitory antibodies against EBA140. Values are expressed as a percentage of invasion using non-exposed donors. All samples were tested in duplicate and values represent means. Figure 12. Inhibition of both SA-dependent and SA-independent invasion pathways (e.g. EBA175, EBA140, EBA181 and Rh2) acts synergistically to inhibit invasion of human erythrocytes. Antibodies were generated to specific domains of EBA175, EBA140, EBA181 and PfRh2b in rabbits. Protein G purified antibodies (IgG) from these sera were obtained and used to test inhibition of merozoite invasion at 1 mg/ ml in wild type 3D7 as well as lines in which the gene encoding different ligands had been disrupted i.e. 3D7A175, 3D7A140, 3D7A175/140 and 3D7A181. Anti-EBA140 antibodies inhibited parental 3D7 approximately 20% and this is disappears in 3D7A140 as would be expected for specific inhibition of function. Similarly, antibodies to EBA175 inhibit 3D7 merozoite invasion approximately 18% and this does not occur for 3D7A175 again showing that function of this ligand is specifically inhibited. Importantly, antibodies targeting Rh2 inhibit invasion of parasites lacking EBA1 75, or EBAI74 and EBA1 40, to a greater extent than inhibition of wild-type parasites indicating that the SA-dependent and SA-independent invasion pathways are the major pathways of invasion into human erythrocytes, and that inhibition of these two pathways acts to synergistically inhibit invasion. 15 DETAILED DESCRIPTION OF THE INVENTION The present invention is predicated on the finding that antibodies raised against erythrocyte binding antigen (EBA) proteins of Plasmodium falciparum are capable of inhibiting invasion of the parasite into human red blood cells. The invasion of red blood cells is a key event in the infection of a subject with the malaria parasite, and it is therefore proposed that EBA proteins may be used as antigens in the formulation of a vaccine against malaria. Accordingly, in one aspect, the present invention provides an immunogenic molecule comprising a contiguous amino acid sequence of a erythrocyte binding antigen (EBA) of a strain of Plasmodium falciparum, wherein when administered to a subject the molecule is capable of inducing an invasion-inhibitory immune response to the strain. This approach to formulating a vaccine for malaria is distinguished from approaches of the prior art, and is indeed contrary to the general teaching of the prior art prior to the present invention. Previous work characterizing the function of EBA proteins (and also the reticulocyte binding protein homologue (Rh) proteins) in human red cell (erythrocyte) invasion by the malaria parasite Plasmodium falciparum has demonstrated that these molecules are not essential for red cell invasion since the genes encoding these molecules (e.g. EBA175, EBA140, EBA1 81, Rh1, Rh2a, Rh2b and Rh4) can be disrupted in different Plasmodium falciparum lines without an obvious effect on blood stage growth rates. Also, antibodies raised in rabbits and mice to Rh2a and Rh2b are unable to inhibit invasion of Plasmodium falciparum into untreated red cells in vitro, again suggesting that these molecules are not essential for invasion of red cells. Furthermore, recent work examining Rh4 (Gaur et al. (2007) PNAS in press) has identified that while antibodies to both native Rh4 and a recombinant protein encoding a region of Rh4 (rRH43) inhibited the binding of these proteins to red cells, the same antibodies failed to block invasion of red cells, causing the authors to conclude that Rh4 is inaccessible for antibody-mediated inhibition of the invasion process. In contrast, the applicants proposal that Rh proteins are capable of eliciting a protective immune response suggests that reticulocyte-binding protein homologues are accessible to the human immune system, that human antibodies to these proteins inhibit invasion of Plasmodium falciparum into red cells, and that antibodies to these proteins result in immunity to malaria in humans. A study by Duraisingh et al. (2003; EMBO J 22:1047) demonstrated that antibodies to 16 Rh2a and Rh2b are unable to inhibit invasion of Plasmodium falciparum into untreated red cells. This work also demonstrated that Rh2a is not expressed by MCAMP, FCB1, T994 or FCR3, and Rh2b, in addition to being absent from D10, is not expressed by MCAMP, FCB1, T994 or FCR3, further suggesting that Rh2a and Rh2b are not essential for invasion of red cells. The growth and merozoite invasion rate of Plasmodium falciparum parasites in which the Rh2a and Rh2b genes have been disrupted is unchanged relative to their wild-type parent lines, suggesting that these molecules are not essential for invasion of wild-type parasites into normal erythrocytes. Therefore therapeutics targeting these non-essential invasion pathways would not be expected to be invasion-inhibitory (Duraisingh et a. (2003) EMBO J 22:1047). In complete contrast to the findings of the aforementioned authors, the present invention demonstrates that human antibodies to Rh proteins inhibit invasion. Figure 1 shows that human antibodies to Rh proteins inhibit invasion. The inhibitory activity of serum antibodies from children and adults resident in a malaria endemic region of coastal Kenya was compared against different W2mef and 3D7 parasite lines with different invasion phenotypes. While EBA and Rh proteins are not essential for invasion as discussed above, these molecules play a role in invasion of enzyme treated red cells. In particular, neuraminidase removes sialic acid residues from the erythrocyte surface and blocks invasion pathways dependent on sialic acid present on both glycophorin A and other receptors, trypsin treatment cleaves proteins such as glycophorin A and C, but does not affect glycophorin B, and chymotrypsin cleaves a non-overlapping set of proteins including glycophorin B and band 3 on the erythrocyte surface. Using this approach, invasion phenotypes can be broadly classified into two main groups: i) sialic acid (SA)-dependent invasion, demonstrated by poor invasion of neuraminidase-treated erythrocytes (neuraminidase cleaves SA on the erythrocyte surface), and ii) SA independent invasion, demonstrated by efficient invasion of neuraminidase-treated erythrocytes, involves Rh2 and Rh4. SA-dependent (neuraminidase-sensitive) invasion of enzyme treated cells involves the three known EBAs (EBA175, EBA181, EBA140), Rh1. EBA175 and EBA140 bind to glycophorin A and C, respectively. EBA181 binds to SA on the erythrocyte surface and to band 4.1 protein. W2mef-wt uses SA-dependent invasion mechanisms (EBA- and Rh1-dependent), whereas invasion of W2mefAEBA175 is largely SA-independent (Rh2 and Rh4-dependent). In comparative inhibition assays (Figure 1), 27% of samples differentially inhibited the two lines (e.g. samples 56, 109, 17 and 135 in Figure 1A), indicating that the inhibitory activity of acquired antibodies is influenced by the invasion pathway being used (Figure 1 and 2). Although W2mefAEBA175 has switched to use a largely SA-independent invasion pathway, it remains possible that other ligands involved in SA-dependent invasion (e.g. EBA140, EBA181, Rhi) may still be functional to some extent in W2mefAEBA175, despite the switch in phenotype. To inhibit these interactions, and more clearly compare antibodies against SA-dependent versus SA-independent invasion pathways, antibody inhibition assays were performed using W2mefAEBA175 and neuraminidase-treated erythrocytes, in comparison to inhibition of W2mef-wt with normal erythrocytes (Figure 2B). This approach further emphasizes differences in antibody activity linked to variation in invasion phenotype. The proportion of samples showing differential inhibition of the two lines was 48% versus 27% when using normal erythrocytes with both lines. The extent of differences in inhibitory activity was strongly increased for some individual samples (e.g. sample 355 in Figure 3A). This indicates that the inhibitory activity of antibodies against ligands of SA-independent invasion (e.g. Rh2 and Rh4) was enhanced once the residual activity of SA-dependent ligands (e.g. EBA175, EBA140, EBA181 and Rhi) is inhibited by neuraminidase treatment of erythrocytes. Differential inhibition by samples was also observed with W2mef-wt compared to W2mefSelNm (Figure 1B and 2C). The latter isolate is genetically intact and its phenotype was generated by selection for invasion of neuraminidase-treated erythrocytes. Like W2mefAEBA175, it uses an alternate SA-independent invasion pathway and has upregulated expression of Rh4. It still expresses EBA1 75 but does not depend on this ligand for invasion. 35% of samples from children and adults were found to differentially inhibit the two lines (e.g. samples 196 and 436, Figure 1B), confirming that a change in invasion phenotype, or pathway, can substantially alter the efficacy of inhibitory antibodies. As expected, the inhibition of W2mefSeINm and W2mefAEBA175 by samples was highly correlated (r=0.61; n=80; p<0.001) as these isolates invade via the same pathway and only differ by the presence of EBA175. Antibody dependent inhibition of W2mefSelNm invasion into neuraminidase-treated erythrocytes (Figure 2D), compared to W2mef-wt in normal erythrocytes, was tested to more clearly evaluate antibodies against SA-independent (Rh2- and Rh4-dependent) versus SA-dependent invasion (EBA- and Rhi-dependent pathways). Overall, 45% of samples differentially inhibited the two lines. Some samples showed greater differences in the inhibition of 18 W2mef-wt and W2mefSeNm than when normal erythrocytes were used (e.g. samples 196 and 436 in Figure 1B), indicating that human antibodies to SA independent ligands (e.g. Rh2 and Rh4) inhibit invasion. Differential antibody inhibition of 3D7 lines with different invasion phenotypes further confirmed that variation in invasion phenotypes influences the activity of inhibitory antibodies (Figure IC and Figure 3, A and B). The proportion of samples that differentially inhibited parental 3D7 versus 3D7AEBA175 was 26% when using normal erythrocytes and 37% when using neuraminidase-treated erythrocytes with 3D7AEBA175. These combined results with W2mef and 3D7 lines clearly established that the availability of alternate pathways for erythrocyte invasion is immunologically important and a mechanism for evasion of acquired invasion-inhibitory antibodies of SA-independent invasion ligands (e.g. Rh2 and Rh4) and SA-dependent ligands (e.g. EBA175, EBA140, EBA181 and Rhl). Of those samples that differentially inhibited W2mef-wt versus W2mefAEBA175 (cultured with normal erythrocytes), 26 of 27 inhibited the parental W2mef more than W2mefAEBA175 (P<0.001; Figure 2) indicating inhibitory antibodies targeting EBA175 and other ligands of SA-dependent invasion (e.g. EBA140, EBA181 and Rh1). Overall, the mean inhibition of W2mef-wt by all samples (39.4%) was significantly greater than W2mefAEBA175 (29.4%; p<0.01) (Figure 2). When W2mefAEBA175 was cultured with neuraminidase-treated erythrocytes to inhibit any residual SA-dependent interactions, there was an increase in the difference in the mean inhibition of W2mef-wt versus W2mefAEBA175 by samples (a difference of 18.9% versus 10% using untreated erythrocytes; p<0.01; Figure 4). Antibodies from 60% of children 55 years inhibited W2mef-wt to a greater extent than W2mefAEBA175 (Figure 2B) (e.g. inhibiting EBA1 75, EBA140, EBA181 and Rh1), whereas among adults, 22% showed this pattern of inhibition (p=0.019). Similar to results from assays using W2mefAEBA175, 31% of samples inhibited W2mef-wt more than W2mefSelNm (Type A response; Figure 4C), whereas only 4% inhibited W2mefSelNm more than W2mef-wt (p<0.001). Additionally, the mean inhibition of W2mef-wt (39.4%) by all samples was greater than W2mefSelNm (20%; p<0.01) (Figure 4). Furthermore, serum samples inhibited the invasion of 3D7-wt into normal erythrocytes more than 3D7AEBA175 using neuraminidase-treated erythrocytes (Figure 5B). This indicates the presence of antibodies against the ligands of SA-dependent invasion (EBA175, EBA140, EBA181 and Rh1). In contrast to W2mef, disruption of EBA175 in 3D7 does not lead to a major switch in invasion phenotype. 19 3D7AEBA175 shows slightly greater resistance to the effect of neuraminidase-treatment of erythrocytes compared to 3D7-wt, and increased sensitivity to inhibition by chymotrypsin-treatment of erythrocytes, consistent with the loss of function of EBA1 75. Invasion-inhibitory antibodies to SA-independent invasion ligands (e.g. Rh2 and Rh4) were examined by identifying human serum samples that inhibited W2mefAEBA175 or 3D7AEBA175 more than the corresponding parental parasites. Invasion of W2mefAEBA175 or 3D7AEBA175 into neuraminidase-treated erythrocytes is dependent on ligands of the SA-independent invasion pathway (e.g. Rh2 and Rh4). Using the W2mef line, 5% of samples (Figure 2B) showed inhibition of ligands of the SA independent invasion pathway (e.g. Rh2 and Rh4) and inhibited invasion of W2mefAEBA175 into neuraminidase-treated erythrocytes more effectively than W2mef wt. Furthermore, 13% inhibited W2mefselNm more than W2mef-wt (e.g sample 436, Fig 1B). Inhibition of ligands of the SA-independent invasion pathway (e.g. Rh2 and Rh4) was more prevalent with 3D7 parasite lines than W2mef (p<0.001). A substantial number of samples inhibited 3D7AEBA175 more than 3D7-wt (18% of samples when using normal erythrocytes and 16% when using neuraminidase-treated erythrocytes; Figure 5, A and B). No children 55 years inhibited W2mefAEBA175 more than W2mef-wt (Figure 2, A and B). Furthermore, antibodies to SA-dependent (EBA175, EBA140, EBA181 and Rhi) and SA-independent invasion pathway ligands (e.g. Rh2 and Rh4) are acquired in an age dependant manner. Figure 6 shows that antibody levels to EBA175 (both 3D7 and W2mef alleles), EBA140, EBA181, Rh2 and Rh4 were positively associated with increasing age. As discussed supra the present invention is predicated on the finding that EBA proteins of Plasmodium falciparum are capable of eliciting invasion-inhibitory immune responses in humans. The Duffy-binding like (DBL) proteins include erythrocyte-binding antigen (EBA)175, EBA140 (also known as BAEBL) and EBA181 (also known as JSEBL). Another DBL gene family member, eba165 (also known as PEBL) of Plasmodium falciparum, appears not to be expressed as a functional protein. These proteins are orthologs of DBL proteins identified in Plasmodium vivax. The cysteine-rich dual DIBL domains found toward the N-terminus of EBA175 (called F1 and F2 domains) mediates 20 binding to its cognate receptor, and it is likely that similar domains in EBA140 and EBA181 also play receptor-binding roles. C-terminal of a transmembrane domain, is a cytoplasmic tail of the DBL proteins that does not appear to be directly linked to the actin-myosin motor. The structure of Plasmodium falciparum EBA175 is disclosed herein as SEQ ID NOs; 5 and 6. The F1 and F2 domains of EBA175 are at amino acids 158 to 397, and 462 to 710, respectively. The transmembrane domain of EBA175 is located at amino acids 1425 to 1442. The structure of Plasmodium falciparum EBAI81 is disclosed herein as SEQ ID NOs; 7 and 8. The F1 and F2 domains of EBA181 are at amino acids 129 to 371, and 433 to 697, respectively. The transmembrane domain of EBA181 is located at amino acids 1488 to 1510. The structure of Plasmodium falciparum EBA140 is disclosed herein as SEQ ID NOs; 9 and 10. The F1 and F2 domains of EBA140 are at amino acids 154 to 405, and 456 to 706, respectively. The transmembrane domain of EBA1 40 is located at amino acids 1134 to 1153. As discussed supre the present invention is predicated on the finding that Rh proteins of Plasmodium falciparum are capable of eliciting invasion-inhibitory immune responses in humans. The reticulocyte-binding protein (RBP) proteins were identified as homologs of rhoptry proteins in Plasmodium yoelii and Plasmodium vivax. Plasmodium vivax is a parasite of humans that preferentially invades reticulocytes, and it expresses two homologs of the Py235 family, PvRBP1 and PvRBP2. These proteins bind to reticulocytes but not normocytes (i.e. erythrocytes), suggesting that they are responsible for the host-cell preference of this species. A 500-amino-acid region that showed homology between the Py235 and PvRBP-2 protein families was used to search the Plasmodium falciparum (3D7 parasite) genome sequence databases, identifying five reticulocyte-binding protein homologue (Rh) genes containing the homologous region; Rhi (RBP1), Rh2a (RBP2a), PfRh2b (RBP2b), and Rh4 (RBP4); a fifth, Rh3 (RBP3), does not appear to be expressed as a protein. Rh2a and Rh2b have a putative signal sequence at the N terminus and a potential transmembrane domain followed by a short cytoplasmic tail at the C terminus, similar to the structures of Py235, PvRBP-1, and PvRBP-2. The structure of Plasmodium falciparum Rh2b is disclosed herein as SEQ ID NOs; 1 and 2. The structure of Plasmodium falciparum Rh2a is disclosed herein as SEQ ID NOs; 11 and 12. Analysis of Rh2a and Rh2b has identified a region showing homology to the "0045457 Spectrin repeat" domain (SUPERFAMILY Accession: SSF46966) at amino acids 1735 to 1833, and a region showing homology to the 21 "UPF0103 YJR008W C21ORF19-LIKE CEREVISIAE P47085 SACCHAROMYCES CHROMOSOME C20RF4 PA5G0009 IPF893" domain (PRODOM Accession: PD006364) at amino acids 2133 to 2259 of Rh2a and amino acids 2058 to 2184 of Rh2b. The transmembrane domain of Rh2a is located at amino acids 3066 to 3088. The transmembrane domain of Rh2b is located at amino acids 3113 to 3135. The structure of Plasmodium falciparum Rh4 is disclosed herein as SEQ ID NOs; 3 and 4. Analysis of Rh4 has identified a region showing homology to the "0044828 MTH1 187YkoF-like" domain (SUPERFAMILY Accession: SSF89957) at amino acids 1031 to 1141. The transmembrane domain of Rh4 is located at amino acids 1627 to 1649. The structure of Plasmodium falciparum Rh1 is disclosed herein as SEQ ID NOs; 13 and 14. The transmembrane domain of Rh4 is located at amino acids 2898 to 2920. As discussed supra, enzyme treatment of red cells has allowed examination of the receptors to which the Rh and DBL proteins bind. In particular, DBL proteins bind erythrocytes in a sialic-acid-dependent manner as neuraminidase treatment of the host cell ablates binding. EBA175 and EBA140 bind to glycophorin A and C, respectively, and while sialic acid on these receptors is essential for binding, the protein backbone is also important for specificity. EBA181 and Rh1 also bind to glycosylated erythrocyte receptors, although their identity is currently unknown. In contrast, there is no evidence that Rh2a directly binds to erythrocytes. Rh2b and Rh4 have been implicated in merozoite invasion since disruption of the corresponding gene causes these parasites to change the receptor they use for invasion on enzyme-treated red cells. Antibodies that inhibit the growth of blood stage Plasmodium falciparum parasites in vitro are found in the sera of some, but not all, individuals living in malaria endemic regions (Marsh, et al (1989) Trans. R. Soc. Trop. Med. Hyg. 83:293, Brown, et al (1982) Nature. 297:591, Brown, et al. (1983) Infect. Immun. 39:1228, Bouharoun-Tayoun, et al. (1990) J. Exp. Med. 172:1633-1641). Inhibitory antibodies are likely to contribute to the clinical immunity observed in highly exposed individuals but their overall significance to protection remains unclear. Inhibitory antibodies may act in a manner that is independent of complement or other cellular mediators and function by preventing invasion of erythrocytes by the extracellular merozoite form of the parasite. A role for invasion-inhibitory antibodies in immunity to malaria has not been previously demonstrated. One practical reason for this is that there has been a lack of robust in 22 vitro inhibition assays that account for confounding factors present in serum that can cause non-specific inhibitory, or indeed growth-promoting, effects. Although in vitro inhibition assays have been used for some time to assess antibodies to Plasmodium falciparum merozoite antigens and have provided a useful guide as to the inhibitory activity of a particular serum or monoclonal antibody, the problems associated with accurate quantification of this activity, especially in whole serum, are well recognized in the field. This problem has now been overcome with the development of an assay that allows accurate quantification of molecule-specific inhibitory antibodies in whole serum. This assay involves a comparison of the inhibitory effect of a given serum on two isogenic parasite lines that differ only in the gene (or genes) of interest. Using this assay, the invasion-inhibitory activity of antibodies present in serum obtained from adults that are clinically immune to malaria may be determined. The present invention requires that the immunogenic molecule is capable of inducing an invasion-inhibitory immune response in the subject. As used herein, the term "invasion inhibitory" is intended to include the complete prevention of invasion of an invasion competent erythrocyte for the life-span of the subject. The term is also intended to include the partial prevention of invasion, as measured by for example, the proportion of a population of invasion-competent erythrocytes that are invaded, the number of attempts by which it is necessary for a given parasite to invade an erythrocyte, the time taken for a parasite to invade an erythrocyte, and the number of parasites required to ensure that a single erythrocyte is invaded. The complete or partial inhibition of invasion may be for a short period of time (such as several hours), an intermediate period of time (such as weeks, or months), or a protracted period of time (such as years or decades). The inhibition of invasion may be measured in vivo or in vitro. For the avoidance of doubt, the term "invasion" is intended to include the entire invasion process such that the complete parasite enters the cytoplasm, and is completely encircled by the cytoplasm. The term also includes components of the entire invasion process such as the binding of the parasite to the surface of the erythrocyte, the reorientation of the apical end of the parasite to contact the erythrocyte surface, entry of the parasite into a parasitophorous vacuole, release of protein from apical organelles, and the shedding of parasite surface protein by proteases. Furthermore, the term "invasion" includes both SA dependent and SA-independent invasion pathways. Immune 23 responses to these pathways are known as type-A and type-B inhibitory responses, respectively. The present invention includes immunogenic molecules capable of eliciting an immune response against a wild-type strain of P falciparum, or any of the following strains: 3D7, W2MEF, GHANA1, VI_S, RO-33, PREICH, HB3, SANTALUCIA, 7G8, SENEGAL3404, FCC-2, K1, RO-33, D6, DD2, or D10, or any other known or newly isolated strain of Plasmodium falciparum. An isolate or strain of Plasmodium falciparum is a sample of parasites taken from an infected individual on a unique occasion. Typically, an isolate is uncloned, and may therefore contain more than one genetically distinct parasite clone. A Plasmodium falciparum line is a lineage of parasites derived from a single isolate, not necessarily cloned, which have some common phenotype (e.g. drug-resistance, ability to invade enzyme treated red cells etc.). A Plasmodium falciparum clone is the progeny of a single parasite, normally obtained by manipulation or serial dilution of uncloned parasites and then maintained in the laboratory. All the members of a clone have been classically defined as genetically identical, but this is not necessarily the case, since members of the clone may undergo mutations, chromosomal rearrangements, etc, which may survive in in vitro culture conditions. While the immunogenic molecule will typically include amino acid sequences found in an Rh protein of the strain for which protection is desired, this is not necessarily required. Typically, the immunogenic molecule is a polypeptide, or includes a polypeptide region. As used herein, the term "polypeptide" refers to amino acid polymers of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. Polypeptides can occur as single chains or associated chains. In one form of the immunogenic molecule, the EBA molecule is EBA175 (PlasmoDB Accession No: MAL7P1.176), and the contiguous amino acid sequence is found in SEQ 24 ID NO: 5: MKCNISIYFFASFFVLYFAKARNEYDIKENEKFLDVYKEKFNELDKKKYGNVQKTDKKIF TFIENKLDILNNSKFNKRWKSYGTPDNIDKNMSLINKHNNEEMFNNNYQSFLSTSSLIKQ NKYVPINAVRVSRILSFLDSRINNGRNTSSNNEVLSNCREKRKGMKWDCKKKNDRSNYVC IPDRRIQLCIVNLSIIKTYTKETMKDHFIEASKKESQLLLKKNDNKYNSKFCNDLKNSFL DYGHLAMGNDMDFGGYSTKAENKIQEVFKGAHGEISEHKIKNFRKKWWNEFREKLWEAML SEHKNNINNCKNIPQEELQITQWIKEWHGEFLLERDNRSKLPKSKCKNNTLYEACEKECI DPCMKYRDWIIRSKFEWHTLSKEYETQKVPKENAENYLIKISENKNDAKVSLLLNNCDAE YSKYCDCKHTTTLVKSVLNGNDNT IKEKREHIDLDDFSKFGCDKNSVDTNTKVWECKKPY KLSTKDVCVPPRRQELCLGNIDRIYDKNLLMIKEHILAIlAIYESRILKRKYKNKDDKEVC KIINKTFADIRDIIGGTDYWNDLSNRKLVGKINTNSNYVHRNKQNDKLFRDEWWKVIKKD VWNVISWVFKDKTVCKEDDIENIPQFFRWFSEWGDDYCQDKTKMIETLKVECKEKPCEDD NCKRKCNSYKEWISKKKEEYNKQAKQYQEYQKGNNYKMYSEFKSIKPEVYLKKYSEKCSN LNFEDEFKEELHSDYKNKCTMCPEVKDVPISIIRNNEQTSQEAVPEESTEIAHRTETRTD ERKNQEPANKDLKNPQQSVGENGTKDLLQEDLGGSRSEDEVTQEFGVNHGIPKGEDQTLG KSDAIPNIGEPETGISTTEESRHEEGHNKQALSTSVDEPELSDTLQLHEDTKENDKLPLE SSTITSPTESGSSDTEETPSISEGPKGNEQKKRDDDSLSKISVSPENSRPETDAKDTSNL LKLKGDVDISMPKAVIGSSPNDNINVTEQGDNISGVNSKPLSDDVRPDKNHEEVKEHTSN SDNVQQSGGIVNMNVEKELKDTLENPSSSLDEGKAHEELSEPNLSSDQDMSNTPGPLDNT SEETTERISNNEYKVNEREGERTLTEYEDIVLKSHMNRESDDGELYDENSDLSTVNDES EDAEAKMKGNDTSEMSHNSSQHIESDQQKNDMKTVGDLGTTHVQNEISVPVTGEIDEKLR ESKESKIHKAEEERLSHTDIHKINPEDRNSNTLHLKDIRNEENERHLTNQNINISQERDL QKHGFHTMNNLHGDGVSERSQINHSHHGNRQDRGGNSGNVLNMRSNNNNFNNIPSRYNLY DKKLDLDLYENRNDSTTKELIKKLAEINKCENEISVKYCDHMIHEEIPLKTCTKEKTRNL CCAVSDYCMSYFTYDSEEYYNCTKREFDDPSYTCFRKEAFSSMPYYAGAGVLFIILVILG ASQAKYQRLEKINKNKIEKNVN The nucleotide sequence of EBA181 (PlasmoDB Accession No: PFA0125c) is given below (SEQ ID NO: 7) MKGKMNMCLFFFYSILYVVLCTYVLGISEEYLKERPQGLNVETNNNNNNNNNNNSNSNDA MSFVNEVIRFIENEKDDKEDKKVKIISRPVENTLHRYPVSSFLNIKKYGRKGEYLNRNSF VQRSYIRGCKGKRSTHTWICENKGNNN ICIPDRRVQLCITALQDLKNSGSETTDRKLLRD KVFDSAMYETDLLWNKYGFRGFDDFCDDVKNSYLDYKDVIFGTDLDKNNISKLVEESLKR FFKKDSSVLNPTAWWRRYGTRLWKTMIQPYAHLGCRKPDENEPQINRWILEWGKYNCRLM KEKEKLLTGECSVNRKKSDCSTGCNNECYTYRSL INRQRYEVS ILGKKYIKVVRYTIFRR KIVQPDNALDFLKLNCSECKDIDFKPFFEFEYGKYEEKCMCQSYIDLKIQFKNNDICSFN AQTDTVSSDKRFCLEKKEFKPWKCDKNS FETVHHKGVCVSPRRQGFCLGNLNYLLNDDIY NVHNSQLLIE I IMASKQEGKLLWKKHGT ILDNQNACKYINDSYVDYKDIVIGNDLWNDNN SIKVQNNLNLIFERNFGYKVGRNKLFKTIKELKNVWWILNRNKVWESMRCGIDEVDQRRK TCERIDELENMPQFFRWFSQWAHFFCKEKEYWELKLNDKCTGNNGKSLCQDKTCQNVCTN MNYWTYTRKLAYEIQSVKYDKDRKLFSLAKDKNVTTFLKENAKNCSNIDFTKIFDQLDKL FKERCSCMDTQVLEVKNKEMLSIDSNSEDATDISEKNGEEELYVNHNSVSVASGNKEIEK SKDEKQPEKEAKQTNGTLTVRTDKDSDRNKGKDTATDTKNSPENLKVQEHGTNGET IKEE PPKLPESSETLQSQEQLEAEAQKQKQEEEPKKKQEEEPKKKQEEEQKREQEQKQEQEEEE QKQEEEQQIQDQSQSGLDQSSKVGVASEQNE ISSGQEQNVKSSS PEVVPQETTSENGSSQ DTKISSTEPNENSVVDRATDSMNLDPEKVHNENMSDPNTNTEPDASLKDDKKEVDDAKKE LQSTVSRIESNEQDVQSTPPEDTPTVEGKVGDKAEMLTSPHATDNSESESGLNPTDDIKT 25 TDGVVKEQEILGGGESATETSKSNLEKPKDVEPSHEISEPVLSGTTGKEESELLKSKSIE TKGETDPRSNDQEDATDDVVENSRDDNNSLSNSVDNQSNVLNREDPIASETEVVSEPEDS SRIITTEVPSTTVKPPDEKRSEEVGEKEAKEIKVEPVVPRAIGEPMENSVSVQSPPNVED VEKETLISENNGLHNDTHRGNISEKDLIDIHLLRNEAGSTILDDSRRNGEMTEGSESDVG ELQEHNFSTQQKDEKDFDQIASDREKEEIQKLLNIGHEEDEDVLKMDRTEDSMSDGVNSH LYYNNLSSEEKMEQYNNRDASKDREEI LNRSNTNTCSNEHSLKYCQYNERNKDLLETCSE DKRLHLCCEISDYCLKFFNFKSIEYFDCTQKEFDDFTYNCFRKQRFTSMHYIAGGGITAL LLFILGSASYRKNLDDEKGFYDSNLNDSAFEYNNNKYNKLPYMFDQQINVVNSDLYSEGI YDDTTTF The sequence of EBA 140 (PlasmoDB Accession No: MAL13P1.60) is provided below (SEQ ID NO: 9) MKGYFNIYFLIPLIFLYNVIRINESIIGRTLYNRQDESSDISRVNSPELNNNHKTNIYDS DYEDVNNKLINSFVENKSVKKKRSLSFINNKTKSYDIIPPSYSYRNDKFNSLSENEDNSG NTNSNNFANTSEISIGKDNKQYTFIQKRTHLFACGIKRKSIKWICRENSEKITVCVPDRK IQLCIANFLNSRLETMEKFKEIFLISVNTEAKLLYNKNEGKDPSIFCNELRNSFSDFRNS FIGDDMDFGGNTDRVKGYINKKFSDYYKEKNVEKLNNIKKEWWEKNKANLWNHMIVNHKG NISKECAIIPAEEPQINLWIKEWNENFLMEKKRLFLNIKDKCVENKKYEACFGGCRLPCS SYTSFMKKSKTQMEVLTNLYKKKNSGVDKNNFLNDLFKKNNKNDLDDFFKNEKEYDDLCD CRYTATIIKSFLNGPAKNDVDIASQINVNDLRGFGCNYKSNNEKSWNCTGTFTNKFPGTC EPPRRQTLCLGRTYLLHRGHEEDYKEHLLGASIYEAQLLKYKYKEKDENALCSIIQNSYA DLADIIKGSDIIKDYYGKKMEENLNKVNKDKKRNEESLKIFREKWWDENKENVWKVMSAV LKNKETCKDYDKFQKIPQFLRWFKEWGDDFCEKRKEKIYSFESFKVECKKKDCDENTCKN KCSEYKKWIDLKKSEYEKQVDKYTKDKNKKMYDNIDEVKNKEANVYLKEKSKECKDVNFD DKIFNESPNEYEDMCKKCDEIKYLNEIKYPKTKHDIYDIDTFSDTFGDGTPISINANINE QQSGKDTSNTGNSETSDSPVSHEPESDAAINVEKLSGDESSSETRGILDINDPSVTNNVN EVHDASNTQGSVSNTSDITNGHSESSLNRTTNAQDIKIGRSGNEQSDNQENSSHSSDNSG SLTIGQVPSEDNTQNTYDSQNPHRDTPNALASLPSDDKINEIEGFDSSRDSENGRGDTTS NTHDVRRTNIVSERRVNSHDFIRNGMANNNAHHQYITQIENNGIIRGQEESAGNSVNYKD NPKRSNFSSENDHKKNIQEYNSRDTKRVREEIIKLSKQNKCNNEYSMEYCTYSDERNSSP GPCSREERKKLCCQISDYCLKYFNFYSIEYYNCIKSEIKSPEYKCFKSEGQSSIPYFAAG GILVVIVLLLSSASRMGKSNEEYDIGESNIEATFEENNYLNKLSRIFNQEVQETNISDYS EYNYNEKNMY In one form of the composition, where the EBA is EBA175 the contiguous amino acid sequence is found in SEQ ID NO: 5. The scope of the invention includes mutations of the sequence described in SEQ ID NO: 5. Preferably, mutations for EBA175 include N at amino acid 157 replaced with S, E at amino acid 274 replaced with K, K at amino acid 279 replaced with E, K at amino acid 286 replaced with E, D at amino acid 336 replaced with Y, K at amino acid 388 replaced with N, P at amino acid 390 replaced with S, E at amino acid 403 replaced with K, K at amino acid 448 replaced with E, K at amino acid 478 replaced with N K at amino acid 481 replaced with I, N at amino acid 577 replaced with K, Q at amino acid 584 replaced with K, R at amino acid 664 replaced with S, S at 26 amino acid 768 replaced with N, E at amino acid 923 replaced with K, K at amino acid 932 replaced with E, E at aminQ acid 1058 replaced with V, or G at amino acid 1100 replaced with D. In one form of the composition, where the EBA is EBA181 the contiguous amino acid sequence is found in SEQ ID NO: 7. The scope of the invention includes mutations of the sequence described in SEQ ID NO: 7. Preferably, mutations for EBA181 include the V at amino acid 64 replaced with L, Q at amino acid 364 replaced with H, V at amino acid 363 replaced with D, R at amino acid 358 replaced with K, N at amino acid 414 replaced with I, K at amino acid 443 replaced with Q, P at amino acid 878 replaced with Q, E at amino acid 884 replaced with Q, E at amino acid 1885 replaced with K, Q at amino acid 890 replaced with E, P at amino acid 1197 replaced with L, K at amino acid 1219 replaced with N, D at amino acid 1433 replaced with Y or N, or K at amino acid 1518 replaced with E. In one form of the composition where the EBA is EBA140 the contiguous amino acid sequence is found in SEQ ID NO:9. Preferably, mutations for EBA140 include the V at amino acid 19 replaced with 1, L at amino acid 112 replaced with F, I at amino acid 185 replaced with V, N at amino acid 239 replaced with S, K at amino acid 261 replaced with T. In another form of the composition, where the contiguous amino acid sequence of the EBA protein is found in the region between the F2 domain and the transmembrane domain of the EBA protein. More particularly, the contiguous amino acid sequence may be found in the region from about residue 746 to about residue 1339 of the EBA protein. In one form of the composition, where the EBA is EBA140 the contiguous amino acid sequence is found in the region from about residue 746 to about residue 1045 of EBA1 40. Where the EBA is EBA175 the contiguous amino acid sequence is found in the region from about residue 761 to about residue 1271 of EBA1 75. Where the EBA is EBA181 the contiguous amino acid sequence is found in the region from about residue 755 to about residue 1339 of EBA181. 27 As for the EBA protein, in one form of the immunogenic molecule, the contiguous amino acid sequence of the EBA protein comprises about 5 or more amino acids. In another form, the contiguous amino acid sequence molecule comprises about 8, 10, 20, 50, or 100 amino acids. The skilled person is capable of routine experimentation designed to identify the shortest efficacious sequence, or the length of sequence that provides the greatest or most effective invasion-inhibitory response in the subject. Applicant proposes that Rh4 may be involved in invasion using the SA-independent pathway in enzyme treated red cells, and that inhibiting Rh4-mediated invasion is important in treating or preventing infection. However, recent data (Gaur et al. PNAS in press) has suggested that a region of Rh4 known as rRH4 30 (comprising amino acids 328 to 588 of Rh4) and native Rh4 bind strongly to neuraminidase treated erythrocytes. Importantly this work demonstrated that while antibodies to the region of Rh4 encoded by amino acids 328 to 588 block binding of the native protein to red cells, these antibodies fail to block invasion, leading the authors to conclude that Rh4 is inaccessible for antibody-mediated inhibition of the invasion process. The authors propose that this inaccessibility may be explained by Rh4 being released after formation of the tight junction during invasion, and consequently antibodies have no access, or the receptor may form the junction too rapidly following merozoite attachment such that interaction with the antibody is not possible. The authors conclude that Rh4 will probably not be an effective candidate in vaccine development. In contrast, the present invention provides that Rh4 is an effective target of the immune response in humans. Figure 7C shows that an 88 kDa region of Rh4 of Plasmodium falciparum strain 3D7 binds to erythrocytes (amino acids 28 to 766 of Rh4; e.g. amino acids 28 to 766 of SEQ ID NO: 3), whereas a 42kDa region of Rh4 (amino acids 853 to 1163) is unable to bind erythrocytes. This is consistent with recent work demonstrating that a region of Rh4 (rRh4 3 0 ; amino acids 328 to 588) is able to bind to enzyme treated red cells (Gaur et al. PNAS in press). However, Gaur et al demonstrate that while rRh4 30 is able to block invasion of Plasmodium falciparum strain Dd2 into neuraminidase treated red cells, rRh4 30 does not block invasion of Plasmodium falciparum strain 3D7 into neuraminidase treated red cells. Furthermore, rRh4 30 is unable to block invasion of untreated red cells, and antibodies to Rh4 fail to block red cell invasion. In contrast, the 28 present invention demonstrates that Rh proteins (including Rh4) are targets of acquired antibodies that inhibit invasion (Figure 1 B, and C, Figure 2 A and B, Figure 3 A and B, Figure 6E). In combination with the differential inhibition of parasite lines that vary in their invasion phenotype, but not genotype, suggests that members of the EBA and Rh proteins may therefore be effective candidates for vaccine development. To examine the acquisition of invasion-inhibitory antibodies observed in serum samples from children and adults resident in the Kilifi District, Kenya, in 1998 (a year that was preceded with a relatively high incidence of malaria in the region) (EXAMPLES 1 to 7) (Figures 1 to 5), recombinant Rh and EBA proteins were utilized (Figure 6). Human antibodies to EBA175 were detected (Figure 6A and B) in the serum samples used to identify invasion-inhibitory antibodies (Figures 1 to 5). In particular, antibodies recognizing the region of EBA175 between from about the F2 domain to about the transmembrane domain of EBA175 were detected and acquired in an age-dependent manner. In particular, antibodies recognizing the region of EBA175 from amino acid 760 to 1271 of EBA175 (e.g. SEQ ID NO: 5) were detected and acquired in an age dependent manner. Comparison of inhibition of 3D7 and 3D7AEBA175 allows examination of human invasion-inhibitory antibodies specifically targeting EBA175. 15% of children and 17% of adults inhibited 3D7-wt more than 3D7AEBA175 (Figure 3A), indicating individuals in the population have invasion-inhibitory antibodies against EBA175. These antibodies were responsible for up to 47% of the total inhibitory activity measured in some individuals (Figure 5), indicating that EBA175 is an important target of invasion-inhibitory antibodies. In particular, invasion-inhibitory antibodies recognized the region of EBA175 from amino acid 760 to 1271 of EBA175. To further examine the role of invasion-inhibitory antibodies to EBA175 in protection from malaria, the association of antibodies to EBA175 with time to first infection following drug treatment was examined in the same cohort of children in northern Papua New Guinea (Figure 10 A and B). In particular, antibodies recognizing the region of EBA175 between from about the F2 domain to about the transmembrane domain of EBA175 were associated with reduced risk of clinical malaria. In particular, antibodies recognizing the region of EBA175 from amino acid 760 to 1271 of EBA175 (e.g. SEQ ID NO: 5) were 29 associated with reduced risk of clinical malaria. Human antibodies to EBA181 were detected (Figure 6D) in the serum samples used to identify invasion-inhibitory antibodies (Figures 1 to 5). In particular, antibodies recognizing the region of EBA181 between from about the F2 domain to about the transmembrane domain of EBA181 were detected and acquired in an age-dependent manner. In particular, antibodies recognizing the region of EBA181 from amino acid 755 to 1339 of EBA181 (e.g. SEQ ID NO: 7) were detected and acquired in an age dependent manner. To further examine the role of invasion-inhibitory antibodies to EBA181 in protection from malaria, the association of antibodies to EBA181 with time to first infection following drug treatment was examined in the same cohort of children in northern Papua New Guinea (Figure 10 A and C). In particular, antibodies recognizing the region of EBA181 between from about the F2 domain to about the transmembrane domain of EBA181 were associated with reduced risk of clinical malaria. In particular, antibodies recognizing the region of EBA181 from amino acid 755 to 1339 of EBA181 (e.g. SEQ ID NO: 7) were associated with reduced risk of clinical malaria. Human antibodies to EBA140 were detected (Figure 6C) in the serum samples used to identify invasion-inhibitory antibodies (Figures 1 to 5). In particular, antibodies recognizing the region of EBA140 between from about the F2 domain to about the transmembrane domain of EBA140 were detected and acquired in an age-dependent manner. In particular, antibodies recognizing the region of EBA140 from amino acid 746 to 1045 of EBA140 (e.g. SEQ ID NO: 9) were detected and acquired in an age dependent manner. To further examine the role of invasion-inhibitory antibodies to EBA140 in protection from malaria, the association of antibodies to EBA140 with time to first infection following drug treatment was examined in the same cohort of children in northern Papua New Guinea (Figure 10 A and D). In particular, antibodies recognizing the region of EBA140 between from about the F2 domain to about the transmembrane domain of EBA140 were associated with reduced risk of clinical malaria. In particular, antibodies recognizing the region of EBA140 from amino acid 746 to 1045 of EBA140 (e.g. SEQ ID NO: 9) were 30 associated with reduced risk of clinical malaria. Comparison of inhibition of 3D7 and 3D7AEBA140 allows examination of human invasion-inhibitory antibodies specifically targeting EBA140. Serum samples from children and adults inhibited 3D7-wt more than 3D7AEBA140 (Figure 11), indicating individuals in the population have invasion-inhibitory antibodies against EBA140, indicating that EBA175 is an important target of invasion-inhibitory antibodies. In particular, invasion-inhibitory antibodies recognized the region of EBA140 from amino acid 746 to 1045 of EBA140. Human antibodies to Rh2 were detected (Figure 6F) in the serum samples used to identify invasion-inhibitory antibodies (Figures 1 to 5). In particular, antibodies recognizing the region of Rh2 between about 31 amino acids N-terminal of the Prodom -PDO06364 homology region to about the transmembrane domain of Rh2 were detected and acquired in an age-dependent manner. In particular, antibodies recognizing the region of Rh2 from amino acid 2027 to 2533 of Rh2 (e.g. SEQ ID NO: 1) were detected and acquired in an age-dependent manner. Also, antibodies recognizing the region of Rh2 from amino acid 2098 to 2597 of Rh2 were detected and acquired in an age dependent manner (Figure 8A). Also, antibodies recognizing the region of Rh2 from amino acid 2616 to 3115 of Rh2 were detected and acquired in an age-dependent manner (Figure 8B). To further examine the role of invasion-inhibitory antibodies to Rh2 in protection from malaria, the association of antibodies to Rh2 with time to first infection following drug treatment was examined in children in northern Papua New Guinea (Figure 9). In particular, human antibodies recognizing Rh and EBA proteins were associated with reduced risk of clinical malaria. In particular, antibodies recognizing the region of Rh2 between about 31 amino acids N-terminal of the Prodom PD006364 homology region to about the transmembrane domain of Rh2 were associated with reduced risk of clinical malaria. In particular, antibodies recognizing the region of Rh2 from amino acid 2027 to 3115 of Rh2 (e.g. SEQ ID NO: 1) were associated with reduced risk of clinical malaria (Figure 9). In particular, antibodies recognizing the region of Rh2 from amino acid 2098 to 2597 of Rh2 were associated with reduced risk of clinical malaria (Figure 9A). Also, antibodies recognizing the region of Rh2 from amino acid 2616 to 3115 of Rh2 were 31 associated with reduced risk of clinical malaria (Figure 9B). Human antibodies to Rh4 were detected (Figure 6E) in the serum samples used to identify invasion-inhibitory antibodies (Figures 1 to 5). In particular, antibodies recognizing the region of Rh4 between from about the MTH1187/YkoF-like superfamily domain to about the transmembrane domain of Rh4 were detected and acquired in an age-dependent manner. In particular, antibodies recognizing the region of Rh4 from amino acid 1160 to 1370 of Rh4 (e.g. SEQ ID NO: 3) were detected and acquired in an age-dependent manner. To further examine the role of invasion-inhibitory antibodies to Rh4 in protection from malaria, the association of antibodies to Rh4 with time to first infection following drug treatment was examined in the same cohort of children in northern Papua New Guinea. In particular-, antibodies recognizing the region of Rh4 from about the MTH1187/YkoF like superfamily domain to about the transmembrane domain of Rh4 were associated with reduced risk of clinical malaria. In particular, antibodies recognizing the region of Rh4 from amino acid 1160 to 1370 of Rh4 (e.g. SEQ ID NO: 3) were associated with reduced risk of clinical malaria. In one form of the immunogenic molecule, the contiguous amino acid sequence comprises about 5 or more amino acids. In another form, the contiguous amino acid sequence molecule comprises about 8, 10, 20, 50, or 100 amino acids. The skilled person is capable of routine experimentation designed to identify the shortest efficacious sequence, or the length of sequence that provides the greatest or most effective invasion-inhibitory response in the subject. Similarly, the skilled person understands that strict compliance with any amino acid sequence disclosed herein is not necessarily required, and he or she could decide by a matter of routine whether any further mutation is deleterious or preferred. Thus, the immunogenic molecules of the present invention include sequences having 50% or more identity (e.g. 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or more) to any protein disclosed herein. The immunogenic molecules also include variants (e.g. allelic variants, homologs, orthologs, paralogs, mutants, etc.). The molecules may lack one or more amino acids (e.g. 1, 2, 3, 4, 5, 6, 7, 32 8, 9, 10, 15, 20, 25 or more) from the C-terminus and/or one or more amino acids (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more) from the N-terminus. Expression of the immunogenic molecules of the invention may take place in Plasmodium, however other heterologous hosts may be utilised. The heterologous host may be prokaryotic (e.g. a bacterium) or eukaryotic. It is preferably E. coli, but other suitable hosts include Bacillus subtilis, Vibrio cholerae, Salmonella typhi, Salmonella typhimurium, Neisseria lactamica, Neisseria cinerea, Mycobacteria (e.g. M.tuberculosis), yeasts, etc. The immunogenic molecules of the present invention may be present in the composition as individual separate polypeptides. Generally, the recombinant fusion proteins of the present invention are prepared as a GST-fusion protein and/or a His tagged fusion protein. Polypeptides of the invention can be prepared by various means (e.g. recombinant expression, purification from cell culture, chemical synthesis, etc.) and in various forms (e.g. native, fusions, non-glycosylated, lipidated, etc.). They are preferably prepared in substantially pure form (i.e. substantially free from other Plasmodial or host cell proteins). While the immunogenic molecule may comprise a single antigenic region, by the use of well-known recombinant DNA methods, more than one antigenic region may be included in a single immunogenic molecule. At least two (i.e. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) antigens can be expressed as a single polypeptide chain (a 'hybrid' polypeptide). Hybrid polypeptides offer two principal advantages: first, a polypeptide that may be unstable or poorly expressed on its own can be assisted by adding a suitable hybrid partner that overcomes the problem; second, commercial manufacture is simplified as only one expression and purification need be employed in order to produce two polypeptides which are both antigenically useful. Hybrid polypeptides can be represented by the formula NH2A-(-X-L-)n-B-COOH, wherein: X is an amino acid sequence of a Plasmodium falciparum antigen as defined herein; L is an optional linker amino acid sequence; A is an optional N-terminal amino acid sequence; B is an optional C-terminal amino acid sequence; and n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. 33 If a -X- moiety has a leader peptide sequence in its wild-type form, this may be included or omitted in the hybrid protein. In some embodiments, leader peptides (if present) will be deleted except for that of the -X- moiety located at the N-terminus of the hybrid protein i.e. a leader peptide of Xi will be retained, but the leader peptides of X 2 ... X, will be omitted. This is equivalent to deleting all leader peptides and using the leader peptide of X 1 as moiety -A-. For each n instances of (-X-L-), linker amino acid sequence -L- may be present or absent. For instance, when n=2 the hybrid may be NHrX-L-XrLrCOOH, NHrXr.Xr

