Hassan Adam S, Houle Sébastien, Labrie Lydia, Perera Dilhan J, Dozois Charles M, Ward Brian J, Ndao Momar
Department of Microbiology & Immunology, McGill University, Montreal, QC, Canada.
Infectious Diseases and Immunity in Global Health (IDIGH), Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
NPJ Vaccines. 2023 Feb 27;8(1):27. doi: 10.1038/s41541-023-00599-w.
Schistosomiasis threatens hundreds of millions of people worldwide. The larval stage of Schistosoma mansoni migrates through the lung and adult worms reside adjacent to the colonic mucosa. Several candidate vaccines are in preclinical development, but none is designed to elicit both systemic and mucosal responses. We have repurposed an attenuated Salmonella enterica Typhimurium strain (YS1646) to express Cathepsin B (CatB), a digestive enzyme important for the juvenile and adult stages of the S. mansoni life cycle. Previous studies have demonstrated the prophylactic and therapeutic efficacy of our plasmid-based vaccine. Here, we have generated chromosomally integrated (CI) YS1646 strains that express CatB to produce a viable candidate vaccine for eventual human use (stability, no antibiotic resistance). 6-8-week-old C57BL/6 mice were vaccinated in a multimodal oral (PO) and intramuscular (IM) regimen, and then sacrificed 3 weeks later. The PO + IM group had significantly higher anti-CatB IgG titers with greater avidity and mounted significant intestinal anti-CatB IgA responses compared to PBS control mice (all P < 0.0001). Multimodal vaccination generated balanced T1/T2 humoral and cellular immune responses. Production of IFNγ by both CD4 and CD8 T cells was confirmed by flow cytometry (P < 0.0001 & P < 0.01). Multimodal vaccination reduced worm burden by 80.4%, hepatic egg counts by 75.2%, and intestinal egg burden by 78.4% (all P < 0.0001). A stable and safe vaccine that has both prophylactic and therapeutic activity would be ideal for use in conjunction with praziquantel mass treatment campaigns.
血吸虫病威胁着全球数亿人。曼氏血吸虫的幼虫阶段会在肺部迁移，成虫则栖息在结肠黏膜附近。目前有几种候选疫苗正处于临床前开发阶段，但尚无一种旨在引发全身和黏膜反应。我们对减毒鼠伤寒沙门氏菌菌株（YS1646）进行了改造，使其表达组织蛋白酶B（CatB），这是一种对曼氏血吸虫生命周期的幼虫和成虫阶段都很重要的消化酶。先前的研究已经证明了我们基于质粒的疫苗的预防和治疗效果。在此，我们构建了染色体整合（CI）的表达CatB的YS1646菌株，以生产一种最终可供人类使用的可行候选疫苗（稳定性好，无抗生素抗性）。对6 - 8周龄的C57BL/6小鼠采用多模式口服（PO）和肌肉注射（IM）方案进行接种，3周后处死。与PBS对照小鼠相比，PO + IM组的抗CatB IgG滴度显著更高，亲和力更强，并且产生了显著的肠道抗CatB IgA反应（所有P < 0.0001）。多模式接种产生了平衡的T1/T2体液和细胞免疫反应。通过流式细胞术证实了CD4和CD8 T细胞均产生IFNγ（P < 0.0001和P < 0.01）。多模式接种使虫体负荷降低了80.4%，肝脏虫卵计数降低了75.2%，肠道虫卵负荷降低了78.4%（所有P < 0.0001）。一种具有预防和治疗活性的稳定且安全的疫苗将是与吡喹酮大规模治疗运动联合使用的理想选择。
