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 被认为对有效的艾滋病毒疫苗至关重要。应用靶向的天然Env样三聚体的合理疫苗设计 相应的生殖系B细胞受体已经发展成为最有希望的策略。然而，到目前为止， 接种率未超过50%。该计划的目的是确定早期决定因素， bNAb前体诱导，重点是佐剂和宿主微生物群的作用，利用广泛和综合的 组学方法来破译与bNAb发展相关的机制。在艾滋病毒感染中，血浆 bNAb在少数成年人中形成，并且仅在几年后形成，而感染HIV的婴儿中的bNAb可以在 在感染后一年就能检测到。有趣的是，从婴儿中分离的bNAb似乎需要更少的 体细胞超突变达到与成人bNAb相似的宽度，这意味着潜在的不同机制 bNAb的发展。我们目前的初步数据表明，免疫婴儿恒河猴（RM）与 用TLR 7，8佐剂3 M-052佐剂化的BG 505种系靶向（GT）1.1 SOSIP三聚体产生了免疫抑制剂。 在5只动物中的3只中诱导VRC 01样CD 4结合位点bNAb前体，频率与 在成人RM中观察到（6/12）。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。尽管有额外的免疫接种，其余2 婴儿RM没有出现这种中和信号，表明早期事件在驱动bNAb中至关重要 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， 虽然不是所有的bNAb，进一步支持微生物群在bNAb发育中的潜在作用。 婴儿免疫系统和微生物群的动态状态可以用来优化 bNAb通过HIV疫苗。利用婴儿BG 505 GT1.1 SOSIP疫苗模型和应用系统 通过生物学方法，我们将确定bNAb诱导的发育途径是如何被 通过不同佐剂（项目1）、微生物组（项目2）和免疫调节剂（项目3）调节疫苗初免。 宿主免疫和微生物群之间的相互作用（生物统计学和计算分析[BCA]核心）。 这些项目将得到非人类灵长类动物（NHP）和B细胞核心的支持， 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， 对BG 505产生或不产生bNAb的疫苗接种者之间的应答和分子特征 GT1.1通过佐剂（项目1）和微生物群（项目2）调节疫苗初免的SOSIP疫苗接种。 目标3将开发整合免疫、微生物组和分子特征的建模方法， bnAb前体的开发。该计划的结果将确定入职的关键决定因素 bNAb前体在未来的研究中，我们将调整这些因素，以优化艾滋病毒疫苗的策略。的 新开发的计算模型将有助于疫苗筛选bNAb的发展潜力。