COOH

5 NHrXi-Li-XrCOOH, NH 2 -X1-X2-L2-COOH, etc. Linker amino acid sequence(s) -L- will typically be short (e.g. 20 or fewer amino acids i.e. 19, 18, 17,16, 15, 14, 13,12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1). Examples comprise short peptide sequences which facilitate cloning, poly-glycine linkers (i.e. comprising Glyn where n = 2, 3, 4, 5, 6, 7, 8, 9, 10 or more), and histidine tags (i.e. His, where n = 3, 4, 5, 6, 7, 8, 9, 10 or more). Other suitable linker amino acid sequences will be apparent to those skilled in the art. A useful linker is GSGGGG, with the Gly-Ser dipeptide being formed from a BamHl restriction site, thus aiding cloning and manipulation, and the (Gly) 4 tetrapeptide being a typical poly-glycine linker. The same variants apply to (-Y-L-). Therefore, for each m instances of (-Y-L-), linker amino acid sequence -L- may be present or absent. -A- is an optional N-terminal amino acid sequence. This will typically be short (e.g. 40 or fewer amino acids i.e. 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1). Examples include leader sequences to direct protein trafficking, or short peptide sequences which facilitate cloning or purification (e.g. histidine tags i.e. Hisr where n = 3, 4, 5, 6, 7, 8, 9, 10 or more). Other suitable N-terminal amino acid sequences will be apparent to those skilled in the art. If X 1 lacks its own N-terminus methionine, -A- is preferably an oligopeptide (e.g. with 1, 2, 3, 4, 5, 6, 7 or 8 amino acids) which provides an N-terminus methionine. -B- is an optional C-terminal amino acid sequence. This will typically be short (e.g. 40 or fewer amino acids i.e. 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1). Examples 34 include sequences to direct protein trafficking, short peptide sequences which facilitate cloning or purification (e.g. comprising histidine tags i.e. His,, where n = 3, 4, 5, 6, 7, 8, 9, 10 or more), or sequences which enhance protein stability. Other suitable C-terminal amino acid sequences will be apparent to those skilled in the art. Most preferably, n is 2 or 3. The invention provides a process for producing an immunogenic molecule of the invention, comprising the step of synthesising at least part of the immunogenic molecule by chemical means. Polypeptides used with the invention can be prepared by various means (e.g. recombinant expression, purification from cell culture, chemical synthesis, etc.). Recombinantly-expressed proteins are preferred, particularly for hybrid polypeptides. Polypeptides used with the invention are preferably provided in purified or substantially purified form i.e. substantially free from other polypeptides (e.g. free from naturally occurring polypeptides), particularly from other Plasmodium or host cell polypeptides, and are generally at least about 50% pure (by weight), and usually at least about 90% pure i.e. less than about 50%, and more preferably less than about 10% (e.g. 5%) of a composition is made up of other expressed polypeptides. Thus the antigens in the compositions are separated from the whole organism With which the molecule is expressed. The present invention provides compositions comprising an immunogenic molecule as described herein. Compositions of the invention can be combined with pharmaceutically acceptable excipient. Such excipients include any excipient that does not itself induce the production of antibodies harmful to the individual receiving the composition. Suitable carriers are typically large, slowly metabolised macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, sucrose, trehalose, lactose, and lipid aggregates (such as oil droplets or liposomes). Such carriers are well known to those of ordinary skill in the art. The vaccines may also contain diluents, such as water, saline, glycerol, etc. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present. Sterile pyrogen-free, phosphate-buffered physiologic saline 35 is a typical carrier. The pH of the composition is preferably between 6 and 8, preferably about 7. The pH may be maintained by the use of a buffer. A phosphate buffer is typical. The composition may be sterile and/or pyrogen-free. The composition may be isotonic with respect to humans. Compositions may include sodium saits (e.g. sodium chloride) to give tonicity. A concentration of 10+/-2 mg/ml NaCl is typical. Compositions may also comprise a detergent e.g. a Tween (polysorbate), such as Tween 80. Detergents are generally present at low levels e.g. <0.01%. Compositions may comprise a sugar alcohol (e.g. mannitol) or a disaccharide (e.g. sucrose or trehalose) e.g. at around 15-30 mg/mI (e.g. 25 mg/ml), particularly if they are to be lyophilised or if they include material which has been reconstituted from lyophilised material. The pH of a composition for lyophilisation may be adjusted to around 6.1 prior to lyophilisation. The composition may further comprise an antimalarial that is useful for the treatment of Plasmodial infection. Preferred antimalarials for use in the compositions include the chloroquine phosphate, proguanil, primaquine, doxycycline; mefloquine, clindamycin, halofantrine, quinine sulphate, quinine dihydrochloride, gluconate, primaquine phosphate and sulfadoxine. The compositions of the invention may also comprise one or more immunoregulatory agents. Preferably, one or more of the immunoregulatory agents include(s) an adjuvant. The adjuvant may be selected from one or more of the group consisting of a THI adjuvant and TH2 adjuvant, further discussed below. Adjuvants which may be used in compositions of the invention include, but are not limited to those described in the following passages. Mineral containing compositions suitable for use as adjuvants in the invention include mineral salts, such as aluminium salts and calcium salts. The invention includes mineral salts such as hydroxides (e.g. oxyhydroxides), phosphates (e.g. hydroxyphosphates, orthophosphates), sulphates, etc. (e.g. see chapters 8 & 9 of Powell & Newman (eds.) 36 Vaccine Design (1995) Plenum), or mixtures of different mineral compounds, with the compounds taking any suitable form (e.g. gel, crystalline, amorphous, etc.), and with adsorption being preferred. The mineral containing compositions may also be formulated as a particle of metal salt (WOOO/23105). A typical aluminium phosphate adjuvant is amorphous aluminium hydroxyphosphate with PO4/Al molar ratio between 0.84 and 0.92, included at 0.6 mg A1 3 */ml. Adsorption with a low dose of aluminium phosphate may be used e.g. between 50 and 100 pg Al** per conjugate per dose. Where an aluminium phosphate it used and it is desired not to adsorb an antigen to the adjuvant, this is favoured by including free phosphate ions in solution (e.g. by the use of a phosphate buffer). Oil emulsion compositions suitable for use as adjuvants in the invention include oil-in water emulsions and water-in-oil emulsions. A submicron oil-in-water emulsion may include squalene, Tween 80, and Span 85 e.g. with a composition by volume of about 5% squalene, about 0.5% polysorbate 80 and about 0.5% Span 85 (in weight terms, 4.3% squalene, 0.5% polysorbate 80 and 0.48% Span 85), known as 'MF595' (57-59 chapter 10 of Powell & Newman (eds.) Vaccine Design (1995) Plenum; chapter 12 of O'Hagen (ed.) Vaccine Adjuvants: Preparation Methods and Research Protocols (Volume 42 of Methods in Molecular Medicine series)). The MF59 emulsion advantageously includes citrate ions e.g. 10 mM sodium citrate buffer. An emulsion of squalene, a tocopherol, and Tween 80 can be used. The emulsion may include phosphate buffered saline. It may also include Span 85 (e.g. at 1%) and/or lecithin. These emulsions may have from 2 to 10% squalene, from 2 to 10% tocopherol and from 0.3 to 3% Tween 80, and the weight ratio of squalene tocopherol is preferably <1 as this provides a more stable emulsion. One such emulsion can be made by dissolving Tween 80 in PBS to give a 2% solution, then mixing 90ml of this solution with a mixture of (5 g of DL-a-tocopherol and 5ml squalene), then microfluidising the mixture. The resulting emulsion may have submicron oil droplets e.g. with an average diameter of between 100 and 250nm, preferably about 180nm. 37 An emulsion of squalene, a tocopherol, and a Triton detergent (e.g. Triton X-100) can be used. An emulsion of squalane, polysorbate 80 and poloxamer 401 ("PluronicTM L 121") can be used. The emulsion can be formulated in phosphate buffered saline, pH 7.4. This emulsion is a useful delivery vehicle for muramyl dipeptides, and has been used with threonyl-MDP in the "SAF-1" adjuvant, (0.05-1% Thr-MDP, 5% squalane, 2.5% Pluronic L121 and 0.2% polysorbate 80). It can also be used without the Thr-MDP, as in the "AF" adjuvant (Hariharan et al. (1995) Cancer Res 55:3486-9) (5% squalane, 1.25% Pluronic L121 and 0.2% polysorbate 80). Microfluidisation is preferred. Complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA) may also be used. Saponin formulations may also be used as adjuvants in the invention (see for example Chapter 22 of Powell & Newman (eds.) Vaccine Design (1995) Plenum). Saponins are a heterologous group of sterol glycosides and triterpenoid glycosides that are found in the bark, leaves, stems, roots and even flowers of a wide range of plant species. Saponin from the bark of the Quillaia saponaria Molina tree have been widely studied as adjuvants. Saponin can also be commercially obtained from Smilax ornata (sarsaprilla), Gypsophilla paniculata (brides veil), and Saponaria officianalis (soap root). Saponin adjuvant formulations include purified formulations, such as QS21, as well as lipid formulations, such as ISCOMs. QS21 is marketed as StimulonTh. Saponin compositions have been purified using HPLC and RP-HPLC. Specific purified fractions using these techniques have been identified, including QS7, QS 17, QS 8, QS21, QH-A, QH-B and QH-C. Preferably, the saponin is QS21. A method of production of QS21 is disclosed in ref. 63. Saponin formulations may also comprise a sterol, such as cholesterol (WO96/33739). As discussed supra, combinations of saponins and cholesterols can be used to form unique particles called immunostimulating complexs (ISCOMs) (see for example Chapter 23 of Powell & Newman (eds.) Vaccine Design (1995) Plenum). ISCOMs typically also include a phospholipid such as phosphatidylethanolamine or 38 phosphatidylcholine. Any known saponin can be used in ISCOMs. Preferably, the ISCOM includes one or more of QuilA, QHA and QHC. ISCOMs are further described in W096/33739, EP-A-01 09942, W096111711). Optionally, the ISCOMS may be devoid of additional detergent WO00107621. A review of the development of saponin based adjuvants can be found in Barr et al. (1998) Advanced Drug Delivery Reviews 32:247-271 and Sjolanderet et al. (1998) Advanced Drug Delivery Reviews 32:321-338. Virosomes and virus-like particles (VLPs) can also be used as adjuvants in the invention. These structures generally contain one or more proteins from a virus optionally combined or formulated with a phospholipid. They are generally non-pathogenic, non replicating and generally do not contain any of the native viral genome. The viral proteins may be recombinantly produced or isolated from whole viruses. These viral proteins suitable for use in virosomes or VLPs include proteins derived from influenza virus (such as HA or NA), Hepatitis B virus (such as core or capsid proteins), Hepatitis E virus, measles virus, Sindbis virus, Rotavirus, Foot-and-Mouth Disease virus, Retrovirus, Norwalk virus, human Papilloma virus, HIV, RNA-phages, Qp-phage (such as coat proteins), GA-phage, fr-phage, AP205 phage, and Ty (such as retrotransposon Ty protein pi). VLPs are discussed further in (Niikura et al. (2002) Virology 293:273-280, Lenz et al. (2001) J Immunol 166:5346-5355, Pinto et al. (2003) J Infect Dis 188:327 338, Gerber et al. (2001) Virol 75:4752-4760, W003/024480 and W003/024481). Virosomes are discussed further in, for example, Gluck et al. (2002) Vaccine 20:B10 B1 6. Adjuvants suitable for use in the invention include bacterial or microbial derivatives such as non-toxic derivatives of enterobacterial lipopolysaccharide (LPS), Lipid A derivatives, immunostiinulatory oligonucleotides and ADP-ribosylating toxins and detoxified derivatives thereof. Non-toxic derivatives of LPS include monophosphoryl lipid A (MPL) and 3-0-deacylated MPL (3dMPL). 3dMPL is a mixture of 3 de-O-acylated monophosphoryl lipid A with 4, 5 or 6 acylated chains. A preferred "small particle" form of 3 De-O-acylated monophosphoryl lipid A is disclosed in ref. 77. Such "small particles" of 3dMPL are small 39 enough to be sterile filtered through a 0.22 pm membrane (EP-A-0689454v). Other non toxic LPS derivatives include monophosphoryl lipid A mimics, such as aminoalkyl glucosamine de phosphate derivatives e.g. RC-529 (Johnson et al (1999) Bioorg Med Chem Left 9:2273-2278, Evans et al. (2003) Expert Rev Vaccines 2:219-229). Lipid A derivatives include derivatives of lipid A from Escherichia coli such as OM-174. OM- 174 is described for example in Meraldi et al. (2003) Vaccine 21:2485-2491, Pajak et al. (2003) Vaccine 21:836-842. Immunostimulatory oligonucleotides suitable for use as adjuvants in the invention include nucleotide sequences containing a CpG motif (a dinucleotide sequence containing an unmethylated cytosine linked by a phosphate bond to a guanosine). Double-stranded RNAs and oligonucleotides containing palindromic or poly(dG) sequences have also been shown to be immunostimulatory. The CpG's can include nucleotide modifications/analogs such as phosphorothioate modifications and can be double-stranded or single-stranded. Kandimalla et al (2003) Nucleic Acids Research 31: 2393-2400, W002/26757 and W099/62923 disclose possible analog substitutions e.g. replacement of guanosine with 2'-deoxy-7 deazaguanosine. The adjuvant effect of CpG oligonucleotides is further discussed in Krieg (2003) Nature Medicine -9:831-835, McCluskie et al. (2002) FEMS Immunology and Medical Microbiology 32:179-185, W098/40100, US patent 6,207,646, US patent 6,239,116 and US patent 6,429,199. The CpG sequence may be directed to TLR9, such as the motif GTCGTT or TTCGTT (Kandimalla et at. (2003) Biochemical Society Transactions 31 (part 3):654-658). The CpG sequence may be specific for inducing a TH1 immune response, such as a CpG-A ODN, or it may be more specific for inducing a B cell response, such a CpG-B ODN. CpG-A and CpG-B ODNs are discussed in refs. Blackwell et al. (2003) J Immunol 170:4061-4068, Krieg (2002) Trends Immunol 23:64-65. Preferably, the CpG is a CpG-A ODN. Preferably, the CpG oligonucleotide is constructed so that the 5' end is accessible for receptor recognition. Optionally, two CpG oligonucleotide sequences may be attached at 40 their 3' ends to form "immunomers". See, for example, Kandimalla et al. (2003) Biochemical Society Transactions 31 (part 3):654-658, Kandimalla et al (2003), BBRC 306:948-953, Bhagat et al. (2003) BBRC 300:853-861 and WO03/035836. Other immunostimulatory oligonucleotides include a double-stranded RNA or an oligonucleotide containing a palindromic sequence, or an oligonucleotide containing a poly(dG) sequence. Bacterial ADP-ribosylating toxins and detoxified derivatives thereof may be used as adjuvants in the invention. Preferably, the protein is derived from E.coli (E.coli heat labile enterotoxin "LT"), cholera ("CT"), or pertussis ("PT"). The use of detoxified ADP ribosylating toxins as mucosal adjuvants is described in W095/17211 and as parenteral adjuvants in W098/42375. The toxin or toxoid is preferably in the form of a holotoxin, comprising both A and B subunits. Preferably, the A subunit contains a detoxifying mutation; preferably the B subunit is not mutated. Preferably, the adjuvant is a detoxified LT mutant such as LT-K63, LT-R72, and LT-G192. The use of ADP-ribosylating toxins and detoxified derivatives thereof, particularly LT-K63 and LT-R72, as adjuvants can be found in Beignon et al. (2002) Infect Immun 70:3012-3019, Pizza et al. (2001) Vaccine 19:2534-2541, Pizza et al. (2000) Int J Med Microbiol 290:455-461, Scharton-Kersten et al. (2000) Infect Immun 68:5306-5313, Ryan et al. (1999) Infect Immun 67:6270-6280, Partidos et al. (1999) Immunol Lett 67:209-216, Peppoloni et al. (2003) Expert Rev Vaccines 2:285-293, Pine et al. (2002) J Control Release 85:263-270. Numerical reference for amino acid substitutions is preferably based on the alignments of the A and B subunits of ADP-ribosylating toxins set forth in Domenighini et al. (1995) Mol Microbiol 15:1165-1167, specifically incorporated herein by reference in its entirety. Human immunomodulators suitable for use as adjuvants in the invention include cytokines, such as interleukins (e.g. IL-15 IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, IL-17, IL-18 (W099/40936), IL-23, IL27 (Matsui M. et al. (2004) J. Virol 78: 9093) etc.) (W099/44636), interferons (e.g. interferon-y), macrophage colony stimulating factor, tumor necrosis factor and macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta (Lillard JW et al, (2003) Blood 101(3):807-14). Bioadhesives and mucoadhesives may also be used as adjuvants in the invention. 41 Suitable bioadhesives include esterified hyaluronic acid microspheres (Singh et al) (2001) JCont Release 70:267-276) or mucoadhesives such as cross-linked derivatives of poly(acrylic acid), polyvinyl alcohol, polyvinyl pyrollidone, polysaccharides and carboxymethylcellulose. Chitosan and derivatives thereof may also be used as adjuvants in the invention (WO99127960). Microparticles may also be used as adjuvants in the invention. Microparticles (i.e. a particle of -100nm to -150pm in diameter, more preferably -200nm to -30pm in diameter, and most preferably -500nm to -10pm in diameter) formed from materials that are biodegradable and non-toxic (e.g. a poly(a-hydroxy acid), a polyhydroxybutyric acid, a polyorthoester, a polyanhydride, a polycaprolactone, etc.), with poly(lactide-co glycolide) are preferred, optionally treated to have a negatively-charged surface (e.g. with SDS) or a positively-charged surface (e.g. with a cationic detergent, such as CTAB). Examples of liposome formulations suitable for use as adjuvants are described in US patent 6,090,406, US patent 5,916,588, EP-A-0626169. Adjuvants suitable for use in the invention include polyoxyethylene ethers and polyoxyethylene esters (WO99/52549). Such formulations further include polyoxyethylene sorbitan ester surfactants in combination with an octoxynol (WOO1/21207) as well as polyoxyethylene alkyl ethers or ester surfactants in combination with at least one additional non-ionic surfactant such as an octoxynol (WOO1/21152). Preferred polyoxyethylene ethers are selected from the following group: polyoxyethylene-9-lauryl ether (laureth 9), polyoxyethylene-9-steoryl ether, polyoxytheylene-8-steoryl ether, polyoxyethylene-4-lauryl ether, polyoxyethylene-35 lauryl ether, and polyoxyethylene-23-lauryl ether. Phosphazene adjuvants include poly(di(carboxylatophenoxy)phosphazene) ("PCPP") as described, for example, in references Andrianov et al. (1998) Biomaterials 19:109-115 and Payne et ai. (1998) Adv Drug Delivery Review 31:185-196. Examples of muramyl peptides suitable for use as adjuvants in the invention include N acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-normuramyl-L-alanyl-D isoglutamine (nor-MDP), and N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1' 42 2'-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamine MTP-PE). Imidazoquinoline adjuvants include Imiquimod ("R-837") (US 4,680,338 and US 4,988,815), Resiquimod ("R-848") (W092115582), and their analogs; and salts thereof (e.g. the hydrochloride salts). Further details about immunostimulatory imidazoquinolines can be found in references Stanley (2002) Clin Exp Dermatol 27:571-577, Wu et al. (2004) Antiviral Res. 64(2):79-83, Vasilakos et al. (2000) Cell Immunol. 204(1):64-74, US patents 4689338, 4929624, 5238944, 5266575, 5268376, 5346905, 5352784, 5389640, 5395937, 5482936, 5494916, 5525612, 6083505, 6440992, 6627640, 6656938, 6660735, 6660747, 6664260, 6664264, 6664265, 6667312, 6670372, 6677347, 6677348, 6677349, 6683088, 6703402, 6743920, 6800624, 6809203, 6888000 and 6924293 and Jones (2003) Curr Opin Investig Drugs 4:214-218. Thiosemicarbazone adjuvants include those disclosed in W02004/060308. Methods of formulating, manufacturing, and screening for active compounds are also described in W02004/060308. The thiosemicarbazones are particularly effective in the stimulation of human peripheral blood mononuclear cells for the production of cytokines, such as TNF a. Tryptanthrin adjuvants include those disclosed in W02004/064759. Methods of formulating, manufacturing, and screening for active compounds are also described in W02004/064759. The thiosemicarbazones are particularly effective in the stimulation of human peripheral blood mononuclear cells for the production of cytokines, such as TNF a. Various nucleoside analogs can be used as adjuvants, such as (a) Isatorabine (ANA 245; 7-thia- 8-oxoguanosine) and prodrugs thereof; (b) ANA975; (c) ANA-025-1; (d) ANA380; (e) the compounds disclosed in US 6,924,271, US2005/0070556 and US 5,658,731, or (f) a pharmaceutically acceptable salt of any of (a) to (g), a tautomer of any of (a) to (g), or a pharmaceutically acceptable salt of the tautomer. Q. Lipids linked to a phosphate-containing acyclic backbone Adjuvants containing lipids linked to a phosphate-containing acyclic backbone include the TLR4 antagonist E5564 (Wong et al. (2003) J Clin Pharmacof 43(7):735-42 and US2005/0215517). 43 Small molecule immunopotentiators useful ad adjuvants include N2-methyl-1-(2 methylpropyl)-l H-imidazo(4,5-c)quinoline-2,4-diamine; N2,N2-dimethyl-1-(2 methylpropyl)-1 H-imidazo(4,5-c)quinoline-2,4-diamine; N2-ethyl-N2-methyl-I -(2 methylpropyl)-I H-imidazo(4,5-c)quinoline-2,4-diamine; N2-methyl-1 -(2-methylpropy) N2-propyl-1 H-imidazo(4,5-c)quinoline-2,4-d iamine; 1-(2-methylpropyl)-N2-propyl-1 H imidazo(4,5-c)quinoline-2,4-diamine; N2-butyl-1 -(2-methylpropyl)-1 H-imidazo(4,5 c)quinoline-2,4-diamine; N2-butyl-N2-methyl-1 -(2-methylpropyl)-1 H-imidazo(4,5 c)quinorme-2,4-diamine; N2-methyl-1 -(2-methylpropyl)-N2-pentyl-I H-imidazo(4,5 c)quinoline-2,4-diamine; N2-methyl-1-(2-methylpropy)-N2-prop-2-enyl-1H-imidazo(4,5 c)quinoline-2,4- diamine; 1 -(2-methylpropyl)-2-((phenylmethyl)thio)-1H-imidazo (4,5 c)quinolin-4-amine; 1-(2-methylpropyl)-2-(propylthio)-1H-imidazo(4,5-c)quinolin-4-amine; 2-((4-amino-1-(2-methylpropyl)-1H-imidazo(4,5-c)quinolin-2-yl)(methyl)amino)ethanol; 2 ((4-amino-1-(2-methylpropyl)-1H-imidazo(455-c)quinolin-2-yl)(methyl)amino)ethyl acetate; 4-amino-1-(2-methylpropyl)-1 ,3-dihydro-2H-imidazo(4,5-c)quinolin-2-one; N2 butyl-1-(2-methylpropyl)-N4,N4-bis(phenylmethyl)-1 H-imidazo(4,5-c)quinoline-2,4 diamine; N2-butyl-N2-methyl-1-(2-methylpropyl)-N4,N4-bis(phenylmethyl)-1

