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

项目摘要 由结核分枝杆菌（Mtb）引起的结核病（TB）仍然是发病的主要原因， 艾滋病毒感染者和艾滋病病毒阳性者特别容易受到感染。唯一获得许可的结核病疫苗是 减毒卡介苗（BCG），用于婴儿皮内注射。虽然BCG提供了大量 虽然它在儿童时期对非肺结核的保护作用，但它对成人肺结核发病率的影响很小。最近 在猕猴中的研究已经通过静脉注射BCG或 粘膜的然而，BCG可导致免疫抑制接受者的疾病，包括HIV+儿童。 最近，一种更加减毒的BCG菌株BCG1419 c已被证明在无胸腺小鼠中是安全的， 在小鼠和豚鼠中均具有免疫原性，且在小鼠和豚鼠中均比BCG更有效 结核病模型在本提案中，我们将使用我们的结核病儿童食蟹猴（MCM）模型， 当通过临床上更易翻译的粘膜途径给药时，测试BCG和BCGβ1419 c。使用MCM 1-2 年龄更接近于目前针对卡介苗接种的儿科人群。我们将 使用一套强大的测定来表征BCG和BCGβ1419 c在这些年轻MCM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。我们将 通过用毒性结核分枝杆菌攻击动物来确定这些疫苗的保护效力， 使用我们完善的定量PET/CT成像、病理学和结核菌负荷评估保护作用 措施在目标2中，我们将使用类似的方法来定义安全性、免疫原性和保护功效 SIV+青少年MCM中的BCG和BCGβ1419 c，模拟HIV+儿童， 改进的结核病疫苗。 我们将检验我们的假设，即这种更减毒的BCGβ 1419 c将是安全的、免疫原性的，并保护免于 Mtb粘膜给药时，以青少年MCM与和不预先存在的SIV感染。这种多PI 一项提案组建了一个由三名在结核病、艾滋病毒和艾滋病领域具有互补专长的科学家组成的小组， SIV，免疫学，儿科传染病。此外，我们已经建立了一个 这是一个富有成效的合作关系，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.