Cluster 1 - Candidate Antigens
WP1.1. Development of a vaccine based on MSP-1 Block 2
Protection against P. falciparum challenge has been achieved by vaccination of Aotus lemurinus monkeys with recombinant antigens based on Block 2, an N-terminal part of MSP1. Together with the demonstration of the correlation between antibodies to Block 2 and protection from malaria in sero-epidemiological studies in human populations, these results provide strong support for further development of vaccines based on MSP1 Block 2. Elements derived from all known MSP1 Block 2 sequences of P. falciparum will be incorporated into synthetic polypeptides, engineered such that the known diversity within the global parasite population is covered within one polypeptide sequence. The results of small animal immunisations with the soluble polyproteins, consisting of multi-allelic tandem arrays of Block 2 sequences will determine optimal presentation of the vaccine antigen. The most promising candidate(s) from this comparison will be developed as formulations for pre-clinical and clinical testing.
Work Package Leader: UEDIN
WP1.2. Preclinical approach to an asexual vaccine candidate based on MSP-2
Further development of the two dimorphic C-terminal fragments of the MSP-2 protein derived from 3D7 and FC-27 P. falciparum strains as a combined vaccine candidate is supported by several results. Both fragments are recognised by 100% of sera from adult immune donors and almost all of the children under five years of age. An association of protection from clinical malaria and antibodies to the 3D7 fragments has been found. Purified antibodies to 3D7 fragment inhibit parasite growth in a monocyte dependent growth inhibition. Both fragments are immunogenic in mice and antibodies recognise infected erythrocytes and the vaccine Combination B, including MSP1, MSP2 & RESA, has shown an efficacy of 62% to reduce parasite density in Papua New Guinean children (Genton et al., 2002). The reduction of 3D7 genotypes in vaccines demonstrates a specific effect of the MSP2 component in protection. Thus, the addition of the FC-27 MSP-2 counterpart is obligatory to obtain a high degree of protection. The two fragments corresponding to the MSP-2 dimorphic C-terminal region present little polymorphism. Indeed, synthetic peptides are, in general, superior for purity and speed than any other platform to obtain clear pre-clinical data and GMP products before entering clinical trial (MSP3, GLURP and CS). Furthermore, synthetic antigens are also superior when used in proliferation and ELISA for monitoring clinical trial. In terms of reactogenicity, they are safe, and in terms of immunogenicity, there is no data indicating superiority of equivalent recombinant material. If phase I-II clinical trials are successful, options are opened for further development using the most adequate production platforms.
Work Package Leader: CHUV
WP1.3. Hybrid molecules to overcome merozoite target diversity
A construct comprising two copies of Domains I and II of AMA1, flanking one copy of MSP119 has been made and expressed in yeast. An expression product containing a single MSP119 module linked C-terminally to a single AMA1 module engineered to lack this site, has been produced and is expressed intact. Both modules fold correctly as assessed by mAb antibody binding and the pathway is now open to construct a multimeric yeast expressed protein. This project will consist of selecting a preferred combination of modules expressed in near cGMP, scalable conditions in the P. pastoris system. To compare this product’s ability to induce growth inhibitory antibodies, the single target vaccine candidates, and simple fusion products comprising one copy of AMA1 and MSP119, will undergo preclinical assay.
Work Package Leader: BPRC