Project 2: Microbial determinants of HIV broadly-neutralizing antibody precursor induction in infants

项目2：婴儿中HIV广泛中和抗体前体诱导的微生物决定因素

• 批准号: 10731282
• 负责人: Kristina De Paris
• 金额: $ 31.11万
• 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/10731282
• 关键词: Adjuvant; Adult; Animals; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Automobile Driving; B-Cell Antigen Receptor; B-Lymphocytes; Bacteria; Binding Sites; Bioinformatics; Cell Lineage; Clinical Trials; Clone Cells; Computer Analysis; Cross Reactions; Data; Data Analyses; Development; Disparate; Ensure; Environment; Epitopes; Evolution; Frequencies; Future; Generations; Genes; Gnotobiotic; Goals; HIV; HIV Infections; HIV envelope protein; HIV vaccine; HIV-1; Human; Immune; Immune response; Immune system; Immunization; Immunoglobulin G; Immunophenotyping; Individual; Infant; Infection; Intervention; Knock-in Mouse; Life; Mediating; Metagenomics; Microbe; Outcome; Pathway interactions; Phenotype; Play; Process; Research; Role; Shotguns; Testing; Translations; Vaccinated; Vaccination; Vaccine Design; Vaccinee; Vaccines; Viremia; Virus Diseases; Work; commensal bacteria; commensal microbes; cross reactivity; design; early phase clinical trial; fecal microbiome; host microbiome; immunoregulation; interest; microbial; microbial signature; microbiome; microbiome components; microbiota; microorganism; mouse model; neutralizing antibody; nonhuman primate; novel; novel strategies; programs; rational design; response; simian human immunodeficiency virus; synergism; translational potential; vaccination strategy; vaccine response; vaccine strategy; vaccine-induced antibodies; young adult

Abstract – Project 2 Globally, 600,000 young adults become infected with HIV-1 each year. Therefore, there is an urgent need to develop an early life vaccine strategy that protects young adults from HIV infection. This early life vaccine should elicit protective broadly neutralizing antibodies (bNAbs), which have been shown to be effective against infection in nonhuman primates and humans. Newer, rationally designed native-like HIV envelope trimer-based vaccines that engage germline B cell receptors and drive evolution of bNAbs have been developed. These B cell lineage- based vaccines induce bNAb precursors in 50–60% of infant and adult nonhuman primates, and early clinical trial data suggests some humans also develop bNAbs. While these findings offer significant promise that the long-standing goal of an effective HIV vaccine is on the horizon, there is a gap in our understanding of the determinants of bNAb induction that results in only half of vaccinees developing a favorable response. It is now clear that the microbiome is intricately intertwined with the development and modulation of the immune system, and that these microbiome–immune interactions are critical for vaccine responses. Our preliminary data confirm that the microbiome is a necessary and modifiable factor that influences vaccine responses, with specific bacterial taxa positively associated with antibody titers resulting from immunization with HIV Env-based vaccines. Thus, Project 2 proposes to define specific microbial features that can be harnessed as an endogenous adjuvant to help—along with optimal exogenous adjuvants identified by Project 1—drive induction of HIV bNAb precursors after vaccination with the BG505 GT1.1 SOSIP trimer immunogen. Specifically, Aim 1 of this project will couple shotgun metagenomic data and microbe–phenotype triangulation, a novel microbiome discovery platform we developed, to define microbial features that associate with the induction of HIV bNAb precursors. Aim 2 will test the hypothesis that some commensal bacteria predispose towards beneficial vaccine responses by helping induce vaccine-elicited antibodies that are cross-reactive with the microbiome. To enhance the translational potential of our work, we will examine microbiome cross-reactive antibodies in both infant NHPs and humans. Finally, Aim 3 will develop a gnotobiotic human B cell lineage knock-in mouse model to experimentally define the role of the microbiome in bNAb precursor induction, including functionally validating the bioinformatically identified microbial features. Taken together, the results of this Project will elucidate specific microbes that modulate the immune landscape such that a greater percentage of B cell lineage-based vaccine recipients develop bNAb precursors. Ultimately, these adjuvant-like microbes can be incorporated into future vaccine strategies.

摘要 – 项目 2 全球每年有 600,000 名年轻人感染 HIV-1。因此，迫切需要 制定生命早期疫苗策略，保护年轻人免受艾滋病毒感染。这种早期生命疫苗应该 引发保护性广泛中和抗体 (bNAb)，该抗体已被证明可有效抵抗感染 在非人类灵长类动物和人类中。更新、合理设计的类天然 HIV 包膜三聚体疫苗 已经开发出与生殖系 B 细胞受体结合并驱动 bNAb 进化的药物。这些 B 细胞谱系 - 基于疫苗的疫苗可在 50-60% 的婴儿和成年非人灵长类动物中诱导 bNAb 前体，并且早期临床 试验数据表明，一些人也产生了 bNAb。虽然这些发现提供了重要的希望， 有效的艾滋病毒疫苗的长期目标即将到来，但我们对艾滋病毒疫苗的理解存在差距 bNAb 诱导的决定因素导致只有一半的疫苗接种者产生良好的反应。现在是 明确微生物组与免疫系统的发育和调节错综复杂地交织在一起， 这些微生物组与免疫相互作用对于疫苗反应至关重要。我们的初步数据证实 微生物组是影响疫苗反应的必要且可改变的因素，具有特定的 细菌分类群与基于 HIV Env 的疫苗免疫产生的抗体滴度呈正相关。 因此，项目 2 建议定义可用作内源佐剂的特定微生物特征 与项目 1 确定的最佳外源佐剂一起帮助推动 HIV bNAb 的诱导 使用 BG505 GT1.1 SOSIP 三聚体免疫原接种后的前体。具体而言，该项目的目标 1 将鸟枪法宏基因组数据和微生物表型三角测量结合起来，这是一种新的微生物组发现 我们开发了一个平台，用于定义与 HIV bNAb 前体诱导相关的微生物特征。 目标 2 将检验以下假设：某些共生细菌易于产生有益的疫苗反应 通过帮助诱导疫苗引发的与微生物组发生交叉反应的抗体。为了增强 我们工作的转化潜力，我们将检查两种婴儿 NHP 中的微生物组交叉反应抗体 和人类。最后，Aim 3 将开发一种限生人类 B 细胞谱系敲入小鼠模型，以 通过实验确定微生物组在 bNAb 前体诱导中的作用，包括功能验证 生物信息学鉴定的微生物特征。总而言之，该项目的结果将阐明具体的 调节免疫环境的微生物，使基于 B 细胞谱系的疫苗的比例更高 接受者开发 bNAb 前体。最终，这些类似佐剂的微生物可以被纳入未来的 疫苗策略。