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: 10350674
• 负责人: Genevieve Giny Fouda Amou ou
• 金额: $ 69.46万
• 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 2022-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350674
• 关键词: 3 year old; Address; 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; HIV-infected adolescents; Immune; Immune system; Immunity; Immunization; Immunogenetics; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Individual; Infant; Life; Link; Maps; Measures; Mediating; Modeling; Monoclonal Antibodies; Pediatric cohort; Persons; 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; 3 year old; Address; 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; HIV-infected adolescents; Immune; Immune system; Immunity; Immunization; Immunogenetics; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Individual; Infant; Life; Link; Maps; Measures; Mediating; Modeling; Monoclonal Antibodies; Pediatric cohort; Persons; 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

抽象的 2016年，据估计，有610,000名15至24岁的年轻人被新感染 与艾滋病毒。防止青少年艾滋病毒感染可能需要在儿童期服用疫苗 为了在性首次亮相之前获得保护性免疫。由于成人和早期的差异 免疫系统，了解儿童艾滋病毒特异性抗体反应的发展至关重要 指导小儿种群中HIV疫苗的实施。先前研究HIV的研究 儿童的功能抗体的大小有限，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，1）儿童可能会较早发展中和广度 比成年人； 2）儿童的血浆神经刺激宽度可能是由多克隆抗体介导的 对于一种或两种抗体特异性负责广度的成年人； 3）婴儿广泛 与成年BNAB相比，中和抗体（BNAB）可能具有较低的体细胞超突变水平。 由于这些先前研究的样本量很小，因此限制了它们的发现的概括，所以我们有 从完整的小儿队列研究中获得了大量的ART ART样本，幼稚的HIV感染的儿童 研究早期HIV特异性抗体反应的发展。使用初步实验 这些标本表明，总体上，1至3岁的孩子的中和广度明显更大 比成年人，这表明在儿童中诱导广泛的神经化可能比成年人更容易。 重要的是，通过疫苗接种对儿童进行广泛的神经化的启发将需要池的存在 具有发展BNAB的B细胞（BNAB前体）的潜力。然而，尽管最近的研究表明 可以在健康成年人中以低频率检测到BNAB前体，这是BNAB前体的频率 儿童目前未知。这项研究的总体目标是评估HIV特异性的发展 幼儿的抗体反应。我们的主要重点是BNAB响应，但因为1）最近的研究 已经表明FC效应功能是成人神经化宽度的预测指标，而2）非 - 中和反应与临床前研究的保护有关，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。我们假设早期的生命免疫景观为引发带来优势 成人免疫系统上受保护的HIV特异性抗体的。我们的具体目的是：1）量化和 在大量的HIV感染儿童中，表征HIV神经化的广度； 2）：评估协会 在多功能的AB反应和神经感染儿童的广度发育之间；和 最后3）量化HIV未感染儿童中潜在BNAB前体的频率。这项研究会 增加对儿童艾滋病毒BNAB和非中和抗体发育的当前理解，并有助于 确定早期生命中的免疫抑制是否有利于促进保护性抗体反应