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 在全球范围内，每年有60万名年轻人感染了HIV-1。因此，迫切需要 制定一种早期生命疫苗策略，可保护年轻人免受艾滋病毒感染。这种早期生命疫苗应该 引起受保护的广泛中和抗体（BNAB），已证明对感染有效 在非人类隐私和人类中。较新的，理性设计的类似于原生的HIV信封基于基于触发的疫苗 已经开发了与生殖线B细胞接收器和BNAB的驱动进化。这些B细胞谱系 - 基于50-60％的婴儿和成人非人类隐私和早期临床的疫苗可诱导BNAB前体 试验数据表明，一些人也会发展为BNAB。尽管这些发现提供了重大的保证 有效的艾滋病毒疫苗的长期目标即将到来，我们对 BNAB诱导的决定因素仅导致一半的疫苗产生有利的反应。现在 显然，微生物组与免疫系统的发展和调节复杂地交织在一起， 这些微生物组 - 免疫相互作用对于疫苗反应至关重要。我们的初步数据确认 微生物组是影响疫苗反应的必要且可修改的因素，具体 与基于HIV Env的疫苗免疫有关的抗体滴度呈正相关的细菌分类群。 那就是，项目2的提议定义了可以利用的特定微生物特征，这些特征可以利用 提供帮助 - 以及由项目1确定的最佳外源调节器 - 驱动HIV BNAB的驱动 BG505 GT1.1 SOSIP三聚体免疫原疫苗接种后的前体。具体来说，该项目的目标1 将夫妇shot弹枪宏基因组数据和微生物 - 表型三角剖分，这是一种新型的微生物组发现 我们开发的平台是为了定义与HIV BNAB前体诱导相关的微生物特征。 AIM 2将检验以下假设，即某些共生细菌易于有益疫苗反应 通过帮助诱导与微生物组交叉反应的疫苗吸引的抗体。增强 我们工作的翻译潜力，我们将检查两个婴儿NHP的微生物组交叉反应抗体 和人类。最后，AIM 3将开发出gnotobiotic人B细胞谱系敲入小鼠模型 实验定义微生物组在BNAB前体诱导中的作用，包括在功能上验证 生物信息鉴定的微生物特征。综上所述，该项目的结果将阐明特定 调节免疫景观的微生物，使得基于B细胞谱系的疫苗更大的比例 接收者会发展BNAB前体。最终，这些类似调整的微生物可以纳入将来 疫苗策略。