The development of a malaria vaccine represents currently one of the most important scientific challenges in global public health. One approach is the design of a subunit vaccine that incorporates several malaria protein antigens for which there is evidence of protective immunity from epidemiological data and/or experimental animal challenge models. Currently, the development of such subunit vaccines is hampered by lack of highly effective and human-compatible antigen delivery systems that are driving suitable protein antigen-specific immune responses in humans and have an appropriate safety profile. Furthermore, production of synthetic or recombinant proteins that stably mimic the native structure of the corresponding malaria antigens to induce effective humoral immune responses is a major challenge. Since no vaccine against a human parasitic disease is currently available, it is believed that novel approaches and technologies are required for the development of such vaccines.
The Molecular Immunology unit of the Swiss Tropical Institute in cooperation with Pevion Biotech Ltd. (Dr. R. Zurbriggen) and the Institute for Organic Chemistry of the University of Zürich (Prof. J. Robinson) is developing a candidate malaria vaccine based on synthetic peptides displayed on the surface of immuno-potentiating reconstituted influenza virosomes (IRIV). IRIV represent an innovative antigen delivery system derived from a mixture of natural and synthetic phospholipids and influenza surface glycoproteins. We have demonstrated that IRIV are suitable to elicit strong immune responses against peptide antigens attached to their surface via phospholipids anchors. Using an iterative antigen optimisation process, we have developed synthetic peptides mimicking the native structure of surface loops of two key Plasmodium falciparum vaccine candidate antigens, the circumsporozoite surface protein (CSP) of sporozoites and the apical membrane antigen 1 (AMA-1) of merozoites. Pre-clinical development and characterisation of virosomal formulations of the two peptides, designated PEV301 and PEV302, was supported by the Commission for Technology and Innovation of the Bundesamt für Berufsbildung und Technologie.
In a phase I clinical trial at the University Hospital of Basel we have demonstrated the safety and immunogenicity of PEV301 and PEV302 given in two different doses alone or in combination. At appropriate antigen doses, both vaccine components elicited already after two injections long-lived peptide-specific IgG antibody responses in all volunteers immunized. IRIV seem to have both an immunopotentiating adjuvant-like activity and to act as carrier system providing T cell help to malaria antigen specific B lymphocytes via influenza antigen-specific T cells. Correlations between high parasite binding IgG titers with positivity in PEV301 peptide specific lympho-proliferation assays indicate that malaria peptide-specific T cells can provide additional T cell help. Importantly, all volunteers had pre-existing influenza antigen specific immune responses that did not negatively affect the vaccine-induced humoral and cellular immune responses. Purified immunoglobulins from PEV302 immunized volunteers inhibited substantially sporozoite migration and invasion of hepatocytes in vitro. Combined delivery of the two IRIV-formulated peptides did not interfere with immunogenicity of either peptide, demonstrating the suitability of the IRIV system for development of multi-valent subunit vaccines. After the recent finalisation of a phase IIa clinical trial at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford University (Prof. A. Hill), the safety and immunogenicity of the two components PEV301 and PEV302 is now tested in malaria-exposed Africans.
Since we assume that an effective malaria subunit vaccine has to incorporate more than two antigens, we are developing peptide mimetics of additional key Plasmodium falciparum vaccine candidate antigens. Within the framework of the European Malaria Vaccine Development Association, an integrated project under the Sixth Framework Programme of the European Community, pre-clinical profiling of four new components is currently being finalized. Overall goal of the project is to formulate a cost effective, multi-stage, multi-component malaria vaccine preparation that provides protection against the disease and can be employed in endemic areas most in need. The project will generally further the development of an urgently needed, versatile, human-compatible antigen delivery platform that allows stimulation of different compartments and effector functions of the adaptive immune system.
Prof. Gerd Pluschke
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