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 糖蛋白 (Env) 的广泛中和抗体 (bNAb) 的诱导是 被认为对于有效的 HIV 疫苗设计至关重要，应用针对目标的天然 Env 样三聚体。 然而，迄今为止，bNAb 前体已发展成为最有前途的策略。 产量尚未超过疫苗的 50%。该计划的目标是确定疫苗的早期决定因素。 bNAb 前体诱导，重点关注佐剂和宿主微生物群的作用，利用广泛和综合的方法 组学方法破译与 HIV 感染、血浆中 bNAb 发育相关的机制。 bNAb 在少数成年人体内形成，并且仅在几年后才形成，而感染 HIV 的婴儿中的 bNAb 可能是在 早在感染后一年就检测到，从婴儿中分离出的 bNAb 似乎需要较少。 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 我们提供了对幼年恒河猴 (RM) 进行免疫接种的初步数据。 BG505 种系靶向 (GT)1.1 SOSIP 三聚体与 TLR7,8 佐剂 3M-052 佐剂导致 在 5 只动物中的 3 只中诱导 VRC01 样 CD4 结合位点 bNAb 前体，频率与 在成人 RM 中观察到（12 名婴儿 RM 的血浆抗体）也针对更广泛的表位。 与成人 RM 相比，表明尽管进行了额外的免疫接种，但其余 2 例具有更高的多反应性。 婴儿 RM 并未形成这种中和特征，这表明早期事件对于驱动 bNAb 至关重要 在婴儿的发育中，早期免疫力部分是由许多微生物群的多反应性决定的。 尽管并非所有 bNAb 都进一步支持微生物群在 bNAb 开发中的潜在作用，但我们一直在努力 可以利用婴儿免疫系统和微生物群的动态来优化诱导 利用婴儿 BG505 GT1.1 SOSIP 疫苗模型和应用系统生产 bNAb。 通过生物学方法，我们将确定 bNAb 诱导的发育途径是如何通过 通过不同佐剂（项目 1）、微生物组（项目 2）和 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）。 该项目将得到非人类灵长类动物 (NHP) 和 B 细胞核心的支持，并有组织和 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。 产生或不产生 bNAb 来响应 BG505 的疫苗之间的反应和分子特征 GT1.1 SOSIP 疫苗接种通过佐剂（项目 1）和微生物群（项目 2）调节疫苗初始量。 目标 3 将开发整合免疫、微生物组和分子特征来预测的建模方法 bnAb 前体的开发 该计划的结果将确定诱导过程中的关键决定因素。 在未来的研究中，我们将调节这些因素来优化 HIV 疫苗策略。 新开发的计算模型将促进 bNAb 开发潜力的疫苗筛选。