A randomized, controlled Phase 1b trial of the Sm-TSP-2 Vaccine for intestinal schistosomiasis in healthy Brazilian adults living in an endemic area

Abstract

Background Recombinant Schistosoma mansoni Tetraspanin-2 formulated on Alhydrogel (Sm-TSP-2/Alhydrogel) is being developed to prevent intestinal and hepatic disease caused by S. mansoni. The tegumentary Sm-TSP-2 antigen was selected based on its unique recognition by cytophilic antibodies in putatively immune individuals living in areas of ongoing S. mansoni transmission in Brazil, and preclinical studies in which vaccination with Sm-TSP-2 protected mice following infection challenge. Methods A randomized, observer-blind, controlled, Phase 1b clinical trial was conducted in 60 healthy adults living in a region of Brazil with ongoing S. mansoni transmission. In each cohort of 20 participants, 16 were randomized to receive one of two formulations of Sm-TSP-2 vaccine (adjuvanted with Alhydrogel only, or with Alhydrogel plus the Toll-like receptor-4 agonist, AP 10–701), and 4 to receive Euvax B hepatitis B vaccine. Successively higher doses of antigen (10 μg, 30 μg, and 100 μg) were administered in a dose-escalation fashion, with progression to the next dose cohort being dependent upon evaluation of 7-day safety data after all participants in the preceding cohort had received their first dose of vaccine. Each participant received 3 intramuscular injections of study product at intervals of 2 months and was followed for 12 months after the third vaccination. IgG and IgG subclass antibody responses to Sm-TSP-2 were measured by qualified indirect ELISAs at pre- and post-vaccination time points through the final study visit. Results Sm-TSP-2/Alhydrogel administered with or without AP-10-701 was well-tolerated in this population. The most common solicited adverse events were mild injection site tenderness and pain, and mild headache. No vaccine-related serious adverse events or adverse events of special interest were observed. Groups administered Sm-TSP-2/Alhydrogel with AP 10–701 had higher post-vaccination levels of antigen-specific IgG antibody. A significant dose-response relationship was seen in those administered Sm-TSP-2/Alhydrogel with AP 10–701. Peak anti-Sm-TSP-2 IgG levels were observed approximately 2 weeks following the third dose, regardless of Sm-TSP-2 formulation. IgG levels fell to low levels by Day 478 in all groups except the 100 μg with AP 10–701 group, in which 50% of subjects (4 of 8) still had IgG levels that were ≥4-fold higher than baseline. IgG subclass levels mirrored those of total IgG, with IgG1 being the predominant subclass response. Conclusions Vaccination of adults with Sm-TSP-2/Alhydrogel in an area of ongoing S. mansoni transmission was safe, minimally reactogenic, and elicited significant IgG and IgG subclass responses against the vaccine antigen. These promising results have led to initiation of a Phase 2 clinical trial of this vaccine in an endemic region of Uganda. Trial registration NCT03110757.

Transmission Modelling for Human Non-Zoonotic Schistosomiasis Incorporating Vaccination: Guiding Decision- and Policymaking

“…Only a few candidates, though not on the market yet, advanced to clinical phases, i.e., Sm14 or S. mansoni fatty acid-binding protein (FABP) in ongoing phase II [2,8,[167][168][169], Sm-TSP-2/Sm-TSP-2Al ® or S. mansoni tetraspanin in phase I [170][171][172][173][174], Smp80/SchistoShield ® or S. mansoni large-subunit calpain in ongoing phase I [52,[175][176][177], and Sh28GST/Bilhvax ® or S. haematobium glutathione S-transferase in phase III [60,[178][179][180][181][182]. The latter was discontinued, lacking efficacy [165].…”

“…Referring to vaccine candidates in clinical phases [44] reveals that Sm-TSP-2/ Sm-TSP-2Al ® [170][171][172][173][174], Sm14 [8,167,169,263,264], and Sh28GST/Bilhvax ® [165,265,266] were tested in healthy and exposed adults, which is different to model constructs (Table 1). Only Sm14 [8,168] and Sh28GST [181,182] were also assessed among healthy and infested children.…”

“…A total of 30 ug and 100 ug over 10 ug rSm-TSP-2 induced the highest IgG titers at 4.5 months post-immunization, with waning at 5.5 months among all arms [172,173]. Sm-TSP-2/Alhydrogel was also administered to healthy, exposed Brazilian male and non-pregnant female adults aged 18-50 years in a phase Ib safety, reactogenicity, and immunogenicity trial with 12-month follow-up [171,174]. IgG and IgG subclass immunoglobulins, with IgG1 being preponderant across arms, peaked two weeks after administering the third dose.…”

Human growth factor-mediated signalling through lipid rafts regulates stem cell proliferation, development and survival of Schistosoma mansoni

“…In direct contact with host blood, this unique, specialized organ, which comprises a syncytial cytoplasm overlaid with double-bilayer membrane, supports vital parasite processes such as osmoregulation, blood glucose uptake and host immune evasion [12][13][14][15]. Many potential anti-schistosome vaccine targets, such as tetraspanins and Smp80/calpain also reside in the outer membrane layer [16,17], signifying its importance to parasite survival.…”

Gut microbiota and immune profiling of microbiota-humanised versus wildtype mouse models of hepatointestinal schistosomiasis

“…Despite global efforts to eliminate this disease via mass administration of anthelmintics (i.e., praziquantel, PZQ) [4][5][6], re-infection rates are often staggeringly high, and emergence of drug resistance remains a tangible threat [7]. The search for alternative control strategies resulted in the identification of candidate vaccine targets (e.g., G4LZI3 protein, aspartyl aminopeptidase, microRNA-124-3p, S. mansoni cathepsins B1 and L3) [8][9][10][11][12] some of which are currently being tested in clinical trials (i.e., Sm-p80, Schistosoma mansoni tetraspanin-2 and Sm14) [13][14][15]. While promising, no vaccine is currently available for large-scale use, and thus new and sustainable strategies are urgently needed to control the disease and limit schistosomiasis-associated immunopathology [16].…”