Recent Advances and Methodological Considerations on Vaccine Candidates for Human Schistosomiasis

Abstract

Schistosomiasis remains a neglected tropical disease of major public health concern with high levels of morbidity in various parts of the world. Although considerable efforts in implementing mass drug administration programs utilizing praziquantel have been deployed, schistosomiasis is still not contained. A vaccine may therefore be an essential part of multifaceted prevention control efforts. In the 1990s, a joint United Nations committee promoting parasite vaccines shortlisted promising candidates including for schistosomiasis discussed below. After examining the complexity of immune responses in human hosts infected with schistosomes, we review and discuss the antigen design and preclinical and clinical development of the four leading vaccine candidates: Sm-TSP-2 in Phase 1b/2b, Sm14 in Phase 2a/2b, Sm-p80 in Phase 1 preparation, and Sh28GST in Phase 3. Our assessment of currently leading vaccine candidates revealed some methodological issues that preclude a fair comparison between candidates and the rationale to advance in clinical development. These include (1) variability in animal models - in particular non-human primate studies - and predictive values of each for protection in humans; (2) lack of consensus on the assessment of parasitological and immunological parameters; (3) absence of reliable surrogate markers of protection; (4) lack of well-designed parasitological and immunological natural history studies in the context of mass drug administration with praziquantel. The controlled human infection model - while promising and unique - requires validation against efficacy outcomes in endemic settings. Further research is also needed on the impact of advanced adjuvants targeting specific parts of the innate immune system that may induce potent, protective and durable immune responses with the ultimate goal of achieving meaningful worm reduction.

Clinical Applications of Isothermal Diagnosis for Human Schistosomiasis

“…Given the recent advances in schistosomal vaccine candidates [8] and the lack of consensus in standardized parameters assessing protection in humans impeded by the lack of diagnostic tools as per WHO's ASSURED criteria suggests to consider expanding isothermal detection techniques to the field of vaccinology. In summary, LAMP and RPA reached species-dependent sensitivity up to 100% and detection in the femtogram range within clinical applications for diagnosing human schistosomiasis; hybridale DNA was found in nanogram amounts.…”

“…S. haematobium causes urogenital pathologies such as dysuria and hematuria and so called female genital schistosomiasis (FGS) if eggs are deposited in the female genitalia [6]. FGS impairs fertility, e.g., ectopic pregnancy and miscarriage, and susceptibility to viruses, e.g., human immunodeficiency virus [7] and papillomavirus, and progressing to malignancies augmented by calcification, e.g., squamous cell carcinomas and sandy patches [8][9][10][11][12]. Ectopic excess egg deposition or erroneous migrating adult worms within the central nervous Acute schistosomiasis or Katayama fever seen among individuals without past parasitic exposure presents as debilitating febrile illness coupled with, e.g., headache, myalgia, fatigue, diarrheal, as well as respiratory symptoms, and hepato-and/or splenomegaly following an incubation period of up to 10-12 weeks.…”

“…Praziquantel (PZQ) is commonly used [7] to treat schistosomiasis and eliminate adult schistosomes by changing irreversibly the permeability and stability of their tegument, but it requires prevailing host immune defense mechanisms for complete efficacy [13]. Control and prevention measures should be complemented by vaccination given the advances in this field to achieve long-term protection against transmission, infection, and disease recurrence [8].…”

Vaccines for Human Schistosomiasis: Recent Progress, New Developments and Future Prospects

“…Importantly, Sm-p80-specific IgE antibodies are not detectable in sera from individuals living in S. mansoni endemic areas [55,56], thereby removing the potential risk of vaccine-induced hypersensitivity reactions. A phase 1a clinical trial using Sm-p80 formulated in GLA-SE (SchistoShield ® , Seattle, DC, USA) has commenced in infectionnaïve adults in the United States, and this will be followed by a Phase 1b dose-escalation trial among African adults, with a planned future age de-escalation study in school-aged children [57].…”

“…In schistosomes, these enzymes (28GSTs) play critical roles in host immune modulation during infection, including annulling the capacity of epidermal Langerhans cells to move to the draining lymph nodes [63], the binding of testosterone and the detoxification of xenobiotic compounds [64,65]. Since its characterization in the late 1990s, data from several efficacy studies using the Sh28GST vaccine in murine and nonhuman primate models of S. haematobium infection and disease showed protective immunity following cercarial challenge with profound effects on tissue egg pathology and excretion [35,57]. An initial Phase 1 study assessed the safety, tolerability and immunogenicity of recombinant Sh28GST (rSh28GST) adsorbed to Alhydrogel (Bilhrvax ® Lille, France) in healthy Caucasian adults, and showed that the vaccine was well-tolerated and elicited a strong Th2-biased immune response [66].…”