EFFECT OF NEONATAL BCG ADMINISTRATION ON INNATE AND ADAPTIVE IMMUNE RESPONSES TO INFECTION WITH ROTAVIRUS LIVE ATTENUATED VACCINE STRAIN IN HIV-EXPOSED AND UNEXPOSED INFANTS

新生儿卡介苗给药对暴露和未暴露婴儿轮状病毒减毒活疫苗株感染的先天和适应性免疫反应的影响

• 批准号: 10431803
• 负责人: Marisa Marcia Mussi-Pinhata
• 金额: $ 15.55万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431803
• 关键词: Address; Adjuvant; Adult; Age; Agonist; Antigen-Presenting Cells; Area; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Brazil; Breast Feeding; Cells; Cellular Immunity; Cessation of life; Characteristics; Child; Clinical; Conflict (Psychology); Country; DNA Methylation; Defect; Development; Dose; Epigenetic Process; Generations; Genetic; HIV; HIV-exposed uninfected infant; Hospitalization; Humoral Immunities; Immune; Immune response; Immunity; Immunization; In Vitro; Individual; Infant; Infection; Innate Immune Response; Intervention; Kinetics; Laboratories; Life; Measures; Mediating; Memory; Modeling; Mononuclear; Morbidity - disease rate; Mycobacterium tuberculosis; Natural Immunity; Neonatal; Outcome Measure; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Policies; Population; Predisposition; RNA; Research; Rotavirus; Safety; Sample Size; Swab; System; Time; Training; Translating; Tuberculosis; Umbilical Cord Blood; Vaccines; Viral; Viremia; Virus; Virus Replication; Yellow Fever Vaccine; adaptive immune response; base; cancer therapy; clinical application; cytokine; design; epidemiology study; high risk; high risk infant; immunological intervention; improved; improved outcome; in vivo; infant infection; infant morbidity/mortality; microorganism; mortality; neonate; pathogen; protective effect; rectal; response; standard of care; young adult

Project Summary BCG is a potent stimulator of innate immunity and has been used as an adjuvant in cancer therapy. BCG has also been shown to improve TB-unrelated infant morbidity and mortality and improve infant responses to vaccines in countries where BCG is routinely administered to neonates. However, epidemiologic studies have generated conflicting results due to their design and/or to the different BCG products. Here we propose to study the nonspecific protective effect of BCG by investigating innate and adaptive immune responses to infection with the rotavirus live attenuated vaccine virus (RoV) as a surrogate of infection. We will measure responses in Brazilian infants, who receive BCG in the first week of life per standard of care (BCG+), and in US infants, who do not receive BCG (BCG-). We will also investigate the mechanism of BCG's nonspecific protection against heterologous infections. Our results may create a framework for immune modulatory interventions in infants, who have higher infectious morbidity and mortality and lower responses to vaccines compared with older children and young adults. Moreover, we will investigate the effect of BCG both in HIV- exposed uninfected (HEU) and in HIV-unexposed (HUU) infants. HEU are a growing population with increased susceptibility to infections, hospitalization and death and with multiple innate and adaptive immune defects compared with HUU, which makes them important candidates for boosting immune interventions. We hypothesized that the protective effect of BCG against heterologous infections in infants is mediated by activation of trained innate immunity that controls the initial stages of infection and supports generation of robust adaptive immune responses.This hypothesis will be addressed in the following Specific Aims: Aim 1. To assess the magnitude of innate and adaptive immune responses to RoV and their association with viral clearance in BCG+ HEU and HUU in comparison with BCG- HEU and HUU. We will measure innate immune cell phenotypes, cytokine expression, RoV-specific humoral and cellular immunity, and RoV shedding, after administration of the RoV vaccine at 6 weeks of age. Aim 2. To investigate the functional and epigenetic effect of BCG on innate immunity and develop an in vitro system that reproduces this effect using BCG and pattern recognition receptor (PRR) agonists. We will develop an in vitro system of BCG stimulation that reproduces the NK, γδ T and antigen presenting cell phenotypic and DNA methylation profiles observed after in vivo BCG administration. Then we will develop a cocktail of PRR agonists that reproduces the effect of in vitro BCG stimulation and could be translated for clinical use as an immune boosting agent for HEU and other high risk infants. Impact. Using objective laboratory-based outcome measures and an ample sample size, this study will provide the highly needed definitive proof of the beneficial effect of BCG heterologous immune stimulation in infants.

项目概要 卡介苗是先天免疫的有效刺激剂，已被用作癌症治疗的佐剂。卡介苗有 还被证明可以改善与结核病无关的婴儿发病率和死亡率，并改善婴儿对结核病的反应 在常规给新生儿注射卡介苗的国家接种疫苗。然而，流行病学研究表明 由于其设计和/或不同的 BCG 产品而产生了相互矛盾的结果。在此我们建议 通过研究先天性和适应性免疫反应来研究卡介苗的非特异性保护作用 用轮状病毒减毒活疫苗病毒（RoV）感染作为感染的替代物。我们将测量 根据标准护理 (BCG+) 在出生第一周接受卡介苗治疗的巴西婴儿的反应，以及 未接受卡介苗治疗的美国婴儿 (BCG-)。我们还将研究BCG非特异性作用的机制。 防止异源感染。我们的结果可能会为免疫调节创建一个框架 对感染率和死亡率较高且对疫苗反应较低的婴儿进行干预 与年龄较大的儿童和年轻人相比。此外，我们将研究卡介苗对艾滋病毒的影响 暴露于未感染者 (HEU) 和未暴露于 HIV 者 (HUU) 的婴儿。 HEU 人口不断增长， 容易感染、住院和死亡，并患有多种先天性和适应性免疫缺陷 与 HUU 相比，这使它们成为增强免疫干预的重要候选者。我们 假设卡介苗对婴儿异源感染的保护作用是通过 激活训练有素的先天免疫，控制感染的初始阶段并支持产生 强大的适应性免疫反应。这一假设将在以下具体目标中得到解决： 目标 1. 评估对 RoV 及其病毒的先天性和适应性免疫反应的程度 与 BCG-HEU 和 HUU 相比，BCG+ HEU 和 HUU 与病毒清除的相关性。 我们将测量先天免疫细胞表型、细胞因子表达、RoV 特异性体液和细胞 6 周龄注射 RoV 疫苗后的免疫力和 RoV 脱落。 目标 2. 研究卡介苗对先天免疫的功能和表观遗传效应，并开发一种 使用 BCG 和模式识别受体 (PRR) 激动剂重现这种效应的体外系统。 我们将开发一种体外 BCG 刺激系统，可复制 NK、γδ T 和抗原呈递细胞 体内 BCG 给药后观察到的表型和 DNA 甲基化谱。然后我们将开发一个 PRR 激动剂混合物，可重现体外 BCG 刺激的效果，并可转化为 临床用作 HEU 和其他高危婴儿的免疫增强剂。 影响。使用客观的基于实验室的结果测量和充足的样本量，本研究将提供 急需明确的证据来证明卡介苗异源免疫刺激对婴儿的有益作用。