Abstract
BackgroundClinical profiling of two components for a synthetic peptide-based virosomal malaria vaccine has yielded promising results, encouraging the search for additional components for inclusion in a final multi-valent vaccine formulation. This report describes the immunological characterization of linear and cyclized synthetic peptides comprising amino acids 211-237 of Plasmodium falciparum merozoite surface protein (MSP-3).MethodsThese peptides were coupled to phosphatidylethanolamine (PE); the conjugates were intercalated into immunopotentiating reconstituted influenza virosomes (IRIVs) and then used for immunizations in mice to evaluate their capacity to elicit P. falciparum cross-reactive antibodies.ResultsWhile all MSP-3-derived peptides were able to elicit parasite-binding antibodies, stabilization of turn structures by cyclization had no immune-enhancing effect. Therefore, further pre-clinical profiling was focused on FB-12, a PE conjugate of the linear peptide. Consistent with the immunological results obtained in mice, all FB-12 immunized rabbits tested seroconverted and consistently elicited antibodies that interacted with blood stage parasites. It was observed that a dose of 50 μg was superior to a dose of 10 μg and that influenza pre-existing immunity improved the immunogenicity of FB-12 in rabbits. FB-12 production was successfully up-scaled and the immunogenicity of a vaccine formulation, produced according to the rules of Good Manufacturing Practice (GMP), was tested in mice and rabbits. All animals tested developed parasite-binding antibodies. Comparison of ELISA and IFA titers as well as the characterization of a panel of anti-FB-12 monoclonal antibodies indicated that at least the majority of antibodies specific for the virosomally formulated synthetic peptide were parasite cross-reactive.ConclusionThese results reconfirm the suitability of IRIVs as a carrier/adjuvant system for the induction of strong humoral immune responses against a wide range of synthetic peptide antigens. The virosomal formulation of the FB-12 peptidomimetic is suitable for use in humans and represents a candidate component for a virosomal multi-valent malaria subunit vaccine.
Highlights
Clinical profiling of two components for a synthetic peptide-based virosomal malaria vaccine has yielded promising results, encouraging the search for additional components for inclusion in a final multi-valent vaccine formulation
It is generally assumed that a multi-stage, multi-component vaccine is required to provide sufficient protection against Plasmodium falciparum malaria [1,2]
One approach is the design of a subunit vaccine that incorporates several synthetic peptide antigens for which there is evidence of protective immunity from in vitro parasite growth inhibition assays, experimental malaria infection models and/or immuno-epidemiological studies
Summary
Clinical profiling of two components for a synthetic peptide-based virosomal malaria vaccine has yielded promising results, encouraging the search for additional components for inclusion in a final multi-valent vaccine formulation. It is generally assumed that a multi-stage, multi-component vaccine is required to provide sufficient protection against Plasmodium falciparum malaria [1,2]. One approach is the design of a subunit vaccine that incorporates several synthetic peptide antigens for which there is evidence of protective immunity from in vitro parasite growth inhibition assays, experimental malaria infection models and/or immuno-epidemiological studies. Synthetic subunit vaccines focus immune responses on antigenic determinants relevant for protection, avoiding the induction of deleterious immune responses as observed during P. falciparum infection [4]. The development of synthetic peptide vaccines is often hampered by limited intrinsic immunostimulatory properties and the lack of cross-reactivity of elicited antibodies with native target antigens
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