Abstract
The large extracellular loop of the Schistosoma mansoni tetraspanin, Sm-TSP-2, when fused to a thioredoxin partner and formulated with Freund's adjuvants, has been shown to be an efficacious vaccine against murine schistosomiasis. Moreover, Sm-TSP-2 is uniquely recognised by IgG1 and IgG3 from putatively resistant individuals resident in S. mansoni endemic areas in Brazil. In the present study, we expressed Sm-TSP-2 at high yield and in soluble form in E. coli without the need for a solubility enhancing fusion partner. We also expressed in E. coli a chimera called Sm-TSP-2/5B, which consisted of Sm-TSP-2 fused to the immunogenic 5B region of the hookworm aspartic protease and vaccine antigen, Na-APR-1. Sm-TSP-2 formulated with alum/CpG showed significant reductions in adult worm and liver egg burdens in two separate murine schistosomiasis challenge studies. Sm-TSP-2/5B afforded significantly greater protection than Sm-TSP-2 alone when both antigens were formulated with alum/CpG. The enhanced protection obtained with the chimeric fusion protein was associated with increased production of anti-Sm-TSP-2 antibodies and IL-4, IL-10 and IFN-γ from spleen cells of vaccinated animals. Sera from 666 individuals from Brazil who were infected with S. mansoni were screened for potentially deleterious IgE responses to Sm-TSP-2. Anti-Sm-TSP-2 IgE to this protein was not detected (also shown previously for Na-APR-1), suggesting that the chimeric antigen Sm-TSP-2/5B could be used to safely and effectively vaccinate people in areas where schistosomes and hookworms are endemic.
Highlights
Schistosomiasis ranks among the most important infectious diseases in tropical regions, resulting in a loss of between 4.5 and 92 million Disability-Adjusted Life Years (DALYs) annually and almost 300,000 deaths in sub-Saharan Africa alone [1,2,3]
IgE against Sm-TSP-2 or Na-APR-1 has not been detected in the blood of residents from an area in Brazil that is endemic for schistosomes and hookworms, indicating that vaccines based on these molecules would be unlikely to generate allergic reactions in recipients from developing countries
We reported the production of a chimeric form of Sm-TSP-2, consisting of Sm-TSP-2 fused to the immunodominant and neutralizing 5B region of the hookworm aspartic protease Na-APR-1, termed Sm-TSP-2/5B [17]
Summary
Schistosomiasis ranks among the most important infectious diseases in tropical regions, resulting in a loss of between 4.5 and 92 million Disability-Adjusted Life Years (DALYs) annually and almost 300,000 deaths in sub-Saharan Africa alone [1,2,3]. Molecules lodged in the apical membrane of the schistosome tegument represent vulnerable targets for immunological attack by host antibodies due to their intimate association with the host immune system. One such family of molecules – predicted by proteomic analyses of the schistosome tegument to be accessible to host immunoglobulin [10] – is the tetraspanin integral membrane proteins. The second extracellular loop of one of these schistosome tetraspanins, Sm-TSP-2, has proven to be an effective anti-schistosomiasis vaccine, eliciting 57–64% protection in mice vaccinated with the antigen followed by challenge with S. mansoni cercariae [12]. Sm-TSP-2 was strongly recognised by IgG1 and IgG3 from putatively resistant but not from chronically infected individuals [12], further highlighting the promise of this antigen as a subunit vaccine against human schistosomiasis
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