Determinants of HIV broadly-neutralizing antibody precursor induction in infants

婴儿中 HIV 广泛中和抗体前体诱导的决定因素

• 批准号: 10731276
• 负责人: Kristina De Paris
• 金额: $ 158.46万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731276
• 关键词: Adjuvant; Adult; Animals; Antibodies; Antibody-Producing Cells; Automobile Driving; B cell differentiation; B-Cell Antigen Receptor; B-Lymphocytes; B-cell receptor repertoire sequencing; Binding Sites; Bioinformatics; Biometry; Cell Lineage; Cell secretion; Cells; Complex; Computer Analysis; Computer Models; Cross Reactions; Data; Development; Dose; Early identification; Emulsions; Epitopes; Event; Frequencies; Future; Glycoproteins; Goals; HIV; HIV Infections; HIV envelope protein; HIV vaccine; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunization; Immunize; Immunoglobulin Somatic Hypermutation; Immunology; Individual; Infant; Infection; Innate Immune Response; Knowledge; Life; Macaca mulatta; Mature B-Lymphocyte; Metagenomics; Minority; Modeling; Molecular Profiling; Natural Immunity; Pathway interactions; Plasma; Role; Shapes; Statistical Data Interpretation; Systems Biology; TLR7 gene; Testing; Vaccinated; Vaccination; Vaccine Design; Vaccinee; Vaccines; age group; biological systems; computerized tools; design; gene regulatory network; host microbiota; microbiome; microbiome signature; microbiota; neutralizing antibody; nonhuman primate; programs; response; sexual debut; transcriptomics; vaccine candidate; vaccine evaluation; vaccine strategy; vaccine trial

ABSTRACT – OVERALL The induction of broadly neutralizing antibodies (bNAbs) against the HIV envelope glycoprotein (Env) is considered vital for an effective HIV vaccine. Rational vaccine design applying native Env-like trimers that target the respective germline B cell receptor have evolved as the most promising strategy. Yet, so far, bNAb precursor yields have not exceeded 50% of vaccinees. The goal of this Program aims to identify early determinants of bNAb precursor induction, with a focus on the role of adjuvants and host microbiota, utilizing broad and integrated omics approaches to decipher the mechanisms associated with bNAb development. In HIV infection, plasma bNAbs develop in a minority of adults and only after several years, whereas bNAbs in infants with HIV can be detected as early as one year post infection. Interestingly, bNAbs isolated from infants appear to require less somatic hypermutations to achieve similar breadth as bNAbs of adults, implying potentially different mechanisms of bNAb development. We present preliminary data that immunization of infant rhesus macaques (RM) with BG505 germline-targeting (GT)1.1 SOSIP trimers adjuvanted with the TLR7,8 adjuvant 3M-052 resulted in the induction of VRC01-like CD4 binding site bNAb precursors in 3 of 5 animals, a frequency comparable to that observed in adult RM (6 of 12). Plasma antibodies of infant RM also targeted a broader array of epitopes compared to adult RM, indicative of greater polyreactivity. Despite additional immunizations, the remaining 2 infant RM did not develop this neutralization signature, suggesting that early events are critical in driving bNAb development. In infants, early immunity is partially defined by the evolving microbiota. The polyreactivity of many, although not all, bNAbs, further supports a potential role of microbiota in bNAb development We hypothesize that the dynamic state of the infant immune system and microbiota can be exploited to optimize the induction of bNAbs by HIV vaccines. Leveraging the infant BG505 GT1.1 SOSIP vaccine model and applying systems biology approaches, we will identify how the developmental pathways of bNAb induction are altered by the modulation of the vaccine prime by different adjuvants (Project 1), the microbiome (Project 2), and the interactions between host immunity and microbiota (Biostatistics and Computational Analysis [BCA] Core). The Projects will be supported by the Nonhuman Primate (NHP) and the B Cell Cores, with organizational and fiscal support by the Administrative Core. In Aims 1 and 2, we will define differences in early immune responses and molecular signatures between vaccinees who do or do not develop bNAbs in response to BG505 GT1.1 SOSIP vaccination by modulating the vaccine prime via adjuvants (Project 1) and microbiota (Project 2). Aim 3 will develop modeling approaches that integrate immune, microbiome, and molecular signatures to predict the development of bnAb precursors. The results of the Program will identify critical determinants in the induction of bNAb precursors. In future studies, we will modulate these factors to optimize HIV vaccine strategies. The newly developed computational models will facilitate vaccine screening for the potential of bNAb development.

摘要 - 总体 针对HIV包膜糖蛋白（ENV）的广泛中和抗体（BNAB）的诱导是 认为对有效的HIV疫苗至关重要。理性疫苗设计采用针对目标的本地env样三聚体 相对种系B细胞接收器已进化为最有前途的策略。然而，到目前为止，BNAB前体 产量不超过疫苗的50％。该计划的目标旨在确定 BNAB前体诱导，重点是调节器和宿主微生物群的作用 OMICS方法是破译与BNAB开发相关的机制。在HIV感染中，血浆 BNAB在少数成年人中发展，仅在几年后，而艾滋病毒婴儿的bnabs可以是 最早在感染后一年。有趣的是，从婴儿中孤立的BNAB似乎需要更少 躯体超血以实现与成年人的BNAB相似的广度，这意味着潜在的机制 BNAB开发。我们介绍了初步数据，即带有婴儿恒河猕猴（RM）免疫数据 BG505种系靶向（GT）1.1 SOSIP三聚体通过TLR7,8调整3M-052导致 在5只动物中有3只诱导VRC01样CD4结合位点BNAB前体BNAB前体，这一频率与此相当 在成年RM中观察到（12个中的6个）。婴儿RM的血浆抗体也针对更广泛的表位 与成人RM相比，表明多反应性更高。尽管有其他免疫接种，剩下的2 婴儿RM没有发展此谈判签名，这表明早期事件对于驾驶BNAB至关重要 发展。在婴儿中，早期免疫力部分由不断发展的微生物群定义。许多人的多反应性 尽管不是全部，BNABS进一步支持微生物群在BNAB开发中的潜在作用，但我们假设 可以探索婴儿免疫系统和微生物群的动态状态，以优化诱导 HIV疫苗的BNAB。利用婴儿BG505 GT1.1 SOSIP疫苗模型和应用系统 生物学方法，我们将确定BNAB诱导的发展途径如何通过 通过不同的调节器（项目1），微生物组（项目2）和 宿主免疫与微生物群（生物统计学和计算分析[BCA]核心）之间的相互作用。 这些项目将得到非人类灵长类动物（NHP）和B细胞核的支持，并由组织和 行政核心的财政支持。在目标1和2中，我们将定义早期免疫的差异 响应BG505的疫苗之间的反应和分子特征 GT1.1 SOSIP疫苗通过调节器（项目1）和微生物群（项目2）调节疫苗素。 AIM 3将开发建模方法，以整合免疫，微生物组和分子特征来预测 BNAB前体的发展。该计划的结果将确定归纳的关键决定者 BNAB前体。在未来的研究中，我们将调节这些因素以优化HIV疫苗策略。这 新开发的计算模型将促进疫苗筛查，以实现BNAB开发的潜力。