The targeted development of a new generation vaccine for schistosomiasis
Keywords: Schistosomiasis in Africa, Skin stage specific antigens, Bioinformatics, Glycan arrays, Gene microarrays, Resistant and susceptible populations, Engineered antibodies as adjuvants
TheSchistoVac will search for exposed proteins and/or glycans of the vulnerable skin stage schistosomula, as safe and effective vaccines. The stage-specific vaccine target selection strategy is based on state-of-the-art schistosomal transcriptomics and glycomics technologies and data, and unique serum and sample libraries from endemic areas. Preclinical in vitro and in vivo testing of protective antigens with respect to cellular responses and effective parasite killing are part of the development pipeline. A unique SME-led approach to potentiate the effect of immunisation by use of engineered antibodies will be incorporated into the development of successful vaccine candidate antigens.
Schistosomiasis is an exceptionally chronic infection caused by the trematode worms of Schistosoma mansoni, S. haematobium and S. japonicum. More than 200 million people in many of the most resource-deprived regions of the developing world are chronically infected with blood-dwelling schistosome worms. Infection with these worms can cause chronic debilitating morbidity and result in a massive economic and social burden that is often underestimated. The current strategy for control of infection and morbidity of schistosomiasis depends on repeated mass treatments with the only available drug, praziquantel, a safe single dose drug treatment that is effective against all species of schistosomes. A major impediment to the sustainable success of this strategy is that rapid reinfection occurs after treatment, particularly in young children living in endemic areas. Thus, adequate schistosomiasis control would require, if it were possible, the repeated administration of hundreds of millions of drug treatments on a regular basis. Moreover, continuous mass treatments eventually will induce praziquantel-resistant strains of schistosomes and there is evidence of increased rebound morbidity. Although new drugs would be useful in case resistance develops, even new drugs cannot prevent rapid re-infection after treatment, indicating a real need for a vaccine.
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Schistosomes ensure their long term survival by a sophisticated, almost perfect, array of immune evasion mechanisms. However, despite their strategies for survival, careful human studies in disease endemic areas over the last 30 years have shown that an important form of natural human immunity does occur against all three schistosome species that cause major clinical disease, vouching for the feasibility of vaccine development. Important recent data indicate that human immunity may be directed against the early post-penetration skin stage larvae. Although antigens expressed by schistosome larvae have been studied before as vaccine candidates, no success has been booked. It has become clear that the pattern of expression of antigens on life cycle stages might be a very important consideration that could affect the level of immune reactivity to a vaccine candidate. This knowledge would have to be incorporated into any strategy that aims to develop a prophylactic vaccine.
With advances made in Schistosome Genome Project, it has become possible to use microarrays for the transcription profiling of S. mansoni genes over 15 life stages. Mining of this unique data set through advanced bioinformatics provides a unique opportunity to rapidly select candidates of interest. Moreover, progress in glycomics is providing researchers with possibilities to consider this important, but as yet elusive group of molecules, as vaccine candidates. Combining the advanced knowledge on schistosome immunoepidemiology with technological possibilities of defining stage specific molecules, the scene is set for a serious attempt at developing a vaccine against schistosome infection.
The project TheSchistoVac proposes to identify the unique skin stage molecules, as well as adult worm cross-reactive skin stage molecules, which are recognized by antibodies of defined resistant populations. The candidates will be tested in in vitro parasite killing assays and will be taken into the field to assess their reactivity at the cellular level with specialized T and B cells. The most promising antigens will be tested in in vivo models of resistance to infection with the final aim of developing candidates for an effective prophylactic vaccine against schistosome infections.
(A) Using bioinformatics, post-genomic selection of target antigens that are expressed on skin stage larvae alone or skin stage larvae and adult worms
(B) Selection of promising candidates by antibody screening of defined resistant and susceptible populations
(C) Selection of candidates after pre-clinical in vitro evaluation in schistosomula killing assays
(D) Patterns of recognition of antigens by T and B cells of endemic population classified as resistant and susceptible
(E) Ranking of most promising candidates following pre-clinical in vivo testing in animal models
(F) Use of a novel engineered antibodies to enhance immunogenicity of the promising candidates
At the end of the project, it is expected that a panel of highly immunogenic antigens expressed on skin stage larvae are ready for entry into human studies.
Candidates for a vaccine against Schistosoma mansoni infection, ready for testing in adults, children and neonates. A potential template for development of vaccines against S. haematobium and S. japonicum.