H

imidazo(4,5- c)quinoline-2,4-diamine; N2-methyl-1-(2-methylpropyl)-N4,N4 bis(phenymethyl)-1 H-imidazo(4,5-c)quinolne-2,4-diamine; N2,N2-dimethyl-1-(2 methylpropyl)-N4,N4-bis(phenylmethyl)-1H-imidazo(4,5- c)quinoline-2,4-diamine; 1- (4 amino-2-(methyl(propyl)amino)-1H-imidazo(4,5-c)quinolin-1-yl)-2-methylpropan-2-ol; 1 (4-amino-2-(propylaniino)-1H-imidazo(4,5-c)quinolin-1-yl)-2-methylpropan-2-ol; N43N4 dibenzyl-1-(2-methoxy-2-methylpropyl)-N2propyl-1H-imidazo(4,5-c)quinoline-2,4 diamine. One potentailly useful adjuvant is an outer membrane protein proteosome preparation prepared from a first Gram- negative bacterium in combination with a liposaccharide preparation derived from a second Gram-negative bacterium, wherein the outer membrane protein proteosome and liposaccharide preparations form a stable non covalent adjuvant complex. Such complexes include "IVX-908", a complex comprised of Neisseria meningitidis outer membrane and lipopolysaccharides. They have been used as adjuvants for influenza vaccines (WO02/072012). Other substances that act as immunostimulating agents are disclosed in Vaccine Design 44 ((1995) eds. Powell & Newman. ISBN: 030644867X. Plenum) and Vaccine Adjuvants: Preparation Methods and Research Protocols (Volume 42 of Methods in Molecular Medicine series) (ISBN: 1-59259-083-7. Ed. O'Hagan). Further useful adjuvant substances include: Methyl inosine 5 '-monophosphate ("MIMP") Signorelli & Hadden (2003) Int Immunopharmacol 3(8):1177); a polyhydroxlated pyrrolizidine compound (W02004/064715), examples include, but are not limited to: casuarine, casuarine-6-a-D glucopyranose, 3-epz-casuarine, 7-epz-casuarine, 3,7-diepz-casuarine, etc; a gamma inulin (Cooper (1995) Phar Biotechnol 6:559) or derivative thereof, such as algammulin; compounds disclosed in PCT/US2005/022769; compounds disclosed in W02004/87153, including: Acylpiperazine compounds, Indoledione compounds, Tetrahydraisoquinoline (THIQ) compounds, Benzocyclodione compounds, Aminoazavinyl compounds, Aminobenzimidazole quinolinone (ABIQ) compounds (US6,606617, W0021018383), Hydrapthalamide compounds, Benzophenone compounds, Isoxazole compounds, Sterol compounds, Quinazilinone compounds, Pyrrole compounds (WO/04/018455), Anthraquinone compounds, Quinoxaline compounds, Triazine compounds, Pyrazalopyrimidine compounds, and Benzazole compounds (WO03/082272); loxoribine (7-allyl-8-oxoguanosine) (US 5,011,828); a formulation of a cationic lipid and a (usually neutral) co-lipid, such as aminopropyl- dimethyl-myristoleyloxy-propanaminium bromide diphytanoylphosphatidyl- ethanolamine ("VaxfectinTM") or aminopropyl-dimethyl-bis dodecyloxy-propanaminium bromide-dioleoylphosphatidyl-ethanolamine ("GAP DLRIE:DOPE"). Formulations containing (±)-N-(3-aminopropyl)-N,N-dimethyl-2,3 bis(syn-9-tetradeceneyoxy)-i- propanaminium salts are preferred (US6,586,409). The invention may also comprise combinations of aspects of one or more of the adjuvants identified above. For example, the following adjuvant compositions may be used in the invention: (1) a saponin and an oil-in-water emulsion (W099/11241); (2) a saponin (e.g. QS21) + a nontoxic LPS derivative (e.g. 3dMPL) (WO94/00153); (3) a saponin (e.g. QS21) + a non-toxic LPS derivative (e.g. 3dMPL) + a cholesterol; (4) a saponin (e.g. QS21) + 3dMPL + IL-12 (optionally + a sterol) (W098/57659); (5) combinations of 3dMPL with, for example, QS21 and/or oil-in-water emulsions (EP0835318, EP0735898, EP0761231); (6) RibiTM adjuvant system (RAS), (Ribi Immunochern) containing 2% squalene, 0.2% Tween 80, and one or more bacterial cell wall components from the group consisting of monophosphorylipid A (MPL), trehalose dimycolate (TDM), and cell wall skeleton (CWS), preferably MPL + CWS (Detox T M ); and 45 (7) one or more mineral salts (such as an aluminum salt) + a non-toxic derivative of LPS (such as 3dMPL). In one embodiment of the invention the composition comprises a Plasmodium falciparurn invasion protein of the EBA family. As discussed supra, EBA proteins have also been found by the Applicants to be capable of eliciting an invasion-inhibitory immune response. The use of compositions containing combinations of Rh and EBA proteins relates to the Applicants further discovery that the Plasmodium falciparum parasite is capable of evading the host immune response by switching from the use of one invasion protein to another. For example, if the parasite initially utilised a Rh-mediated invasion pathway the host will generate antibodies capable of blocking the method of entry. The parasite is capable of then using an alternative pathway (such as an EBA-mediated pathway) in order to evade the host immune response. Data provided herein establishes that the invasion-inhibitory activity of naturally acquired antimalarial antibodies is influenced by phenotypic variation in erythrocyte invasion pathways and suggests that the use of alternative invasion pathways may act as a mechanism of immune evasion. These findings indicate members of the EBA and Rh invasion ligand families are key targets of inhibitory antibodies. This knowledge is highly significant for understanding the acquisition of malarial immunity and the capacity of Plasmodium falciparum to cause repeated infections, and will aid the prioritisation and validation of candidate vaccine antigens. This establishes, in Plasmodium falciparum, the presence of a novel mechanism of immune evasion among microbial pathogens, which may be relevant to other organisms. Comparing antibody inhibition of W2mef lines with different invasion phenotypes enabled a clear evaluation of the effect of variation in invasion pathway use on the efficacy of inhibitory antibodies (EXAMPLES 1 to 6). W2mefAEBA175 uses an alternate SA independent invasion pathway compared to the parental W2mef-wt (SA-dependent). Many samples that inhibited the parental W2mef lost their inhibitory activity against W2mefAEBA175, providing evidence that a switch in invasion pathway use can facilitate immune evasion. These results were confirmed using W2mefSelNm, a line that is genetically intact and uses a SA-independent pathway following selection for invasion into neuraminidase-treated erythrocytes. The present invention also demonstrates that 46 invasion pathway use alters susceptibility to inhibitory antibodies using a genetically different isolate, 3D7. By varying the use of different members of the EBA and Rh ligand families, Plasmodium falciparum appears to evade invasion-inhibitory antibodies targeting specific EBA and Rh proteins. In addition to explaining the lack of phenotype observed for Plasmodium falciparum lines disrupted for these molecules on untreated red cells, this surprising result explains the lack of invasion inhibition observed using antibodies to the Rh family of molecules on untreated cells (e.g. Rh2, as discussed supra). The present invention demonstrates that effective immunity may depend on the presence of antibodies against a broad range of invasion ligands, in particular antibodies against both SA-dependent invasion and SA-independent invasion ligands, and defines the ligands responsible for this immune invasion (e.g. Rhi, Rh2, Rh4, EBA175, EBA181, and EBA140). Greater inhibition of W2mef-wt compared to W2mefAEBA175 or W2mefSelNm by samples from exposed donors points to antibodies targeting the EBAs and Rh1, which define the SA-dependent pathway. EBA175 is the major target of these antibodies as it is essential for utilisation of the SA-dependent invasion pathway in enzyme treated red cells. Disruption of EBA175 in W2mef results in a switch to an alternative SA independent invasion pathway in enzyme treated red cells that is Rh4-dependent. This indicates that EBA175 is the major determinant of erythrocyte SA-dependent invasion in W2mef-wt parasites. On the other hand, greater inhibition of W2mefAEBA175 or W2mefSeINm compared to W2mef-wt indicates the presence of human invasion inhibitory antibodies against Rh4 and Rh2, as discussed supra and demonstrated in Figures 1, 2, and 3. Furthermore, Figure 12 demonstrates antibodies to Rh2 inhibit Plasmodium falciparum lines in which SA-dependent invasion has been reduced by disruption of EBA175 or EBA140 into normal untreated red cells. This demonstrates that there is synergy between the inhibition of invasion by targeting both major pathways of invasion (SA-dependent and SA-independent) into untreated red cells. By targeting the ligands that mediate invasion via these pathways (e.g. Rh1, Rh2, Rh4, EBA175, EBA140 and EBA181), invasion-inhibition on untreated cells is achieved. In particular, rabbit antibodies recognizing the region of Rh2 between about 31 amino acids N terminal of the Prodom PD006364 homology region to about the transmembrane domain of Rh2 inhibited invasion of Plasmodium falciparum parasites on untreated red cells in which EBA175 or EBA140 or EBA175 and EBA140 has been disrupted relative to wild 47 type Plasmodium falciparum (Figure 12). In particular, antibodies recognizing the region of Rh2 from amino acid 2027 to 3115 of Rh2 (e.g. SEQ ID NO: 1) inhibited invasion on untreated red cells. In particular, antibodies recognizing the region of Rh2 from amino acid 2616 to 3115 of Rh2 inhibited invasion on untreated red cells. Given the demonstration of the advantages gained by targeting two discrete invasion pathways, one embodiment of the composition comprises a contiguous amino acid sequence of a reticulocyte-binding protein homologue (Rh) protein of the strain of Plasmodium falciparum, wherein when administered to a subject the Rh protein is capable of inducing an invasion-inhibitory immune response to the strain. The Rh may be Rh1, Rh2a, Rh2b or Rh4. In one form of the immunogenic molecule, the Rh molecule is Rh2b, and the contiguous amino acid sequence is found in SEQ ID NO: 1: SEQ ID NO: 1 Amino acid sequence of Rh2b (PlasmoDB Accession No: MAL13P1.176) MKRSLINLENDLFRLEPISYIQRYYKKNINRSDIFHNKKERGSKVYSNVSSFHSFIQEGK EEVEVFSIWGSNSVLDHIDVLRDNGTVVFSVQPYYLDIYTCKEAILFTT SFYKDLDKSSI TKINEDIEKFNEEIIKNEEQCLVGGKTDFDNLLIVLENAEKANVRKTLFDNTFNDYKNKK SSFYNCLKNKKNDYDKKIKNIKNE ITKLLKNIESTGNMCKTESYVMNNNLYLLRVNEVKS TPIDLYLNRAKELLESSSKLVNPIKMKLGDNKNMYSIGYIHDEIKDIIKRYNFHLKHIEK GKEYIKRITQANNIADKMKKDELIKKIFESSKHFASFKYSNEMISKLDSLFIKNEEILNN LFNN IFNIFKKKYETYVDMKTIESKYTTVMTLSEHLLEYAMDVLKANPQKPIDPKANLDS EVVKLQIKINEKSNELDNAISQVKTLIIIMKSFYDIIISEKASMDEMEKKELSLNNYIEK TDYILQTYNIFKSKSNIINNNSKNISSKYITIEGLKNDIDELNSLISYFKDSQETLIKDD ELKKNMKTDYLNNVKYIEENVTHINEIILLKDSITQRIADIDELNSLNLININDFINEKN I SQEKVSYNLNKLYKGSFEELESELSHFLDTKYLFHEKKSVNELQTILNTSNNECAKLNF MKSDNNNNNNNSNIINLLKTELSHLLSLKENIIKKLLNHIEQNIQNSSNKYTITYTDINN RMEDYKEEIESLEVYKHTIGNIQKEYILHLYENDKNALAVHNTSMQILQYKDAIQNIKNK ISDDIKILKKYKEMNQDLLNYYEILDKKLKDNTYIKEMHTASLVQITQYIPYEDKTISEL EQEFNNNNQKLDNILQDINAMNLNTNILQTLN IGINACNTNNKNVERLLNKKIELKNI LN DQMKI IKNDDIIQDNEKENFSNVLKKEEEKLEKELDDIKFNNLKMDIHKLLNSYDHTKQN IESNLKINLDSFEKEKDSWVHFKSTIDSLYVEYNICNQKTHNTIKQQKNDIIEL IYKRIK DINQEIIEKVDNYYSLSDKALTKLKSIHFN IDKEKYKNPKSQENIKLLEDRVMI LEKKIK E DKDALIQIKNLSHDHFVNADNEKKKQKEKEEDDEQTHYSKKRKVMGDIYKDIKKNLDEL NNKNLIDITLNEANKIESEYEKILIDDICEQITNEAKKSDTIKEKIESYKKDIDYVDVDV SKTRNDHHLNGDKIEDSFFYEDTLNYKAYFDKLKDLYEN INKLTNESNGLKSDAHNNNTQ VDKLKEINLQVFSNLGNIIKYVEKLENTLHELKDMYEFLETIDINKILKS IHNSMKKSEE YSNETKKIFEQSVNITNQFI EDVEILKTSINPNYESLNDDQIDDNIKSLVLKKEEISEKR KQVNKYITDIESNKEQSDLHLRYASRSIYVIDLFIKHEIINPSDGKNFDI IKVKEMINKT KQVSNEAMEYANKMDEKNKDIIKIENELYNLINNNIRSLKGVKYEKVRKQARNAIDDINN IHSNIKTILTKSKERLDEIKKQPN IKREGDVLNNDKTKIAYITIQINNGRIESNLLNILN MKHNIDTILNKAMDYMNDVSKSDQIVINIDSLNMNDIYNKDKDLLINILKEKQNMEAEYK KMNEMYNYVNETEKEIIKHKKNYEIRIMEHIKKETNEKKKKFMESNNKSLTTLMDSFRSM FYNEYINDYNINENFEKHQNILNEIYNGFNESYNI INTKMTEIINDNLDYNEIKEIKEVA QTEYDKLNKKVDELKNYLNNIKEQEGHRLIDYIKEKIFNLYIKCSEQQNI IDDSYNYITV 48 KKQYIKTIEDVKFLLDSLNTIEEKNKSVALEICTNKEDIKNLLKHVIKLANFSGIIVMS DTNTEITPENPLEDNDLLNLQLYFERKHEITSTLENDSDLELDHLGSNSDESIDNLKVYN DIIELHTYSTQILKYLDNIQKLKGDCNDLVKDCKELRELSTALYDLKIQITSVINRENDI SNNIDIVSNKLNEIDAIQYNFEKYKEIFDNVEEYKTLDDTKNAYIVKKAEILKNVDINKT KEDLDIYFNDLDELEKSLTLSSNEMEIKTIVQNSYNSFSDINKNINDIDKEMKTLIPMLD ELLNEGHNIDISLYNFIIRNIQIKIGNDIKNIREQENDTNICFEYIQNNYNFIKSDISIF NKYDDHIKVDNYISNNIDVVNKHNSLLSEHVINATNIIENIMTSIVEINEDTEMNSLEET QDKLLELYENFKKEKNIINNNYKIVHFNKLKEIENSLETYNSISTNFNKINETQNIDILK NEFNNIKTKINDKVKELVHVDSTLTLESIQTFNNLYGDLMSNIQDVYKYEDINNVELKKV KLYIENITNLLGRINTFIKELDKYQDENNGIDKYIEINKENNSYIIKLKEKANNLKENFS KLLQNIKRNETELYNINNIKDDIMNTGKSVNNIKQKFSSNLPLKEKLFQMEEMLLNINNI MNETKRISNTDAYTNITLQDIENNKNKENNNMNIETIDKLIDHIKIHNEKIQAEILIIDD AKRKVKEITDNINKAFNEITENYNNENNGVIKSAKNIVDKATYLNNELDKFLLKLNELLS HNNNDIKDLGDEKLILKEEEERKERERLEKAKQEEERKERERIEKEKQEKERLEREKQEQ LKKEALKKQEQERQEQQQKEEALKRQEQERLQKEEELKRQEQERLEREKQEQLQKEEELR KKEQEKQQQRNIQELEEQKKPEIINEALVKGDKILEGSDQRNMELSKPNVSMDNTNNSPI SNSEITESDDIDNSENIHTSHMSDIESTQTSHRSNTHGQQISDIVEDQITHPSNIGGEKI THNDEISITGERNNISDVNDYSESSNIFENGDST INTSTRNTSSTHDESHISPISNAYDH VVSDNKKSMDENIKDKLKIDESITTDEQIRLDDNSNIVRIDSTDQRDASSHGSSNRDDDE ISHVGSDIHMDSVDIHDSIDTDENADHRHNVNSVDSLSSSDYTDTQKDFSSIIKDGGNKE GHAENESKEYESQTEQTHEEGIMNPNKYSISEVDGIKLNEEAKHKITEKLVDIYPSTYRT LDEPMETHGPNEKFHMFGSPYVTEEDYTEKHDYDKHEDFNNERYSNHNKMDDFVYNAGGV VCCVLFFASITFFSMDRSNKDECDFDMCEEVNNNDHLSNYADKEEIIEIVFDENEEKYF Mutations of SEQ ID NO:1 are also included in the scope of this invention and include embodiments whereby D at amino acid 2471 is replaced with A, K at amino acid 2560 is replaced with E, K at amino acid 3090 is replaced with N, N at amino acid 3116 replaced with T, N at amino acid 3116 is replaced with Y. More particularly, the contiguous amino acid sequence may found in the region between about 31 amino acids N-terminal of the Prodom PD006364 homology region to about the transrrembrane domain of Rh2b. The contiguous amino acid sequence may also be found in the region from about residue 2027 to 3115 of Rh2b, or more particularly from about residue 2027 to about residue 2533 of Rh2b. In another form of the immunogenic molecule the contiguous amino acid sequence is found in the region from about residue 2098 to about residue 2597, or the region from about 2616 to 3115 of Rh2b. In one form of the immunogenic molecule, the Rh. molecule is Rh2a, and the contiguous amino acid sequence is found in SEQ ID NO: 11: 49 SEQ ID NO: 11 Amino acid sequence of Rh2a (PlasmoDB Accession No: PF1 3_0198) NKTTLFCSISFCNIIFFFLELSHEHFVGQSSNTHiGASSVTDFNFSEEKNLKSFEGKNNNN DNYASINRLYRKKYMKRSLINLENDLFRLEPISYIQRYYKKNTNRSDI FHNKKERGSKV YSNVSSFHS FIQEGKEEVEVFSIWGSNSvLDHI DVLRDNGTVVFSVQPYYLDT YTCXEAX LFTTSFYKDLDKSSITKINEDI EKFNEEIIKNEEQCLVGGKTDFDNLLIVLENAEKANVR KTLFDNTFNDYKNKKSS FYNCLKNKKNDYDKKIKNIKNEI TKLLKNIESTGNNCKTESYV MNNNLYLLRVNEVKSTPI DLYILNRAKELLESSSKLVNPIKMKLGDNKNMYSIGYIHDEIK DIIKRYNFHLKHIEKGKEYIKRXTQANNIADKMKDELIKKIFESSKHFASFKYSNEMIS KLDSLFIKNEEILNNLFNNIFNI FKKKYETYVDMKTIESKYTTVATLSEHLLEYANDVLK ANFOKFI DPKANLDSEVVKLQIKDINbEKSNELDNAISQVKTLI IIMKSFYDI II SEKASMD EMEKKEIJSLNNYIEKTDYILQTYNIFICSKSNIINNNSKNISSKYITIEGLKNDIDELNSL ISYEKDSOETLIKDDELKKNMKTDYLNNVKYEENVTH-INEIILLKDSITQRIADIDELN SLNLININDFINEKNI SQEKVSYNLNICLYKCSFEELESELS-FLDTKYLFHEKKSVNELQ TILNTSNNECAXLNFMKSDNNNNNNNSNIINLLKTELSHLLSLKENI IKKLLNHIEQNIO N SSNKYTITYTDINNRMEDYKEEI ESLEVYKHTIGNIQKEYILHLYEN DKNALAV-NTSM QILQYKDAIQNIKNKI SDDIKILKKYKENNQDLLNYYETJJDKKLKDNTYIKEMHTASLVQ I TQYIPYEDKTISELEQEFNNNNQKLDNILQDINAMNLNINILQTLNIGINACNINNKNV EI-LLNKKIEILcNILNDQMIIZNDDI IQDNEKENFSNVLKKEEEKLEKELDDIKFNNLKM DIHKLLNSYDHTKQNIESNLKINLDSFEKEKDSWVMFKSTIDSLYVEYNICNQKTHNTIK QQKNDI IELIYKRKDINQEIIEKVDNYYSLSDKALTKLKSHFNIDKEKYCNPKSQENI KLLEDRVMIIJEKKIRE DKOLALIQI KNLSH!IVNADNEKKKQKEKEEDDEQTHYSKKRCV MGDIYKDIKKNLDELNNKNLIDITLNEANKIESEYEKILIDDICEQITNEAKKSDTIKEK I ESYKKDI DYVDVDVSKTRNDHHLNGDKIHDSFFYEDTLNYKAYFDKLKDLYENINKLTN ESNGTJKS DAHNNNTQVDKLKEINLQVFSNLGNIIKYVKENTLELCDMYEFLETTDIN KILKSIHNS?4KKSEEYSNETKKIFEQSVNITNQFIEDvEILKTS INPNYESLNDDOLDDN IKSLVLKKEEISEKRKQVNKYITDIESNCEQSDLNLRYASRS IYVIDLFIKHEIINPSDG CN FDT TKVDEINKTKQVSNEAMEYANKMDEKNKDI IDIENELYNLINNNIRSLKGVKYE KVRKQARNAI DDINNIHSNIKTILTKSKERLDEIKKQPNIKREGDVLNNDKTCIAYITIQ INNGRIESNLINILNMKHNIDTILNKAMDYNNDVSKSDQIVINIDSLNMNDIYNKDKDLL IN ILKEKQNHEAEYKKMNENYNYVNETEKEI IKHKKNYEIRIMEH IKKETNEKKKKFMES NNKSLTTLNDSFRSMFYNEYINDYNINENFEKNQNILNE IYNGFNESYNIINTKMTEI IN ONLDYNEIKEIKEVAQTEYDKLNKKVDELKNYLNNIKEQEGHRLIDYIREKI FNLYIKCS EQQNII DDSYNYITVKXQYIKTIEDVKFLLDSLNTIEEKNKSVANLEJCTNKEDIKNLLK HVIKLANFSGIIVNSDTNTEITPENPLEJNDLLNLQLYFERKHE ITSTLEN DSDLELDHL GSNS DES IDNLKVYNDIIELHTYSTQI LKYLDNIQKLKGDCNDLVKDCKELRELSTALYD LKIQITSVINRENDISNNIDIVSNKLNEIDAIQYNFEKYKEIFDNVEEYKTLDDTKNAYI VKKAEILKNVDINKTKEDLDIYFNDLDELEKSLTLSSNENEIKTIVQNSYNS FSDINKNI NDIDKEMKTLIPMLDELLNEGHNIDISLYNFTIRNIQIKIGNDIKNIREQENDTNICFEY IQNNYNE'IKSDISIFNKYDDHIKVDNYISNNIDVVNKHNSLLSEHVINATNIIENIMTSI VEINEDTEMNSLEETQDKLLELYENFUCEKNI INNNYKIVHFNPCLKEIENSLETYNSI ST NFNKINETQNIDILKNEFNNI KTKINDKVKELVHVDSTLTLESIQTFNNLYGDLNSNIOD VYKYEDI NNVELKKVKLYIENTTNLLGRTNTFIKEJDKYQDENNGI DKYIEINKENNSYI IKLKEKANNLKSNFSKLLQNIKRNETELYNINNIKDDIMNTGKSVNNIKQKFSSNLFLKE KLFQMEEMLLNINNIMNETKRI SNTAAYTNITLQDIENNKNKENNNMNIETI DILIDHIK INNEKI QAE ILlITDDAKRKVKEITDNINKAFNEI TENYNNENNGVI KSAKNIVDEATYLN NELDKFLLKLNELLSHNNNDI KDLGDEKLTLKEEEERKERERLEKAKQEEERKERERI EK EKQEKERLERZKQEQLKKEEELRKKEQERQEQQQKEEALI<RQEQERLQKEEELKRQEQER LEREKOEQLQKEEELKRQEQSRLQKEEALKRQEQERLQKEEELKRQEQERLEREKQEQLQ KEEELKRQEQERLQKEEALFCROEOERLQKEEIELKRQEoERLERKKIELAEREQHIKSKLE S DMVKII KDELTKEKDEII KNKIIKLRHSLEQKWLKHLQNILSLKIDSLLNKNDEVIKDN ETQLKTNILNSLKNQLYLNLKRELNEI IKEYEENQKKILHSNQLVNDSJJEQKTNRLVDIK PTKHGDIYTNKLSDNETEMLITSKEKKDETESTKRSGTDHTNSSESTTDDNTNDRNFSRS KNLSVAIYTAGSVALCVLI FSSIGLLLIKTNSGDNNSNEINEAFEPNDDVLF'KEKDEI IE 50 ITFNDNDSTI Mutations of SEQ ID NO:11 are also included in the scope of this invention and include embodiments whereby A at amino acid 2546 is replaced with D, E at amino acid 2613 is replaced with G, R at amino acid 2723 is replaced with K, K at amino acid 2725 replaced with 0. More particularly, the contiguous amino acid sequence may found in the region between about 31 amino acids N-terminal of the Prodom PD006364 homology region to about the transmembrane domain of Rh2a. The contiguous amino acid sequence may also be found in the region from about residue 2133 to about residue 3065 of Rh2a. In another form of the immunogenic molecule the contiguous amino acid sequence is found in the region from about residue 2098 to about residue 2597, or the region from about residue 2616 to about residue 3115 of Rh2a. SEQ ID NO: 13 Amino acid sequence of Rh1 (PlasmoDB Accession No: PFD0110w) MQRWIFCNIVLHILIYLAEFSHEQESYSSNEKIRKDYSDDNNYEPTPSYEKRKKEYGKDE SYIKNYRGNNFSYDLSKNSSIFLHMGNGSNSKTLKRCNKKKNIKTNFLRPIEEEKTVLNN YVYKGVNFLDTIKRNDSSYKFDVYKDTSFLKNREYKELITMQYDYAYLEATKEVLYLIPK DKDYHKFYKNELEKILFNLKDSLKLLREGYIQSKLEMIRIHSDIDILNEFHQGNIINDNY FNNEIKKKKEDMEKYIREYNLYIYKYENQLKIKIQKLTNEVSINLNKSTCEKNCYNYILK LEKYKNIIKDKINKNKDLPEIYIDDKSFSYTFLKDVINNKIDIYKTISSFISTQKQLYYF EYIYIMNKNTLNLLSYNIQKTDINSSSKYTYTKSHFLKDNHILLSKYYTAKFIDILNKTY YYNLYKNKILLFNKYI IKLRNDLKEYAFKSIQFIQDKIKKHKDELSIENILQEVNNIYIK YDTSINEISKYNNLIINTDLQIVQQKLLEIKQKKNDITHKVQLINHIYKNIHDEILNKKN NEITKIIINNIKDHKKDLQDLLLFIQQIKQYNILTDHKITQCNNYYKEIIKMKEDINHIH IYIQPILNNLHTLKQVQNNKIKYEEHIKQILQKIYDKKESLKKIILLKDEAQLDITLLDD LIQKQTKKQTQTQTQTQKQTLIQNNETIQLISGQEDKHESNPFNHIQTYIQQKDTQNKNI QNLLKSLYNGNINTFIDTISKYILKQKDIELTQHVYTDEKINDYLEEIKNEQNKI DKTID DIKIQETLKQITHIVNNIKTIKKDLLKSFIQHLIKYMNERYQNMQQGYNNLTNYINQYEE ENNNMKQYITTIRNIQKIYYDNIYAKEKEIRSGQYYKDFITSRKNIYNIRENISKNVDMI KNEEKKKIQNCVDKYNSIKQYVKMLKNGDTQDENNNNNNDIYDKLIVPLDSIKQNIDKYN TEHNFIT FTNKINTHNKKNQEMMEEFIYAYKRLKILKILNISLKACEKNNKSINTLNDKT QELKKIVTHEIDLLQKDILTSQISNKNVLLLNDLLKEIEQYIIDVHKLKKKSNDLFTYYE QSKNYFYFKNKKDNFDIQKTINKMNEWLAIKNYINEINKNYQTLYEKKINVLLHNSKSYV QYFYDHI INLILQKKNYLENTLKTKIQDNEHSLYALQQNEEYQKVKNEKDQNEIKKIKQL IEKNKNDILTYENNIEQIEQKNIELKTNAQNKDDOIVNTLNEVKKKIIYTYEKVDNQISN VLKNYEEGKVEYDKNVVQNVNDADDTNDIDEINDIDEINDIDEINDI DEINDIDEIKDID HIKHFDDTKHFDDIYHADDTRDEYHIALSNYIKTELRNINLQEIKNNIIKIFKEFKSAHK E IKKESEQINKEFTKMDVVINQLRDIDRQMLDLYKELDEKYSEFNKTKIEEINNIRENIN NVEIWYEKNI IEYFLRHMNDQKDKAAKYMENIDTYKNNIE IISKQINPENYVETLNKSNM 51 YSYVEKANDLFYKQINNIIINSNQLKNEAFTIDELQNIQKNRKNLLTKKQQTIQYTNEIE NIFNEIKNINNILVLTNYKSILQDISQNINHVSIYTEQLHNLYIKLEEEKEQMKTLYHKS NVLHNQINFNEDAFINNLLINIEKIKNDITHIKEKTNIYMIDVNKSKNNAQLYFHNTLRG NEWCEYLKNLKNSTNQQITLQELKQVQENVEKVKDIYNQTIKYEEEIKKNYHIITDYENK INDILHNSFIKQINMESSNNKKQTKQIIDIINDKTFEEHIKTSKTKINMLKEQSQMKHTD KTLLNEQALKLFVDINSTNNNLDNMLSEINSIQNNIHTYIQEANKSFDKFKIICDQNVND LLNKLSLGDLNYMNHLKNLQNEIRNMNLEKNFMLDKSKKIDEEEKKLDILKVNISNINNS LDKLKKYYEEALFQKVKEKAEIQKENIEKIKQEINTLSDVFKKPFFFIQLNTDSSQHEKD INNNVETYKNNIDEIYNVFIQSYNLIQKYSSEIFSSTLNYIQTKEIKEKSIKEQNQLNQN EKEASVLLKNIKINETIKLFKQIKNERQNDVHNIKEDYNLLQQYLNYMKNEMEQLKKYKN DVHMDKNYVENNNGEKEKLLKETISSYYDKINNINNKLYIYKNKEDTYFNNMIKVSEILN IIIKKKQQNEQRIVINAEYDSSLINKDEEIKKEINNQIIELNKHNENISNIFKDIQNIKK - QSQDIITNMNDMYKSTILLVDIIQKKEEALNKQKNILRNIDNILNKKENIIDKVIKCNCD DYKDILIQNETEYQKLQNINHTYEEKKKSIDILKIKNIKQKNIQEYKNKLEQMNTIINQS IEQHVFINADILQNEKIKLEEIIKNLDILDEQIMTYHNSIDELYKLGIQCDNHLITTISV VVNKNTTKIMIHIKKQKEDIQKINNYIQTNYNIINEEALQFHRLYGHNLISEDDKNNLVH IIKEQKNIYTQKEIDISKIIKHVKKGLYSLNEHDMNHDTHMNIINEHINNNILQPYTQLI NMIKDIDNVFIKIQNNKFEQIQKYIETTKSLEQLNKNINTDNLNKLKDTQNKLINIETEM KHKQKQLINKMNDIEKDNITDQYMHDVQQNIFEPITLKMNEYNTLLNDNHNNNINNEHOF NHLNSLHTKIFSHNYNKEQQQEYITNIMQRIDVFINDLDTYQYEYYFYEWNQEYKQIDKN KINQHINNIKNNLIHVKKQFEHTLENIKNNENIFDNIQLKKKDIDDITININNTKETYLK ELNKKKNVTKKKKVDEKSEINNHHTLQHDNQNVEQKNKIKDHNLITKPNNNSSEESHQNE QMKEQNKNILEKQTRNIKPHHVHNHNHNHNQNQKDSTKLQEQDISTHKLHNTIHEQQSKD NHQGNREKKQKNGNHERMYFASGIVVSILFLFSFGFVINSKNNKQEYDKEQEKQQQNDFV CDNNKMDDKSTQKYGRNQEEVMEIFFDNDYI The present invention includes a mutated form of SEQ ID NO:13. It is known to the skilled person that there are a large number of single nucleotide polymorphism in Rh1 and these and any other mutations are included within the scope of the invention. More particularly, the contiguous amino acid sequence may found in the region between about amino acid residue 1 to transmembrane domain of Rh1. The contiguous amino acid sequence may also be found in the region from about residue 1 to about residue 2897 of Rh1. In one form of the immunogenic molecule, the Rh protein is Rh4, and the contiguous amino acid sequence is found in SEQ ID NO: 3 (PlasmoDB Accession No: PFD1150c), as disclosed below. MNKN ILWITFFYFLFFLLDMYQGNDAIPSKEKKNDPEADSKNSQNQHDINKTHHTNNNYD LNIKDKDEKKRKNDNLINNYDYSLLKLSYNKNQDIYKNIQNGQKLKTDI ILNSFVQINSS NI LMDE IENYVKKYTESNRIMYLQFKYIYLQSLNITVSFVPPNSPFRSYYDKNLNKDINE