Project 2: RNA vaccination in early life to induce potent and broad HIV Env-specific antibody responses

项目 2：生命早期的 RNA 疫苗接种可诱导有效且广泛的 HIV 包膜特异性抗体反应

• 批准号: 9893373
• 负责人: Genevieve Giny Fouda Amou ou
• 金额: $ 54.68万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893373
• 关键词: 19 year old; Adjuvant; Adolescence; Adult; Affect; Africa South of the Sahara; Age; Age-Years; Antibodies; Antibody Response; Antigens; Automobile Driving; B-Cell Development; B-Lymphocytes; Biological Markers; Cell Communication; Cells; Childhood; Collaborations; Data; Development; Epitopes; Exhibits; Formulation; Frequencies; Generations; Goals; HIV; HIV Infections; HIV vaccine; HIV-1; Helper-Inducer T-Lymphocyte; Hepatitis B Vaccines; Human; Immune; Immune system; Immunity; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Immunology; Individual; Infant; Infection; Kinetics; Life; Link; Macaca mulatta; Malawi; Mediating; Messenger RNA; Modeling; Molecular; Molecular Conformation; Molecular Profiling; Mutation; Nucleosides; Pathway interactions; Plasma; Proteins; RNA; RNA vaccine; Receptors, Antigen, B-Cell; Rhesus; Rodent; Site-Directed Mutagenesis; Structure of germinal center of lymph node; System; Systems Biology; Testing; Time; Translations; Vaccination; Vaccine Design; Vaccines; Virus; Virus Diseases; Woman; age group; base; bioinformatics pipeline; design; efficacy study; env Gene Products; gp160; immunogenicity; infancy; interest; lipid nanoparticle; microbial; microbiome; microorganism interaction; neonatal infection; neutralizing antibody; nonhuman primate; novel; novel vaccines; pre-clinical; preadolescence; predictive signature; prevent; protective efficacy; response; sexual debut; simian human immunodeficiency virus; tool; vaccine response; vaccine trial; young adult; young woman

ABSTRACT – Project 2 Globally, about 600,000 young adults (15-24 years of age) became infected with HIV-1 in 2017. Young women age 15-19 years are most affected, and HIV-infection in this age group continue to rise. Therefore, a vaccine to prevent HIV acquisition in young adults remains a top priority and needs to be effective prior to sexual debut. The induction of broadly neutralizing antibodies (bnAbs) represents a major goal in HIV vaccine design. Yet, so far, preclinical vaccine trials have only yielded modest results in eliciting bnAbs. Thus, novel vaccine strategies are needed. Here, we propose to employ an HIV Env mRNA vaccine and to start vaccination in early life to allow for the necessary time to develop bnAbs. Our rationale is based on data that bnAbs in HIV-infected infants develop earlier and at higher frequencies compared to HIV-infected adults. Furthermore, bnAbs in HIV- infected infants exhibit lower somatic hypermutation and, in contrast to adults, are more frequently directed against multiple epitopes. These findings suggest that the infant immune landscape might be better equipped for the development of bnAbs. Indeed, infants have higher frequencies of follicular T helper (TFH) cells that are critical in driving germinal center B cell responses. Our mRNA vaccines will be packaged in lipid nanoparticles (LNPs) that exert potent adjuvant activity for TFH and allow for sustained antigen release; both criteria have been associated with neutralization breadth. Our preliminary data confirm that a nucleoside-modified HIV Env gp160 mRNA-LNPs can induce potent TFH and GC responses and promote the induction of tier 1 and tier 2 nAbs in adult rhesus macaques (RMs). Based on this premise, we hypothesize that an HIV Env gp160 mRNA-LNP vaccine administered in early life allows for the time to mature vaccine-induced antibody responses with broadly neutralizing and/or Fc-mediated effector functions that can be boosted in childhood, and that protection against HIV acquisition in adolescence is superior to that achieved by vaccination in preadolescence. We will test this hypothesis by comparing the immunogenicity of the same HIV vaccine given either to infant or to preadolescent RMs and determine the protective efficacy against intrarectal SHIV acquisition in adolescence (Aim 1). By applying several systems biology approaches and bioinformatic pipelines, we will identify the developmental pathways resulting in bnAb responses. We will use system immunology approaches to characterize the molecular and microbial signatures that accompany effective vaccination within each of the age groups, further refining the vaccine strategies, including adjuvant design (Aims 2 and 3). To enhance the translational potential of our NHP studies, we will perform an analysis of Hepatitis B vaccine-induced B cell responses in rhesus and human infants in parallel. These data are expected to inform the optimal age, intervals, number of boosts, and immune cell and microbial interactions that must be generated through vaccination and adjuvant selection to achieve protective immunity.

摘要 – 项目 2 2017 年，全球约有 600,000 名年轻人（15-24 岁）感染了 HIV-1。 年轻女性 15-19 岁年龄段受影响最大，该年龄段的艾滋病毒感染率持续上升。因此，疫苗 预防年轻人感染艾滋病毒仍然是首要任务，并且需要在首次性行为之前有效。 广泛中和抗体（bnAb）的诱导代表了 HIV 疫苗设计的一个主要目标。然而，所以 到目前为止，临床前疫苗试验在诱导 bnAb 方面仅取得了有限的成果。因此，新的疫苗策略 需要。在这里，我们建议使用 HIV Env mRNA 疫苗，并在生命早期就开始接种疫苗，以 留出必要的时间来开发 bnAb。我们的理由基于 HIV 感染者中 bnAb 的数据 与感染艾滋病毒的成年人相比，婴儿发育更早且频率更高。此外，HIV 中的 bnAb 受感染的婴儿表现出较低的体细胞超突变，并且与成人相比，更频繁地被定向 对抗多个表位。这些发现表明婴儿的免疫环境可能会更好 用于 bnAb 的开发。事实上，婴儿具有更高频率的滤泡 T 辅助细胞 (TFH) 对于驱动生发中心 B 细胞反应至关重要。我们的 mRNA 疫苗将包装在脂质纳米颗粒中 （LNP）对 TFH 发挥有效的佐剂活性并允许持续释放抗原；两个标准都有 与中和广度相关。我们的初步数据证实，核苷修饰的 HIV Env gp160 mRNA-LNP 可诱导有效的 TFH 和 GC 反应，并促进 1 级和 2 级的诱导 成年恒河猴 (RM) 中的 nAb。基于这个前提，我们假设 HIV Env gp160 生命早期注射 mRNA-LNP 疫苗可以让疫苗诱导的抗体有时间成熟 具有广泛中和和/或 Fc 介导的效应功能的反应可以在儿童时期得到增强， 青春期预防艾滋病毒感染的效果优于在青少年时期接种疫苗所达到的效果 青春期前。我们将通过比较相同 HIV 疫苗的免疫原性来检验这一假设 对于婴儿或青春期前的 RM 并确定对直肠内 SHIV 的保护功效 青春期习得（目标 1）。通过应用多种系统生物学方法和生物信息学 管道，我们将确定导致 bnAb 反应的发育途径。我们将使用系统 免疫学方法来表征伴随有效的分子和微生物特征 每个年龄组内的疫苗接种，进一步完善疫苗策略，包括佐剂设计 （目标 2 和 3）。为了增强 NHP 研究的转化潜力，我们将进行以下分析： 乙型肝炎疫苗在恒河猴和人类婴儿中同时诱导 B 细胞反应。这些数据是预期的 告知最佳年龄、间隔时间、加强次数以及必须遵守的免疫细胞和微生物相互作用 通过疫苗接种和佐剂选择产生以实现保护性免疫。