Safety and Immunogenicity of rSh28GST Antigen in Humans: Phase 1 Randomized Clinical Study of a Vaccine Candidate against Urinary Schistosomiasis

Abstract

Background Treatment of urinary schistosomiasis by chemotherapy remains challenging due to rapid re-infection and possibly to limited susceptibility to praziquantel treatment. Therefore, therapeutic vaccines represent an attractive alternative control strategy. The objectives of this study were to assess the safety and tolerability profile of the recombinant 28 kDa glutathione S -transferase of Schistosoma haematobium (rSh28GST) in healthy volunteers, and to determine its immunogenicity. Methodology Volunteers randomly received 100 µg rSh28GST together with aluminium hydroxide (Alum) as adjuvant (n = 8), or Alum alone as a comparator (n = 8), twice with a 28-day interval between doses. A third dose of rSh28GST or Alum alone was administered to this group at day 150. In view of the results obtained, another group of healthy volunteers (n = 8) received two doses of 300 µg of rSh28GST, again with a 28-day interval. A six-month follow-up was performed with both clinical and biological evaluations. Immunogenicity of the vaccine candidate was evaluated in terms of specific antibody production, the capacity of sera to inhibit enzymatic activity of the antigen, and in vitro cytokine production. Principal Findings Among the 24 healthy male participants no serious adverse events were reported in the days or weeks after administration. Four subjects under rSh28GST reported mild reactions at the injection site while a clinically insignificant increase in bilirubin was observed in 8/24 subjects. No hematological nor biochemical evidence of toxicity was detected. Immunological analysis showed that rSh28GST was immunogenic. The induced Th2-type response was characterized by antibodies capable of inhibiting the enzymatic activity of rSh28GST. Conclusions rSh28GST in Alum did not induce any significant toxicity in healthy adults and generated a Th2-type immune response. Together with previous preclinical results, the data of safety, tolerability and quality of the specific immune response provide evidence that clinical trials with rSh28GST could be continued in humans as a potential vaccine candidate against urinary schistosomiasis.

Biophysical and formulation studies of theSchistosoma mansoniTSP-2 extracellular domain recombinant protein, a lead vaccine candidate antigen for intestinal schistosomiasis

“…To date, two candidate vaccines are in clinical trials, including Sh28GT targeting S. hematobium and Sm14 targeting S. mansoni. 5,6 The Sabin Vaccine Institute Product Development Partnership (PDP) is developing a recombinant vaccine comprised of the extracellular domain of the S. mansoni tetraspanin surface antigen known as Sm-TSP-2 ( Fig. 1).…”

The helminth parasite proteome at the host–parasite interface – Informing diagnosis and control

“…In addition, anti-oxidative proteins, glycolytic enzymes and calcium binding proteins were identified in the ESP of S. mansoni. Many of the proteins identified by these studies are potential vaccine candidates, like GST (Balloul et al, 1987;Riveau et al, 2012).…”

Back to the future for antiparasite vaccines?

“…Dozens of genes encoding vaccine antigens have been cloned, expressed and tested, primarily in mouse models, in a 'point and shoot' approach, often without much rationale for antigen selection. Only one antigen thus far, Sh28-GST, has progressed to clinical trials for human schistosomiasis [19] and efficacy data are not yet available. Two other antigens, Sm-TSP-2 and Sm14, are progressing towards Phase I trials based on human immunoepidemiological and/or animal challenge studies [20].…”