TCHSIQTLLNNLISSKIIFKMTETTKEQILLLWNNKKISQQNYNQENQEKSKMIDSENEK LEKYTNKFEHNIKPHIEDIEKKVNEYINNSDCHLTCSKYKTIINNYIDEIITTNTNIYEN KYNLPQERIIKNYNHNGINNDDNFIEYNILNADPDLRSHFITLLVSRKQLIYIEYIYFIN KHIVNKIQENFKLNQNKYIHFINSNNAVNAAKEYEYIIKYYTTFKYLQTLNKSLYDSIYK HKINNYSHNTEDLINQLQHKINNLMIISFDKNKSSDLMLQCTNIKKYTDDICLSIKPKAL 52 EVEYLRNINKHINKNEFLNKFMQNETFKKNIDDKIKEMNNIYDNIYIILKQKFLNKLNEI IQNHKNKQETKLNTTTIQELLQLLKDIKEIQTKQIDTKINTFNMYYNDIQQIKIKINQNE KEIKKVLPQLYIPKNEQEYIQIYKNELKDRIKETQTKINLFKQILELKEKEHYITNKHTY LNFTHKTIQQILQQQYKNNTQEKNTLAQFLYNADIKKYIDELIPITQQIQTKMYTTNNIE HIKQILINYIQECKPIQNISEHTIYTLYQEIKTNLENIEQKIMQNIQQTTNRLKINIKKI FDQINQKYDDLTKNINQMNDEKIGLRQMENRLKGKYEEIKKANLQDRDIKYIVQNNDANN NNNNIIIINGNNQTGDYNHILFDYTHLWDNAQFTRTKENINNLKDNIQININNIKSIIRN LQNELNNYNTLKSNSIHIYDKIHTLEELKILTQEINDKNVIRKIYDIETIYQNDLHNIEE IIKNITSIYYKINILNILIICIKQTYNNNKSIESLKLKINNLTNSTQEYINQIKAIPTNL LPEHIKQKSVSELNIYMKQIYDKLNEHVINNLYTKSKDSLQFYINEKNYNNNHDDHNDDH NDVYNDIKENEIYKNNKLYECIQIKKDVDELYNIYDQLFKNISQNYNNHSLSFVHSINNH MLSIFQDTKYGKHKNQQIILSDIENIIKQNEHTESYKNLDTSNIQLIKEQIKYFLQIFHTL QENITTFENQYKDLIIKMNHKINNNLKDITHIVINDNNTLQEQNRIYNELQNKIKQIKNV SDVFTHNINYSQQILNYSQAQNSFFNIFMKFQNINNDINSKRYNVQKKITEIINSYDIIN YNKNNIKDIYQQFKNIQQQLNTTETQLNHIKQNINHFKYFYESHQTISIVKNMQNEKLKI QEFNKKIQHFKEETQIMINKLTQPSHIHLHKMKLPITQQQLNTILHRNEQTKNATRSYNM NEEENEMGYGITNKRKNSETNDMINTTIGDKTNVLKNDDQEKGKRGTSRNNNIHTNENNI NNEHTNENNINNEHTNEKNINNEHANEKNIYNEHTNENNINYEHPNNYQQKNDEKISLQH KTINTSQRTIDDSNMDRNNRYNTSSQQKNNLHTNNNSNSRYNNNHDKQNEHKYNQGKSSG KDNAYYRIFYAGGITAVLLLCSSTAFFFIKNSNEPHHIFNIFQKEFSEADNAHSEEKEEY LPVYFDEVEDEVEDEVEDEDENENEVENENEDFNDI The present invention includes a mutated form of SEQ ID NO:3. Mutations that are included within the scope of the invention include those whereby Y at amino acid 12 is replaced with A, L at amino acid 143 is replaced with I, N at amino acid 435 is replaced with K, Q at amino acid 438 is replaced with K, T at amino acid 506 replaced with K, N at amino acid 771 is replaced with S, N at amino acid 844 is replaced with I, K at amino acid 1482 is replaced with R, or N at amino acid 1498 is replaced with I. More particularly, the contiguous amino acid sequence is found in the region from about the MTH1187/YkoF-like superfamily domain to about the transmembrane domain of Rh4. In another form of the immunogenic molecule, the contiguous amino acid sequence is found in the region from about residue 1160 to about residue 1370 of Rh4. Based on results presented herein, Applicant proposes that a broad inhibitory response against functional epitopes of invasion ligands may be needed to convey substantial protective immunity. It is proposed that vaccines should preferably target multiple invasion ligands in order to be fully effective and ameliorate parasite immune evasion strategies. An effective vaccine may include ligands involved in both SA-dependent and 53 SA-independent invasion. In light of this, it will still be appreciated that immune responses against only single ligands will nonetheless be useful. Similarly, the skilled person understands that strict compliance with any amino acid sequence disclosed herein is not necessarily required, and he or she could decide by a matter of routine whether any further mutation is deleterious or preferred. Thus, the immunogenic molecules of the present invention include sequences having 50% or more identity (e.g. 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or more) to any protein disclosed herein. The immunogenic molecules also include variants (e.g. allelic variants, homologs, orthologs, paralogs, mutants, etc.). The molecules may lack one or more amino acids (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more) from the C-terminus and/or one or more amino acids (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more) from the N-terminus. Some forms of the composition contain more than one EBA-derived immunogenic molecule, or more than one Rh-derived immunogenic molecule. The composition may contain any combination of two or more immunogenic molecules derived from Rh1, Rh2a, Rh2b and Rh4. The composition may contain any combination of two or more immunogenic molecules derived from EBA175, EBA140 and EBA181. It is further contemplated that any combination of Rh-derived immunogenic molecules with EBA derived immunogenic molecules may be present in the composition. As alluded to by the aforementioned disclosure, the invention further provides a composition of the invention for use as a medicament. Accordingly, in a further aspect the present invention provides a method of treating or preventing a condition caused by or associated with infection by Plasmodium falciparum comprising administering to a subject in need thereof an effective amount of a composition as described herein. The medicament is a malarial vaccine in one form of the composition. Vaccines according to the present invention may either be prophylactic (i.e. to prevent infection) or therapeutic (i.e. to treat infection), but will typically be prophylactic. Accordingly, the invention includes a method for the therapeutic or prophylactic treatment of Plasmodium falciparum infection in an animal susceptible to Plasmodium falciparum infection comprising administering to said animal a therapeutic or prophylactic 54 amount of the immunogenic compositions of the invention. The compositions of the invention may elicit both a cell mediated immune response as well as a humoral immune response in order to effectively address a Plasmodium intracellular infection. This immune response will preferably induce long lasting antibodies and a cell mediated immunity that can quickly respond upon exposure to Plasmodium. Two types of T cells, CD4 and CD8 cells, are generally thought necessary to initiate and/or enhance cell mediated immunity and humoral immunity. CD8 T cells can express a CD8 co- receptor and are commonly referred to as Cytotoxic T lymphocytes (CTLs). CD8 T cells are able to recognized or interact with antigens displayed on MHC Class I molecules. CD4 T cells can express a CD4 co-receptor and are commonly referred to as T helper cells. CD4 T cells are able to recognize antigenic peptides bound to MHC class Il molecules. Upon interaction with a MHC class 11 molecule, the CD4 cells can secrete factors such as cytokines. These secreted cytokines can activate B cells, cytotoxic T cells, macrophages, and other cells that participate in an immune response. Helper T cells or CD4+ cells can be further divided into two functionally distinct subsets: TH1 phenotype and TH2 phenotypes which differ in their cytokine and effector function. Activated TH1 cells enhance cellular immunity (including an increase in antigen-specific CTL production) and are therefore of particular value in responding to intracellular infections. Activated TH1 cells may secrete one or more of IL-2, IFN-gamma, and TNF beta. A TH1 immune response may result in local inflammatory reactions by activating macrophages, NK (natural killer) cells, and CD8 cytotoxic T cells (CTLs). A THI immune response may also act to expand the immune response by stimulating growth of B and T cells with IL-12. TH1 stimulated B cells may secrete igG2a. Activated TH2 cells enhance antibody production and are therefore of value in responding to extracellular infections. Activated TH2 cells may secrete one or more of IL-4, IL-5, IL-6, and IL- 10. A TH2 immune response may result in the production of IgGI. IgE, IgA and memory B cells for future protection. 55 An enhanced immune response may include one or more of an enhanced THI immune response and a TH2 immune response. An enhanced THI immune response may include one or more of an increase in CTLs, an increase in one or more of the cytokines associated with a THI immune response (such as IL-2, IFN-gamma, and TNF-beta), an increase in activated macrophages, an increase in NK activity, or an increase In the production of lgG2a. Preferably, the enhanced TH1 immune response will include an increase in lgG2a production. A TH1 immune response may be elicited using a TH1 adjuvant. A TH1 adjuvant will generally elicit increased levels of IgG2a production relative to immunization of the antigen without adjuvant. TH1 adjuvants suitable for use in the invention may include for example saponin formulations, virosomes and virus like particles, non-toxic derivatives of enterobacterial lipopolysaccharide (LPS), immunostimulatory oligonucleotides. lnimunostimulatory oligonucleotides, such as oligonuclectides containing a CpG motif, are preferred TH1 adjuvants for use in the invention. An enhanced TH2 immune response may include one or more of an increase in one or more of the cytokines associated with a TH2 immune response (such as iL-4, IL-5, IL-6 and IL-10), or an increase in the production of IgGI, IgE, IgA and memory B cells. Preferably, the enhanced TH2 immune resonse will include an increase in IgGI production. A TH2 immune response may be elicited using a TH2 adjuvant. A TH2 adjuvant will generally elicit increased levels of IgGI production relative to immunization of the antigen without adjuvant. TH2 adjuvants suitable for use in the invention include, for example, mineral containing compositions, oil-emulsions, and ADP-ribosylating toxins and detoxified derivatives thereof. Mineral containing compositions, such as aluminium salts are preferred TH2 adjuvants for use in the invention. Preferably, the invention includes a composition comprising a combination of a TH1 adjuvant and a TH2 adjuvant. Preferably, such a composition elicits an enhanced TH1 and an enhanced TH2 response, i.e., an increase in the production of both IgGi and 56 IgG2a production relative to immunization without an adjuvant. Still more preferably, the composition comprising a combination of a THI and a TH2 adjuvant elicits an increased THi and/or an increased TH2 immune response relative to immunization with a single adjuvant (i.e., relative to immunization with a TH1 adjuvant alone or immunization with a TH2 adjuvant alone). The immune response may be one or both of a THI immune response and a TH2 response. Preferably, immune response provides for one or both of an enhanced THI response and an enhanced TH2 response. The THI/TH2 response in mice may be measured by comparing IgG2a and IgGI titres, while the TH1/TH2 response in man may be measured by comparing the levels of cytokines specific for the two types of response (e.g. the IFN-y/IL-4 ratio). In one form of the method of treatment or preventiorrthe subject is a human. The human may be an infant, a child, an adolscent, or an adult. Use of the vaccine may be especially important in women in child-bearing years. Pregnant women, particularly in the second and third trimesters of pregnancy are more likely to develop severe malaria than other adults, often complicated by pulmonary oedema and hypoglycemia. Maternal mortality is approximately 50%, which is higher than in non-pregnant adults. Fetal death and premature labor are common. One way of montoring vaccine efficacy for therapeutic treatment involves monitoring Plasmodium falciparum infection after administration of the compositions of the invention. One way of checking efficacy of prophylactic treatment involves monitoring immune responses systemically (such as monitoring the level of IgGI and lgG2a production) against the Plasmodium antigens in the compositions of the invention after administration of the composition. Serum Plasmodium specific antibody responses may be determined post-immunisation and post-challenge. The uses and methods are for the prevention and/or treatment of a disease caused by Plasmodium (e.g. malaria) and/or its clinical manifestations (e.g. prostration, impaired consciousness, respiratory distress (acidotic breathing), multiple convulsions, circulatory collapse, pulmonary oedema (radiological), abnormal bleeding, jaundice, heemoglobinuria, etc.). 57 The compositions of the present invention can be evaluated in in vitro and in vivo animal models prior to host, e.g., human, administration. For example, in vitro neutralization an/or invasion inhibition is suitable for testing vaccine compositions (such as immunogeniclimmunoprotective compositions) directed toward Plasmodium. Reaction to the vaccine may be evaluated in vitro and in vivo following host e.g. human, administration. For example, response to vaccine compositions may examined by Enzyme-Linked ImmunoSorbent Assay (ELISA). For example, ELISA may be conducted as follows: Plates (e.g. flat-bottomed microtiter plates (Maxisorp from Nunc A/S or High Binding from Costar, Cat. No. 3590) may be coated with 50 pL of peptide solution or crude parasite antigen at 10 pg/mL in coating buffer. Keep the plate at 4"C overnight. With many proteins or peptides, PBS can be used as a coating solution. Block with 100 pL of 0.5% BSA in coating buffer for 3 to 4 h at 37"C. Wash 4 times with 0.9% NaC plus 0.05% Tween. Add 50 pL of serum samples diluted 1:1000; leave them for 1 h at 37"C. Wash 4 times with 0.9% NaCl plus 0.05% Tween. Add 50 pL of ALP-conjugated or biotinylated anti-Ig of appropriate specificity at the recommended concentration in Tween-buffer; leave for 1 h at 37"C. Wash the sample 4 times with 0.9% NaCl plus 0.05% Tween. If biotinylated antibody has been used, add 50 pL of streptavidin-ALP diluted 1:2000 in-Tween-buffer; leave the sample for 1 h at 37 0 C. Wash the sample 4 times with 0.9% NaC plus 0.05% Tween. Develop the sample with 50 pL of NPP (1 tablet/5 mL of substrate buffer) and read at OD 4 as. Infection may be established using typical signs and symptoms of malaria. The signs and symptoms of malaria, such as fever, chills, headache and anorexia. Preferably, more specific methods of diagnosis are preferred e.g. using a scoring matrix of clinical symptoms, light microscopy which allows quantification of malaria parasites (e.g. thick or thin film blood smears from patients stained with acridine orange or Giemsa, rapid diagnostic tests (e.g. immunochromatographic tests that detect parasite-specific antigens e.g. HRP2, parasite lactate dehydrogenase (pLDH), aldolase etc) in a finger prick blood sample, and polymerase-chain reaction. Vaccine efficacy may be measured e.g. by examining the number and frequency of cases of malaria (e.g. asexual Plasmodium falciparum at any level plus a temperature 58 greater than or equal to 37.5"C and headache, myalgia, arthralgia, malaise, nausea, dizziness, or abdominal pain), time to first infection with Plasmodium falciparum, parasitemia, geometric mean parasite density in first clinical episode, adverse events, anaemia (measured by for example packed cell volume less than 25% or less than 15%), absence of parasites at the end of immunization, proportion of individuals with seroconversion to the antigens of the present invention at e.g. day 75 post immunization, proportion with "efficacious sercconversion" to the antigens of the present invention (4 fold elevation in antibody titre) at day 75, number of symptomatic Plasmodium falciparum cases after 1, 2, or 3 doses, number of days until Plasmodium falciparum positive blood slide, density of Plasmodium falciparum, prevalence of Plasmodium falciparum, Plasmodium vivax, and Plasmodium malaria, levels of anti-Rh or anti-EBA (e.g. Rh1, Rh2, Rh4, EBA175, EBA181, EBA140 etc.) antibody by ELISA, geometric mean parasite density in first clinical episode, lymphocyte proliferation to Rh or EBA (e.g. Rh1, Rh2, Rh4, EBA175, EBA181, EBA140 etc.) T-cell responses to antigen frequency of fever, malaise, nausea, Malaria requiring hospital admission, cerebral malaria (e.g. Blantyre coma score <2) etc. The vaccine may be administered using a variety of vaccination regimes familiar to the skiller person. In one form of the invention, the vaccine composition may be administered post antimalarial treatment. Preferred antimalarials for use include the chloroquine phosphate, proguanil, primaquine, doxycycline, mefloquine, clindamycin, halofantrine, quinine sulphate, quinine dihydrochloride, gluconate, primaquine phosphate and sulfadoxine. For example, blood stage parasitaemia may be cleared with Fansidar (25 mg sulfadoxine/0.75 mg pyrimethamine per kg body weight) before each vaccination. In another form of the invention antimalarial (e.g. Fansidar) treatment is given 1 to 2 weeks before the doses (e.g. first and third doses). In another form of the invention antimalarial (e.g. Fansidar) treatment is given before the first dose. In another form of the invention, 3 doses of vaccine composition (e.g. 0.5 mg adsorbed onto 0.312 g alum in 0.125 mL) is administered in 3 doses, 2 mg per dose to > 5 year olds, 1 mg to under 5 year olds, at weeks 0, 4, and 25. In another form of the invention, 3 doses of vaccine composition (e.g. 1 mg per dose) are given subcutaneously at weeks 0, 4, and 26. In another form of the invention, 3 doses of vaccine composition is administered on days 0, 30, and 180 at different doses (e.g. 1 mg; 0.5 mg). In another 59 form of the invention, 3 doses of vaccine composition is administered at 3 to 4 month intervals either intramuscularly or subcutaneously. In another form of the invention 3 doses of vaccine composition is administered subcutaneously on days 0, 30, and about day 180. In another form of the invention, the vaccine composition is administered in 2 doses at 4-week intervals (e.g. 0.55 mL per dose containing 4 pg or 15 pg or 13.3 pg of each antigen). In another form of the invention, 3 doses of the vaccine composition is administered (e.g. 25 pg in 250 pL AS02A adjuvant) intramuscularly in deltoid (in alternating arms) at 0, 1, and 2 months. In another form of the invention 4 doses of the vaccine composition is given (e.g. 50 pg per 0.5 mL dose) on days 0, 28, and 150; and dose 4 given in the following year. In another form of the invention, where the vaccine is a DNA vaccine, the vaccine composition is administered in two doses (e.g. 2 mg on days 0 and 21 (2 intramuscular injections each time, 1 into each deltoid muscle). In another form of the invention, where the vaccine composition comprises an immunogenic molecule covalently linked to another molecule (e.g. Pseudomonas aeruginosa toxin A) the composition is administered in 3 doses (e.g. at 1, 8, and 24 weeks). The present invention may be used to generate invasion-inhibitory antibodies useful as in vitro diagnostic reagents, or as therapeutics for passive immunization. The term "antibody" includes intact immunoglobulin molecules, as well as fragments thereof which are capable of binding an antigen. These include hybrid (chimeric) antibody molecules; F(ab')2 and F(ab) fragments and Fv molecules; non-covalent heterodimers; single-chain Fv molecules (sFv); dimeric and trimeric antibody fragment constructs; minibodies; humanized antibody molecules; and any functional fragments obtained from such molecules, as well as antibodies obtained through non-conventional processes such as phage display. Preferably, the antibodies are monoclonal antibodies. Methods of obtaining monoclonal antibodies are well known in the art. Various immunoassays (e.g., Western blots, ELISAs, radioimmunoassays, immunohistochemical assays, immunoprecipitations, invasion-inhibition assays, or other immunochernical assays known in the art) can be used to identify antibodies having the desired specificity. Numerous protocols for competitive binding or immunoradiometric assays are well known in the art. Such immunoassays typically involve the measurement of complex formation between an immunogen and an antibody which specifically binds to the immunogen. A preparation of antibodies which specifically bind to a particular 60 antigen typically provides a detection signal at least 5-, 10-, or 20-fold higher than a detection signal provided with other proteins when used in an immunochemical assay. Preferably, the antibodies do not detect other proteins in immunochemical assays and can inimunoprecipitate the particular antigen from solution. The surface-exposed antigens of the invention can be used to immunize a mammal, such as a mouse, rat, rabbit, guinea pig, monkey, or human, to produce polyclonal antibodies. If desired, an antigen can be conjugated to a carrier protein, such as bovine serum albumin, thyroglobulin, and keyhole limpet hemocyanin. Depending on the host species, various adjuvants can be used to increase the immunological response. Such adjuvants include those described above, as well as those not used in humans, for example, Freund's adjuvant. Monoclonal antibodies which specifically bind to an antigen can be prepared using any technique which provides for the production of antibody molecules by continuous cell lines in culture. These techniques include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EBV-hybridoma technique. In addition, techniques developed for the production of "chimeric antibodies," the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity, can be used. Monoclonal and other antibodies also can be "humanized" to prevent a patient from mounting an immune response against the antibody when it is used therapeutically. Such antibodies may be sufficiently similar in sequence to human antibodies to be used directly in therapy or may require alteration of a few key residues. Sequence differences between rodent antibodies and human sequences can be minimized by replacing residues which differ from those in the human sequences by site directed mutagenesis of individual residues or by grating of entire complementarity determining regions. Alternatively, humanized antibodies can be produced using recombinant methods, as described below. Antibodies which specifically bind to a particular antigen can contain antigen binding sites which are either partially or fully humanized. Alternatively, techniques described for the production of single chain antibodies can be 61 adapted using methods known in the art to produce single chain antibodies which specifically bind to a particular antigen. Antibodies with related specificity, but of distinct idiotypic composition, can be generated by chain shuffling from random combinatorial immunoglobin libraries. Single-chain antibodies also can be constructed using a DNA amplification method, such as PCR, using hybridoma cDNA as a template. Single-chain