Use of an Sm-p80-Based Therapeutic Vaccine to Kill Established Adult Schistosome Parasites in Chronically Infected Baboons

Abstract

No vaccines are available for human use for any parasitic infections, including the helminthic disease schistosomiasis. Sm-p80, the large subunit of Schistosoma mansoni calpain, is a leading antigen candidate for a schistosomiasis vaccine. Prophylactic and antifecundity efficacies of Sm-p80 have been tested using a variety of vaccine approaches in both rodent and nonhuman primate models. However, the therapeutic efficacy of a Sm-p80-based vaccine had not been determined. In this study, we evaluated the therapeutic efficacy of Sm-p80 by using 2 different strategies and 3 Sm-p80-based vaccine formulations in baboons. Vaccine formulations were able to decrease established adult worms by 10%-36%, reduce retention of eggs in tissues by 10%-57%, and decrease egg excretion in feces by 13%-33%, compared with control formulations. Marked differences were observed in B and T cell immune correlates between vaccinated and control animals. This is the first report of killing of established adult schistosome worms by a vaccine. In addition to distinct prophylactic efficacy of Sm-p80, this study adds to the evidence that Sm-p80 is a potentially important antigen with both substantial prophylactic and therapeutic efficacies. These data reinforce that Sm-p80 should be moved forward along the path toward human clinical trials.

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

“…Induction of Th2 responses are thought to be associated with the recruitment of basophils and eosinophils which are thought to be involved in schistosomulae killing (El Ridi and Tallima 2013). Our results showed that Sm-p80 vaccine formulated in GLA-SE induced mixed Th1 (IFN-γ, TNF-α, IL-2 and IL-12) and Th2-type immune responses which appeared to correlate with the cross-species protection observed in this S. japonicum model of infections which was in agreement with our previous studies on S. mansoni infection models (Karmakar et al 2014a; Karmakar et al 2014b). The downregulation of IL-17 observed in the S. japonicum /mouse studies (Trials 1 and 2) might not be entirely non-beneficial as studies have shown that blocking IL-17 cytokine production in S. japonicum -infected mice resulted in the reduction of granuloma formation and fibrosis (Chen et al 2013; Zhang et al 2012).…”

“…Over the last two decade, we have employed a systematic approach to developing Sm-p80-based vaccine for schistosomiasis control. Several studies by our group using various Sm-p80-based vaccination strategies have demonstrated high levels of prophylactic and therapeutic efficacy against S. mansoni infections in both mice and baboons (Ahmad et al 2009a; Ahmad et al 2009b; Ahmad et al 2009c; Karmakar et al 2014a; Karmakar et al 2014b; Le et al 2014; Zhang et al 2010b; Zhang et al 2011); efficacy levels obtained with Sm-p80 vaccine are comparable to previously obtained data with S. mansoni radiation attenuated (RA) cercariae vaccine, which is a gold standard for anti-schistosome protective immunity. Immunizations with the RA vaccine have been demonstrated to show significant protection levels ranging from 56% to as high as 80% following cercariae challenge (Anderson et al 1999; Ganley-Leal et al 2005; Sher et al 1982; Wilson et al 1999).…”

“…With respect to the schistosomiasis vaccine development, Sm-p80 is now considered one of the leading candidates (Mo et al 2014; Molehin et al 2016). Several studies by our group have shown that Sm-p80 vaccine is highly efficacious against S. mansoni infections in mice and baboons (Ahmad et al 2009a; Ahmad et al 2009b; Ahmad et al 2009c; Karmakar et al 2014b; Le et al 2014). Of equal importance is the finding from our recent study which showed that Sm-p80 vaccine formulated in Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE) conferred cross-species prophylactic protection against S. haematobium infections in both hamster and baboon models (Karmakar et al 2014a).…”

Development of a schistosomiasis vaccine

“…Similarly, in another cross-species protection experiment, the Sm-p80 vaccine produced a 25% reduction in S. haematobium adult worms and an egg load reduction in the urinary bladder by 64% in vaccinated baboons [25;56]. In addition, Sm-p80 vaccine formulations were able to decrease established adult worms in a chronic infection of baboons by 10%–36%, reduce retention of eggs in tissues by 10%–57%, and decrease egg excretion in feces by 13%–33%, compared with control formulations [57]. To our knowledge, this is the first single vaccine to have demonstrated significant protection against all three major species of schistosomes that infect humans.…”

“…This is primarily due to the observations relating to the vaccine mediated killing of schistosomula primarily in lungs [27;65]. However, recent studies have shown that in addition to elimination of juvenile worms from lungs, vaccine-mediated killing can also be achieved of established adult worms in mice [66] and in chronically schistosome-infected baboons [57]. …”