Immune correlates of tuberculosis and non-tuberculosis infectious morbidity in Southern African HIV-exposed, uninfected infants.

南部非洲暴露于艾滋病毒的未感染婴儿中结核病和非结核病感染发病率的免疫相关性。

• 批准号: 10092091
• 负责人: Kathleen Powis
• 金额: $ 74.77万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-13 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092091
• 关键词: Address; Adult; African; Antigens; BCG Live; BCG Vaccine; Bacille Calmette-Guerin vaccination; Birth; Birth History; Botswana; CD4 Positive T Lymphocytes; Child; Cicatrix; Clinical; Country; Data; Development; Diarrhea; Disease; Disease Outcome; Enrollment; Environment; Epidemic; Epigenetic Process; Flow Cytometry; Goals; HIV; HIV Seronegativity; HIV-exposed uninfected infant; Health; Immune; Immune response; Immunity; Immunization; Immunize; Immunologics; Incidence; Infant; Infrastructure; Intervention; Life; Logistic Regressions; Maternal and Child Health; Meningeal Tuberculosis; Miliary Tuberculosis; Morbidity - disease rate; Mothers; Mycobacterium tuberculosis; Natural Immunity; Newborn Infant; Nucleic Acid Amplification Tests; Organizational Policy; Outcome; Peripheral Blood Mononuclear Cell; Persons; Phagocytosis; Pregnant Women; Prevalence; Production; Public Health; Pulmonary Tuberculosis; Recording of previous events; Reporting; Research; Resources; Respiratory Tract Infections; Risk; Risk Factors; South Africa; Specimen; Superoxides; T cell response; Testing; Training; Translating; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; Vulnerable Populations; Whole Blood; Woman; World Health Organization; antiretroviral therapy; diarrheal disease; efficacy trial; experience; high risk infant; histone modification; improved; infancy; infant morbidity; monocyte; mortality; mycobacterial; novel; novel vaccines; pathogen; pathogenic bacteria; pathogenic virus; perinatal HIV; peripheral blood; prevent; prospective; randomized trial; respiratory; response; scale up; success; transcriptome; vaccine development; vaccine trial

PROJECT SUMMARY/ABSTRACT Over one million infants born to women living with HIV are spared from vertical HIV acquisition. This public health success is attributable to scaling up of maternal antiretroviral treatment (ART), with current World Health Organization (WHO) policies recommending lifetime ART for persons living with HIV, including pregnant women. Yet, HIV-exposed uninfected (HEU) infants in resource-constrained settings experience 2- to 4-fold higher infectious cause morbidity and mortality compared with HIV-unexposed (HU) infants in the same settings. This is primarily due to diarrheal disease and respiratory illness, including tuberculosis (TB). HEU children also experience 20-fold increased incidence of latent TB infection (LTBI) compared with HIV- unexposed (HU) children. Several studies have described immune abnormalities among HEU children, which might explain a portion of HEU infant vulnerability. In both Botswana and South Africa, also settings with high TB and HIV prevalence, bacille Calmette-Guérin (BCG) immunization rates at birth exceed 98%. While some studies have shown that BCG vaccination protects against TB meningitis and disseminated TB in HU infants and may have heterologous effects that extend beyond TB protection, the reported alterations in HEU infant immunity may impact the efficacy of the BCG vaccine both in directly protecting against TB and in providing the non-specific immune protection. Leveraging two existing prospective observational maternal-child health studies underway in Botswana and South Africa, respectively, each of which is following both HEU and HU infants from birth and beyond infancy, we will use data and specimens from 900 infants (600 HEU infants) to evaluate BCG vaccine-induced specific and non-specific immune responses while using immunological studies to assess correlates of BCG vaccine protection. Specifically, we will 1) Define TB-related and TB- independent causes of morbidity and mortality in BCG vaccinated HEU and HU infants; 2) Define immune correlates of risk for tuberculosis infection in HEU infants using polychromatic flow cytometry to compare conventional and unconventional T-cell responses to BCG vaccination; 3) Explore the effect of HIV exposure on BCG-induced peripheral blood monocytes. We anticipate that study findings will inform TB vaccine development for HEU infants,and might identify further potential interventions to protect against infectious morbidity and mortality more frequently experienced by this vulnerable population of infants.

项目摘要/摘要 艾滋病毒携带者妇女所生的100多万婴儿免于垂直感染艾滋病毒。这个公众 健康方面的成功归功于加强孕产妇抗逆转录病毒治疗(ART)，与《世界卫生组织》合作 世界卫生组织(WHO)建议艾滋病毒携带者(包括孕妇)终身接受抗逆转录病毒治疗的政策 女人。然而，在资源有限的环境中，感染艾滋病毒的未感染(HEU)婴儿的经历是2-4倍 与未接触艾滋病毒(HU)的婴儿相比，相同情况下感染原因的发病率和死亡率更高 设置。这主要是由于腹泻病和呼吸系统疾病，包括结核病。高浓缩铀 与艾滋病毒相比，儿童潜在结核病感染(LTBI)的发病率也增加了20倍 未暴露(HU)儿童。几项研究已经描述了HEU儿童的免疫异常，这 可能在一定程度上解释了HEU婴儿的脆弱性。在博茨瓦纳和南非，也设置了高 在结核病和艾滋病毒流行的情况下，卡介苗出生时的接种率超过98%。虽然有些人 研究表明，接种卡介苗可预防结核脑膜炎和婴儿传播结核病。 并且可能具有超越结核病保护的异源影响，报道的HEU婴儿的变化 免疫可能会影响卡介苗在直接预防结核病和提供 非特异性免疫保护。利用现有的两个前瞻性观察母婴健康 博茨瓦纳和南非正在分别进行研究，每项研究都在跟踪高浓缩铀和胡 从出生到婴儿期以后，我们将使用900名婴儿(600名HEU婴儿)的数据和样本 利用免疫学研究评估卡介苗诱导的特异性和非特异性免疫反应 评估卡介苗保护的相关因素。具体地说，我们将1)定义结核病相关和结核病- 卡介苗接种HEU和HU婴儿发病和死亡的独立原因；2)确定 应用多色流式细胞术检测HEU婴儿结核病感染风险的免疫相关研究 比较常规和非常规T细胞对卡介苗接种的反应；3)探索HIV的影响 卡介苗诱导的外周血单核细胞暴露。我们预计研究结果将告知结核病 针对HEU婴儿的疫苗开发，并可能确定进一步的潜在干预措施以预防 这一易受伤害的婴儿群体更容易感染发病率和死亡率。