antibodies can be mono- or bispecific, and can be bivalent or tetravalent. A nucleotide sequence encoding a single-chain antibody can be constructed using manual or automated nucleotide synthesis, cloned into an expression construct using standard recombinant DNA methods, and introduced into a cell to express the coding sequence, as described below. Alternatively, single-chain antibodies can be produced directly using, for example, filamentous phage technology. Antibodies which specifically bind to a particular antigen also can be produced by inducing in vivo production in the lymphocyte population or by screening immunoglobulin libraries or panels of highly specific binding reagents. Chimeric antibodies can be constructed. Binding' proteins which are derived from immunoglobulins and which are multivalent and multispecific, such as "diabodies" can also be prepared. Antibodies can be purified by methods well known in the art. For example, antibodies can be affinity purified by passage over a column to which the relevant antigen is bound. The bound antibodies can then be eluted from the column using a buffer with a high salt concentration. In another aspect the present invention provides use of a composition described herein in the manufacture of a medicament for the treatment or prevention of a condition caused by or associated with infection by Plasmodium falciparum. A further aspect of the invention provides a method of screening for the presence of a Plasmodium falciparum invasion-inhibitory antibody directed against a reticulocyte 62 binding homologue protein (Rh) of a strain of Plasmodium falciparum in a subject, comprising obtaining a biological sample from the subject and identifying the presence or absence of an antibody capable of binding to an immunogenic molecule as described herein. The method may further comprise identifying the presence of a Plasmodium falciparum invasion-inhibitory antibody directed against an erythrocyte binding antigen (EBA) of a strain of Plasmodium falciparum in a subject comprising identifying the presence or absence of an antibody capable of binding to an immunogenic molecule as described herein. The invention also provides nucleic acid encoding a polypeptide immunogenic molecule of the invention. The nucleotide sequence of Rh2b is given below (SEQ ID NO: 2) ATGAAGAGATCGCTTATAAATTTAGAAAATGATCTTTTTAGATTAGAACCTATATCTTAT ATTCAAAGATATTATAAGAAGAATATAAACAGATCTGATATTTTTCATAATAAAAAAGAA AGAGGTTCCAAAGTATATTCAAATGTGTCTTCATTCCATTCTTTTATTCAAGAGGGTAAA GAAGAAGTTGAGGTTTTTTCTATATGGGGTAGTAATAGCGTTTTAGATCATATAGATGTT CTTAGGGATAATGGAACTGTCGTTTTTTCTGTTCAACCATATTACCTTGATATATATACG TGTAAAGAAGCCATATTATTTACTACATCATTTTACAAGGATCTTGATAAAAGTTCAATT ACAAAAATTAATGAAGATATTGAAAAATTTAACGAAGAAATAATCAAGAATGAAGAACAA TGTTTAGTTGGTGGGAAAACAGATTTTGATAATTTACTTATAGTTTTAGAAAATGCGGAA AAAGCAAATGTTAGAAAAACATTATTTGATAATACATTTAATGATTATAAAAATAAGAAA TCTAGTTTTTACAATTGTTTGAAAAATAAAAAAAATGATTATGATAAGAAAATAAAGAAT ATAAAGAATGAGATTACAAAATTGTTAAAAAATATTGAAAGTACAGGAAATATGTGTAAA ACGGAATCATATGTTATGAATAATAATTTATATCTATTAAGAGTGAATGAAGTTAAAAGT ACACCTATTGATTTATACTTAAATCGAGCAAAAGAGCTATTAGAATCAAGTAGCAAATTA GTTAATCCTATAAAAATGAAATTAGGTGATAATAAGAACATGTACTCTATTGGATATATA CATGACGAAATTAAAGATATTATAAAAAGATATAATTTTCATTTGAAACATATAGAAAAA GGAAAAGAATATATAAAAAGGATAACACAAGCAAATAATATTGCAGACAAAATGAAGAAA GATGAACTTATAAAAAAAATTTTTGAATCCTCAAAACATTTTGCTAGTTTTAAATATAGC AATGAAATGATAAGCAAATTAGATTCGTTATTTATAAAAAATGAAGAAATACTTAATAAT TTATTCAATAATATATTTAATATATTCAAGAAAAAATATGAAACATATGTAGATATGAAA ACAATTGAATCTAAATATACAACAGTAATGACTCTATCAGAACATTTATTAGAATATGCA ATGGATGTTTTAAAAGCTAACCCTCAAAAACCTATTGATCCAAAAGCAAATCTGGATTCA GAAGTAGTAAAATTACAAATAAAAATAAATGAGAAATCAAATGAATTAGATAATGCTATA AGTCAAGTAAAAACACTAATAATAATAATGAAATCATTTTATGATATTATTATATCTGAA AAAGCCTCTATGGATGAAATGGAAAAAAAGGAATTATCCTTAAATAATTATATTGAAAAA ACAGATTATATATTACAAACGTATAATATTTTTAAGTTAA GTAATATTATAAATAAT AATAGTAAAAATATTAGTTCTAAATATATAACTATAGAAGGGTTAAAAAATGATATTGAT GAATTAAATAGTCTTATATCATATTTTAAGGATTCACAAGAAACATTAATAAAAGATGAT GAATTAAAAAAAAACATGAAAACGGATTATCTTAATAACGTGAAATATATAGAAGAAAAT GTTACTCATATAAATGAAATTATATTATTAAAAGATTCTATAACTCAACGAATAGCAGAT ATTGATGAATTAAATAGTTTAAATTTAATAAATATAAATGATTTTATAAATGAAAAGAAT ATATCACAAGAGAAAGTATCATATAATCTTAATAAATTATATAAAGGAAGTTTTGAAGAA TTAGAATCTGAACTATCTCATTTTTTAGACACAAAATATTTGTTTCATGAAAAAAAAAGT GTAAATGAACTTCAAACAAT TTTAAATACATCAAATAATGAATGTGCTAAATTAAATTTT ATGAAATCTGATAATAATAATAATAATAATAATAGTAAtATAATTAACTTGTTAAAAACT 63 CAATTAAGTCATCTATTAATCTTIAATATATAAAACTTTTAATCATATA GAACAAAATATTCAAAACTCATCL'&ATAAGTATACTATTACATATACTGATATTAAJTAAT AGAATGGAAGATTATAAAGAAGAAATCGAAAGTTTAGAAGTATATAAACATACCATTGGA AATATACAAAAAGAATATATATTACATTTATATCACAATGATAAAAATGCTTTAGCTGTA CATAATACATCAATGCAAATATTACAATATAGATGCTATAC ATATAAATA ATTTCTGATGATATAAAATTTTAAAGAATATAAAGAAATGAATCAGATTTATT\JXJT TATTATGAAATTCTAGATAAAAAATTACAAATATACATATATCAAGAAAJTGCATACT GCTTCTTTAGTTCAAATAACTCAATATATTCCTTATGAAGATAAACAATAGTGAACTT GAGCAAGAATTTAATAATAATAAT CAAAAACTTGATAATATATTACAAGATATCAATGCA ATGAATTTAAATATAAATATTCTCCWCCTTAATATTGGTATAAATGCATGTAATACA AATAATAAAAATGTGAATATACAAAATATAAATTTAA GACATAATAAAATACTAATCAAATAAAAACT TCATTTAAAAAGGAAATAAAAATAAGTTAAT AATAATTTGAAAATGGACATTCATAAATTGTTGAATTCGTATGACCATACAAAGCAAAAT ATAGAAAGCAATCTTAAA\TAATTTAGATTCTTTCGAAGGGAAAAAJGATAGTTGGGTT CATTAATCAAAATTTTGGATTAAAGATAAGC CATAATACTATCAAACAACAAAAAAPATGATATCATAGAACTTATTTATCGTATA GATATAAATCAAGAAATAATCGAAAAGGTAGATAATTATTATTCCCTGTCAGATAJ\JGCC TTAACTAAACTTAAATCTATTCATTTTAATATTGATG GGAATATATCCCA21. AGTCAAGAAAATATTAAATTATTAGAAGATAGAGTTATGATACTTGAGAUAAAGATTAAG GAAGATAAAGATGCTTTAATACAAATTAAGAATTTATCACATGATCATTTTGTAAATGCT GATAATGAGAAAAAAAAGCAGAAGGAGAAGGAGGAGGACGACGACAJAACACATATAGT AAAAGAATAGGGTTTTAGAATAAAACAAGGT AATAATAAAAATTTGATAGATATTACTTTAAATGAAGCAAATAAAATAGAATCAGAATAT GAAAAAATATTAATTGATGATATTTGTGAACAATTACAATGAGCXAJAAAAGTGAT ACTATTAAGGAAAAAATCGAATCATATAAAAAAGATATTGATTATGTAGATGTGGACGTT TCCAAAACGAGGA&CGATCATCATTTGAAGGAGAT~AJ\JTACATGATTCTTTTTTTTAT GAGTCTAATTAGAATTGTATAAGTTTTAATT AACAAGTTAACAAATGAATCAAATGGATTAAAAAGTGATGCTCATAATAACAACACACAA GTTGATAAACTAAAAGAATTAATTTACAAGTATTCAGCAATTTAGGTATATTA TATGTTGAAAAACTTGAGAATACATTACATGAACTTAP.AGATATGTACGATTTCTAGAA ACACAATAAATTAAATATAATGAGAAACGAA TAATAGACAAAAATGACACGAAAACATATTT GAGTTGATTGAAGCATACCACAGAGTAAGTA CAATAGTAAAATATGTTAAAAGATTCAAAG AAACAAGTGAATAAATACATAACAGATATTGAATCTAATAAAGAACAATCAGATTTACAT TTACGATATGCATCTAGAAGTATATATGTTATTGATCTTTTTATACATGATAATA AATCCTAGCGATGGAAAAAATTTTGATATTATAAAGGTTAAAGAAATGATAAATAA.ACC AAACAAGTTTCWATGAAGCTATGGAATATGCTATAAATGGATGAAAAT1AGGAC ATTATAAAAATAGAAJ\ATGAACTTTATAATTTAATTAATAATAACATCCGTTCATTAAJJAA GGGGTAAAATATGAAJAAAGTTAGGAAACAAGCAAGAATCCATTGATGATATAJATAAT ATACATTCTAATATTAAhAACGATTTTAACCAAATCTAAAGAACGATTAGATGAGATTAAG AAACAACCTAACATTAAAAGAGAGGTGATGTTTTAATATGATAJACCpjAjTAGCT TATATTACAATACAAATAATAACGGAAGAATAGAATCTAATTTATTTATATTAT ATGAAACATAACATAGATACTATCTTGAATAAAGCTATGGATTATATGAATGA7GTATCA AAATCTGACCAGATTGTTATTAATATAGATTCTTTGAATATGAACGATATATATAATAAG GATAAAGATCTTTTAATAATATTTTAAGAAACAGAATATGGAGGCAGAATATA AAATGAATGAAATGTATAATTACGTTAATGA cAGA AGATATpAACATzAAA AAATAGAAAGATAGACAAnAAAGACAAGA AAAAAA AAATTTATGGAATCTAATAACAAATCATTAACTACTTTAATCGATTCATTCAGATCTATG TTTTATAATGAATATATAIATGATTATAATATAJ&ATGAAATTTTGAAACATCAAALAT ATTGAGATTTAGATATGACTTAATTATCAAT 64 ACTGAATTATAAATGATAATTTAGATTATAATGAAATAAGAAATTAAAGAAGTAGCA CAAACAGAATATGATAAACTTATAAAAGTTGATGAATTAAAAAATTATTTGATAAT ATTAAGAACAAGAAGGACATCGATTAATTGATTATATAAAAGAAAAATATTTA&,TTA TATATAAAATGTTCAGAACAACAAAATATAATAGATGATTCTTATAATTATATTACAGTT AAAAAACAGTATATTAAAACTATITGAAGATGTGAAATTTTTATTAGATTCATTGAACACA ATGAAAAAAACGACATCAAATGATAAAAGTT AAATTCTACTTAAATGGAATTCGTTATTAGC GATACAAATACGGAAATAACTCCAGAT AATCCTTTAGAAGATAATGATTTATTAAATTTA CAATTATATTTTGAAAGAAAACATGAAATAACATCAACATTGGAAAATGATTCTGATTTA GAGTTAGATCATTTAGGTAGTAATTCGGATGAATCTATAGATAATTTJ\AGGTTTATJXT GATATTATAGAATTACACACATATTCAACACAATTCTTAAATATTTAcATAATATTCAA AACTTAAAGGAGATTGCAATGATTTAGTA4AGGATTGTAAAGAATTACGTGAATTGTCT ACGGCATTATATGATTTAAAATACAAATTACTAGTGTAATTATAGAGAAAA~JTGATATT TCAAATAATATTGATATTGTATCTAATAAATTAAATGAJATAGATGCTATACAATATAAT TTTGAAAAATATAAAGAAATTTTTGATAAT GTAGAAGAATATAAAACATTAGATGATACA AAATCTTTGAAAGCGAATTAAAGAAAAAAAC AAAGAAGATTTAGATATATATTTTATGACTTAGACopATTAGAxsAJTCTCTTACATTA TCATICTAATGAAATGGAAATTAAAACAATAGTACAGAACTCATATAJATTCGTTTTCTGAT ATTAATAAGAACATTAATGATATTGATAAAGAAATGAAAACACTGATCCCTATGCTTGAT GATATATAGAAATTGTAACTAAATTAATAAA ATTCAGATTAAAATAGGTAATGATATAAAAAATATAAGAGAACAGGAAAJATGATACTAAJT ATTTTGGAATAATATTATTAAAATAAAGACT AATAAATATGATGATCATATAAAAGTAGATAATTATATATCTAATAATATTGATGTTGTC AATAAACATAATAGTTTATTAAGTGAACATGTTATAAATGC-TACW-aTATTATAGAGAXT ATTATGACAAGTATTGTCGAAATAAATGAAGATACAGAAATGAATTCTTTAGA&GAGACA CAGCATATGATTTAATTTAAAAAAAATTATA AATTATAAAATAGTACATTTTAATAAATTAAAAGAAATAGAAAATAGTTTAGAGACATAT AATTCAATATCAACCTTTAAT AATTGACACTATAATATTTTAA AATGAATTTAATAATATCAAAACAAATTAATGATAAGT\J\JAGAJTTAGTTCATGTT GATAGTACATTAACACTTGAATCAATTCAAACGTTTAATAATrTTATATGGTGACTTGATG TCATTCAAGAAAAAGAGTTATAGTATGAAGT AAATTATATATAGAAAATATTACAAATTTATTAGGAAGAATAAACACATTCATAAAGGAG TTAGACAAATATCAGGATGAAAATAATGGTATAGATAAGTATATAGAATCAATAAGGAUX AATAATAGTTATATAATAAATTGAAAGAAAAAGCCAATAATCTAAAGGAAAATTTCTCA AAAT TATTACAAAATATAAAAAGAAATGAA CT GAATTATATAATATAAATAACATAAAG GAGTTAGAAGGAACGAATAAAACAATTCATA TTGCCACTAAAAGAAAAATTATTTCWATGGAAGAGATGTTACTTAATATAATAATATT ATGAATGAAACGAAAGAATATCAAACACGGATGCATATACTI\JTATAAJCTCTCCAGGAT ATTGAAAATAATAAAAATAAAGAAAATAATAATATGAATATTGAAX2CAATTGATAATTA ATAGATCATATAAAATACATAATGAAAATACAAGCAGAATATTAATATTGAGAT GCCAAAAGAAAAGTAAAGGAAATAACAGATAATATTAACAAGGCTTTTAATCAAATTACA GAAAATTATAATAATGAAAATAATGGGGTAATTAAATCTGCAAAAATATTGTCGATAA GCTACTTATTTAAATAATGAATTAGATAAATTTTTATTGAAJTTGXJATGPJ\TTATTAAGT CAATAATAAAAGTTGTGTAAATAATAAAGAA GAAAGAAAAGAAAGAGAAAGATTGGAAAAGCGAAACAAGAAGAAGWAGAAAAGAGAGA GAAAGAATAGAAAAAGAAAAACAAGAGAAAGAAAGACTGGAPAGAGAGWACAAGAACAA C TAAAAAAAGAAG CAT TA AAAAACAAGAGCAAGAAAGACAAGAACAACAACPAAAACAA GAAGCATTAAAAAGACAAGAACAAGAACGACTACAAAAGAAGAAGATTAAJ\GACAA GACAAAGTGAGGGACAGAACAAAAAGAATAG AAAAACGAAAACAAAAATTCAATAAGGAAAA CCTGAAATAATAATGAAGCATTGGTAAGGGGGATP2ATACTAGAGGAXGT GATCAG AGAAATATGGAATTAAGCAAACCTAACGTTAGTATGGATAATACTAATAATAGTCCA&TT 65 AGTAACAGTG7AAATTACAGAAAGCGAT GATATTGATAACAGTGAAAATATACATACTAGT CATATGAGTGACATCGAAAGTACACAAACTAGTCATAGAAGTAACACCCATGGGCAACAA ATCAGTGATATTGTTGAAGATCAAATTAcACATCcTAGTAATAkTT GGAGGAGAAAAAATT ACCTAGTAATCACCGTGAGATAATGGTTATA TATAGTGAAAGTAGCAACATATTTGAAATGGTGACAGTACTATATACCAGTACAAGA AACACGTCTAGTACACATGATGAATCCCATATAAGTCCTATCAGCAATGCGTATGATCAT GTGTCGTAAAAAGAGAGAACTAAAAATAAAGATAGAT GAAAGTATAACTACAGATGAACAAATAAGATTAGATGATAATTCTAATATTGTTAGAATT GATAGTACTGACCAACGTGATGCTAGTAGTCATGGTAGTAGTAATAGGGATGATGATGAA ATAAGTCATGTTGGTAGCGACATTCATATGGATAGTGTTGATATTCATGATAGTATTGAC ACTGATGAAAATGCTGATCACAGACATAiXTGTTAACTCTGTTGATAGTCTTAGTTCTAGT GATTACACTGATACACAGAAAGACTTTAGTAGTATTATTAcATccGGcGTAA~cAGA GGACATGCTGAGAATGAATCTAAAGAATATGAATCCCAACAGpCwAACAATGAAGAA GGAATTATGAATCCAAATAATATTCAATTAGTGAAGTTGATGGTATT TTATGA GAAGCTAAACATA1V4ATTACAGAAAAACTGGTAGATATCTATCCTTCTACATATAGAJiCA CTTGATGAACCTATGGAAAGACATGGTCCAAATGAJXAAATTTCATATGTTTGGTAGTCCA TAGACGAAGTAAGAAACTATTAAGAGAATCA AAGAGTTCACAACAAGGTATCTTTAGTGGAT GTTTGTTGTGTATTATTTTTTGCAAGTATTACTTTCTTTTCTATGGACAGATC\ATAAJG GATGAATGCGATTTTGATATGTGTGAAGAAGTAAATAATAATGATCACTTATCGAATTAr GCGTAGAAATTGATGGTTAGAAGAAAAATTA The nucleotide sequence of Rh4 is given below (SEQ ID NO:4) ATGAATAAGAATATATTGTGGATAACTTTTTTTTATTTTTTATTTTTTCTGTTGGATATG TACCAAGGAAATGACGCAATTCCCTCAAA\GAAAAAAAAAA CGATCCAGAAGOAGATTCT AAACCCGACAAGTTATAACCCAAGAATATTA CTGAATATTAAGGATAAAGATGAGAAAAAAAGAAAAAATGATAATTTAATCAATAATTAT GATCCCTTAGTTTAATAGACAAAAAAGAAAA AA TGGCGAAAAGCTTAAAACAGACATAATATTAAACTCATTGTTCgAxAvTAAvTTCATCA AACATATTAATGGATGAAATAGAAAATTATGTGAAAAAATATACGGAATCGAATCGTATT ATGTACTTACAATTTAAATATATATATCTACAATCCTTAAATATAACAGTATCTTTTGTA CCTCCGAATTCACCATTTCGAAGTTATTATGACAAAAATTAAATAAAGATATAATG\AA ACTTGTCATTCCATACAAACACTTCTAAACAATCTAATATcTTCCAAAATTATATTTAAA ATGTTAGAAACTACAAAAGAACAAATATTACTTTTATGGAATAACAAAAAAATTAGTCAA CAATAATAGAACAAAAATAAGTGTCGAAGAA CTAGAAAAGTACACAAACAAGTTTGAACATAATATCAAACCTCATATAGAAGATATAGAG AAAATATATTTATATCGTGCTTAAGTAATTA ACAATTATCAATAATTATATAGATGAAATAATAACAACTAATACAACATATAGAAAAJC AATTACACCAACATACAAATTACTAGTTATA GATGATAATTTTATAGAATATATATTCTTAATGCAGATCCTGATTTAAJGATCTCATTTT ATAACACTTCTTGTTTCAAGAAAACAATTAATCTATATTGAATATATTTATTTTATTAAC AACTTGAAAATCAAACTTATAACAAAAAAAA T TTATTAATTCAAATAATGCTGTTAATGCTGCTAAAGATATGA2XTATATCATPJ\JAJTAT TATACTACATTCAAATATCTACAGACATTAAATAAAT CATTATACGACTCTATATATAAA CATAAAATAAATAATTATTCTCATAACATTGAACATCTTATAAACCAACTACAAJCATA ATTAATAACCTAATGAT TATCTCATTCGATATAATCATCAGATTTATGTTACAA TGTACAAATATAABAAATATACCGATGATATATGTTTATCCATTAACCTAAAJGCATTA GAAGTCGAATATTTAGAAATTAATAAACACATCCAJTGATTCC pJATA TTCATGCAAAACGAAACATTTAAAAAAATATAGATGATAATCAAGWPTGATAAT ATTCAATTTTTAATAACAATCTACATAAGAT 66 TTACACTCTAAGGTATAAAAAAACAACAAACAATGATACAAAAATTAAT ACTTTTAATATGTATTATAACGATATACA PAATPAAGATTAATCAAATGAA TT TAAGCAAATTTTAGAATTAGA)GAACATTATATTACAACA ATACATAC CTAAATTTTACACACAAAACTATTCAACAATATTACAACAACATATAdxAxxsCzxAAA GAATTAATACCTATCACACAACAATACAACCAATGTATACAAAcATATATAGAA CAATACATCCTATAAACAATTACTTCAAAAC GAACATACTATT TATACACTATAT GAAGAATCAAAC? T CTG GIAACAT CGAACAG AAATTCAAAAACACAAATGTAAAAAATAAAT -TTACATATAAAAGCATACAAAAAACATATA GAAAAAATTGGGTTACGACAATGGAATAGGTTGAGGGAATATGAAGAJTA&JA AAGGCAAATCTTCAAGATAGGGACATAATATATAGTCCTAATGATGCTAATAAT AAATAATTATTATAGTATACACGTATTACCT TTCTTCGATTATACTCACCTTTGGGATAATGCACAATTTACTAGAACAnAGAA\ATAPA AAACTAAAATTCATACAAAATTAAGAATAAA TTACAAAACGAACTAAACAATTATAATACTCTTAAAAGCAATTCCATCCATATTTATGAT AAAAAAATGAATAAAATACCAAATAGTAATT ATCAGAAAATATATGATATTGAACCATATATCAAATGATTTACATACATA11JXGP ATTATTAAAAATATTACAAGCATTTATTACAAAATAAATATCTTWATATATTAATTATT TGCCAT CAAACAAACATATAATA \TAATAAAT CCATTGAA GCT TAAA t ACT TAAI&ATTAAT AACTTAACAAATTCAACACAAGAATATATTAATCAAATAAAGCTATCCCAACTAATTTA TTACCAGAACATATAAAACAAAAAATTAACGACTAATATTTATATGA\ACAXATA TATGATAAATTAAATGAACATGTTATTIATAATTTATATACAAAATCAXAAGGATTCATTA CAATTTTATATTAACGAAAAAAATTATAATAATAATCATGATGATCATAATGATGACCAT AATGATGTATATAATGATATCAAAGAAAATAAATATATAAATAATAAATTATACGAA TGCATACAAATCAAAAAGGATGTAGACGAATTATATAATATTTATGATCAACTCTTTAAAJ AATATATCCCAAAATTATAATAACCACTCCCTTAGTTTTCTACATTCAATAAATAATCAT ATGCTATCTATTTTT CAAGATACTAAATATGGAAAACACp.AAAATCAACAAATCCTATCC GATATASAAAATATTATAAAACAAAATGAACACACAGAATCATATAAAPJATTTAGACACA AGTAATATACAACTAATAAGAACAAATT.AAATATTTCTTACAAATATTTCATATACTT CAAGAAAATATAACCACTT TCCAAAATCAATATAAAGATTTAATTATCAAAATGAACCAT AAAATTAATAATAATCTAAAGATATTACACATATTGTCATAAAJCGATAACJ\TACATTA CAAGAACAAAATCGTATTTATAACGAACTTCAAIACAAAATTAAACAAATAJAJ\AATGTC AGTGATGTATTCACACATAATATTAATTACAGTCAACAAATATTAAATTATTCT CAAGCA CAATGTTTATTTTTAATTAACTATAGTTATG AAACGATATAATGTACAAAAAAATTACAGAGATATCA4TTCATATGATATAATAAAJT TAACAATAACAGTTTTCAATCAATTCAACAT AATACAACAGAAACGCAATTGAATCATATAAAACAAAATATTAATCATTTCAJATATTTT TAGACCTAACTTTTGAAGAAGAATAAATAAT CAAGAATTCAACAAAAAAATACAACACTTCAAGGAAGACACAJ\ATTATGATAJACAAG TTAATACAACCTAGCCACATACATTTACATflJATGTTGCCTATAACTCAACA55p3\ CTTAATACAATTCTTCATAGAAATGAACAAACAAAAAATGCTACAAGAAGTTACAATATG AATCAGGAGGAAAATGAAATGGGATATGGCATAACTAATAAAAGGAAAAATAGTGAGACA AATGACATGATAAATACCACCATAGGAGACAAGACAATGTCTTAAAAAAT GATGATCAA GAAAAAGGTAAAAGGGGAACTTCCAGAAATAATAATATTCATACAAATGAAAATAATATA AATAATGAACATACAAATGAAATAATATAATAATGAACATACTGAAGAATATA AATAATGAACATGCAAATGAAGAATATATATAATGAACATACAATGAJAAATpATATA AATTATGAACATCCAAATATTATCAACAAAAAAATGATGAAAJ\ATATCACTACAACAT AAAACAATTAATACATCACAACGTACCATAGATGATTCGAATATGGATCGAAATAATAGA 67 TATAACACATCATCACAACAAAAAAATAATTTGCATACAAATAATAATAGTAATAGTAGA TACAACAATAACCATGATAAACAAAATGAACATAAATATAATCAAGGAAAATCTTCAGGG AAAGATAACGCATATTATAGAATTTTTTATGCTGGAGGAATTACAGCTGTCTTACTTTTA TGTTCAAGTACTGCATTCTTTTTTATAAAAAACTCTAATGAACCACATCATATTTTTAAT ATTTTTCAAAAGGAATTTAGTGAAGCAGATAATGCACATTCAGAAGAAAAAGAAGAATAT CTACCTGTCTATTTTGATGAAGTTGAAGATGAAGTTGAAGATGAAGTTGAAGATGAAGAT GAAAATGAAAATGAAGTTGAAAATGAAAATGAAGATTTTAATGACATATGA The nucleotide sequence of EBA175 is given below (SEQ ID NO: 6) ATGAAATGTAATATTAGTATATATTTTTTTGCTTCCTTCTTTGTGTTATATTTTGCAAAA GCTAGGAATGAATATGATATAAAAGAGAATGAAAAATTTTTAGACGTGTATAAAGAAAAA TTTAATGAATTAGATAAAAAGAAATATGGAAATGTTCAAAAAACTGATAAGAAAATATTT ACTTTTATAGAAAATAAATTAGATATTTTAAATAATTCAAAATTTAATAAAAGATGGAAG AGTTATGGAACTCCAGATAATATAGATAAAAATATGTCTTTAATAAATAAACATAATAAT GAAGAAATGTTTAACAACAATTATCAATCATTTTTATCGACAAGTTCATTAATAAAGCAA AATAAATATGTTCCTATTAACGCTGTACGTGTGTCTAGGATATTAAGTTTCCTGGATTCT AGAATTAATAATGGAAGAAATACTTCATCTAATAACGAAGTTTTAAGTAATTGTAGGGAA AAAAGGAAAGGAATGAAATGGGATTGTAAAAAGAAAAATGATAGAAGCAACTATGTATGT ATTCCTGATCGTAGAATCCAATTATGCATTGTTAATCTTAGCATTATTAAAACATATACA AAAGAGACCATGAAGGATCATTTCATTGAAGCCTCTAAAAAAGAATCTCAACTTTTGCTT AAAAAAAATGATAACAAATATAATTCTAAATTTTGTAATGATTTGAAGAATAGTTTTTTA GATTATGGACATCTTGCTATGGGAAATGATATGGATTTTGGAGGTTATTCAACTAAGGCA GAAAACAAAATTCAAGAAGTTTTTAAAGGGGCTCATGGGGAAATAAGTGAACATAAAATT AAAAATTTTAGAAAAAAATGGTGGAATGAATTTAGAGAGAAACTTTGGGAAGCTATGTTA TCTGAGCATAAAAATAATATAAATAATTGTAAAAATATTCCCCAAGAAGAATTACAAATT ACTCAATGGATAAAAGAATGGCATGGAGAATTTTTGCTTGAAAGAGATAATAGATCAAAA TTGCCAAAAAGTAAATGTAAAAATAATACATTATATGAAGCATGTGAGAAGGAATGTATT GATCCATGTATGAAATATAGAGATTGGATTATTAGAAGTAAATTTGAATGGCATACGTTA TCGAAAGAATATGAA3ACTCAAAAAGTTCCAAAGGAAAATGCGGAAAATTATTTAATCAAA ATTTCAGAAAACAAGAATGATGCTAAAGTAAGTTTATTATTGAATAATTGTGATGCTGAA TATTCAAAATATTGTGATTGTAAACATACTACTACTCTCGTTAAAAGCGTTTTAAATGGT AACGACAATACAATTAAGGAAAAGCGTGAACATATTGATTTAGATGATTTTTCTAAATTT GGATGTGATAAAAATTCCGTTGATACAAACACAAAGGTGTGGGAATGTAAAAAACCTTAT AAATTATCCACTAAAGATGTATGTGTACCTCCGAGGAGGCAAGAATTATGTCTTGGAAAC ATTGATAGAATATACGATAAAAACCTATTAATGATAAAAGAGCATATTCTTGCTATTGCA ATATATGAATCAAGAATATTGAAACGAAAATATAAGAATAAAGATGATAAAGAAGTTTGT AAAATCATAAATAAAACTTTCGCTGATATAAGAGATATTATAGGAGGTACTGATTATTGG AATGATTTGAGCAATAGAAAATTAGTAGGAAAAATTAACACAAATTCAAATTATGTTCAC AGGAATAAACAAAATGATAAGCTTTTTCGTGATGAGTGGTGGAAAGT TATTAAAAAAGAT GTATGGAATGTGATATCATGGGTATTCAAGGATAAAACTGTTTGTAAAGAAGATGATATT C-AAAATATACCACAATTCTTCAGATGGTTTAGTGAATGGGGTGATGATTATTGCCAGGAT AAAACAAAAATGATAGAGACTCTGAAGGTTGAATGCAAAGAAAAACCTTGTGAAGATGAC AATTGTAAACGTAAATGTAATTCATATAAAGAATGGATATCAAAAAAAAAAGAAGAGTAT AATAAACAAGCCAAACAATACCAAGAATATCAAAAAGGAAATAATTACAAAATGTATTCT GAATTTAAATCTATAAAACCAGAAGTTTATTTAAAGAAATACTCGGAAAAATGTTCTAAC CTAAATTTCGAAGATGAATTTAAGGAAGAATTACATTCAGATTATAAAAATAAATGTACG ATGTGTCCAGAAGTAAAGGATGTACCAATTTCTATAATAAGAAATAATGAACAAACTTCG CAAGAAGCAGT TCCTGAGGAAAGCACTGAAATAGCACACAGAAZCGGAAACTCGTACGGAT GAACGAAAAAATCAGGAACCAGCAAATAAGGATTTAAAGAATCCACAACAAAGTGTAGGA GAGAACGGAACTAAAGATTTATTACAAGAAGATTTAGGAGGATCACGAAGTGAAGACGAA 68 GTGACACAAGAATTTGGAGTAAATCATGGAATACCTAAGGGTGAGGATCAAACGTTAGGA AAATCTGACGCCATTCCAAACATAGGCGAACCCGAAACGGGAATTTCCACTACAGAAGAA AGTAGACATGAAGAAGGCCACAATAAACAAGCATTGTCTACTTCAGTCGATGAGCCTGAA TTATCTGATACACTT CAATTGCATGAAGATACTAAAGAAAATGATAAACTACCCCTAGAA TCATCTACAATCACATCTCCTACGGAAAGTGGAAGTTCTGATACAGAGGAAACTCCATCT ATCTCTGAAGGACCAAAAGGAAATGAACAAAAAAAACGTGATGACGATAGTTTGAGTAAA ATAAGTGTATCACCAGAAAATTCAAGACCTGAAACTGATGCTAAAGATACTTCTAACTTG TTAAAATTAAAAGGAGATGTTGATATTAGTATGCCTAAAGCAGTTATTGGGAGCAGTCCT AATGATAATATAAATGTTACTGAACAAGGGGATAATATTTCCGGGGTGAATTCTAAACCT TTATCTGATGATGTACGTCCAGATAAAAATCATGAAGAGGTGAAAGAACATACTAGTAAT TCTGATAATGTTCAACAGTCTGGAGGAATTGTTAATATGAATGTTGAGAAAGAACTAAAA GATACTTTAGAAAATCCTTCTAGTAGCTTGGAT GAAGGAAAAGCACATGAAGAATTATCA GAACCAAATCTAAGCAGTGACCAAGATATGTCTAATACACCTGGACCTTTGGATAACACC AGTGAAGAAACTACAGAAAGAATTAGTAATAATGAATATAAAGTTAACGAGAGGGAAGGT GAGAGAACGCTTACTAAGGAATATGAAGATATTGTTTTGAAAAGTCATATGAATAGAGAA TCAGACGATGGTGAATTATATGACGAAAATTCAGACTTATCTACTGTAAATGATGAATCA GAAGACGCTGAAGCAAAAATGAAAGGAAATGATACATCTGAAATGTCGCATAATAGTAGT CAACATATTGAGAGTGATCAACAGAAAAACGATATGAAAACTGTTGGTGATTTGGGAACC ACACATGTACAAAACGAAATTAGTGTTCCTGTTACAGGAGAAATTGATGAAAAATTAAGG GAAAGTAAAGAATCAAAAATTCATAAGGCTGAAGAGGAAAGATTAAGTCATACAGATATA CATAAAATTAATCCTGAAGATAGAAATAGTAATACATTACATTTAAAAGATATAAGAAAT GAGGAAAACGAAAGACACTTAACTAATCAAAACATTAATATTAGTCAAGAAAGGGATTTG CAAAAACATGGATTCCATACCATGAATAATCTACATGGAGATGGAGTTTCCGAAAGAAGT CAAATTAATCATAGTCATCATGGAAACAGACAAGATCGGGGGGGAAATTCTGGGAATGTT TTAAATATGAGATCTAATAATAATAATTTTAATAATATTCCAAGTAGATATAATTTATAT GATAAAAAATTAGATTTAGATCTTTATGAAAACAGAAATGATAGTACAACAAAAGAATTA ATAAAGAAATTAGCAGAAATAAATAAATGTGAGAACGAAATTTCTGTAAAATATTGTGAC CATATGATTCATGAAGAAATCCCATTAAAAACATGCACTAAAGAAAAAACAAGAAATCTG TGTTGTGCAGTATCAGATTACTGTATGAGCTATTTTACATATGATTCAGAGGAATATTAT AATTGTACGAAAAGGGAATTTGATGATCCATCTTATACATGTTTCAGAAAGGAGGCTTTT TCAAGTATGCCATATTATGCAGGAGCAGGTGTGTTATTTATTATATTGGTTATTTTAGGT GCTTCACAAGCCAAATATCAAAGGTTAGAAAAAATAAATAAAAATAAAATTGAGAAGAAT GTAAATTAA The nucleotide sequence of EBAIi81 is given below (SEQ ID NO:8) ATGAAAGGGAAAATGAATATGTGTTTGTTTTTTTTCTATTCTATATTATATGTTGTATTA TGTACCTATGTATTAGGTATAAGTGAAGAGTATTTGAAGGAAAGGCCCCAAGGTTTAAAT GTTGAGACTAATATAATAATAATAATAATA ATAATAATAGTAATAGTAACGATGCG ATGTCTTTTGTAAATGAAGTAATAAGGTTTATAGAAAACGAGAAGGATGATAAAGAAGAT AAAAAAGTGAAGATAATATCTAGACCTGTTGAGAATACATTACATAGATATCCAGTTAGT TCTTTTCTGAATATCAAAAAGTATGGTAGGAAAGGGGAATATTTGAATAGAAATAGTTTT GTTCAAAGATCATATATAAGGGGTTGTAAAGGAAAAAGAAGCACACATACATGGATATGT GAAAATAAAGGGAATAATAATATATGTATTCCTGATAGACGTGTACAATTATGTATAACA GCTCTTCAAGATTTAAAAAATTCAGGATCTGAAACGACTGATAGAAAATTATTAAGAGAT AAAGTATTTGATTCAGCTATGTATGAAACTGATTTGTTATGGAATAAATATGGTTTTCGT GGATTTGATGATTTTTGTGACGATGTAAAAAATAGTTATTTAGATTATAAAGATGTTATA TTTGGAACCGATTTAGATAAAAATAATATATCAAAGTTAGTAGAGGAATCATTAAAACGT TTTTTTAAAAAAGATAGTAGTGTACTTAATCCTACTGCTTGGTGGAGAAGGTATGGAACA AGACTATGGAAAACTATGATACAGCCATATGCTCATTTAGGATGTAGAAAACCTGATGAG AATGAACCTCAGATAAATAGATGGATTCTGGAATGGGGGAAATATAATTGTAGATTAATG 69 AAGGGP,\-AAAAATTTTACAGAGATGTCTGTAAAGAAAAATCGACTGC TCACCAGATAGGGTTCTTGATTATAAAAAAA GAGCTCTCTATATTAGGAAAAAATATATTAAAGTAGTACGATATACTATATTTAGGAGA AAAATAGTT CAACCTCATAATGCTTTGGATTTTTTATATAATTGTTCTGAGTGTAAJG GATATTCATTTTAAACCCTTTTTTGAATTTGAATATGGTATAT CAACAAJAAATCTATG TGCACTTTGTTAATCATTAATAGTTTTCTTA GCCACGTCGTCACAAAGTTGCTAAGAAATTA CCATGGAAATGTGATAAAAATTCTTTTGAAACAGTTCATCATJAAGGTGTATGTGTGTCA CCGAGAAGACAAGGTTTTTGTTTAGGAATTT GAACTATCTACTGAATGATCATATTTAT AATGTACATAATTCACAACTACTTATCGAAATTATAATGGCTTCTAACAGAAcGAAAG TTTAGAAACTGAATCTGTACGAGAGAAAAAA GAATAGTATTAGTTGTATGATATAGATAACA TCTATAAAAGTTCAAAATAATTTAATTTAATTTTTGAAAGATTTTGGTTATN\JAGTT GGAAGAAATAAACTCTTTAACAATTWGATTAAAATCTATGCTGGATATTAT AGATAGAGGACAGGTTGATGCAGAACAGAAA ACTTAAATGTACAAACAGCCATTTGTGTTAA TGGAATCTTTAGAAGATTGGATAATATAAAG ACGTAATGAACTAGCGGTAAAGCAAGGGATA ATGAATTATTGGACATATACTAGAAATTACTTATGAATACATCCGTJX.PTATGAT AAGTGAATTTGCTCAAGCAATTATCTTTAGA AAGAAATGTTAAAATTAAAAATGTACTAAAT TTAGAAAGTAGAGAAACATTAAGAAACAGAT TTTTTGCCATGGAAGGAAAAAGGGAATGGGA GATAAGAACCATTTATGCCATGATAGATGAA AGTAAGGATGAAAAGCAACCTGAAAGAAGCAAACAAACTAATGG;J\CTTTA\CCGTA CGAT~-AGTCGTGACAGAAGTCGTCGTCAAA TCCTAATTAATCGACTGACATGGACAAAGAA CCCAATACGACTTAAATAATAAGAATAAGAA