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，成功的疫苗很可能必须引起保护性抗体反应。无论抗体介导的保护机制是什么，抗体持久性和适当的T细胞帮助都是艾滋病疫苗开发中的重大问题。抗体持久性的问题在RV144试验中可以清楚地看到。第一年的保护力是最高的，但随着与降低感染风险相关的抗V2抗体的出现，保护力迅速减弱到背景水平。抗体持久性差并不是RV144独有的。它发生在同样使用gp120免疫原的VAX003/VAX004疗效试验中，在人类和非人类灵长类动物的gp120疫苗试验中反复观察到它。对gp120的抗体持久性差与第二个主要问题交织在一起。如何在不建立在暴露部位增加艾滋病毒复制的肥沃领域、钝化保护或增加获取的情况下，获得必要的CD4+T细胞帮助。在使用Ad5Hu-HIV“T细胞疫苗”作为免疫原的STEP/Phambili试验中，疫苗激发的CD4+T细胞和先天免疫反应似乎与获得性增加有关。有报道称，在非人类灵长类动物(NHP)模型中，除了AdHu5外，还使用了其他载体和免疫原，与疫苗相关的获取增加。综上所述，任何基于抗体的HIV疫苗要想有效，必须解决抗体持久性和T细胞“平衡”这两个方面的问题。这一要求为艾滋病毒疫苗的开发引入了一种新的概念，其基础是实现“平衡的”T细胞和体液反应，这与目前侧重于一只手臂或另一只手臂或寻求最大限度地同时最大化两只手臂的方法形成鲜明对比。对这一概念的探索构成了拟议计划的基础，该计划将检验核心假设，即艾滋病毒候选疫苗可以引发持久的抗体反应，并得到有利于保护的平衡的CD4+T细胞分布的支持。这一假设是基于研究人员发表的工作和RM模型中可靠的初步数据。这一假设将通过三个互动性很强的项目来检验。罗伯特·C·加洛博士(IHV)将领导该计划。Anthony L.DeVico博士(IHV)将领导项目1，该项目利用DNA/蛋白质联合免疫协议来测试有关浆细胞亚群的处置以及它们如何确定抗gp120抗体反应的异常糟糕的持久性的假设。乔治·K·刘易斯博士(IHV)将领导项目2确定疫苗如何诱导CD4+T细胞减弱抗体介导的保护。Guido Silvestri博士(Emory)将领导项目3确定疫苗引发的CD4+T细胞和有利于持久保护的先天免疫特征的表型。就主要结果而言，这项工作有望完全确定抗Env抗体持久性差的机制，并克服这一问题，同时保持不会削弱保护的CD4+T细胞的“安全”水平。预计这些结果将从根本上推动艾滋病疫苗的开发，而广泛持久的保护是艾滋病疫苗的圣杯。