An Immunomics Approach to Schistosome Antigen Discovery: Antibody Signatures of Naturally Resistant and Chronically Infected Individuals from Endemic Areas

Schistosomiasis is a neglected tropical disease that is responsible for almost 300,000 deaths annually. Mass drug administration (MDA) is used worldwide for the control of schistosomiasis, but chemotherapy fails to prevent reinfection with schistosomes, so MDA alone is not sufficient to eliminate the disease, and a prophylactic vaccine is required. Herein, we take advantage of recent advances in systems biology and longitudinal studies in schistosomiasis endemic areas in Brazil to pilot an immunomics approach to the discovery of schistosomiasis vaccine antigens. We selected mostly surface-derived proteins, produced them using an in vitro rapid translation system and then printed them to generate the first protein microarray for a multi-cellular pathogen. Using well-established Brazilian cohorts of putatively resistant (PR) and chronically infected (CI) individuals stratified by the intensity of their S. mansoni infection, we probed arrays for IgG subclass and IgE responses to these antigens to detect antibody signatures that were reflective of protective vs. non-protective immune responses. Moreover, probing for IgE responses allowed us to identify antigens that might induce potentially deleterious hypersensitivity responses if used as subunit vaccines in endemic populations. Using multi-dimensional cluster analysis we showed that PR individuals mounted a distinct and robust IgG1 response to a small set of newly discovered and well-characterized surface (tegument) antigens in contrast to CI individuals who mounted strong IgE and IgG4 responses to many antigens. Herein, we show the utility of a vaccinomics approach that profiles antibody responses of resistant individuals in a high-throughput multiplex approach for the identification of several potentially protective and safe schistosomiasis vaccine antigens.

血吸虫病（Schistosomiasis）是一种被忽视的热带病，每年造成近30万例死亡。目前全球范围内采用群体药物干预（Mass drug administration, MDA）开展血吸虫病防控，但化学治疗无法阻断血吸虫的再感染，因此仅依靠群体药物干预不足以根除该疾病，亟需开发预防性疫苗。本研究借助巴西血吸虫病流行区系统生物学与纵向研究的最新进展，首次采用免疫组学方法筛选血吸虫病疫苗抗原：研究团队主要选取表面衍生蛋白，通过体外快速翻译系统进行表达制备，并将其打印制备出首个针对多细胞病原体的蛋白质芯片。研究依托巴西已建立的成熟队列，根据曼氏血吸虫（S. mansoni）感染强度对受试者进行分层，分为疑似抗性（Putatively Resistant, PR）个体与慢性感染（Chronically Infected, CI）个体，通过芯片检测针对上述抗原的IgG亚类与IgE应答，以识别可区分保护性与非保护性免疫应答的抗体特征。此外，通过检测IgE应答，本研究还可识别出若在流行人群中作为亚单位疫苗使用时，可能引发潜在有害超敏反应的抗原。通过多维聚类分析发现，与慢性感染个体对多种抗原产生强烈IgE与IgG4应答不同，疑似抗性个体仅针对少量新发现且已得到充分表征的表面（被膜）抗原，产生显著且强劲的IgG1应答。本研究证实了疫苗组学策略的实用性，该方法可通过高通量多重检测手段分析抗性个体的抗体应答，从而筛选出多种兼具保护潜力与良好安全性的血吸虫病疫苗抗原。