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 在全球范围内，2017年大约有60万名年轻人（15-24岁）感染了HIV-1。 15-19岁的年龄受到影响最大，并且该年龄段的HIV感染继续增加。因此，一种疫苗 预防年轻人的艾滋病毒收购仍然是重中之重，在性行会之前必须有效。 广泛中和抗体（BNAB）的诱导代表了HIV疫苗设计中的主要目标。但是，是的 远处的临床前疫苗试验仅在引发bnabs时产生适度的结果。那是新颖的疫苗策略 需要。在这里，我们建议采用HIV Env mRNA疫苗，并在早期开始疫苗 留出必要的时间来开发bnabs。我们的理由是基于在HIV感染的数据的数据 与感染HIV的成年人相比，婴儿早于较早的频率。此外，艾滋病毒中的bnabs 受感染的婴儿暴露于较低的体细胞超突变，与成年人相反，更频繁地定向 反对多个表位。这些发现表明，婴儿免疫景观可能是更好的装备 用于开发bnabs。实际上，婴儿具有较高的卵泡T助手（TFH）细胞的频率 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）执行TFH潜在可调活动并允许持续抗原释放；这两个标准都有 我们与神经化广度有关。我们的初步数据证实了核修饰的HIV Env GP160 mRNA-LNP可以诱导潜在的TFH和GC响应，并促进第1层和第2层的诱导 成人恒河猕猴（RMS）中的nabs。基于此前提，我们假设HIV Env GP160 在早期使用的mRNA-LNP疫苗可以使疫苗诱导的抗体的时间 具有广泛中和和/或FC介导的效应子功能的响应，可以在童年时期提高 而且，在青少年的保护中，免受艾滋病毒收购的保护优于通过疫苗接种而获得的。 前青年。我们将通过比较给定的同一HIV疫苗的免疫原性来检验该假设 要么对婴儿或前RMS，并确定直肠内SHIV的保护效率 在青少年的收购（AIM 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响应的发展途径。我们将使用系统 免疫学方法来表征可容纳有效的分子和微生物特征 每个年龄段的疫苗，进一步完善疫苗策略，包括调整设计 （目标2和3）。为了增强NHP研究的翻译潜力，我们将对 肝炎B疫苗诱导的恒河猴和人类婴儿的B细胞反应并联。这些数据是预期的 为了告知最佳年龄，间隔，波斯数量以及免疫细胞和微生物相互作用，必须是 通过疫苗生成并调整选择以实现保护性免疫。