Safety and efficacy of the rSh28GST urinary schistosomiasis vaccine: A phase 3 randomized, controlled trial in Senegalese children

Abstract

BackgroundUrinary schistosomiasis, the result of infection by Schistosoma haematobium (Sh), remains a major global health concern. A schistosome vaccine could represent a breakthrough in schistosomiasis control strategies, which are presently based on treatment with praziquantel (PZQ). We report the safety and efficacy of the vaccine candidate recombinant 28-kDa glutathione S-transferase of Sh (rSh28GST) designated as Bilhvax, in a phase 3 trial conducted in Senegal.Methods and findingsAfter clearance of their ongoing schistosomiasis infection with two doses of PZQ, 250 children aged 6–9 years were randomized to receive three subcutaneous injections of either rSh28GST/Alhydrogel (Bilhvax group) or Alhydrogel alone (control group) at week 0 (W0), W4, and W8 and then a booster at W52 (one year after the first injection). PZQ treatment was given at W44, according to previous phase 2 results. The primary endpoint of the analysis was efficacy, evaluated as a delay of recurrence of urinary schistosomiasis, defined by a microhematuria associated with at least one living Sh egg in urine from baseline to W152. During the 152-week follow-up period, there was no difference between study arms in the incidence of serious adverse events. The median follow-up time for subjects without recurrence was 22.9 months for the Bilhvax group and 18.8 months for the control group (log-rank p = 0.27). At W152, 108 children had experienced at least one recurrence in the Bilhvax group versus 112 in the control group. Specific immunoglobulin (Ig)G1, IgG2, and IgG4, but not IgG3 or IgA titers, were increased in the vaccine group.ConclusionsWhile Bilhvax was immunogenic and well tolerated by infected children, a sufficient efficacy was not reached. The lack of effect may be the result of several factors, including interference by individual PZQ treatments administered each time a child was found infected, or the chosen vaccine-injection regimen favoring blocking IgG4 rather than protective IgG3 antibodies. These observations contrasting with results obtained in experimental models will help in the design of future trials.Trial registrationClinicalTrials.gov NCT 00870649

Safety of P28GST, a Protein Derived from a Schistosome Helminth Parasite, in Patients with Crohn’s Disease: A Pilot Study (ACROHNEM)

“…The P28GST protein was produced as a recombinant protein (rSh28GST) from Saccharomyces cerevisiae cultures (TGY73.4-pTG8889 strain). The manufacturing process was conducted according to good manufacturing practice (GMP) guidelines, by Eurogentec S.A. (Seraing, Belgium), as described previously [7]. The rSh28GST clinical batch (M-BIX-P03/225a) was lyophilized under GMP conditions by Miltenyi (Bergisch Gladbach, Germany), with 225 µg (±10%) per vial.…”

“…The causal relationships between AEs and P28GST treatment were established according to the method of Bégaud et al [10], and classified as follows: not related, possibly related, probably related, and certainly related. SAEs that were suspected to be related to P28GST treatment, but never previously described, were called suspected, unexpected serious adverse reactions (SUSARs) [6,7]. Safety outcomes were assessed at baseline (pre-inclusion visit), at inclusion, and at months 1, 2, 3, 4, 6, 9, and 12.…”

“…P28GST was first developed as a vaccine against schistosomiasis. In that context, P28GST demonstrated safety and tolerability, both in adults [6] and children (NCT 00870649 [7]). P28GST was also tested in experimental colitis, where it reduced colonic inflammation.…”

Schistosomiasis vaccine development: update on human clinical trials

“…A phase 1 human clinical trial showed that rSh28GST adsorbed to Alhydrogel induced a Th2-dependent immune response in immunized healthy subjects and was well tolerated [37]. The same authors also reported that the co-administration of rSh28GST and PZQ was also well tolerated in healthy volunteers during a Phase 2 clinical trial [38]. However, in a recent phase 3 trial design to investigate the safety, immunogenicity and efficacy of rSh28GST in infected children, no sufficient efficacy was observed.…”

“…However, in a recent phase 3 trial design to investigate the safety, immunogenicity and efficacy of rSh28GST in infected children, no sufficient efficacy was observed. Some of the reasons suggested by the authors for lack of efficacy were possible counter effects of repeated PZQ administration and vaccine regimen geared towards blocking IgG4 production rather than induction of protective IgG3 antibodies [38].…”