Defining the Immunogenicity and Efficacy of a Durable BCG Vaccine Strategy Optimized for Preventing TB in Pediatric HIV Infection

项目总结 由结核分枝杆菌(Mtb)引起的结核病(TB)仍然是发病率和 全球范围内的死亡率和艾滋病毒携带者特别容易受到影响。唯一获得许可的结核病疫苗是活的 减毒卡介苗(BCG)，用于婴儿皮内注射。虽然BCG提供了大量的 在儿童时期预防非肺结核病，它对成人肺结核病发病率影响很小。近期 对猕猴的研究表明，通过静脉或静脉注射卡介苗，可以显著预防结核病。 从粘膜上看。然而，卡介苗可能会导致免疫抑制的接受者患病，包括HIV+儿童。 最近，一种更弱的卡介苗菌株，卡介苗𝚫1419c，已被证明在无瘤小鼠中是安全的， 对小鼠和豚鼠均有免疫原性，对小鼠和豚鼠均比卡介苗有效 结核病的模型。在这项提案中，我们将使用我们的儿科毛里求斯食蟹猴(MCM)结核病模型来 卡介苗和卡介苗𝚫1419c，如果由更临床可翻译的粘膜途径给药，则同时进行检测。使用MCM 1-2 年龄更接近于目前接种卡介苗的儿科人群。我们会 用一套强大的检测方法鉴定卡介苗和卡介苗𝚫1419c在这些年轻的小鼠心肌细胞中的免疫原性， 包括多参数流式细胞术、单细胞RNAseq、血清学和表观遗传学分析。我们会 通过用强毒结核分枝杆菌攻击动物来确定这些疫苗的保护效果，然后 使用我们完善的定量PET/CT成像、病理和结核分枝杆菌负荷来评估保护 措施。在目标2中，我们将使用类似的方法来定义安全性、免疫原性和保护效力 卡介苗和卡介苗𝚫1419c在SIV+青少年心肌梗死中，建模艾滋病毒+儿童谁最能受益于 改进的结核病疫苗。 我们将测试我们的假设，即更弱的卡介苗𝚫1419c将是安全的，免疫原性的，并防止 当MTB经粘膜给药给有和没有SIV感染的幼年MCM时。这是多路PI Proposal组建了一个由三名在结核病、艾滋病毒领域拥有互补专业知识的知名科学家组成的团队 以及SIV、免疫学和儿科传染病。此外，我们已经有了一个既定的 建立富有成效和协作的关系，确保成功完成这一重要项目。

PROJECT SUMMARY Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) remains a major cause of morbidity and mortality worldwide and HIV+ individuals are particularly susceptible. The only licensed TB vaccine is the live attenuated Bacillus Calmette-Guerin (BCG) that is given intradermally to infants. While BCG provides substantial protection against non-pulmonary TB in childhood, it has little impact on pulmonary TB rates in adults. Recent studies in macaques have elicited striking protection from TB by instead delivering BCG intravenously or mucosally. However, BCG can cause disease in immunosuppressed recipients, including HIV+ children. Recently, a more attenuated BCG strain, BCG𝚫1419c, has been shown to be safe in athymic mice, immunogenic in both mice and guinea pigs, and more efficacious than BCG in both murine and guinea pigs models of TB. In this proposal, we will use our pediatric Mauritian cynomolgus macaque (MCM) model of TB to test both BCG and BCG𝚫1419c when given by the more clinically translatable mucosal route. Using MCM 1-2 years of age more closely resembles the pediatric population currently targeted for BCG vaccination. We will characterize the immunogenicity of BCG and BCG𝚫1419c in these young MCM using a suite of powerful assays, including multiparameter flow cytometry, single cell RNAseq, serology, and epigenetic analysis. We will determine the protective efficacy of these vaccines by challenging the animals with virulent Mtb and then assessing protection using our well-established and quantitative PET/CT imaging, pathology, and Mtb burden measures. In Aim 2, we will use a similar approach to define the safety, immunogenicity and protective efficacy of both BCG and BCG𝚫1419c in SIV+ juvenile MCM, modeling HIV+ children who could most benefit from an improved TB vaccine. We will test our hypothesis that this more attenuated BCG𝚫1419c will be safe, immunogenic, and protect from Mtb when administered mucosally to juvenile MCM with and without pre-existing SIV infection. This multi-PI proposal assembles a team of three established scientists with complimentary expertise in the fields of TB, HIV and SIV, immunology, and pediatric infectious diseases. Furthermore, we already have an established productive and collaborative relationship, ensuring successful completion of this important project.