Data generated in this study indicate that from the 2 different vaccination strategies used with Sm-p80–based vaccine, recombinant Sm-p80 formulated in TLR7 and TLR9 agonists provides the best levels of prophylactic efficacy in baboons (52%–58%). These levels of protection have not been previously obtained with any schistosome antigen in large animal models. In addition, there is now consensus that a vaccine that confers an initial 50% protection in humans should be effective in reducing overall morbidity and mortality [9
], and in all likelihood would be an appropriate first-generation schistosomiasis vaccine [37
]. Because baboons present a disease of schistosomiasis comparable to that in humans [38
] and provide an excellent model for vaccine efficacy determination studies [14
], detection of high levels of Sm-p80–mediated protection in this model further strengthens the validity of Sm-p80 as a vaccine candidate.
A mixed and balanced response of the pro-inflammatory (Th17 and Th1) and anti-inflammatory (Th2) type was observed in this study, but the generation of Th1 response appears to be important in Sm-p80–mediated protection in baboons. The predominant antibody in protected animals is IgG and its subtypes IgG1 and IgG2. In humans, IgG1 is implicated in Th2-type responses in many cases [40
], but it has also been shown to be driven by IL-12 and IFN-γ in a few systems [43
]. IgG2, on the other hand, in most cases is dependent on IL-12 and IFN-γ [42
]. Similarly, enhanced production of IL-2 and IFN-γ in cultures and higher levels of IL-12α messenger RNA in PMBCs stimulated with Sm-p80 further reinforce the importance of Th1 type of responses in animals vaccinated with recombinant protein formulation. The Th17 type of responses may also play some role in providing Sm-p80–mediated protection, as evidenced by the increase in IL-1β, IL-6, and IL-22 messenger RNA levels in PBMCs, splenocytes, and lymph node cells from vaccinated baboons. Essential and synergistic roles for some of these cytokines have been reported in human Th17 differentiation directed by TLR ligand-activated dendritic cells [46
]. A clear increase in the population of CD3+
cells in the rSm-p80 + ODN-10104 group (the best performing strategy) indicates that the vaccine is effective in expanding T cell counts. CD4+
T cells have been reported to be involved in conferring some resistance to humans from reinfection with schistosomes, perhaps by orchestrating many of the effector mechanisms required for human protective immunity. [47
It is also evident from human correlate studies that some schistosome-hyperexposed individuals develop anti–Sm-p80 IgG, but how this correlates with resistance to infection is still unclear. Furthermore, the pediatric population (8–10 years old), which is highly susceptible to schistosome infection, has very low levels, if any, of anti–Sm-p80 IgG and thus a Sm-p80–based vaccine should greatly augment protective immunity. Finally, the lack of prevailing Sm-p80–specific IgE in the human schistosome-infected population provides a good level of confidence that the risk of hypersensitivity reactions following vaccination with Sm-p80 is minimal.
The data presented here provide a clear proof of concept in a nonhuman primate model of schistosomiasis using a recombinant Sm-p80 protein formulation as the basis for further preclinical vaccine development leading to human clinical trials.