Tallima Hatem, Dvořák Jan, Kareem Sahira, Abou El Dahab Marwa, Abdel Aziz Nada, Dalton John Pius, El Ridi Rashika
Zoology Department, Faculty of Science, Cairo University, Giza, Egypt.
Department of Chemistry, School of Science and Engineering, American University in Cairo, New Cairo, Cairo, Egypt.
PLoS Negl Trop Dis. 2017 Mar 27;11(3):e0005443. doi: 10.1371/journal.pntd.0005443. eCollection 2017 Mar.
Schistosomiasis, a severe disease caused by parasites of the genus Schistosoma, is prevalent in 74 countries, affecting more than 250 million people, particularly children. We have previously shown that the Schistosoma mansoni gut-derived cysteine peptidase, cathepsin B1 (SmCB1), administered without adjuvant, elicits protection (>60%) against challenge infection of S. mansoni or S. haematobium in outbred, CD-1 mice. Here we compare the immunogenicity and protective potential of another gut-derived cysteine peptidase, S. mansoni cathepsin L3 (SmCL3), alone, and in combination with SmCB1. We also examined whether protective responses could be boosted by including a third non-peptidase schistosome secreted molecule, glyceraldehyde 3-phosphate dehydrogenase (SG3PDH), with the two peptidases.
METHODOLOGY/PRINCIPAL FINDINGS: While adjuvant-free SmCB1 and SmCL3 induced type 2 polarized responses in CD-1 outbred mice those elicited by SmCL3 were far weaker than those induced by SmCB1. Nevertheless, both cysteine peptidases evoked highly significant (P < 0.005) reduction in challenge worm burden (54-65%) as well as worm egg counts and viability. A combination of SmCL3 and SmCB1 did not induce significantly stronger immune responses or higher protection than that achieved using each peptidase alone. However, when the two peptidases were combined with SG3PDH the levels of protection against challenge S. mansoni infection reached 70-76% and were accompanied by highly significant (P < 0.005) decreases in worm egg counts and viability. Similarly, high levels of protection were achieved in hamsters immunized with the cysteine peptidase/SG3PDH-based vaccine.
CONCLUSIONS/SIGNIFICANCE: Gut-derived cysteine peptidases are highly protective against schistosome challenge infection when administered subcutaneously without adjuvant to outbred CD-1 mice and hamsters, and can also act to enhance the efficacy of other schistosome antigens, such as SG3PDH. This cysteine peptidase-based vaccine should now be advanced to experiments in non-human primates and, if shown promise, progressed to Phase 1 safety trials in humans.
血吸虫病是由血吸虫属寄生虫引起的一种严重疾病，在74个国家流行，影响超过2.5亿人，尤其是儿童。我们之前已经表明，曼氏血吸虫肠道来源的半胱氨酸蛋白酶组织蛋白酶B1（SmCB1），在无佐剂的情况下给药，可在远交系CD-1小鼠中引发针对曼氏血吸虫或埃及血吸虫攻击感染的保护作用（>60%）。在此，我们比较了另一种肠道来源的半胱氨酸蛋白酶——曼氏血吸虫组织蛋白酶L3（SmCL3）单独以及与SmCB1联合使用时的免疫原性和保护潜力。我们还研究了将第三种非肽类血吸虫分泌分子甘油醛-3-磷酸脱氢酶（SG3PDH）与这两种肽酶一起使用是否能增强保护反应。
方法/主要发现：在远交系CD-1小鼠中，无佐剂的SmCB1和SmCL3诱导了2型极化反应，但SmCL3引发的反应远弱于SmCB1诱导的反应。然而，两种半胱氨酸蛋白酶均引起攻击感染的虫体负荷高度显著降低（P < 0.005）（54 - 65%），以及虫卵数量和活力的显著降低。SmCL3和SmCB1联合使用并未诱导出比单独使用每种肽酶更强的免疫反应或更高的保护作用。然而，当这两种肽酶与SG3PDH联合使用时，针对曼氏血吸虫攻击感染的保护水平达到70 - 76%，同时虫卵数量和活力也高度显著降低（P < 0.005）。同样，在用基于半胱氨酸蛋白酶/SG3PDH的疫苗免疫的仓鼠中也实现了高水平的保护。
结论/意义：肠道来源的半胱氨酸蛋白酶在无佐剂的情况下皮下注射给远交系CD-1小鼠和仓鼠时，对血吸虫攻击感染具有高度保护作用，并且还可增强其他血吸虫抗原（如SG3PDH）的功效。这种基于半胱氨酸蛋白酶的疫苗现在应推进到非人灵长类动物实验，如果显示出前景，则应推进到人体1期安全性试验。
