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