Durable Antibody Mediated Protection Against HIV

持久的抗体介导的艾滋病毒保护

• 批准号: 9141189
• 负责人: ROBERT C GALLO
• 金额: $ 321.54万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9141189
• 关键词: AIDS Vaccines; AIDS vaccine development; Achievement; Address; Adjuvant; Antibodies; Antibody Response; Antibody-mediated protection; Antigens; Attenuated; Biological Preservation; Bone Marrow; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Chickenpox; Clinical Trials; Comparative Study; DNA; Data; Development; Electroporation; Elements; Environment; Equilibrium; Face; Formulation; Foundations; Goals; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV immunization; HIV vaccine; Human; IgG3; Immune; Immune response; Immunity; Immunization; Infection; Interleukin-12; Lead; Life; Link; Literature; Macaca; Macaca mulatta; Mediating; Mission; Modeling; Nature; Outcome; Passive Immunization; Pathway interactions; Phenotype; Plasma Cells; Plasmablast; Play; Population; Poxviridae; Proteins; Protocols documentation; Public Health; Publishing; Reaction; Regimen; Reporting; Research; Research Personnel; Risk; Site; Solid; Structure of germinal center of lymph node; T-Cell Activation; T-Lymphocyte; Testing; Time; United States National Institutes of Health; Vaccination; Vaccine Design; Vaccines; Virus-like particle; Work; arm; base; comparative; design; efficacy trial; env Gene Products; env Glycoproteins; killings; nonhuman primate; novel strategies; programs; prophylactic; protective efficacy; public health relevance; response; simian human immunodeficiency virus; transmission process; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine trial; vector

 DESCRIPTION (provided by applicant): The quest for a prophylactic AIDS vaccine is ongoing and it is probable that the successful vaccine must elicit protective antibody responses. Regardless of the mechanism of antibody-mediated protection, antibody persistence and appropriate T cell help are emerging as significant problems in AIDS vaccine development. The problem of antibody persistence is seen clearly in the RV144 trial. Protection was as highest in the first year but waned rapidly to background in parallel with anti-V2 antibodies that were associated with reduced risk of infection. Poor antibody persistence is not unique to RV144. It occurred in the VAX003/VAX004 efficacy trials, also using gp120 immunogens, and it has been observed repeatedly in gp120 vaccine trials in humans and non-human primates. Poor antibody persistence to gp120 is entwined with a second major problem. How to elicit necessary CD4+ T cell help without establishing fertile fields for increased HIV replication at sites of exposure, blunting protection, or increasing acquisition. It appears that vaccine-elicited CD4+ T cell and innate immune responses are associated with increased acquisition in the Step/Phambili trials that used an Ad5Hu- HIV "T-cell vaccine" as the immunogen. There are reports of vaccine-associated increased acquisition in non- human primate (NHP) models using other vectors and immunogens in addition to AdHu5. Taken together, the conjoint problems of antibody persistence and T cell "balance" must be solved for any antibody-based HIV vaccine to be effective. This requirement introduces a new concept for HIV vaccine development based on achieving "balanced" T cell and humoral responses, contrasting sharply with current approaches that focus on one arm or the other, or that seek to maximize both arms in parallel. Exploration of this concept forms the foundation of the proposed program that will test the central hypothesis that an HIV vaccine candidate can elicit durable antibody responses supported by a balanced CD4+ T cell profile that favors protection. This hypothesis is based on published work from the investigators and on solid preliminary data in RM models. This hypothesis will be tested via three highly interactive projects. Dr. Robert C. Gallo (IHV) will lead the program. Dr. Anthony L. DeVico (IHV) will lead Project 1 that exploits DNA/Protein co-immunization protocols to test hypotheses regarding the disposition of plasma cell subsets and how they determine the unusually poor durability of anti-gp120 antibody responses. Dr. George K. Lewis (IHV) will lead Project 2 to determine how vaccine elicited CD4+ T cells attenuate antibody-mediated protection. Dr. Guido Silvestri (Emory) will lead Project 3 to determine the phenotypes of vaccine-elicited CD4+ T cells and innate immune signatures that favor durable protection. In terms of major outcomes, this work is expected to fully identify the mechanism of poor anti-Env antibody persistence and to overcome this problem while maintaining "safe" levels of CD4+ T cells that don't blunt protection. These results are expected to fundamentally advance AIDS vaccine development for which broad durable protection is the Holy Grail.

 描述（由申请人提供）：对预防性艾滋病疫苗的探索正在进行中，并且成功的疫苗很可能必须引发抗体介导的保护机制的保护性抗体反应、抗体持久性和适当的 T 细胞帮助正在出现。 RV144 试验中清楚地看到了艾滋病疫苗开发中的重大问题。保护作用在第一年最高，但与与感染风险降低相关的抗 V2 抗体同时迅速下降。抗体这种持久性并非 RV144 所独有，同样使用 gp120 免疫原的 VAX003/VAX004 功效试验中也出现过这种情况，并且在人类和非人类灵长类动物的 gp120 疫苗试验中也多次观察到这种情况。如何在不建立肥沃区域的情况下诱导必要的 CD4+ T 细胞帮助，以增加暴露部位的 HIV 复制、削弱保护或增加获得性。在使用 Ad5Hu-HIV“T 细胞疫苗”作为免疫原的 Step/Phambili 试验中，疫苗引发的 CD4+ T 细胞和先天免疫反应与获得增加有关。有报道称，非人类体内的疫苗获得增加与疫苗相关。使用除 AdHu5 之外的其他载体和免疫原的灵长类动物 (NHP) 模型 总而言之，任何基于抗体的 HIV 疫苗都必须解决抗体持久性和 T 细胞“平衡”的共同问题。引入了一种基于实现“平衡”T 细胞和体液反应的 HIV 疫苗开发新概念，与目前专注于一侧或另一侧或寻求并行最大化双臂的方法形成鲜明对比。该计划的基础将测试一个中心假设，即候选 HIV 疫苗可以引发持久的抗体反应，并得到有利于保护的平衡 CD4+ T 细胞谱的支持。该假设基于研究人员发表的工作和 RM 的可靠初步数据。这个假设将是。 Robert C. Gallo 博士 (IHV) 将领导该项目，该项目利用 DNA/蛋白质联合免疫方案来测试有关处置的假设。 George K. Lewis 博士 (IHV) 将领导项目 2，以确定疫苗如何引发 CD4+ T 细胞减弱抗体介导的作用。 Guido Silvestri 博士（埃默里大学）将领导项目 3，以确定疫苗引发的 CD4+ T 细胞的表型和有利于持久保护的先天免疫特征，这项工作预计将完全确定不良的机制。抗 Env 抗体的持久性并克服这一问题，同时保持不削弱保护作用的“安全”水平的 CD4+ T 细胞，这些结果有望从根本上推动艾滋病疫苗的开发，而广泛持久的保护是其圣杯。