Neutralizing and non-neutralizing antibody effector functions in HIV infected children

HIV 感染儿童的中和和非中和抗体效应功能

• 批准号: 9889030
• 负责人: Genevieve Giny Fouda Amou ou
• 金额: $ 73.01万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-07 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889030
• 关键词: 3 year old; Address; Adolescent; Adolescent and Young Adult; Adult; Affinity; Age; Animal Model; Animals; Antibodies; Antibody Response; Antibody Specificity; Antigens; B cell repertoire; B-Lymphocytes; Binding; Characteristics; Child; Childhood; Chronic; Cohort Studies; Complement Activation; Development; Epitopes; Frequencies; Goals; HIV; HIV Antibodies; HIV Infections; HIV vaccine; Immune; Immune system; Immunity; Immunization; Immunogenetics; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Individual; Infant; Life; Link; Maps; Measures; Mediating; Modeling; Monoclonal Antibodies; Pediatric cohort; Phagocytosis; Plasma; Population; Reporting; Risk; Sample Size; Sampling; Series; Specificity; Specimen; Testing; Time; Vaccination; Vaccines; Virus; aged; antibody-dependent cell cytotoxicity; cohort; deep sequencing; experimental study; glycosylation; in vivo; mutant; neutralizing antibody; pandemic disease; pediatric human immunodeficiency virus; polyclonal antibody; pre-clinical; preclinical study; prevent; response; sexual debut; vaccine development; vaccine trial

Abstract In 2016, it was estimated that 610,000 young people between the ages of 15 to 24 years were newly infected with HIV. Preventing adolescent HIV infections will likely require the administration of a vaccine in childhood in order to achieve protective immunity prior to sexual debut. Because of differences in the adult and early life immune systems, understanding the development of HIV-specific antibody responses in children is critical to guide the implementation of an HIV vaccine in pediatric populations. Previous studies investigating HIV functional antibodies in children were limited in size, but their results suggested potential important differences between adults and children. It was notably reported that 1) children may develop neutralization breadth earlier than adults; 2) plasma neutralization breadth in children may be mediated by polyclonal antibodies in contrast to adults in which one or two antibody specificities are responsible for breadth; and 3) infant broadly neutralizing antibodies (bnAbs) may have lower levels of somatic hypermutation as compared to adult bnAbs. Because the small sample size of these previous studies limits the generalization of their findings, we have obtained a large panel of samples of ART naïve HIV-infected children from completed pediatric cohort studies to investigate the development of HIV-specific antibody responses in early life. Preliminary experiments using these specimens indicated that overall, 1 to 3-year-old children have significantly more neutralization breadth than adults, suggesting that it could be easier to induce broad neutralization in children than in adults. Importantly, elicitation of broad neutralization in children through vaccination will require the existence of a pool of B cells with the potential to develop bnAbs (bnAb precursors). Yet, while recent studies have demonstrated that bnAb precursors can be detected at low frequency in healthy adults, the frequency of bnAb precursors in children is currently unknown. The overall goal of this study is to assess the development of HIV-specific antibody responses in young children. Our primary focus in on bnAb responses, but because 1) Recent studies have indicated that Fc effector functions are predictors of neutralization breadth in adults and 2) non- neutralizing responses have be associated with protection in preclinical studies and might have contributed to the partial protection observed in the RV144 vaccine trial; we will also measure non-neutralizing functional antibody responses. We hypothesize that the early life immune landscape presents advantages for elicitation of protective HIV-specific antibodies over the adult immune system. Our specific aims are: 1) To quantify and characterize HIV neutralization breadth in a large cohort of HIV-infected children; 2): To assess the association between polyfunctional Ab responses and neutralization breadth development in HIV infected children; and finally 3) To quantify the frequency of potential bnAb precursors in HIV uninfected children. This study will increase current understanding of HIV bnAb and non-neutralizing antibody development in children and help determine if initiating immunization in early life is advantageous for elicitation of protective antibody responses

摘要 2016年，估计有61万名15岁至24岁的年轻人新感染 艾滋病毒携带者。预防青少年艾滋病毒感染可能需要在儿童时期接种疫苗 以便在首次性行为前获得保护性免疫力。由于成年和早期生活的不同 免疫系统，了解儿童中HIV特异性抗体反应的发展对于 指导在儿科人群中实施艾滋病毒疫苗。之前研究艾滋病毒的研究 儿童中的功能性抗体的大小有限，但他们的结果表明了潜在的重要差异。 在成人和儿童之间。值得注意的是，据报道，1)儿童可能会更早地形成中和广度 2)儿童的血浆中和广度可能由多克隆抗体介导。 对于成人，其中一种或两种抗体的特异性决定了广度；以及3)广泛的婴儿 与成人bNAbs相比，中和抗体(BNAbs)的体细胞超突变水平可能较低。 由于之前这些研究的样本量较小，限制了他们的研究结果的推广，我们有 从已完成的儿科队列研究中获得了大量的ART幼稚HIV感染儿童样本 目的：探讨人类免疫缺陷病毒(HIV)特异性抗体反应在生命早期的发展。初步实验使用 这些样本表明，总体而言，1至3岁儿童的中和广度明显更大。 这表明，在儿童中可能比在成年人中更容易诱导广泛的中和。 重要的是，通过接种疫苗在儿童中引发广泛的中和作用将需要存在一个人才库。 有可能产生bNAb(bNab前体)的B细胞。然而，尽管最近的研究表明， BNab前体在健康成人中可以低频率检测到，bNab前体在健康成年人中的频率 儿童目前还不为人所知。这项研究的总体目标是评估艾滋病毒特异性疾病的发展 幼儿的抗体反应。我们主要关注bNab反应，但因为1)最近的研究 已经表明，FC效应函数是成人中和广度的预测因子，以及2)非 在临床前研究中，中和反应与保护有关，并可能有助于 在RV144疫苗试验中观察到的部分保护；我们还将测量非中和功能 抗体反应。我们假设，早期生命的免疫环境对启发性有优势。 成人免疫系统上的保护性艾滋病毒特异性抗体。我们的具体目标是：1)量化和 在一大群感染艾滋病毒的儿童中表征艾滋病毒中和广度；2)：评估这种联系 HIV感染儿童多功能抗体反应和中和广度发育之间的关系；以及 最后，3)量化未感染HIV的儿童中潜在的bNab前体的频率。这项研究将 增加对儿童HIV bNab和非中和抗体发展的当前了解，并帮助 确定在生命早期开始免疫是否有利于激发保护性抗体反应