DNA-based vaccines protect against zoonotic schistosomiasis in water buffalo

Abstract

Schistosomiasis japonica is an endemic, zoonotic disease of major public health importance in China where water buffaloes account for approximately 75% of disease transmission. Interventions that reduce schistosome infection in water buffaloes will enhance their health simultaneously reducing disease transmission to humans. While chemotherapy has proved successful, it requires continued time consuming and expensive mass treatments. A more sustainable option would be development of vaccines that reduce transmission of S. japonicum from bovines to replace bovine chemotherapy. We performed two randomized double blind trials in water buffaloes to determine if DNA vaccines encoding triose-phosphate isomerase (SjCTPI), or the tetraspanin 23 kDa integral membrane protein (SjC23), alone or fused to bovine heat shock protein 70 (Hsp70) could induce a level of immunity conducive to long-term sustainable control. Groups of water buffaloes (15/group) received three intramuscular injections, 4 weeks apart. Booster immunizations were co-administered with a plasmid DNA encoding IL-12. Four weeks after the last injection, water buffaloes were challenged with 1000 cercariae, and vaccine efficacy analyzed 8 weeks later. Water buffaloes vaccinated with SjCTPI-Hsp70 or SjCTPI plasmids had worm burdens reduced by 51.2% and 41.5%, respectively. Importantly, fecal miracidial hatching was reduced by 52.1% and 33.2% respectively compared to control vaccinated water buffaloes. Vaccination with SjC23-Hsp70 and SjC23 plasmids reduced worm burdens by 50.9% and 45.5%, respectively, and fecal miracidial hatching by 52.0% and 47.4%. A mathematical model of schistosome transmission predicts that schistosome vaccines capable of reducing water buffaloes' fecal egg output by 45%, alone or in conjunction with praziquantel treatment, will lead to a significant reduction in transmission of schistosomiasis. Both DNA vaccines tested here exceed this hypothetical level. Indeed, mathematical modeling of SjCTPI-Hsp70 and SjC23-Hsp70 alone and in conjunction with human chemotherapy showed a significant reduction in transmission almost to the point of elimination.

Evaluation of Echinococcus multilocularis tetraspanins as vaccine candidates against primary alveolar echinococcosis

“…Members of the tetraspanin family from different organisms are structurally and functionally related [18,31]. Phylogenetic analysis indicated that TSP2 of E. multilocularis is phylogenetically related to TSP2 [15], Sm23 [20] and SJC23 [21,22] of Schistosoma, the protective antigens against schistosomiasis, while TSP5 is closely related to the T24 antigen of T. solium, a diagnostic antigen for cysticercosis [26]. We suppose that among these proteins, some may be vaccine candidates, while others may be useful as diagnostic antigens.…”

“…Although some tetraspanins have been demonstrated to be potential vaccine candidates against different stages of schistosome infection [19][20][21][22], nothing is known about them in another important platyhelminth E. multilocularis. Recently, many studies have focused on the LEL domain of tetraspanin because of its important functions in mediating protein-protein interactions and homodimerization [30].…”

“…It can be seen from the above results that the reduction in liver cysts for EMY162 and EM95 were lower than for TSP1 (87.9%) and TSP3 (85.1%). Moreover, secondary (intraperitoneal) infection 21 has not been performed to evaluate the vaccination efficacy with these proteins. Although the recombinant protein 14-3-3, showed a higher protection against primary infection than those used in this study, showed no protection against secondary infections in mice.…”

“…The conserved, crucial parts of these proteins-LEL domain (aa 1～aa 81 in figure 1) were compared with other known tetraspanins from helminthes using the Clustal W2 on-line service. Then we used the MegAlign component of DNAStar programme (Version 4.01 DNASTAR, Madison, Wis.) to construct a phylogenetic tree of transmembrane proteins, including the TSP1 to TSP7 tetraspanins of E. multilocularis; the Sm23 [20], Sm25 [23], Sm-TSP1 and Sm-TSP2 proteins of S. mansoni [19]; the Sj23 [21,22] and Sj25 proteins of S. japonicum [24], the Sh23 protein of S.…”

“…The host-parasite interactions are thought to be associated with immune evasion [19], which has resulted in the use of tetraspanins as vaccines interfering with the schistosome survival strategy [19][20][21][22]. Several tetraspanins, TSP1, TSP2 [19] and Sm23 [20] of Schistosoma mansoni, and SJ23 of S. japonicum [21,22] have been reported as potential vaccine candidates against schistosomosis. It is notable that these tetraspanins caused varying reductions in different parasitic stages: adult worms (TSP1, TSP2, Sm23 and SJ23), liver eggs/granulomas (TSP1, TSP2 and SJ23) and intestinal/fecal eggs (TSP2 and SJ23).…”