A vaccine consisting of Schistosoma mansoni cathepsin B formulated in Montanide ISA 720 VG induces high level protection against murine schistosomiasis

Abstract

BackgroundSchistosomiasis is the most important human helminth infection due to its impact on public health. The clinical manifestations are chronic and significantly decrease an individual’s quality of life. Infected individuals suffer from long-term organ pathologies including fibrosis which eventually leads to organ failure. The development of a vaccine against this parasitic disease would contribute to a long-lasting decrease in disease spectrum and transmission.MethodOur group has chosen Schistosoma mansoni (Sm) cathepsin B, a peptidase involved in parasite feeding, as a prospective vaccine candidate. Our experimental formulation consisted of recombinant Sm-cathepsin B formulated in Montanide ISA 720 VG, a squalene based adjuvant containing a mannide mono-oleate emulsifier. Parasitological burden was assessed by determining adult worm, hepatic egg, and intestinal egg numbers in each mouse. Serum was used in ELISAs to evaluate production of antigen-specific antibodies, and isolated splenocytes were stimulated with the antigen for the analysis of cytokine secretion levels.ResultsThe Sm-cathepsin B and Montanide formulation conferred protection against a challenge infection by significantly reducing all forms of parasitological burdens. Worm burden, hepatic egg burden and intestinal egg burden were decreased by 60 %, 62 %, and 56 %, respectively in immunized animals compared to controls (P = 0.0002, P < 0.0001, P = 0.0009, respectively). Immunizations with the vaccine elicited robust production of Sm-cathepsin B specific antibodies (endpoint titers = 122,880). Both antigen-specific IgG1 and IgG2c titers were observed, with the former having more elevated titers. Furthermore, splenocytes isolated from the immunized animals, compared to control animals, secreted higher levels of key Th1 cytokines, IFN-γ, IL-12, and TNF-α, as well as the Th2 cytokines IL-5 and IL-4 when stimulated with recombinant Sm-cathepsin B. The Th17 cytokine IL-17, the chemokine CCL5, and the growth factor GM-CSF were also significantly increased in the immunized animals compared to the controls.ConclusionThe formulation tested in this study was able to significantly reduce all forms of parasite burden, stimulate robust production of antigen-specific antibodies, and induce a mixed Th1/Th2 response. These results highlight the potential of Sm-cathepsin B/Montanide ISA 720 VG as a vaccine candidate against schistosomiasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1444-z) contains supplementary material, which is available to authorized users.

Cross-species prophylactic efficacy of Sm-p80-based vaccine and intracellular localization of Sm-p80/Sm-p80 ortholog proteins during development in Schistosoma mansoni, Schistosoma japonicum, and Schistosoma haematobium

“…Reduction in intestinal egg burden within the host may be associated with a decrease in disease transmission because lower amount of schistosome eggs are released by the host into the environment (Ricciardi et al 2016). Therefore, an effective schistosomiasis vaccine should not only target reduction in worm burden but also the reduction in eggs trapped in host tissue and/or excreted.…”

“…However, the outcomes of these control programs have been largely suboptimal due to insufficient coverage and lack of sustained reduction in the prevalence and transmission of the disease (El Ridi et al 2015; Fonseca et al 2015). Coverage data indicate that less than satisfactory numbers of schistosomiasis-affected people are being treated with PZQ, highlighting the shortcomings of the current control program (Hotez 2009; Ricciardi et al 2016). In addition, these MDA programs would require optimum and continuous distribution of PZQ in endemic areas for sustainable disease control.…”

Sm‐p80‐based vaccine trial in baboons: efficacy when mimicking natural conditions of chronic disease, praziquantel therapy, immunization, and Schistosoma mansoni re‐encounter

“…Reduction in intestinal egg load could be associated with decrease in disease transmission as fewer eggs are passed into the intestinal lumen (and subsequently into the environment) from the mesenteric veins to infect the snail intermediate hosts. 48,52 Both large and small intestines of vaccinated animals had a significant reduction in matured eggs deposited (87.8% and 52.9%, respectively) compared to the control animals. A 48.6% and 82.3% reduction in hatching rate in small and large intestines, respectively, was also recorded in the immunized animals.…”

“…Other vaccination studies, using either a DNA-based vaccine, recombinant antigen, or DNA prime/recombinant protein boost strategies, employ a conventional approach of immunizing naive animals prior to S. mansoni exposure and subsequently assessing vaccine efficacy. 20,21,26,[47][48][49][50] These efficacy studies have moved the field of schistosome vaccine discovery/development forward. However, in our view, they do not fully reflect the complex field conditions that include cycles of infection, treatment, and reinfection.…”

Vaccination against the digestive enzyme Cathepsin B using a YS1646Salmonella entericaTyphimurium vector provides almost complete protection againstSchistosoma mansonichallenge in a mouse model

“…Despite this relatively ‘low bar’, few candidate vaccines have achieved >50% protection in murine or other animal models [10] and even fewer have progressed to human trials [11]. Our group has previously demonstrated 60-70% protection in a S. mansoni murine challenge model by targeting Cathepsin B using intramuscular (IM)-adjuvanted formulations [12, 13]. Cathepsin B (CatB) is a cysteine protease found in the cecum of both the migratory larval form of S. mansoni (ie: the schistosomula) and in the gut of the adult worm.…”