GCCAACAAAAGAAGACAAAAACAAGAAGAACAACCAAAAAJJ\J AACAAGAACAACAACAGAAAAAGAAGAAGAA CAAAACAAGAAGAAGACAACAATACAiGATCAATCACAxJ\JGTGcATTAcATCpAkTCC TCAAAAGTAGCACTAGCGAGTGAACAAnTGTTTCTAGGACAGACAAAACGTA AAAAGCTCTTCACCTGAAGTAGTTCCACAAGAAACAACTAGTGAJ\JAJTGGGTCATCACAJ\ GACACAAAAATATCAAGTACTGAACCAAATGAGAATTCTGTTGTAATAGAGCJIJCAGAT AGAGATAACTAAGTCTATAATTATACAAAAA ACTGACAAGACTAAAAGTAAGAGTGTAGCAAAA CTCACATTTAGATATTATACGAGTAATCCAC GAAGATACTCCTACTGTTGAGGAAAAGTAGGAATAGCAGATGTTAACTTCTCCG CAGGCGTATTATGATAGTTATCATAGCTAAC ACGTGGTTAAACAAAATAGGAGGAGGACGAC TCAAGATTGAACTAGTGTACTCCTAAACGAC GTCTCGTCATGAAAGATAATATAAGAACAAA ACGAAGGGGGAAACAGATCCTCGAAGTAATGACCAAGAAGATGCTACTGACGATGTTGTA GAATGAAAGTAATGCCTTAACTGTACAGATT TTAAATAGAGAAGATCCTATTGCTTCTGAACTGAGTTGTA GTGAJCCTGAGGATTCA AGTAGGATAATCACTACAGAAGTTCCAAGTACTACTGTAACCCCCTGATGAAAACGA TCGAAGAGGAAGACAAGATAATGACGTTCAG GCCATTGGAGAACCAATGGAJAJATTCTGTGAGCGTACAGTCCCCTCCTJXTCTAGJAGAT GTGAAGACTGTTTAATATGTAAATAAAAAAG AATATCAGTCAAAACCATTTAATCGATATTCATTTTTAcATGAAGCGGGTAGTACA ATATTAGATGATTCTAGAAGAAATGGAGAAATGACAGAAGGTAGCGWAGTGATGTTGGA GAATTACAAGAACATAATTTTAGCACACAACAlJ\AGATGAAJ\AGATTTGACCJAATT 70 GCGAGCGATAGAGAAAAAGAAGAAATTCAAAAATTACTTAATATAGGACATGAAGAGGAT GAAGATGTATTAAAAATGGATAGAACAGAGGATAGTATGAGTGATGGAGTTAATAGTCAT TTGTATTATAATAATCTATCAAGTGAAGAAAAAATGGAACAATATAATAATAGAGATGCT TCTAAAGATAGAGAAGAAATATTGAATAGGTCAAACACAAATACATGTTCTAATGAACAT TCAT TAAAATATTGTCAATATATGGAAAGAAATAAGGATTTATTAGAAACATGTTCTGAA GACAAAAGGTTACATTTATGTTGTGAAATATCAGATTATTGTTTAAAATTTTTCAATCCT AAATCGATAGAATACTTTGATTGTACACAAAAAGAATTTGATGACCCTACATATAATTGT TTTAGAAAACAAAGATTTACAAGTATGCATTATATTGCCGGGGGTGGTATAATAGCCCTT TTATTGTT TATTTTAGGTTCAGCCAGCTATAGGAAGAAT TTGGATGATGAAAAAGGATT C TACGATTCTAATTTAAATGATTCTGCTTTTGAATATAATAATAATAAATATAATAAATTA CCTTATATGTTTGATCAACAAATAAATGTAGTAAATTCTGATTTATATTCGGAGGGTATT TATGATGACACAACGACATTTTAA The nucleotide sequence of EBA140 is given below (SEQ ID NO:10) ATGAAAGGATATTTTAATATATATTTTTTAATTCCTTTAATTTTTTTATATAATGTAATA AGAATAAATGAATCAATTATAGGTAGAACACTTTATAATAGACAAGATGAATCATCAGAT ATTTCAAGGGTAAATTCACCCGAATTAAATAATAATCATAAAACTAATATATATGATTCA GATTACGAAGATGTAAATAATAAATTAATAAACAGTTTTGTAGAAAATAAAAGTGTGAAA AAAAAAAGGTCTTTAAGTTTTATAAATAATAAAACAAAATCATATGATATAATTCCACCT TCATATTCATATAGGAATGATAAATTTAATTCACTTTCCGAAAATGAAGATAATTCTGGA AATACAAATAGTAATAATTTCGCAAATACTTCTGAAATATCTATTGGAAAGGATAATAAA CAATATACGTTTATACAGAAACGTACTCATTTGTTTGCTTGTGGAATAAAAAGAAAATCA ATAAAATGGATATGTCGAGAAAACAGTGAGAAAATTACTGTATGTGTTCCTGATAGAAAA ATACAACTATGTATTGCAAATTTTTTAAACTCACGTTTAGAAACAATGGAAAAGTTTAAA GAAATATTTTTAATTTCTGTTAATACAGAAGCAAAATTATTATATAACAAAAATGAAGGA AAAGATCCCTCAATATTTTGTAATGAATTAAGAAATAGTTTTTCAGATTTTAGAAATTCA TTTATAGGTGATGATATGGATTTTGGTGGTAATACAGATAGAGTCAAAGGATATATTAAT AAGAAGTTCTCCGATTATTATAAGGAAAAAAATGTTGAAAAATTAAATAATATCAAAAAA GAATGGTGGGAAAAAAATAAAGCAAATTTGTGGAATCACATGATAGTAAATCATAAAGGA AACATAAGTAAAGAATGTGCCATAATTCCCGCGGAAGAACCTCAAATTAATCTATGGATA AAAGAATGGAATGAAAACTTCTTGATGGAAAAGAAGAGATTGTTTTTAAATATAAAAGAT AAGTGTGTTGAAAACAAAAAATATGAAGCATGTTTTGGTGGATGTAGGCTTCCATGTTCT TCATATACATCATTTATGAAAAAAAGTAAAACACAAATGGAGGTTTTGACGAACTTGTAT AAAAAGAAAAATTCAGGAGTGGATAAAAATAATTTTCTGAATGATCTTTTTAAAAAAAAT AATAAAAATGATTTAGATGATTTTTTCAAAAATGAAAAGGAATATGATGATTTATGTGAT TGCAGATATACTGCTACTATTATTAAAAGTTTTCTAAATGGTCCTGCTAAAAATGATGTA GATATTGCATCACAAATTAATGTTAATGATCTTCGAGGGTTTGGATGTAATTATAAAAGT AATAATGAAAAAAGTTGGAATTGTACTGGAACATTTACGAACAAATTTCCTGGTACATGT GAACCCCCCAGAAGACAAACTTTATGTCTTGGACGTACATATCTTTTACATCGTGGTCAT GAGGAAGATTATAAGGAACATTTACTTGGAGCTTCAATATATGAGGCGCAATTATTAAAA TATAAATATAAGGAAAAGGATGAAAATGCATTGTGTAGTATAATACAAAATAGTTATGCA GATTTGGCAGATATTATCAAGGGAT CGGATATAATAAAAGATTATTATGGTAAAAAAATG GAAGAAAATTTAAATAAAGTAAACAAAGATAAAAAACGTAATGAAGAATCTTTGAAGATT TTTCGTGAAAAATGGTGGGATGAAAACAAGGAGAATGTATGGAAAGTAATGTCAGCAGTA CTTAAAAATAAGGAAACGTGTAAAGATTATGATAAGTTTCAAAAGATTCCTCAATTTTTA AGATGGTTTAAGGAATGGGGAGACGATTTTTGTGAGAAAAGAAAAGAGAAAATATATTCA TTTGAGTCATTTAAGGTAGAATGTAAGAAAAAAGATTGTGATGAAAATACATGTAAAAAT AAATGTAGTGAATATAAAAAATGGATAGATTTGAAAAAAAGTGAATATGAGAAACAAGTT 71 GATAAATACACAAAAGATAAAAATAAAAAGATGTATGATAATATTGATGAAGTAAAAAAT AAAGAAGCCAATGTT TACTTAAAAGAAAAATCCAAAGAATGTAAAGATGTAAAT T TCGAT GATAAAATTTTTAATGAGAGTCCAAATGAATATGAAGATATGTGTAAAAAAT GTGATGAA ATAAAATATTTAAATGAAATTAAATATCCTAAAACAAAACACGATATATATGATATAGAT ACATTTTCAGATACTTTTGGTGATGGAACGCCAATAAGTATTAATGCAAATATAAATGAA CAACAAAGTGGGAAGGATACCTCAAATACTGGAAATAGTGAAACATCAGATTCACCGGTT AGTCATGAACCAGAAAGTGATGCTGCAATTAATGTAGAAAAGTTAAGTGGTGATGAAAGT TCAAGTGAAACAAGAGGAATATTAGATATTAATGATCCAAGTGTTACGAACAATGTCAAT GAAGTTCATGATGCTTCAAATACACAAGGTAGTGTTTCAAATACTTCTGATATAACGAAT GGACATTCGGAAAGTTCCCTGAATAGAACAACGAATGCACAAGATATTAAAATAGGCCGT TCAGGAAATGAACAAAGTGATAATCAAGAAAATAGTTCACATTCTAGTGATAATTCAGGT TCTTTGACAATCGGACAAGTTCCTTCAGAGGATAATACCCAAAATACATATGATTCACAA AACCCTCATAGAGATACACCTAATGCATTAGCATCTTTACCATCAGATGATAAAATTAAT GAAATAGAGGGTTTCGATTCTAGTAGAGATAGT GAAAATGGTAGGGGTGATACAACATCA AATACTCATGATGTACGTCGTACGAATATAGTAAGTGAGAGACGTGTGAATAGCCATGAT TTTATTAGAAACGGAATGGCGAATAACAATGCACATCATCAATATATAACGCAAATTGAG AATAATGGAATCATAAGAGGACAAGAGGAAAGTGCGGGGAATAGTGTTAATTATAAAGAT AATCCAAAGAGGAGTAATTTTTCCTCCGAAAATGATCATAAGAAAAATATACAGGAATAT AATTCTAGAGATACTAAAAGAGTAAGGGAGGAAATAATTAAATTATCGAAGCAAAATAAA TGCAACAATGAATATTCCATGGAATATTGTACCTATTCTGACGAAAGGAATAGTTCACCG GGTCCTTGTTCTAGAGAAGAAAGAAAGAAATTATGTTGTCAGATTTCAGATTATTGTTTA AAATATTTTAACTTTTATTCAATTGAATATTATAATTGTATAAAATCTGAAATTAAAAGT CCAGAATATAAATGTTTTAAAAGCGAGGGTCAATCAAGCATTCCTTATTTTGCTGCTGGA GGTATTTTAGTTGTAATAGTCTTACTTTTGAGTTCAGCATCTAGAATGGGGAAAAGTAAT GAAGAATATGATATAGGAGAATCTAATATAGAAGCAACTTTTGAAGAAAATAATTATTTA AATAAACTATCGCGCATATTTAATCAAGAAGTACAAGAGACAAACATTTCAGATTATTCC GAGTACAATTATAATGAAAAGAATATGTATTAA The nucleotide sequence of Rh2a is given below (SEQ ID NO:12) ATGAAGACCACACTATTTTGTAGCATATCTTTTTGTAATATTATATTTTTCTTCTTAGAA TTAAGTCATGAGCATTTTGTTGGACAATCAAGTAATACCCATGGAGCATCTTCAGTTACT GATTTTAATTTTAGTGAGGAGAAAAATTTAAAAAGTTTTGAAGGGAAGAATAATAATAAT GATAATTATGCTTCAATTAATCGTTTATATAGGAAGAAACCATATATGAAGAGATCGCTT ATAAATTTAGAAAATGATCTTTTTAGATTAGAACCTATATCTTATATTCAAAGATATTAT AAGAAGAATATAAACAGATCTGATATTTTTCATAATAAAAAAGAAAGAGGTTCCAAAGTA TATTCAAATGTGTCTTCATTCCATTCTTTTATTCAAGAGGGTAAAGAAGAAGTTGAGGTT TTTTCTATATGGGGTAGTAATAGCGTTTTAGATCATATAGATGTTCTTAGGGATAATGGA ACTGTCGTTTTTTCTGTTCAACCATATTACCTTGATATATATACGTGTAAAGAAGCCATA TTATTTACTACATCATTTTACAAGGATCTTGATAAAAGTTCAATTACAAAAATTAATGAA GATATTGAAAAATTTAACGAAGAAATAATCAAGAATGAAGAACAATGTTTAGTTGGTGGG AAAACAGATTTTGATAATTTACTTATAGTTTTAGAAAATGCGGAAAAAGCAAATGTTAGA AAAACATTATTTGATAATACATTTAATGATTATAAAAATAAGAAATCTAGTTTTACAAT TGTTTGAAAAATAAAAAAAATGATTATGATAAGAAAATAAAGAATATAAAGAATGAGATT ACAAAATTGTTAAAAAATATTGAAAGTACAGGAAATATGTGTAAAACGGAATCATATGTT ATGAATAATAATTTATATCTATTAAGAGTGAATGAAGTTAAAAGTACACCTATTGATTTA TACTTAAATCGAGCAAAAGAGCTATTAGAATCAAGTAGCAAATTAGTTAATCCTATAAAA ATGAAATTAGGTGATAATAAGAACATGTACTCTATTGGATATATACATGACGAAATTAAA GATATTATAAAAAGATATAATTTTCATTTGAAACATATAGAAAAAGGAAAAGAATATATA AAAAGGATAACACAAGCAAATAATATTGCAGACAAAATGAAGAAAGATGAACTTATAAAA AAAATTTTTGAATCCTCAAAACATTTTGCTAGTTTTAAATATAGCAATGAAATGATAAGC 72 TTTAATATATTCAAAAAAAATGAACATATGTAGATATGCTTGATCTA TATACAACAGTAATGACTCTATCAGAACAT TTATTACAATATGCAATGGATGTTTTAJ4JI GCTAACCCTCAAAAACCTATTGATCCAAAAGCAATCTGATTCAAAGTAGTAAATTA CAAATAAAAATAAATGAGAAATCAAATGAATTAGATPATGCTATAAGTCAAGTAAAAA.JCA CTAATAATAATAATGAAATCATTTTATGATATTATTATATCTGAAAAA\JGCCTCTATGGAT GAAGAAAAGATTCTLATATAATAAACGTAAAT CAAGAATTTTATTIkGATTAAAATAATAATT AGTTCTAAATATATAACTATAGAAGGGTTAAAATGATATTGATGATTAAATAGTCTT ATTAATTAGTCCAALCTATAAAGTATAAAAA ATGAAAACGGATTATCTTAATAACGTGWATATATAGAAGAAAATGTTACTCI TATAJIAT GAATTTATAAATTTATCAGAACGTTGTATAA AGTAATATATTATATTAAAGAAATTTAAGGA GTATCATATAATCTTAATAAATTATATAAAGGAAGTTTTGAAGAATTAGAATCTGAACTA TCTCATTTTTTAGACACAAAATATTTGTTTCATGA~AAAcAAoTG1TAATACTTCxAA ACATTAAAACATAGAGGTATAATTTAACGTA AAATAATAATGATTATACTTAAATATAGCTT TTATTAAAATTAAAAACTTATAAAACAAATA AATACATATTCATCTTATAATAATGAGAGTA AAGAAACAATTGATTTAAAACTGAAAAAAAA TAAATCTTTTAATAAAATCTACGAAATCTAT CAAATATTACAATATAAAGATGCTATACAATATNAT1\2\JAATTTCTGATGATATA AAATTAGATTArAAGACAATATATATTAATT GATAAAAAATTAAAAGATAATACATATATCAAGAAAJTGCATACTGCTTCTTTAGTTCA ATAACTCAATATATTCCTTATGAAGATAACATAGTGAACTTGAGCA\GAATTTAJAT AAATACAACTAATTTACAAACAGATATTATT AAATTCACTAAATGAAATCTTAAAAATAATT GAACACTTACTTAACAAGAAAATTGAATTAAATATATTATGATCTGAATT ATAAAGTAAATCAAATGAAGAATTCATTTAA AAGAAGAATTGAAGATGTAACATTAATTAAT GAATAAATTGATGAGCCTCAGAATTGAGATT AAAATAAATTTAGATTCTTTCGAAAAGGAAAAAGATAGTTGGGTTCATTTTAAAAGTACT ATAGATAGXTTATATGTGGAATATAACATATGTAATCAAAAGACTCATAAJTACTATCXAA CACAAATAACTGATATTTACTTAAAAAACAA ATACAAGTGTATTATCCGCGTAGCTATACTA TCATATTAATAAGAAATTAATCAAGCAAATT AAAVTATTAGAAGATAGAGTTATGATACTTGA~GAAAAAGATTAAGGAAGATAAAGATGCT TTAAAATAATTTAAGTCTTGAAGTAATAAAA AAGCAGAAGGAGAAGGAGGAGGACGACGAACAAACACACTATAGTAAAAJ\JAGAAAAGTA ATGAAAAAAGAATAAAACTGTATAAATAATT ATGTTATTATAGAAAAAAATAATTAAATTAT GATGATATTTGTGAACAAATTACAAATGAGCAAAAAGTGATACTATTAGG2X1\J\ ATCGAATCATATAAAAAAGATATTGATTATGTAGATGTGGACGTTTCCAAAACGAGGAAC GACTATGAGAAAATCTGTCTTTTTAGTCTAA TAAACTTTGTATAAGTTAAGAAAAAAGTAAA GAATCAAATGGATTAAAAAGTGATGCTCATAATAACAACAcATToATAAAJCTAn GAATATAAGATACATAGAAAATAAAGTAAAT GAATCTAAGATAAAAGTCATTTGACACAATA AAAATAAGATAATGAGAGATAAGAAATAGAC AAAAAAATATTTGAACAATCACTAAATATAACTAATCAAT~TTATAGAAGATGTTGAAATA TTAACTTTACCACAGAACTATAGTAATAGTA ATAAAATCACTTGTTCTAAAGAAAGAGGAAATATCCGJAAGJAJXJCAATGJ\TAAAI. TACATAACAGATATTGAMTCTAATAAAGAACAATCAGATTTACATTTACGATATGCATCT AGAAGTATATATGTTATTGATCTT TTTATAAAACATGAAArAATAAATCCTAGCGATGGA AAAAATTTTGATATTATAAAGGTTAAAGAATGATTAACGAAAJCAGTTTCWAT GAGTTGAAGTAAATGTGAAATAGCTAAAAAA AATGAACTTTATAATTTA1TTAATAATAACATCCGTTCATTAAGGGGTAAAAATG7A 73 AAAAGAGAAGGTGATGTTTTAAATAATGATACCAAATAGCTTATATTACh1JTACAA ATAAATAACGGAAGAATAGAATCTTTTATTA.ZTATATTTATGAAACATACATA GATACTACTTGAATAAAGCTATGGATTATATTGATGTATCAATCTQ-ACCAGATT GTATAAAATTTATTACGTTTTAAGAAAACTT ATAAATATTTTAAAGAAAACAGAATATGGGCAGTATAAATGAATGATG TAATAGTAGACGAAGAAATAAAAAAATAGAT AGAATTATGGAACATATAAAAAGAMACAATGAAAAAAAAAAAAXTTTATGGATCT AAACATATATCTATGTTATAACAGTTTAGAA ATAAATGATTATAATATAAATGAAAATTTTGAAACATCATATATTGJATGATA TAATGTTAGACTTAATATAAAAAGCGATAAA GAATTGTAATAAAAGAATAGATGAAAAATTA AAACTTAATAAAAAAGTTGATGAATTAATTATTTGATTATTAJJGAC?\GA GGACATCGATTAATTGATTATATAAAAGAAAATATTTAACTTATATATAAAATGTTCA GACAAATTAAAGTCTTATAATCGTAAAATTT AAATTGAAGGATTTTAGTCTGAAATGAAAAA AATATGAACAAATGATATAGAAAAAATTCTA CATGTTATAAAGTTGGCAAATTTTTCAGGTATTATTGTAJTGTCTGATACWTACGGA ATAACTCCAGAAAATCCTTTAGAGATATGATTTATTAATTTACJATTATATTTTGAA AGAAAACATGAAATAACATCAACATTGGAAAATGATTCTGATTTAGAGTTAGATCATTTA CGTAGTAATTCGGAGAATCTATAGATAATTTAGGTTTATATGTATTATAGATTA CACACATATTCAACACAAITTCTTAAATATTTAGATAJTATTCACTTWAGGAGAT TGCAATGATTTAGTAAAGGATTGTAAAGAATTACGTGAJ\TTGTCTACGGCATTATATGAT TTAAAAATACAAATTACTAGTGTAATTATAGAGAATGATATTTAATATATTGAT ATGACATATAAGATGTGTTCAAATTGAATTA GAAATTTTTGATAATGTAGAAGAATATAAACATTAGATGATACnAAJ\TGCATATATT GTAAAGTAATTAAAGAGTTATAAAAGAATAA ATATATTTTAATGACTTAGACGAATTAGAAJATCTCTTACATTATCATCTAJATGAAATG GAATAAATGAAACCTTATCTTCGTTATAACT AATGATATTGATAAAGAATGAACACTGATCCCTATGCTTGATGTTATTmTGAA GGACAAATATTGATATATCATTATATTTTTATATTAGWTATTCAATTAA1ATA GGATAAAAATTAAACGGAAGTCATTTTTGGA ATCAAATAATTAAAATGTTATTTCAAAAGTA CATATAAAAGTAGATAATTATATATCTAATTATTGATTTGTCAAT~AxCATzATAGT TTTAGGAAGTTATCAAATTAAAATTAGCATT GTGATATAGTCGATATTTTGAAAAAGCATAT GACAAGAATTAAAAAAATTAAAATATTAAAT CATTTTAATAAATTAAGAAATAGAATAGTTTAGAGACATATATTCAATATCAACA AATTAAATATAAAAATAAAATTAAAGATATA ATCAAAACAAAAATTAATGATAAAGTJAAGAA2TTAGTTCATGTTGATAGTACATTAACA CTTGAATCAATTCAACGTTTAATATTTATATGaGACTTGATGTCTATATACAAGAT GTATATAAATATGAAGATATTAATAATGTTGTTGAAGGTGAAATTATATATAGAA AATATTACAAATTTATTAGGAAGAATACACATTCATAAAJGGAGTTAGACATATCAG GAGAAATGAAAAGAAAGATATAGAAATGTTT ATAAAATTGAAAGAAAAGCCAATTCTAGpATTTCTCAAAATTATTAcAAAT ATAAGATAATATAAATAAAACTAGAGTTAGA ACGGATTTATAAAACAAATTTGATTCATAAA AATATCATGAAAGTCTAAAAATTA(ATAAGA AGAATATCAAJCACGGCTGCATATACTATATA\CTCTCCAGGATATTGAATATA AAAAAATAATTATTGAAATGTATATGTAAAA ATCTAGAALTCACGATTATATAGTCAAGAAT AAGGAAATAACAGATAATATTAACAAGGCTTTTAATAATTACAGAATTATATAAT CAAAATAATGGGGTAATTATCTGAAATATTGTCGATGAAGCTACTTATTTAT AAGATGTATTTTGATGATATATATAATAATA ATAGACTGGTAAATAATAAGAAGAAAAAGAG GAAATGAAGGACAAGAGAGAAAAAAAATGAA 74 GAAAAACAACAGAAAGAAAGACTGGAAGAGAGAACAAGAACAACTAAAAAGAAGAA AGACAAGAACAGAACGACTACAAAAAGAAGAATTpAAGCAAGAGCAAAAAGG GAACGACTACAAAAAGAAGAAGCATTAAAAAGACAAGAACAAGAACGACTACAAAAA.GAA AAAGAAGAAGAATTAAAAAGACAAGAACAAGAACGACTACAAAAAGAAGAAGCATTAAAA CTGGAAAGAAAGAAAATCGAGTTAGCAGAAAGAGAACAACACATAAPAAGTAAACTAGAA TCTGATATGGTGAAATAATAAAGGATGAACTAACAAAAGAAAAAGATGAAATAATAAAA AACAAAGATATAAAACTTAGACATAGTTTGGAACAGwATGGTTAAAACATTTACAAAAT ATATTATCGTTAAAAATAGATAGTCTATTAATAAAAATGATGAGGTCATAAAAGATAAT GAGACACAATTGAAACAAATATATTGAACTCATTAApAAATCmjTTATATCTTAATTTG AAACGTGAAGTTAATGAAATTATAAAGGAATACCAAGAAAACCAGAAAAXJIJTATTGCAT TCAAATCAACTTGTTAACGATAGTTTAGAGCAAA\1CTA TAGACTCGTCGATATTXJA CCTACAAGCATGGTGATATATATACTAATAAACTTTCTGATAATGAAACTGAAATCCTG ATAACATCTAAAGAAAAAAAAGATGWACAGAATCAACTAAAAATCAGGAACAGATCAT ACTAATAGTTCGGAAAGTACTACTGATGATAATACCAATGATAGAAATTTTTCTCGATCA AAGAATTTGAGTGTTGCTATATACACAGCAGGAAGTGTAGCTTTATGTGTGTTAATATTT TCTAGTATAGGATTATTACTTATAAAGACTAATAGTGGAGATAACAATTCTAATGAAATT AATGAAGCTTTTGAACCGAATGATGATGTTCTCTTTAAGGAGXAGGATGAApATCATTGAA ATCACTTTTAATGATAATGATAGTACXAfTTXJX The nucleotide sequence of Rid is given below (SEQ ID NO:14) ATGCAAACGTGGATTTTCTGCAACATTGTTTTGCATATATTAATTTACTTAGCAGAATTT AGCCATGAACAGGAAAGTTATTCTTCCAATGAAAAAATAAGAAAGGACTATTCAGATGAT AATAATTATGAACCTACCCCTTCATATGAAAAGAAAJAAGATATCAAAAATGAAX AGTTATATAAAAAATTACAGAGGTAAPAATTTTTCCTATGATTTGTCTAAA.ATTCrAGT ATATTTCTTCACATGGGTAACGGTAGTAACTCGAAAcACATAAAcAATTAACAGAAA AAAAATATAAAGACCAATTTTTTAAGACCTATCGAGGAAGAGAAAACGGTATTmATAAT TATGTATATAAAGGTGTWTTTTTTAGATACATAAAGAATGATTTTTATXJA TTTGATGTTTATAAACATACTTCCTTTTTAAAAAATAGAGAATATAAAGAATTAATTACT ATGCAGTATGATTATCCTTATTTAGAAGCAACAAAAGAGGTTCTTTATTTAATTCCGAAG GATAAAGATTATCACAAATTTTATAAAAATGAACTTGAGAAAATTCTTTTCAATTTAAAA GATTCACTTAAATTATTAAGAGAACGATATATACAAAGCAAACTGGAAATGATTAGAATC CATTCGGATATAGATATATTAATGAGTTTCATCAAGGATATATAACGATATTAT TTTAATAATGAAATAALAAAAAAAGGAAGACATGGAAAAATATATAJ\GAGAATATAAT TTATACATATATAAATATGAAAATCAGCTTAAAATAAAATACAAAATTAACAAXPGAA GTTTCTATAAATTTAAATAAATCTACATGTGAAAAGAATTGTTATAATTATATTTTAAAA TTAGAAAAATATAAAAATATAATAAAAGATAAGATAAATAAATGGAAAGATTTACCAGAA ATATATATTGATGATAAAAGTTTCTCATATACATTTTTAAGATGTAATATAATAAG ATAGATATATATAAAACAATAAGTTCTTTTATATCTACTCAGAAACAATTATATTATTTT GAATATATATATATAATGAATAAAAATACATTAACCTACTTTCATATAATATACAAAAAA ACAGATATAAATTCTAGTAGTAAATACACATATACAAAATCTCATTTTTTAAAIAGATXAT GATATATTGTTATCTAAATATTATACTGCCAAJATTTATTGATATCCTAAATAAAACATAT TATTATAATTTATATAAAATAAAATTCTTTTATTCAATAAATATATTATAAAGCTTAGA AACGATTTAAAAGAATATGCATTTAAATCTATACAATTTATTCAAGATAAAATCAAAAAA CATAAGATGAATTATCCATAGAAATATATACAAAAGTTATAATATATATATAAAA TATGATACTTCGATAAATGAAATATCTAAATArAACAATTTAATTATPAATACTGATTTA CAAATAGTACAACAAAAACTTTTAGAAATCAAACAAAAAAAAAATGATATTACACACAAA GTACAACTTATAAATCATATATATAAAAATATACATGATGAAATATTAAACAAiAAAT AATGAAATAACAAAGATTATTATAAATAATATAAAAGATCATAAAAAAGATTTACAA3AT CTCTTACTATTTATACAACAAATCAAACAATATAATATATTAACAGATCATAAAICTACA CAATGTAATAATTATTATAAGGAAATCATAAAAATCAAAGAAGATATAAJXTCATATTCAT 75 TTAAAAAAAATTATTCTCTTAAZ\AGATGAAGCACAATTAGACATTACCCTCCTCGATGAC CTAATACAAATAATGAGACGATTCAACTTATTTCTGGACAAGJAGATAAACATGAATGC AACATATAAAAACAATCAAAAAAAAATAACT CAATTCTPACTGAATGATTACCTCTGCCATC AATTTTAACAAGTTGATACCAAGTAAAAGAA ATATATTTGAAAAAATGAAACAAAAAGCACA GAAAAAAAGACTAACAAACCTTGTAATTAAC ATAAAGTTCCAGATATCAATATAAAAGAGAG TACGAAGACGGTTAATTACATAATACAAGAA GAAATAAGACAAATCACTCAAACAAATTTA GATAATATATATGCTAAGGAAAAGGAAATTCGCTCGGGACAATATTATJkGGATTTTATC ACTAGAAAATAATTAGGAAAACAAAGAAAGT AAATAGAAGAA~AAAATTTTGTATTATTTAAA TATGTAAAAATGCTTAAAATGGAGACACACAAGATCAATAATAATATAAJTATGAT ATATACGACAAGTTAATTGTCCCCCTTGATTCATAAACAJ&J&TATCGATWATACAA2C ACGAAATTAACTTCATAATATCCTAAGAACA GAAATGATGGAAGAATTCATATATGCATATAGGTTAATTTTAJ\TATTAAAT ATTCTAACTTAAAAATAACACAAATATAAAC CAGATAAAATTAAAGAAAACTTCAAGTTTAC AGCATTAAAAAGTTTATAAGTTTAAGATGAA TATATTATAGATGTACACAAATTAAAAATCAACATCTATTTACTATTATGAA CATCAATATCATTAACAAAGTATTAAAAAAC ATAAATATATGTGTTAAATTTATAATAAAA TATCAAACATTATATGAAAJAATAAATGTACTCCTACATATTCAA~AAATTATGTA CAATACTTTTATGATCATATAATATCTAATTCTTCAJAAAAATTATTTGG~AAT ACTTTAAAGACAAAAATACAAGATAACGAACATTCACTAUATGCTTTACAYACAATGMA GATCAAGTAGAGAAGTCAAGATAGAATACAT ATGAAATAATAAATAATTAACAATACATGAA AAAATATTGAGTTACAAATGCTCTAGGATGATCWATATAATACCTTA AATGAGGTTAAGAAAAAAATAATATATACATATGAGGTAGATATCPJAATATCGAAC GTTAAATAGAAGAAGAGAAGTAATTGAAATT AACGATGCGGATGATACAACGATATTGATGAAATAGAGATATTGATGAATJACGAT ATTGATGAAATAACGATATTGATGATAACATATGATGATAAAGCATTGAC CATATAAAACATTTTGACGATACAAAACATTTTGACGATATATACCATGCTGATGATACA CGGTATCAAACCTCATTTTAGCGATAAAAAA CTGCAAGAAATAACAATATTAJTATTTAAAGTTCAATCTGCACACA GAAATTAAAAAAGAATCAGAACAAATTAATAAAGAATTTACCAAAATGGATGTCGTCATA AATCAATTAGAGATATAGACAGATGCTTGATCTTTATAGATTAGATGpApaxn TATTATTAAACAATGAGATATAAAGGAAATA AATGTGGAAATATGGTATGAAAAAAIUATATAATTGAATATTTCTTACGTCATAGAATGAT CAAAAAGATAAAGCTGCAAATATATGGAJACATTGATACATATp1JJAxTATATTGpAk ATATGAAAAAACAAATTTTGACTAAAACATT TATTCTTATGTAGAAAAGGCTAATGATCTATTTTATACTATAATATATCATA AATAACATAAAGACTTAATGTATAAATTCAA AACAGAAAAAATCTCTTACAAGAACAACAJATTATTCAGTATACTAATAGJA AAAATATAATAATTATACTTATTACATAAAC ATCCTTCAAGATATATCACAAATATAATCATGTTAGTATATATACGGACATTACAT AATTTATATATAAAATTAGAAGAAGAAAGAACAAATGAAACACTCTATCATAAATCA AATGTGTTACATAACCAATTAATTTTATGAAGATGCTTTTATTATAATTTATTAATT AAAAAAATAAAGTTAACTTAGAAACATTTTT ATAGATGTAAACAAATCTAAAAATAATGCTCAACTATATTTTCATATACACTPAAQGGT AAGAAAAATTTAAACTAGATACACACATATT CAAGAATTAAAACAAGTACAAGAfGTGAGAGGPAAAGATATATACATCAPACT ATAAAATATGAAGAAGAATTAAJWAATATCATATTATACAGATTATGAGATAA 76 ATAAATGATATTTTACATAATTATTTATTCAATAAAATGGATCTAC~ATAAT AAAAAACAAACAAAACAAATTATAGACATATAJXACGATAAMACATTTGAGPAACATATA AAAACATCCAAAACCA 1MTAACATGCTAAsGACAATCAATpj CATATAGAC AAACTTTATTAAATGAACAAGCACTCAAATTATTTGTAGATATTAATTCTACTAATAAT AATTTAGATAATATGTTATCTGAATAATTCTATACAXJATAATATACATACATATATC CAAGAAGCAAACAAATCATTTGACAAATTTAAAATTATATGTGATCAJXATGTAAACGAT TTATTAAACAAATTA.AGTTTAGGAGATCTAAATTATATGAATCATTTAAAATcTGCAA AACGAAATAAGAAACATGAATCTAGAAAAATTTCATGTTAGATAAGTxAA~AAATA GAGGAGAAAATGTTTAAATACTTAAAAAATC TTAGATAAATTAAAAAAATATTACGAAGAAGCGCTCTTTCAAAAGGTTJXAGAAAPJ\GCA GAAATTCAAAAGGAAAATATAGAAAAAATAAJAACAAGAAATAAATACACTGAGCGATGTT TTTAAGAAACCATTTTTTTTATACAACTTAATACAGATTcATCACAAcATGApAcAAT ATACAATTGACTTAATATTGTAAAAATTTTT CAATCATATAATTTAATACAAAAATATTCTTCAGAp.ATTTTTTCATCCACCTTGAATTAT ATCACAAAAAAGAATCTAGAAACATAACAA GAAAAGGPIAGCATCTGTTTTATTAAAAAATATAAAAATAAATGAAACCATAAAATTATTT AAACAAATAAAAAATGAAAGAGAAAACGATGTACACAATATAAAAGAGGACTATAACTTG TTACAACAATATTTAAATTATATGAAAAATGAAATGGAACAAT TAAAAAAATATAAAAAT GATGTTCATATGGATAAAAATTATGTTGAAAATATGTGAAAAGAj'xAxTTACTT AAAGAAACCATTTCTTCATATTATGATAAAATAAATAATATAAATAATAAGCTATATATA TATAAAAACAAAGAAGACACTTATTTTAATTATGATCGTATCAGATTTTAAAC ATATTAAAAAACAAGACAGATTAAAGAATTA TCTATATAAGAGAAATAAAGATATACATATA TTAAATAAACATAATGAAAATATTTCCAATATTTTTAAGGATATACAAATATAAAAA\ CAAAGTCAAGATATTATCACAAATATGAACGACATGTATAAAACTACAATCCTTTTAGTA GACATCATACAGAAAAAAGAAGAAGCTcTAAATAAACAAAAAAATATTTTAAGAAATATA GACAATATATTAATMAAGAAATATTATAGATAGTTATAATGTATTGTGAT GATTATAAAGATATCTTAATACAAAACGAAACGGAATATCAAATTACAA2 TATAAAJT CATACATATGAAGAAAbAAAAAAATCAATAGATATATTAAAAATTAAAAATATAAAACAA AAAAATATTCAAGAATATAAAAACAAATTAGAACAAATGAATACAATAATTAATCAAAGT ATAGAACAACATGTATTCATAAACGCTGATATTTTACAAATGAAAAAATAAAATTAGAA GAIXATCATAAAAAATCTAGATATACTAGATGAACAAATTATGAGATATCATAATTCAATA GATGAATTATATAAACTAGGAATACATGTGACAATCATCTAATTACAACTATTAGTGTT GTTGTTAATAAAAATACAACAAAAATTATGATACATATAAJAAACAAAAAGAGGATATA CAAAAAATTAATAACTATATTCAAACAAATTATAATATAATAAATGAAGAAGCTCTACAJ\ TTTCACAGGCTCTATGGACACAATCTTATAACTGAAGATGACAAATAxTTTGGTACAT ATTATAAAAGAACAAAGAATATATATACACAAGGAAATAGATATTTCTAAAxJTAAJTT AAACATCTTAAAAAAGGATTATATTCATTGAATGAACATGATATGAATCATGATACACAT ATGAATATAATAAATGAACATATAAATAATAATATTTTACAACCATACACACAATTAATA AACATGATAAAAGATATTGATAATGTTTTTATAAAAATACAAAATAATAA.ATTC-GAAIAA ATACAAAAATATATAGAAATTATTAAATCTTTAGAACAATTATAAAATAAACACtA GATAATTTAAATAAATTAAAAGATACACAAAACAnATTAATAAnTATAGAAACAGAAATG AAACATAAACAAAAACAATTAATAAACAAAATGAATGATATAGAAAAGGATAATATTACA GATCAATATATGCATGATGTTCAGCALAATATATTTGAACCTATAACATTAAJAATGAAT GAATATAATACATTATTAAATGATAATCATAATAATAATATAAATAATGAACATCAATTT AATCATTTAATAGTCTTCATACAAAAATATTTAGTCATAATTATAATAAGAACAACAA CAAGAATATATAACCAACATCATGCAZAGAATTGATGTATTCATAAATGATTTAGATACT TACCAATATGAATATTATTTTTATGAAVGGAATCAAGAATATAAACAAATAGACAAAAT AAAATAAATCAACATATAAACAATATTAAAAATAATCTAATTCATGTTAAGAAACAATTT GAACACACCTTAGAAAATATAAAAAATAATGAAAATATTTTCGACAACATACAATTGAAA AAAAAAGATATTGACGATATTATTATAAACATTAATAATACAAAAGAAACATATCTAA GAATTGAACAAnAAATGTTAChAAAnAAAAAAGTTGATGAAXATCAGA\ATA AATAATCATCACACATTACAACATGATAATCAMATGTTGAAc ATAATTAJ\J GATCATAATTTAATAACCAAGCCAA\TAACAATTCATCAGAAGAATCTCATCAAAATGA. CAAATGAAAGAACAAAACAAAAATATACTTGAAAAACAAACAAGWATATCAAXICCACAT CATGTTCATAATCATAATCATAATCATAATCAAAATCAAAAAGATTCAACAAAATTACAG GAACAAGATATATCTACACACAAATTACATAATACTATACATGAGCAACAAAGTAAAGAT 77 AATCATCAAGGTAATAGAGAAAAAAAACAAAAAAATGAAACCATGAAAGAATGTATTTT GCCAGTGGAATAGTTGTATCCATTTTAT TTTTATTTAGTTTTGGATTTGTTATAAATAGT AAAAATAATAAACAAGAATATGATAAAGAGCAAGAAAAACAACAACAAAATGATTTTGTA TGTGATAATAACAAAATGGATGATAAAACCACACAAAAATATGGTAGAAATCAAGAAGAG GTAATGGAGATATTTTTTGATAATGATTATATTTAA As a matter of routine, the skilled person will be able to identify the regions of the above nucleic acid molecules that encode the specific regions described for the Rh and EBA proteins described elsewhere herein. The present invention includes those specific nucleotide subsequences, and any alterations that are available by virtue of the degeneracy of the genetic code. Furthermore, the invention provides nucleic acid which can hybridise to these nucleic acid molecules, preferably under "high stringency" conditions (e.g. 65*C in a 0.1 x SSC, 0.5% SDS solution). Nucleic acid according to the invention can be prepared in many ways (e.g. by chemical synthesis, from genomic or cDNA libraries, from the organism itself, etc.) and can take various forms (e.g. single stranded, double stranded, vectors, probes, etc.). They are preferably prepared in substantially pure form (i.e. substantially free from other Plasmodial or host cell nucleic acids). The term "nucleic acid" includes DNA and RNA, and also their analogues, such as those containing modified backbones (e.g. phosphorothioates, etc.), and also peptide nucleic acids (PNA), etc. The invention includes nucleic acid comprising sequences complementary to those described above (e.g. for antisense or probing purposes). The invention also provides a process for producing an immunogenic molecule of the invention, comprising the step of culturing a host cell transformed with nucleic acid of the invention under conditions which induce polypeptide expression. The present invention will now be