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

基本信息

批准号：
10745606
负责人：
Genevieve Giny Fouda Amou ou
金额：
$ 74.92万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-23 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745606
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 Epitope Mapping Epitopes Frequencies Goals HIV HIV Antibodies HIV Infections HIV envelope protein HIV vaccine HIV-infected adolescents Immune Immune system Immunity Immunization Immunogenetics Immunoglobulin G Immunoglobulin Somatic Hypermutation Individual Infant Life Link 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

项目摘要

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，估计有61万名15至24岁的年轻人新感染病毒预防青少年艾滋病毒感染可能需要在儿童时期接种疫苗。由于成年期和早期生活的差异，为了在首次性行为之前获得保护性免疫力。免疫系统，了解儿童艾滋病毒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。儿童的功能性抗体大小有限，但他们的结果表明潜在的重要差异值得注意的是，1）儿童可能更早地发展出中和广度。 2) 相比之下，儿童血浆中和广度可能是由多克隆抗体介导的成人中，一种或两种抗体特异性决定了广度；3) 婴儿广泛；与成人 bnAb 相比，中和抗体 (bnAb) 的体细胞超突变水平可能较低。由于这些先前研究的样本量较小限制了其研究结果的推广，我们有从已完成的儿科队列研究中获得了大量未接受 ART 的 HIV 感染儿童样本使用初步实验研究艾滋病毒特异性抗体反应的发展。这些样本表明，总体而言，1 至 3 岁儿童的中和宽度明显更大比成人更容易，这表明在儿童中诱导广泛的中和作用可能比在成人中更容易。重要的是，通过疫苗接种对儿童进行广泛的中和作用需要建立一个库然而，最近的研究表明，B 细胞具有产生 bnAb（bnAb 前体）的潜力。 bnAb 前体在健康成人中的检测频率较低，目前尚不清楚这项研究的总体目标是评估艾滋病毒特异性的发展。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 效应器功能是成人中和宽度的预测因子，并且 2）非中和反应与临床前研究中的保护作用有关，并可能有助于 RV144 疫苗试验中观察到的部分保护作用；我们还将测量非中和功能我们认为生命早期的免疫状况有利于诱导。我们的具体目标是： 1) 量化和确定成人免疫系统中的保护性 HIV 特异性抗体。描述大量 HIV 感染儿童的 HIV 中和广度特征 2)：评估相关性； HIV感染儿童的多功能抗体反应与中和广度发展之间的关系；最后 3) 量化未感染 HIV 的儿童中潜在 bnAb 前体的频率。增加目前对儿童 HIV bnAb 和非中和抗体发育的了解，并帮助确定在生命早期开始免疫是否有利于引发保护性抗体反应