Do schistosome vaccine trials in mice have an intrinsic flaw that generates spurious protection data?

Abstract

The laboratory mouse has been widely used to test the efficacy of schistosome vaccines and a long list of candidates has emerged from this work, many of them abundant internal proteins. These antigens do not have an additive effect when co-administered, or delivered as SWAP homogenate, a quarter of which comprises multiple candidates; the observed protection has an apparent ceiling of 40–50 %. We contend that the low level of maturation of penetrating cercariae (~32 % for Schistosoma mansoni) is a major limitation of the model since 68/100 parasites fail to mature in naïve mice due to natural causes. The pulmonary capillary bed is the obstacle encountered by schistosomula en route to the portal system. The fragility of pulmonary capillaries and their susceptibility to a cytokine-induced vascular leak syndrome have been documented. During lung transit schistosomula burst into the alveolar spaces, and possess only a limited capacity to re-enter tissues. The acquired immunity elicited by the radiation-attenuated (RA) cercarial vaccine relies on a pulmonary inflammatory response, involving cytokines such as IFNγ and TNFα, to deflect additional parasites into the alveoli. A principal difference between antigen vaccine protocols and the RA vaccine is the short interval between the last antigen boost and cercarial challenge of mice (often two weeks). Thus, after antigen vaccination, challenge parasites will reach the lungs when both activated T cells and cytokine levels are maximal in the circulation. We propose that “protection” in this situation is the result of physiological effects on the pulmonary blood vessels, increasing the proportion of parasites that enter the alveoli. This hypothesis will explain why internal antigens, which are unlikely to interact with the immune response in a living schistosomulum, plus a variety of heterologous proteins, can reduce the level of maturation in a non-antigen-specific way. These proteins are “successful” precisely because they have not been selected for immunological silence. The same arguments apply to vaccine experiments with S. japonicum in the mouse model; this schistosome species seems a more robust parasite, even harder to eliminate by acquired immune responses. We propose a number of ways in which our conclusions may be tested.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1369-9) 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

“…For instance, the resistance against schistosomiasis in individuals that are naturally resistant to schistosome infection (Endemic normal) is associated with Th1 immune response as demonstrated by high level production of interferon gamma (IFN-γ) by peripheral blood mononuclear cells (PBMCs) from these individuals stimulated with schistosome antigens (McManus and Loukas 2008; Viana et al 1994). Furthermore, studies with RA vaccine showed that schistosomulae are killed in the lungs of protected animals as a result of inflammation (Wilson et al 2016). In the RA model, co-administration of IL-12 (a potent Th1 inducing cytokine) with RA vaccine resulted in almost sterile immunity which was associated with a high induction of IFN-γ in an autocrine manner (Wilson and Coulson 2009; Wilson et al 1999; Wilson et al 2016).…”

“…Furthermore, studies with RA vaccine showed that schistosomulae are killed in the lungs of protected animals as a result of inflammation (Wilson et al 2016). In the RA model, co-administration of IL-12 (a potent Th1 inducing cytokine) with RA vaccine resulted in almost sterile immunity which was associated with a high induction of IFN-γ in an autocrine manner (Wilson and Coulson 2009; Wilson et al 1999; Wilson et al 2016). Studies by our group and other colleagues have shown that the production of IFN-γ is associated with protection against schistosome infection in animal models (Ahmad et al 2009c; Le et al 2014; Pearson et al 2012; Varaldo et al 2004; Zhang et al 2011).…”

Sm-p80-Based Schistosomiasis Vaccine: Preparation for Human Clinical Trials

“…Hundreds of antigens have been identified, some of which confer protection of varying degrees and are considered promising though they do not quite reach the level of immunity elicited following vaccination with irradiated cercariae [34;35]. With the exception of a few antigens, the prophylactic efficacy of these antigens has been evaluated only in the murine model which inherently has an apparent ceiling of 40-50% protection [34].…”

“…Hundreds of antigens have been identified, some of which confer protection of varying degrees and are considered promising though they do not quite reach the level of immunity elicited following vaccination with irradiated cercariae [34;35]. With the exception of a few antigens, the prophylactic efficacy of these antigens has been evaluated only in the murine model which inherently has an apparent ceiling of 40-50% protection [34]. Recently, it has been argued with convincing arguments that the low level of maturation of penetrating cercariae (~32% for Schistosoma mansoni) is a major limitation of the model since 68/100 parasites fail to mature in naïve mice due to natural causes [34].…”

“…With the exception of a few antigens, the prophylactic efficacy of these antigens has been evaluated only in the murine model which inherently has an apparent ceiling of 40-50% protection [34]. Recently, it has been argued with convincing arguments that the low level of maturation of penetrating cercariae (~32% for Schistosoma mansoni) is a major limitation of the model since 68/100 parasites fail to mature in naïve mice due to natural causes [34]. We believe that the natural hosts of schistosomes, baboons, are the most relevant model of human clinical manifestations of both acute and chronic disease.…”