more fully described by reference to the following non limiting Examples. EXAMPLE 1: MATERIALS AND METHODS Invasion inhibition assays Methods for measuring invasion-inhibitory antibodies in serum samples have been described and evaluated in detail elsewhere [Persson, et al. J. Clin. Microbiol, (2006) 44:1665-1673]. Plasmodium falciparum lines 3D7-wt, 3D7AEBA175, W2mef-wt, 78 W2mefAEBA175 and W2mefSelNm were cultured in vitro as described [Beeson et al (1999) J. Infect. Dis. 180:464-472]. W2mefSe]Nm was generated from W2mef-wt by selection for invasion into neurmainidase-treated erythrocytes. W2mefSeINm was continuously cultured in neuraminidase-treated erythrocytes to maintain the phenotype. Synchronized (by 5% D-sorbitol) parasites were cultured with human 0+ erythrocytes in RPMI-HEPES medium with hypoxanthine 50 pg/ml, NaHCO3 25mM, gentamicin 20pg/ml, 5% v/v heat-inactivated pooled human Australian sera, and 0.25% Albumax II (Gibco, Invitrogen, Mount Waverley, Australia) in 1% 02, 4% C02, and 95% N2 at 37*C. Invasion inhibition assays were started at late pigmented trophozoite to schizont stage. Inhibitory activity was measured over two cycles of parasite replication. Starting parasitemia was 0.2-0.3%, hematocrit 1%, and cells were resuspended in RPMI-HEPES supplemented as described above. Assays were performed in 96-well U-bottom culture plates (25 pl of cell suspension + 2.5 pl of test sample/well). All samples were tested in duplicate. After 48 hours, 5 pl of fresh culture medium was added. Parasitemia was determined by flow cytornetry (FACSCalibur, Becton Dickinson, Franklin Lakes, NJ) after 80-90 hours using ethidium bromide (10 pg/ml, Bio-Rad, Hercules, CA, USA) to label parasitised erythrocytes. Incubation time was influenced by the stage and synchronicity of parasite cultures at commencement of the assay, and by the length of the lifecycle of the parasite line used. We confirmed the inhibitory effect of treated samples by testing immunoglobulin purified from the same samples (36. All serum samples tested for inhibitory antibodies were first treated to remove non-specific inhibitors that may be present and to equilibrate pH [Persson, et a]. J. Clin. Microbiol. (2006) 44:1665-1673]. Serum samples (100 pl) were dialyzed against phosphate-buffered saline (PBS; pH 7.3) in 50 kDa MWCO microdialysis tubes (2051, Chemicon, Temecula, CA, USA) and subsequently re-concentrated to the original starting volume using centrifugal concentration tubes (100 kDa MWCO; Pall Corp., Ann Arbor, MI, USA). Analysis of flow cytometry data was performed using FlowJo software (Tree Star Inc., Ashland, OR, USA). Antibodies to MSPI 1 9 (raised against GST fusion protein) used in the assays (at 1:10 final dilution) were generated by vaccination of rabbits and were kindly provided by Brendan Crabb. Samples from non-exposed donors were included as negative controls in all assays, and anti-MSP1 and/or anti-AMA1 antibodies acted as a positive control. Samples were tested for inhibition of the different lines in parallel in the same experiments. A difference between the lines of >25% in invasion was designated as the cut-off for differential inhibition by samples. Preadsorption of treated serum samples 79 against erythrocytes did not alter their invasion-inhibitory activity. A selection of sera was also tested for antibodies to the surface of uninfected erythrocytes (maintained in culture) by flow cytometry [Beeson et al (1999) J. Infect. Dis. 180:464-472]; there was very little reactivity against normal erythrocytes and there was no relationship between antibody binding to erythrocytes with invasion-inhibitory activity. Enzyme treatment of erythrocytes Erythrocytes were first washed with RPMIHEPES/ 25mM NaHCO3, pH7.4, and subsequently incubated with neurmainidase (0.067 units/ml; Calbiochem, 45 min) or chymotrypsin (1mg/ml; Worthington Biochemical, 15 min) at 37*C. Control treatment was RPMI-HEPES only. After incubation, chymotrypsin-treated cells were washed once with RPMI-HEPES containing 20% human serum and twice with normal culture medium (containing 5% serum) to inhibit enzyme activity. The neurminidase-treated cells were washed with parasite culture medium three times. Treated erythrocytes were then used in invasion inhibition assays as described. All results presented are comparisons to control-treated cells. Antibodies to recombinant proteins by ELISA 96-well plates (Maxisorp, Nunc, Roskilde, Denmark) were coated with recombinant GST fusion proteins at 0.5 pg/ml in PBS overnight at 4*C. Plates were washed and blocked with 10% skim milk powder (Diploma, Rowville, Australia) in PBS Tween 0.05% for 2 hours. After washing, serum samples (100 pl /well in duplicate), at 11500 dilution in PBS Tween 0.05% plus 5% skim milk, were incubated for two hours. Plates were washed and incubated for one hour with HRP-conjugated anti-human IgG at 1/5000 (Chemicon, Melbourne, Australia) in PBS Tween 0.05% plus 5% milk. After washing, colour was developed by adding OPhenylenediamine (Sigma, Castle Hill, Australia; stopped with concentrated sulphuric acid) or azino-bis(3-ethylbenthiazoline-6-sulfonic acid) liquid substrate system (Sigma- Aldrich, Sydney; stopped with 1% SDS) and absorbance read by spectrophotometry. All washes were performed with PBS containing 0.05% Tween 20, and all incubations were at room temperature. For each serum, the absorbance from wells containing GST only was deducted from the absorbance from EBA or PfRh GST fusion proteins. Positive and negative controls were included on all plates to enable standardisation. Recombinant proteins used were EBA140 (e.g. amino acids 746-1045), EBA175 W2mef and 3D7 alleles (e.g. amino acids 761-1271), EBA181 (e.g. amino acids 80 755-1339), Rh4 (e.g. amino acids 1160-1370), and Rh2 (e.g. amino acids 2027-2533). Schizonts were separated on a 60% Percoll gradient, washed three times in serum-free RPMI 1640, pelleted by centrifugation and resuspended. The cells were lysed through freeze-thawing and the supernatant was preserved. Antibody reactivity of a sample was considered positive if the O.D. was > mean+3SD of the nonexposed controls. Study population and serum samples Serum samples (50 adults and 100 children aged 514 years) were randomly selected from a community-based cross-sectional survey of children and adults resident in the Kilifi District, Kenya, in 1998, a year that was preceded with a relatively high incidence of malaria in the region. The area is endemic for Plasmodium fafciparum. Samples were also obtained from non-exposed adult residents in Melbourne, Australia (n=20) and Oxford, UK (n=20). Ethical approval was obtained from the Ethics Committee of the Kenya Medical Research Institute, Nairobi, Kenya and from the Walter and Eliza Hall Institute Ethics Committee, Melbourne, Australia. All samples were obtained after written informed consent. All serum samples were tested for antibodies by ELISA. A subset of 80 of these samples was randomly selected (26% children <5 years, 49% children 6-14, 25% adults) for use in invasion inhibition assays. The same 80 samples were used in all comparative inhibition assays. Papua New Guinea clinical study 206 children aged 5-14, resident in the Madang Province PNG, were enrolled and treated with artesunate to clear any existing parasitemia (Michon et al., AJTMH (2007) 76(6):997-1008). Children were screened every 2 weeks for the presence of blood-stage parasitemia or any signs or symptoms of clinical illness. Malaria episodes were also identified at participant-initiated visit to the local health clinic. Malaria episodes were defined as presence of fever or symptoms of fever together with a parasitemia of P. falciparum of greater than 5000 parasites/ul. Antibodies were measured to recombinant PfRh and EBA proteins (as described above). Children were categorized into high, medium, or low responder groups to each antigen on the basis of terciles of rankings, and risk of malaria episodes from time zero to 6 months was calculated for each antibody group and plotted; Figures 9 and 10. Statistical analysis 81 Statistical analyses were performed with SPSS and STATA software. The chi squared test or Fischer's exact test was used for comparisons of proportions. For comparisons of continuous variables, Mann-Whitney U test or Kruskal- Wallis tests were used for non parametric data, and t-tests or ANOVA were used for normally-distributed data, as appropriate. Associations between antibodies to recombinant antigens by ELISA and invasion-inhibitory antibodies were examined by two approaches. We tested for correlations between ELISA OD values and total invasion inhibition by samples, or the extent of differential inhibition of two comparison parasite lines, and we compared the mean or median inhibition by samples grouped as high or low responders according to reactivity by ELI SA. For all analyses p<0.05 was classified as statistically significant. EXAMPLE 2: Invasion phenotypes and properties of defined Plasmodium falciparum lines Variants of the clonal parasite lines W2mef and 3D7 using different invasion pathways were used. Targeted disruption of the gene for EBA175, and selection of W2mef for invasion of neuraminidase-treated erythrocytes, generated parasites that used the SA independent pathway. We characterised the invasion phenotypes of these parasite lines by evaluating their invasion into chymotrypsin- and neuraminidase-treated erythrocytes compared to normal erythrocytes. Clear differences between the parasite lines in invasion pathway use or phenotype were demonstrated. Invasion of the parental W2mef wild-type (wt) was sensitive to neuraminidase treatment of erythrocytes (SA-dependent invasion) but moderately resistant to chymotrypsin-treatment of erythrocytes. In contrast, Invasion of W2mef with EBA175 disrupted (W2mefAEBA175) was resistant to neuraminidase treatment (SA-independent invasion) but sensitive to chymotrypsin. Invasion of 3D7-wt and 3D7 with EBA175 disrupted (3D7AEBA175) was resistant to neuraminidase, but the two 3D7 lines differed in their invasion of chymotrypsin-treated erythrocytes invasion in the W2mef line, by repeated selection for invasion of neuraminidase-treated erythrocytes, was also associated with a modest reduction in multiplication rate. No substantial differences were found in the proportions of singly or multiply-infected erythrocytes (this is referred to elsewhere as the selectivity index between the different lines (data not shown). This indicates there is no major reduction in the invasion capacity of the transgenic or selected parasites compared to wild-type. 82 EXAMPLE 3: The use of alternate erythrocyte invasion pathways alters the efficacy of invasioninhibitory antibodies Differential inhibition by acquired antibodies of isogenic lines that differ only in invasion phenotype indicates that alternate pathways may exist as a mechanism of immune evasion. Inhibitory activity of serum antibodies was compared against W2mef and 3D7 parasite lines with different invasion phenotypes. We tested serum antibodies from a selection of children (n=60) and adults (n=20) resident in a malaria-endemic region of coastal Kenya. Total invasion-inhibitory antibodies were common among this population; 68% inhibited W2mef-wt and 62% inhibited 3D7-wt by >25% compared to non-exposed controls. For these studies, differential inhibition was defined as a 2:25% difference in the extent of inhibition between the comparison lines. In all assays we tested inhibition of W2mef-wt and-3D7- wt using untreated erythrocytes, and inhibition of W2mefAEBA175, W2mefSelNm, and 3D7AEBA175 was tested with untreated and neuraminidase-treated erythrocytes. We first compared serum antibody inhibition of W2mef-wt to that of W2mefAEBA175, which has a stable, but different invasion phenotype to the parental W2mef, and has up-regulated expression of Rh4. W2mef-wt uses SA-dependent invasion mechanisms, whereas invasion of W2mefAEBA175 is largely SA-independent. In comparative inhibition assays, we found that 27% of samples differentially inhibited the two lines (e.g. samples 56, 109, and 135 in Figure 1A), indicating that the inhibitory activity of acquired antibodies is influenced by the invasion pathway being used (Figure 1A and 2A). Large differences in inhibitory activity (up to 66%) between the lines were observed for individual samples. Although W2mefAEBA175 has switched to use a SA independent invasion pathway, it remained possible that other ligands involved in SA dependent invasion (e.g. EBA140, EBA181, Rh1) may still be functional to some extent in W2mefAEBA175, despite the switch in phenotype. To inhibit these interactions, and more clearly compare antibodies against SA-dependent versus SA-independent invasion pathways, we also performed antibody inhibition assays using W2mefAEBA175 and neuraminidase-treated erythrocytes, in comparison to inhibition of W2mef-wt with normal erythrocytes (Figure 2B). This approach further emphasized differences in antibody activity linked to variation in invasion phenotype. The proportion of samples showing differential inhibition of the two lines was 48% versus 27% when using normal erythrocytes with both lines. The extent of differences in inhibitory activity was strongly increased for some individual samples (e.g. sample 355 in Figure 1A). This indicates that the inhibitory activity of antibodies against ligands of SA-independent invasion was 83 enhanced once the residual activity of SA-dependent ligands is inhibited by neuraminidase treatment of erythrocytes. Differential inhibition by samples was also observed with W2mef-wt compared to W2mefSelNm (Figure 1B and 2C). The latter isolate is genetically intact and its phenotype was generated by selection for invasion of neuraminidase-treated erythrocytes. Like W2mefAEBA175, it uses an alternate SA independent invasion pathway and has upregulated expression of Rh4. It still expresses EBA175, but does not depend on this ligand for invasion. We found 35% of samples from children and adults differentially inhibited the two lines (e-g. samples 196 and 436, Figure 1 B), confirming that a change in invasion phenotype, or pathway, can substantially alter the efficacy of inhibitory antibodies. As expected, the inhibition of W2mefSelNm and W2mefAEBA175 by samples was highly correlated (r=0.61; n=80; p<0.001) as these isolates invade via the same pathway and only differ by the presence of EBA175. We also test antibodies for inhibition of W2mefSeNm invasion into neuraminidase-treated erythrocytes (Figure 2D), compared to W2mef-wt in normal erythrocytes, to more clearly evaluate antibodies against SA-independent versus SA dependent invasion pathways. Overall, 45% of samples differentially inhibited the two lines. Some samples showed greater differences in the inhibition of W2mef-wt and W2mefSelNm than when normal erythrocytes were used (e.g. samples 196 and 436 in Figure 1 B). Differential antibody inhibition of 3D7 lines with different invasion phenotypes further confirmed that variation in invasion phenotypes influences the activity of inhibitory antibodies (Figure IC and Figure 3, A and B). The proportion of samples that differentially inhibited parental 3D7 versus 3D7AEBA175 was 26% when using normal erythrocytes and 37% when using neuraminidase-treated erythrocytes with 3D7AEBA175. These combined results with W2mef and 3D7 lines clearly established that the availability of alternate pathways for erythrocyte invasion is immunologically important and a likely mechanism for evasion of acquired inhibitory antibodies. Antibody inhibition assays used here have been previously validated and described in detail elsewhere [Persson, et al. J. Clin. Microbiol. (2006) 44:1665-1673]. Differences in the inhibitory activity of individual sera against different parasite lines were confirmed by repeat testing. Overall, results from invasion-inhibitory assays were highly reproducible. For example, repeat testing of 33 samples for inhibition of 3D7-wt and 3D7AEBA175 was highly correlated (r=0.96 for 3D7-wt and r=0.94 for 3D7AEBAI 75; p<0.001). Repeat testing of 40 samples for inhibition using different parasite lines also demonstrated a high correlation between assays (r=0.83; p<0.001). We confirmed that the differential 84 inhibitory activity measured in our assays represented inhibition of invasion, and not an effect on parasite intraerythrocytic development. To do this we tested serum samples in inhibition assays and determined parasitemias at different stages of parasite development, over one and two parasite life-cycles (data not shown). We routinely measured antibody inhibitory activity over two cycles of parasite invasion because this substantially increased the sensitivity of antibody inhibition assays and facilitated the detection of differences in inhibition between parasite lines in this study. Differential inhibition of comparison lines by sera was also observed in single-cycle assays EXAMPLE 4: Antibodies to SA-dependent invasion pathways are common and inhibitory antibodies are acquired against EBA175. Having established that antibodies can differentially inhibit alternate invasion pathways, we next aimed to further define the acquisition of antibodies to SA-dependent invasion in the population. Of those samples that differentially inhibited W2mef-wt versus W2mefAEBA175 (cultured with normal erythrocytes), 26 of 27 had a type-A response, inhibiting the parental W2mef more than W2mefAEBA175 (P<0.001; Figure 2). This pattern of inhibition points to inhibitory antibodies targeting EBA175 and other ligands of SA-dependent invasion. Overall, the mean inhibition of W2mef-wt by all samples (39.4%) was significantly greater than W2mefAEBA175 (29.4%; p<0.01) (Figure 2). When W2mefAEBA175 was cultured with neuraminidase-treated erythrocytes to inhibit any residual SA-dependent interactions, there was an increase in the difference in the mean inhibition of W2mef-wt versus W2mefAEBAI 75 by samples (a difference of 18.9% versus 10% using untreated erythrocytes; p<0.01; Figure 4). Antibodies from 60% of children 5 years inhibited W2mef-wt to a greater extent than W2mefAEBA175 (Figure 2B), whereas among adults, 22% showed this pattern of inhibition (p=0.019). Similar to results from assays using W2mefAEBA175, 31% of samples inhibited W2mefwt more than W2mefSelNm (Type A response; Figure 2C), whereas only 4% inhibited W2mefSelNm more than W2mef-wt (p<0.001). Additionally, the mean inhibition of W2mef-wt (39.4%) by all samples was greater than W2mefSelNm (20%; p<0.01) (Figure 4). The 3D7 parental line invades erythrocytes through largely SA-independent interactions, which limits the usefulness of this parasite line for evaluating antibodies to ligands of SA dependent invasion. However, some samples inhibited the invasion of 3D7-wt into 85 normal erythrocytes more than 3D7AEBA175 using neuraminidase-treated erythrocytes (Figure 3B). This indicates the presence of antibodies against the ligands of SA dependent invasion. In contrast to W2mef, disruption of EBA175 in 3D7 does not lead to a major switch in invasion phenotype. 3D7AEBA175 shows slightly greater resistance to the effect of neuraminidase-treatment of erythrocytes compared to 3D7-wt, and increased sensitivity to inhibition by chymotrypsin-treatment of erythrocytes, consistent with the loss of function of EBA175. Comparing inhibition of 3D7 and 3D7AEBA175 is therefore a useful tool to investigate inhibitory antibodies specifically targeting EBA175. Using this approach, we obtained evidence that EBA175 is a target of inhibitory antibodies, as suggested from studies with W2mef lines. 15% of children and 17% of adults inhibited 3D7-wt more than 3D7AEBA175 (Figure 3A), strongly suggesting that individuals in the population have inhibitory antibodies against EBA175. These antibodies were responsible for up to 47% of the total inhibitory activity measured in some individuals (Figure 3), indicating that EBA175 is an important target of invasion inhibitory antibodies. EXAMPLE 6: Inhibition of invasion by antibodies to Rh proteins (e.g. Rh2 and Rh4). We evaluated the presence of antibodies to ligands of SA-independent invasion by identifying samples that inhibited W2mefAEBA175 or 3D7AEBA175 more than the corresponding parental parasites. Invasion of W2mefAEBA175 or 3D7AEBA175 into neuraminidase-treated erythrocytes is dependent on ligands of the SA-independent invasion pathway. Using the W2mef line, 5% of samples (Figure 2B) showed a type-B response and inhibited invasion of W2mefAEBA175 into neuraminidase-treated erythrocytes more effectively than W2mef-wt. Furthermore, 13% inhibited W2mefselNm more than W2mef-wt (e.g. sample 436, Fig 1 B). Type-B responses were more prevalent with the 3D7 parasite lines than W2mef (p<0.001). A substantial number of samples inhibited 3D7AEBA175 more than 3D7-wt (18% of samples when using normal erythrocytes and 16% when using neuraminidase-treated erythrocytes; Figure 3, A and B). No children 55 years inhibited W2mefAEBA175 more than W2mef-wt (Figure 2, A and B). Samples with type-B responses were only seen among older children and adults (p=not significant). EXAMPLE 7: Acquisition of antibodies to recombinant EBA and Rh proteins. 86 Differential inhibition of parasite lines that vary in their invasion phenotype, but not genotype, indicates that members of the EBA and Rh proteins are targets of invasion inhibitory antibodies. We measured antibodies against recombinant EBA and Rh proteins by ELISA to confirm that these proteins are targets of acquired antibodies. Antibody levels to EBA175 (both 3D7 and W2mef alleles), EBA140, EBA181, Rh2 and Rh4 were positively associated with increasing age (Figure 6), being significantly higher among older than younger subjects (p<0.001). There was little or no reactivity of sera from malaria non-exposed subjects. Antibodies to Plesmodium falciparum schizont extract were also significantly correlated with age (data not shown), consistent with increasing exposure to blood-stage malaria. While the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The invention should therefore not be limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention as broadly described herein. 87

