Functional profile to HIV vaccine elicited antibodies in infants

HIV 疫苗的功能特征在婴儿中引发抗体

• 批准号: 9882942
• 负责人: Genevieve Giny Fouda Amou ou
• 金额: $ 40.11万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9882942
• 关键词: Address; Adjuvant; Adult; Affinity; Antibodies; Antibody Response; Antigens; Antiviral Agents; B-Lymphocytes; Cells; Characteristics; Childhood; Communicable Diseases; Complement Activation; Data; Databases; Development; Evolution; Fc Receptor; Future; Genes; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Human Milk; Immune; Immune response; Immune system; Immunization; Immunize; Immunogenetics; Immunoglobulin G; Infant; Infection; Institutes; Intervention; Length; MF59; Macaca mulatta; Mediating; Memory B-Lymphocyte; Monoclonal Antibodies; Mother-to-child HIV transmission; Mutation; Pathway interactions; Phagocytosis; Plasma; Population; Pregnant Women; Reporting; Risk; Specificity; Technology; Testing; Time; Up-Regulation; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Viral; Viral Antibodies; aluminum sulfate; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; design; efficacy testing; genetic signature; glycosylation; insight; pathogen; pediatric human immunodeficiency virus; prevent; receptor binding; recruit; response; screening; sexual debut; transcriptome; transcriptome sequencing; transmission process; vaccine candidate; vaccine efficacy; vaccine response; vaccine trial; whole genome; Address; Adjuvant; Adult; Affinity; Antibodies; Antibody Response; Antigens; Antiviral Agents; B-Lymphocytes; Cells; Characteristics; Childhood; Communicable Diseases; Complement Activation; Data; Databases; Development; Evolution; Fc Receptor; Future; Genes; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Human Milk; Immune; Immune response; Immune system; Immunization; Immunize; Immunogenetics; Immunoglobulin G; Infant; Infection; Institutes; Intervention; Length; MF59; Macaca mulatta; Mediating; Memory B-Lymphocyte; Monoclonal Antibodies; Mother-to-child HIV transmission; Mutation; Pathway interactions; Phagocytosis; Plasma; Population; Pregnant Women; Reporting; Risk; Specificity; Technology; Testing; Time; Up-Regulation; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Viral; Viral Antibodies; aluminum sulfate; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; design; efficacy testing; genetic signature; glycosylation; insight; pathogen; pediatric human immunodeficiency virus; prevent; receptor binding; recruit; response; screening; sexual debut; transcriptome; transcriptome sequencing; transmission process; vaccine candidate; vaccine efficacy; vaccine response; vaccine trial; whole genome

Eliminating breast milk HIV-1 transmission will likely require a combination of approaches, including immune- based interventions such as a pediatric HIV-1 vaccine. Only a few vaccine trials have included pediatric populations and none of them tested efficacy. Because of differences between the adult and infant immune system, it is unclear if antibodies elicited by HIV vaccination in adults and infants are able to mediate similar effector functions. This study will address this gap by comparing the functional profile of antibodies elicited by the same adjuvanted HIV vaccines in adults and infants. Insights on vaccine protection can be drawn from the moderately effective adult RV144 trial in which a reduced risk of HIV-1 acquisition was associated with high levels of IgG against the HIV-1 Envelope (Env) V1V2 loops. We have demonstrated that infant vaccination with a rgp120/MF59 vaccine induces plasma levels of potentially-protective anti-V1V2 IgG that are 22 times higher than levels found in adult RV144 vaccinees. Importantly, it was recently reported that MF59 does not induce high magnitude potentially-protective antibody responses in adults. Yet, our preliminary data show that infants immunized with the rgp120/MF59 vaccine developed higher magnitude HIV Env-specific responses than adults immunized with the same vaccine. This suggests that distinct adjuvants may differently modulate vaccine- elicited responses in adults and infants. These differences are likely to influence effector functions and dictate vaccine efficacy. The objective of this application is to evaluate the function of infant vaccine-elicited Env- specific antibodies and define the impact of different adjuvants on infant functional antibody responses. Our central hypothesis is that antibodies elicited by infant HIV-1 vaccination are capable of mediating distinct anti- viral effector functions when compared to adult antibodies, and infant antibody functional profile is influenced by the vaccine adjuvant. Our central hypothesis will be tested in the following specific aims: 1) Define the functional profile of HIV vaccine-elicited antibodies in infants in comparison with that of adults immunized with the same HIV Env vaccine; 2) Define the evolution, specificity, and function of mAbs isolated from Env-specific memory B cells of HIV-exposed HIV-vaccinated infants; and 3) Assess the impact of vaccine adjuvants on HIV vaccine antibody Fc-mediated functions in infant rhesus macaques (RMs) and the relationship between specific B cell gene pathways upregulation and effector function. We expect that this study will identify differences in effector functions between adults and infants, highlighting the need to test promising vaccine candidates in pediatric populations. In addition, the identification of gene pathways associated with optimal vaccine responses through our proposed ‘omics approach, will allow for the rational design and screening of infant vaccine and adjuvant candidates for their ability to target these B cell gene signatures.

消除母乳HIV-1传播可能需要采用多种方法，包括免疫 - 基于小儿HIV-1疫苗等基于干预措施。只有少数疫苗试验包括小儿 人群，都没有测试效率。由于成人和婴儿免疫之间的差异 系统，尚不清楚成人和婴儿中HIV疫苗接种引起的抗体是否能够培养媒体 效应器功能。这项研究将通过比较由 成人和婴儿中相同的调整后的HIV疫苗。可以从疫苗保护的见解中得出 适度有效的成人RV144试验，其中降低HIV-1获取风险与高有关 针对HIV-1信封（ENV）V1V2循环的IgG水平。我们已经证明了婴儿疫苗 RGP120/MF59疫苗诱导血浆水平的潜在保护抗V1V2 IgG的水平高22倍 比成年RV144疫苗中发现的水平。重要的是，最近有报道称MF59不影响 成年人的高幅度潜在保护抗体反应。但是，我们的初步数据表明婴儿 用RGP120/MF59疫苗免疫的HIV特异性反应更高 用相同的疫苗免疫。这表明不同的调整可能会不同调节疫苗 - 在成人和婴儿中引起反应。这些差异可能会影响效应子功能并决定 疫苗效率。该应用的目的是评估婴儿疫苗吸收的Env-的功能 特定的抗体并定义了不同的调节器对婴儿功能抗体反应的影响。我们的 中心假设是，婴儿HIV-1疫苗接种引起的抗体能够介导不同的抗体 与成年抗体相比，病毒效应子功能和婴儿抗体功能谱受影响 通过疫苗调节。我们的中心假设将在以下特定目的中进行检验：1）定义 与接受免疫的成年人相比 同一HIV ENV疫苗； 2）定义从ENV特异性分离的mAB的演变，特异性和功能 艾滋病毒暴露于HIV的婴儿的记忆B细胞； 3）评估疫苗调节器对艾滋病毒的影响 疫苗抗体FC介导的婴儿猕猴（RMS）的功能与之间的关系 特定的B细胞基因途径上调和效应子功能。我们希望这项研究将确定 成年人和婴儿之间效应子功能的差异，强调了测试有希望的疫苗的需求 小儿人群中的候选人。另外，鉴定与最佳相关的基因途径 通过我们提出的“ OMICS方法，疫苗的反应”将允许理性设计和筛选 婴儿疫苗和可调候选者的靶向这些B细胞基因特征的能力。