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（由适用提供）：对预防性艾滋病疫苗的追求正在进行中，成功的疫苗必须引起保护性抗体反应是有问题的。不管抗体介导的保护的机制如何，抗体持久性和适当的T细胞帮助都将成为艾滋病疫苗发育中的重大问题。 RV144试验清楚地看到了抗体持久性问题。保护在第一年最高，但与与感染风险降低有关的抗V2抗体并行的背景迅速下降。抗体持久性差并不是RV144独有的。它发生在VAX003/VAX004效率试验中，还使用GP120免疫原子，并且在人类和非人类隐私的GP120疫苗试验中反复观察到。与GP120的抗体持久性不佳与第二个主要问题纠缠在一起。如何在不建立肥沃的领域以增加暴露，钝化保护或增加获取的地点的艾滋病毒复制的情况下引起必要的CD4+ T细胞帮助。看来，在使用AD5HU-HIV“ T细胞疫苗”作为免疫原的步骤/Phambili试验中，疫苗吸收的CD4+ T细胞和先天免疫回报与增加的采集有关。有报道称，除了ADHU5外，还使用其他载体和免疫原模型中疫苗相关的增加了非人类Prime（NHP）模型的获取。综上所述，必须解决任何基于抗体的HIV疫苗的抗体持久性和T细胞“平衡”的联合问题。这项要求基于实现“平衡” T细胞和体液反应的新概念，用于艾滋病毒疫苗的开发，与当前专注于一只手臂或另一只手臂的方法形成鲜明对比，或者试图并行最大化两臂。对此概念的探索构成了拟议程序的基础，该计划将检验中心假设，即艾滋病毒疫苗候选者可以引起持久的抗体反应，该抗体反应由平衡的CD4+ T细胞概况支持，这些抗体均受到保护。该假设基于研究人员的发表工作以及RM模型中的固体初步数据。该假设将通过三个高度互动的项目进行检验。 Robert C. Gallo博士（IHV）将领导该计划。 Anthony L. Devico博士（IHV）将领导Project 1，该项目利用DNA/蛋白质共免疫化方案来检验有关浆细胞​​亚群的处置的假设，以及它们如何确定抗GP120抗体反应的罕见耐用性。 George K. Lewis博士（IHV）将领导项目2，以确定疫苗如何引起CD4+ T细胞减弱抗体介导的保护。 Guido Silvestri博士（Emory）将领导项目3，以确定疫苗吸引的CD4+ T细胞的表型和有利的耐用性保护的先天免疫特征。就主要结果而言，这项工作有望充分确定抗ENV抗体持久性较差的机制，并克服该问题，同时保持“安全”水平的CD4+ T细胞不钝化的CD4+ T细胞。预计这些结果将从根本上推进艾滋病疫苗的开发，而耐久保护是圣杯。