Claims (28)

1. An isolated recombinant immunogenic molecule comprising a contiguous amino acid sequence from about residue 746 to about. residue 1339 of a erythrocyte binding antigen (EBA) protein of a strain of Plasmodium falciparum, wherein when administered to a subject the molecule is capable of inducing an invasion-inhibitory immune response to the strain.

2. An immunogenic molecule according to claim 1 wherein the EBA is selected from the group consisting EBA175, EBA140, and EBA181.

3. An immunogenic molecule according to claim 1 or 2 wherein the contiguous amino acid sequence is found in the region from about residue 746 to about residue 1045 of EBA140.

4. An immunogenic molecule according to claim 1 or 2 wherein the contiguous amino acid sequence is found in the region from about residue A protein .

5. An immunogenic molecule according to claim 1 or 2 wherein the contiguous amino acid sequence is found in the region from about residue 755 to about residue 1339 of EBA181.

6. An immunogenic molecule according to any one of claims 1 to 5 wherein the strain is a wild type strain.

7. A composition comprising an immunogenic molecule according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

8. A composition according to claim 7 comprising a vaccine adjuvant.

9. A composition comprising an isolated recombinant immunogenic molecule comprising a contiguous amino acid sequence from about residue 746 to about residue 1339 of an erythrocyte binding antigen (EBA)of a strain of Plasmodium falciparum involved in sialic-acid-dependant invasion of red cells further comprising a contiguous amino acid sequence of an invasion ligand of a strain of Plasmodium falciparum involved in sialic-acid independent invasion of red cells wherein when administered to a subject the composition is capable of inducing an invasion-inhibitory immune response to the strain. 88

10. A composition according to claim 9 wherein the EBA is selected from the group consisting of EBA175, EBA140, and EBA181.

11. A composition according to claim 9 or 10 wherein the amino acid sequence is found in the region from about residue 746 to about residue 1045 of EBA140.

12. A composition according to claim 9 or 10 wherein the contiguous amino acid sequence is found in the region from about residue 761 to about residue 1271 of EBA1 75.

13. A composition according to claim 9 or 10 wherein where the contiguous amino acid sequence is found in the region from about residue 755 to about residue 1339 of EBA1 81.

14. A composition according to any one of claims 9 to 13 comprising an immunogenic molecule comprising a contiguous amino acid sequence of a reticulocyte-binding protein homologue (Rh) of a strain of Plasmodium falciparum, wherein when administered to a subject the molecule is capable of inducing an invasion-inhibitory immune response to the strain.

15. A composition according to claim 14 wherein the Rh is selected from the group consisting of Rh1, Rh2a, Rh2b and Rh4.

16. A composition according to claim 14 wherein the Rh is Rh2b

17. A composition according to claim 16 wherein where the contiguous amino acid sequence is found in the region between about 31 amino acids N-terminal of the Prodom PD006364 homology region to about the transmembrane domain of Rh2b.

18. A composition according to claim 16 wherein the contiguous amino acid sequence is found in the region from about residue 2027 to 3115 of Rh2b.

19. A composition according to claim 16 wherein the contiguous amino acid sequence is found in the region from about residue 2027 to about residue 2533 of Rh2b.

20. A composition according to claim 16 wherein the contiguous amino acid sequence is found in the region from about residue 2098 to 2597 of Rh2b.

21. A composition according to claim 16 wherein where the contiguous amino acid 89 sequence is found in the region from about residue 2616 to about residue 3115 of Rh2b.

22. A composition according to claim 14 wherein the Rh is Rh4

23. A composition according to claim 22 wherein the contiguous amino acid sequence is found in the region from about the MTH1187/YkoF-like superfamily domain to about the transmembrane domain of Rh4.

24. A composition according to claim 23 wherein the contiguous amino acid sequence is found in the region from about residue 1160 to about residue 1370 of Rh4.

25. A method of treating or preventing a condition caused by or associated with infection by Plasmodium falciparum comprising administering to a subject in need thereof an effective amount of a composition according to any one of claims 7 to 24.

26. Use of a composition according to any one of claims 7 to 24 in the manufacture of a medicament for the treatment or prevention of a condition caused by or associated with infection by Plasmodium falciparum.

28. A method of screening for the presence of a Plasmodium falciparum invasion inhibitory antibody directed against a reticulocyte-binding homologue protein (Rh) of a strain of Plasmodium falciparum in a subject, comprising obtaining a biological sample from the subject and identifying the presence or absence of an antibody capable of binding to an immunogenic molecule according to any one of claims 14 to 24.

29. A method according to claim 28 further comprising identifying the presence of a Plasmodium falciparum invasion-inhibitory antibody directed against an erythrocyte binding antigen (EBA) of a strain of Plasmodium falciparum in a subject comprising identifying the presence or absence of an antibody capable of binding to an immunogenic molecule as defined in any one of claims 1 to 6. 90