Vaccine development in schistosomiasis japonica: Paramyosin as a leading candidate.

摘要

Schistosomiasis is a chronic debilitating disease caused by helminths of the genus Schistosoma, and currently affecting millions in the developing world. Treatment with Praziquantel has reduced severe morbidities, however reinfection is common and subtle morbidities persist. Alternative control strategies such as vaccine-linked chemotherapy show great promise and warrant further development. This thesis describes vaccine development in schistosomiasis japonica, in conjunction with our recently concluded treatment-reinfection study of a Schistosoma japonicum-infected cohort in Leyte, Philippines (N=553). The promising vaccine candidate paramyosin remains under-evaluated due to challenges in large-scale recombinant production, and we address this need with a robust process to express and purify S. japonicum paramyosin (rSj97). Pilot scale production yielded 22.4 mg of >95% pure rSj97, with functional binding and structural properties similar to native paramyosin. Sera collected from the cohort one month post-treatment were analyzed for isotype-specific (IgA, IgE, IgG1, IgG4, total IgG) antibody responses to a panel of schistosome antigens (SWAP, rSj97, rSj67, rSj22) using a multiplexed bead-based assay. Repeated measures regression analysis with reinfection data up to 12 months post-treatment showed that IgE responses to rSj97 solely predicted resistance to reinfection (p=0.018), while IgG4 responses to all antigens associated with susceptibility, after adjusting for potential confounders. In combined IgE and IgG4 analysis to rSj97, individuals with only IgE responses had a 77% lower intensity of reinfection at 12 months post-treatment (p=0.016) compared to individuals with IgG4 but not IgE. Immunoscreening of an S. japonicum expression library for clones differentially recognized by the resistant but not susceptible subpopulation identified a novel vaccine candidate, Sj6-8. Sj6-8 was expressed in E. coli, and a similar repeated measures analysis demonstrated that IgE responses to rSj6-8 was marginally associated with resistance (p=0.065), predicting a 63% lower intensity of reinfection at 12 months post-treatment. Overall, this thesis further supports paramyosin as a leading vaccine candidate for schistosomiasis japonica, and our development of a pilot scale production process for rSj97 paves the way for further pre-clinical and eventual clinical testing of this promising vaccine candidate.