Styliani Karanika, Tianyin Wang, Addis Yilma, Jennie Ruelas Castillo, James T. Gordy, Hannah Bailey, Darla Quijada, Kaitlyn Fessler, Rokeya Tasneen, Elisa M. Rouse Salcido, Harley Harris, Rowan E. Bates, Heeme Ton, Jacob Meza, Yangchen Li, Alannah D. Taylor, Jean J. Zhenq, Jiaqi Zhang, J David Peske, Theodoros Karantanos, Amanda R. Maxwell, Eric Nuermberger, Richard B. Markham, Petros C. Karakousis
{"title":"Therapeutic DNA Vaccine Targeting Mycobacterium tuberculosis Persisters Shortens Curative Tuberculosis Treatment","authors":"Styliani Karanika, Tianyin Wang, Addis Yilma, Jennie Ruelas Castillo, James T. Gordy, Hannah Bailey, Darla Quijada, Kaitlyn Fessler, Rokeya Tasneen, Elisa M. Rouse Salcido, Harley Harris, Rowan E. Bates, Heeme Ton, Jacob Meza, Yangchen Li, Alannah D. Taylor, Jean J. Zhenq, Jiaqi Zhang, J David Peske, Theodoros Karantanos, Amanda R. Maxwell, Eric Nuermberger, Richard B. Markham, Petros C. Karakousis","doi":"10.1101/2024.09.03.611055","DOIUrl":null,"url":null,"abstract":"Mycobacterium tuberculosis (Mtb) is one of the leading infectious causes of death worldwide. There is no available licensed therapeutic vaccine that shortens active tuberculosis (TB) disease drug treatment and prevents relapse, despite the World Health Organization's calls. Here, we show that an intranasal DNA vaccine containing a fusion of the stringent response relMtb gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3α/CCL20, shortens the duration of curative TB treatment in immunocompetent mice. Compared to the first-line regimen for drug-susceptible TB alone, our novel adjunctive vaccine induced greater RelMtb-specific T-cell responses associated with optimal TB control in spleen, blood, lungs, mediastinal lymph nodes, and bronchoalveolar lavage (BAL) fluid. These responses were sustained, if not augmented, over time. It also triggered more effective dendritic cell recruitment, activation, and colocalization with T cells, implying enhanced crosstalk between innate and adaptive immunity. Moreover, it potentiated a 6-month TB drug-resistant regimen, rendering it effective across treatment regimens, and also showed promising results in CD4+ knockout mice, perhaps due to enhanced Rel-specific CD8+ T-cell responses. Notably, our novel fusion vaccine was also immunogenic in nonhuman primates, the gold standard animal model for TB vaccine studies, eliciting antigen-specific T-cell responses in blood and BAL fluid analogous to those observed in protected mice. Our findings have critical implications for therapeutic TB vaccine clinical development in immunocompetent and immunocompromised populations and may serve as a model for defining immunological correlates of therapeutic vaccine-induced protection.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"1 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv - Immunology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.09.03.611055","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Mycobacterium tuberculosis (Mtb) is one of the leading infectious causes of death worldwide. There is no available licensed therapeutic vaccine that shortens active tuberculosis (TB) disease drug treatment and prevents relapse, despite the World Health Organization's calls. Here, we show that an intranasal DNA vaccine containing a fusion of the stringent response relMtb gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3α/CCL20, shortens the duration of curative TB treatment in immunocompetent mice. Compared to the first-line regimen for drug-susceptible TB alone, our novel adjunctive vaccine induced greater RelMtb-specific T-cell responses associated with optimal TB control in spleen, blood, lungs, mediastinal lymph nodes, and bronchoalveolar lavage (BAL) fluid. These responses were sustained, if not augmented, over time. It also triggered more effective dendritic cell recruitment, activation, and colocalization with T cells, implying enhanced crosstalk between innate and adaptive immunity. Moreover, it potentiated a 6-month TB drug-resistant regimen, rendering it effective across treatment regimens, and also showed promising results in CD4+ knockout mice, perhaps due to enhanced Rel-specific CD8+ T-cell responses. Notably, our novel fusion vaccine was also immunogenic in nonhuman primates, the gold standard animal model for TB vaccine studies, eliciting antigen-specific T-cell responses in blood and BAL fluid analogous to those observed in protected mice. Our findings have critical implications for therapeutic TB vaccine clinical development in immunocompetent and immunocompromised populations and may serve as a model for defining immunological correlates of therapeutic vaccine-induced protection.
结核分枝杆菌(Mtb)是导致全球死亡的主要传染病因之一。尽管世界卫生组织发出了呼吁,但目前尚无可缩短活动性结核病(TB)药物治疗和预防复发的特许治疗疫苗。在这里,我们展示了一种含有严格反应 relMtb 基因与编码未成熟树突状细胞靶向趋化因子 MIP-3α/CCL20 基因融合的鼻内 DNA 疫苗,它能缩短免疫功能正常小鼠的结核病治愈治疗时间。与单用药物治疗易感肺结核的一线方案相比,我们的新型辅助疫苗能诱导更多的 RelMtb 特异性 T 细胞应答,从而在脾脏、血液、肺部、纵隔淋巴结和支气管肺泡灌洗液(BAL)中达到最佳肺结核控制效果。这些反应即使没有增强,也会随着时间的推移而持续。它还能更有效地引发树突状细胞的招募、活化以及与 T 细胞的共定位,这意味着先天性免疫和适应性免疫之间的串联得到了增强。此外,它还增强了为期 6 个月的结核病耐药治疗方案,使其在各种治疗方案中都有效,而且在 CD4+ 基因敲除小鼠中也显示出良好的效果,这可能是由于 Rel 特异性 CD8+ T 细胞反应增强的缘故。值得注意的是,我们的新型融合疫苗在非人灵长类动物(结核病疫苗研究的黄金标准动物模型)中也具有免疫原性,在血液和 BAL 液中引起的抗原特异性 T 细胞反应与在受保护小鼠中观察到的反应类似。我们的研究结果对免疫功能健全和免疫功能低下人群的治疗性结核病疫苗临床开发具有重要意义,并可作为确定治疗性疫苗诱导保护的免疫学相关因素的模型。