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

确定针对儿童 HIV 感染中预防结核病而优化的持久 BCG 疫苗策略的免疫原性和功效

• 批准号: 10760444
• 负责人: Lishomwa C Ndhlovu
• 金额: $ 82.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-20 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10760444
• 关键词: 2 year old; Adolescent; Adult; Age; Animal Model; Animals; Attenuated; BCG Live; BCG Vaccine; Bacille Calmette-Guerin vaccination; Biological Assay; Bronchoscopes; Cavia; Child; Childhood; Clinical; Communicable Diseases; Data; Development; Disease; Ensure; Epigenetic Process; Flow Cytometry; HIV; Immune system; Immunity; Immunocompromised Host; Immunology; Immunology procedure; Individual; Infant; Infection; Intravenous; Licensing; Macaca; Macaca fascicularis; Mass Vaccinations; Measures; Modeling; Monitor; Morbidity - disease rate; Mucous Membrane; Mus; Mycobacterium tuberculosis; Nude Mice; PET/CT scan; Pathology; Persons; Population; Predisposition; Productivity; Pulmonary Tuberculosis; Recombinants; Respiratory Mucosa; Risk; Route; SIV; Safety; Scientist; Serology; Side; Testing; Tuberculosis; Tuberculosis Vaccines; Vaccinated; Vaccination; Vaccines; Virulent; Vulnerable Populations; X-Ray Computed Tomography; clinical translation; co-infection; design; global health; guinea pig model; immunogenic; immunogenicity; immunosuppressed; improved; intravenous injection; mature animal; mortality; novel; pediatric human immunodeficiency virus infection; predicting response; prevent; programs; protective efficacy; safety assessment; single-cell RNA sequencing; vaccine candidate; vaccine efficacy; vaccine safety; vaccine strategy; vaccine trial

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.

项目摘要 结核分枝杆菌（MTB）引起的结核病（TB）仍然是发病率和 全球死亡率和艾滋病毒+个体特别容易受到影响。唯一有执照的结核病疫苗是现场直播 减弱的芽孢杆菌塞氏菌（BCG），在婴儿地内给予婴儿。虽然BCG提供了大量 在童年时期对非肺结核的保护，对成人的肺结核率几乎没有影响。最近的 猕猴的研究通过静脉注射或 粘液。但是，BCG会在包括HIV+儿童在内的免疫抑制受体中引起疾病​​。 最近，一种更衰减的BCG菌株BCG𝚫1419C已被证明是在无胸腺小鼠中安全的， 小鼠和豚鼠的免疫原性，并且在鼠和豚鼠中都比BCG更有效 结核病模型。在此提案中，我们将使用小儿毛里求斯cynomolgus猕猴（MCM）模型 当通过更临床翻译的粘膜途径给出时，同时测试BCG和BCG𝚫1419C。使用MCM 1-2 年龄更类似于目前用于BCG疫苗接种的小儿人群。我们将 使用一套强大的测定法，表征这些年轻MCM中BCG和BCG𝚫1419C的免疫原性， 包括多参数流式细胞术，单细胞RNASEQ，血清学和表观遗传分析。我们将 通过用有毒的MTB挑战动物，然后确定这些疫苗的受保护效率 使用我们建立良好和定量的PET/CT成像，病理学和MTB Burnen评估保护 措施。在AIM 2中，我们将使用类似的方法来定义安全性，免疫原性和保护效率 在SIV+少年MCM中的BCG和BCG𝚫1419C中 改善了结核病疫苗。 我们将测试我们的假设，即这种更衰减的BCG𝚫1419C将是安全，免疫原性的 MTB粘液施用对少年MCM施用，而没有预先存在SIV感染的MTB。这个多pi 提案组成了由三名成熟科学家组成的团队，该科学家在结核病领域具有免费专业知识 和SIV，免疫学和小儿传染病。此外，我们已经建立了 生产性和协作关系，确保成功完成了这个重要项目。