Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings

Abstract

Despite mass drug administration programmes with praziquantel, the prevalence of schistosomiasis remains high. A vaccine is urgently needed to control transmission of this debilitating disease. As some promising schistosomiasis vaccine candidates are moving through pre-clinical and clinical testing, we review the immunological challenges that these vaccine candidates may encounter in transitioning through the clinical trial phases in endemic settings. Prior exposure of the target population to schistosomes and other infections may impact vaccine response and efficacy and therefore requires considerable attention. Schistosomes are known for their potential to induce T-reg/IL-10 mediated immune suppression in populations which are chronically infected. Moreover, endemicity of schistosomiasis is focal whereby target and trial populations may exhibit several degrees of prior exposure as well as in utero exposure which may increase heterogeneity of vaccine responses. The age dependent distribution of exposure and development of acquired immunity, and general differences in the baseline immunological profile, adds to the complexity of selecting suitable trial populations. Similarly, prior or concurrent infections with other parasitic helminths, viral and bacterial infections, may alter immunological responses. Consequently, treatment of co-infections may benefit the immunogenicity of vaccines and may be considered despite logistical challenges. On the other hand, viral infections leave a life-long immunological imprint on the human host. Screening for serostatus may be needed to facilitate interpretation of vaccine responses. Co-delivery of schistosome vaccines with PZQ is attractive from a perspective of implementation but may complicate the immunogenicity of schistosomiasis vaccines. Several studies have reported PZQ treatment to induce both transient and long-term immuno-modulatory effects as a result of tegument destruction, worm killing and subsequent exposure of worm antigens to the host immune system. These in turn may augment or antagonize vaccine immunogenicity. Understanding the complex immunological interactions between vaccine, co-infections or prior exposure is essential in early stages of clinical development to facilitate phase 3 clinical trial design and implementation policies. Besides well-designed studies in different target populations using schistosome candidate vaccines or other vaccines as models, controlled human infections could also help identify markers of immune protection in populations with different disease and immunological backgrounds.

Natural Intra- and Interclade Human Hybrid Schistosomes in Africa with Considerations on Prevention through Vaccination

“…The chemotherapeutic at present is the acylated quinoline-pyrazine known as praziquantel (PZQ) that acts against adult schistosomes though poorly against immature schistosome larva by changing irreversibly the permeability and stability of tegumental membranes and needs established host immune defense mechanisms for full efficacy [ 2 , 3 , 14 ]. Anti-worm IgA, IgE and IgG1, IgG2 and IgG3 subclass immunoglobulins are expressed subsequent to treatment resulting in protection against re-infection lasting 6–12 months, and IgG4 subclass immunoglobulins leading to higher susceptibility to re-infection due to IgE blocking [ 15 , 16 ]. However, IgG4 antibody levels decrease with regular repeated treatment.…”

“…The goal is a non-sterilizing immunity with long-term decline in tissue eggs and egg excretion preferably through killing of female worms while preserving concomitant natural immunity induced by less-pathogenic single male worms [ 19 , 20 ]. Since schistosomes do not replicate in definitive hosts, consensus exists that a prophylactic product should reduce adult worm burden among vaccinated, and egg excretion among infected individuals each by at least 75% [ 4 , 16 ]. To date, no vaccine is commercially available also due to known immunoevasion and modulation mechanisms of adult schistosomes, and limited understanding of impacts of recurrent exposures, poly-parasitism, co-infections, and chemotherapeutic treatment on the host immune system [ 16 ].…”

“…Prior exposure to Schistosoma spp. and other infectious agents as well as administration of chemotherapeutic treatment need to be assessed, including baseline immunological and genetic population profiles, as they may impact responses and efficacy to vaccines [ 16 ]. Poly-parasitic, in utero, past, ongoing, and recurrent infections of uncrossed and possibly also crossed Schistosoma spp.…”

Recent Advances and Methodological Considerations on Vaccine Candidates for Human Schistosomiasis

“…Anti-worm rather than anti-egg antibodies are reported to increase after PZQ treatment. Initially, IgG4 leads to higher susceptibility to re-infection due to IgE blocking but a decrease in susceptibility with regular repeated treatment is seen due to decreased IgG4 levels (46,47). The immunoregulatory role of PZQ is driven by the promotion of CD4+ T-cells and differentiation of Type 1 regulatory cells to maintain immune hemostasis and effector cytokine secretion -in particular IL-4, IL-5 and IL-10 (10, 45).…”

“…PZQ may modulate transient and long-term immunological effects, which in turn may augment or antagonize vaccine-induced immune responses and skew towards a more pro-inflammatory response (47,146,176). In Zhang's challenge study (123), the Sm-p80 vaccine exhibited potent prophylactic efficacy against transmission of Sm infection and was associated with significantly less egg-induced pathology compared to unvaccinated control animals.…”