Despite the enormous morbidity attributed to
schistosomiasis, there is still no
vaccine to combat the disease for the hundreds of millions of infected people. The
anthelmintic drug,
praziquantel, is the mainstay treatment option, although its molecular mechanism of action remains poorly defined.
Praziquantel treatment damages the outermost surface of the parasite, the tegument, liberating
surface antigens from dying worms that invoke a robust immune response which in some subjects results in immunologic resistance to
reinfection. Herein we term this phenomenon Drug-Induced Vaccination (DIV). To identify the antigenic targets of DIV
antibodies in
urogenital schistosomiasis, we constructed a recombinant
proteome array consisting of approximately 1,000
proteins informed by various secretome datasets including validated
proteomes and bioinformatic predictions. Arrays were screened with sera from human subjects treated with
praziquantel and shown 18 months later to be either reinfected (chronically infected subjects, CI) or resistant to
reinfection (DIV).
IgG responses to numerous
antigens were significantly elevated in DIV compared to CI subjects, and indeed
IgG responses to some
antigens were completely undetectable in CI subjects but robustly recognized by DIV subjects. One
antigen in particular, a
cystatin cysteine protease inhibitor stood out as a unique target of DIV
IgG, so recombinant
cystatin was produced, and its
vaccine efficacy assessed in a heterologous Schistosoma mansoni mouse challenge model. While there was no significant impact of vaccination with adjuvanted
cystatin on adult worm numbers, highly significant reductions in liver egg burdens (45-55%, P<0.0001) and intestinal egg burdens (50-54%, P<0.0003) were achieved in mice vaccinated with
cystatin in two independent trials. This study has revealed numerous
antigens that are targets of DIV
antibodies in
urogenital schistosomiasis and offer promise as
subunit vaccine targets for a drug-linked vaccination approach to controlling
schistosomiasis.